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WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OXYCODONE HYDROCHLORIDE ORAL SOLUTION Risk of Medication Errors Ensure accuracy when prescribing, dispensing, and administering Oxycodone Hydrochloride Oral Solution. Dosing errors due to confusion between mg and mL, and other oxycodone hydrochloride oral solutions of different concentrations can result in accidental overdose and death [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ] . Addiction, Abuse, and Misuse Because the use of Oxycodone Hydrochloride Oral Solution exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.2) ] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Oxycodone Hydrochloride Oral Solution, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of Oxycodone Hydrochloride Oral Solution are essential [see Warnings and Precautions (5.3) ]. Accidental Ingestion Accidental ingestion of even one dose of Oxycodone Hydrochloride Oral Solution, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.3) ] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Oxycodone Hydrochloride Oral Solution and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.4) , Drug Interactions (7) ]. Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.5) ] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.6) ]. Cytochrome P450 3A4 Interaction The concomitant use of Oxycodone Hydrochloride Oral Solution with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Regularly evaluate patients receiving Oxycodone Hydrochloride Oral Solution and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.7) , Drug Interactions (7) , Clinical Pharmacology (12.3) ].

n of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Regularly evaluate patients receiving Oxycodone Hydrochloride Oral Solution and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.7) , Drug Interactions (7) , Clinical Pharmacology (12.3) ]. WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OXYCODONE HYDROCHLORIDE SOLUTION See full prescribing information for complete boxed warning. Ensure accuracy when prescribing, dispensing, and administering Oxycodone Hydrochloride Oral Solution. Dosing errors due to confusion between mg and mL, and other oxycodone hydrochloride oral solutions of different concentrations can result in accidental overdose and death ( 2.1 , 5.1 ). Oxycodone Hydrochloride Oral Solution exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions ( 5.2 ) Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dosage increase. To reduce risk of respiratory depression, proper dosing and titration of Oxycodone Hydrochloride Oral Solution are essential. ( 5.3 ) Accidental ingestion of Oxycodone Hydrochloride Oral Solution, especially by children, can result in a fatal overdose of oxycodone. ( 5.3 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. ( 5.4 , 7 ) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.5 ) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. ( 5.6 ) The concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone. ( 5.7 , 7 , 12.3 )

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1 INDICATIONS AND USAGE Oxycodone Hydrochloride Oral Solution is indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) is indicated for use in opioid-tolerant adult patients who require higher doses of opioids for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration, and persist over the course of therapy [see Warnings and Precautions (5.2) ] , reserve opioid analgesics, including Oxycodone Hydrochloride Oral Solution, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Oxycodone Hydrochloride Oral Solution is an opioid agonist indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) is indicated for use in opioid-tolerant adult patients who require higher doses of opioids for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. Limitations of Use Because of the risks of addiction, abuse, and misuse, overdose, and death, with opioids, which can occur at any dosage or duration, and persist over the course of therapy, reserve opioid analgesics, including Oxycodone Hydrochloride Oral Solution, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.2 )

2 DOSAGE AND ADMINISTRATION Periodically reassess patients receiving Oxycodone Hydrochloride Oral Solution to evaluate the continued need for opioid analgesics to maintain pain control, for signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse ( 2.5 ) Oxycodone Hydrochloride Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Oxycodone Hydrochloride Oral Solution for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse and misuse. ( 2.1 , 5.2 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Oxycodone Hydrochloride Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.3 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with Oxycodone Hydrochloride Oral Solution, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose ( 2.2 , 5.2 , 5.3 , 5.4 ) Initiate dosing with a range of 5 to 15 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of Oxycodone Hydrochloride Oral Solution. ( 2.3 , 2.4 ) Do not rapidly reduce or abruptly discontinue Oxycodone Hydrochloride Oral Solution in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 , 5.15 ) 2.1 Important Dosage and Administration Instructions Oxycodone Hydrochloride Oral Solution is available in two concentrations: 5 mg per 5 mL (1 mg/mL), and 100 mg per 5 mL (20 mg/mL). Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) is for use in only opioid-tolerant adult patients who have already been receiving opioid therapy. Use this strength only for patients who have already been titrated to a stable analgesic regimen using lower strengths of oxycodone hydrochloride and who can benefit from use of a smaller volume of oral solution. Patients considered to be opioid tolerant are those who are receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid.

o be opioid tolerant are those who are receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. Ensure accuracy when prescribing, dispensing, and administering Oxycodone Hydrochloride Oral Solution to avoid dosing errors due to confusion between mg and mL, and with other oxycodone hydrochloride solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Instruct patients and caregivers on how to accurately measure and take or administer the correct dose of Oxycodone Hydrochloride Oral Solution. Strongly advise patients and caregivers to always use the enclosed graduated measuring cup when administering Oxycodone Hydrochloride Oral Solution 5 mg per 5 mL and always use the enclosed graduated oral syringe when administering Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL) to ensure that the dose is measured and administered accurately. Instruct patients and caregivers to never use household teaspoons or tablespoons to measure Oxycodone Hydrochloride Oral Solution. Oxycodone Hydrocodone Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5) ]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Oxycodone Hydrochloride Oral Solution for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.2) ]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Oxycodone Hydrochloride Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5) ]. 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.2 , 5.3 , 5.4) ].

se disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.2 , 5.3 , 5.4) ]. Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions (5.2) ]. There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Initial Dosage Although it is not possible to list every condition that is important to the selection of the initial dose of Oxycodone Hydrochloride Oral Solution, attention must be given to: the daily dose, potency and characteristics of a full agonist or mixed agonist/antagonist the patient has been taking previously the reliability of the relative potency estimate to calculate the dose of oxycodone HCl needed the degree of opioid tolerance the general condition and medical status of the patient, including the patient's weight and age the balance between pain management and adverse reactions the type and severity of the patient's pain risk factors for abuse or addiction, including a prior history of abuse or addiction Use of Oxycodone Hydrochloride Oral Solution as the First Opioid Analgesic Do not initiate treatment with Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL) in patients who are opioid naïve. Select an alternate product with lower concentration. Initiate treatment with Oxycodone Hydrochloride Oral Solution in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of Oxycodone Hydrochloride Oral Solution. Conversion from Other Opioids to Oxycodone Hydrochloride Oral Solution There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Oxycodone Hydrochloride Oral Solution. It is safer to underestimate a patient's 24-hour Oxycodone Hydrochloride Oral Solution dosage than to overestimate the 24-hour Oxycodone Hydrochloride Oral Solution dosage and manage an adverse reaction due to overdose. If a patient has been receiving opioid-containing medications prior to taking Oxycodone Hydrochloride Oral Solution, the potency of the prior opioid relative to oxycodone should be factored into the selection of the total daily dose (TDD) of oxycodone. In converting patients from other opioids to Oxycodone Hydrochloride Oral Solution close observation and adjustment of dosage based upon the patient's response to Oxycodone Hydrochloride Oral Solution is imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of Oxycodone Hydrochloride Oral Solution may be necessary, especially in patients who have disease states that are changing rapidly. Conversion from Oxycodone Hydrochloride Oral Solution to Extended-Release Oxycodone Hydrochloride The relative bioavailability of Oxycodone Hydrochloride Oral Solution compared to extended-release oxycodone is unknown, so conversion to extended-release oxycodone may lead to increased risk of excessive sedation and respiratory depression.

codone Hydrochloride Oral Solution to Extended-Release Oxycodone Hydrochloride The relative bioavailability of Oxycodone Hydrochloride Oral Solution compared to extended-release oxycodone is unknown, so conversion to extended-release oxycodone may lead to increased risk of excessive sedation and respiratory depression. 2.4 Titration and Maintenance of Therapy Individually titrate Oxycodone Hydrochloride Oral Solution to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Oxycodone Hydrochloride Oral Solution to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.2 , 5.15) ]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Oxycodone Hydrochloride Oral Solution dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5) ] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Oxycodone Hydrochloride Oral Solution Do not rapidly reduce or abruptly discontinue Oxycodone Hydrochloride Oral Solution in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Oxycodone Hydrochloride Oral Solution, there are a variety of factors that should be considered, including the total daily dose of opioid (including Oxycodone Hydrochloride Oral Solution) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Oxycodone Hydrochloride Oral Solution who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks.

of the opioid gradually. For patients on Oxycodone Hydrochloride Oral Solution who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.15) , Drug Abuse and Dependence (9.3) ]

3 DOSAGE FORMS AND STRENGTHS Oxycodone Hydrochloride Oral Solution, USP 5 mg per 5 mL (1 mg/mL) Strength Oral Solution: Each 5 mL of red Oxycodone Hydrochloride Oral Solution, USP contains oxycodone hydrochloride 5 mg. 100 mg per 5 mL (20 mg per mL) Strength Oral Solution: Each 5 mL of yellow Oxycodone Hydrochloride Oral Solution, USP contains oxycodone hydrochloride 100 mg. Oral Solution 5 mg per 5 mL (1 mg/mL) 100 mg per 5 mL (20 mg/mL) ( 3 )

4 CONTRAINDICATIONS Oxycodone Hydrochloride Oral Solution is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.3) ] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions (5.9) ] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.13) ] Hypersensitivity to oxycodone (e.g., angioedema) [see Adverse Reactions (6) ] Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting in absence of resuscitative equipment. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Hypersensitivity to oxycodone. ( 4 )

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. ( 5.8 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic or Debilitated Patients : Regularly evaluate, particularly during initiation and titration. ( 5.9 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.10 ) Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of Oxycodone Hydrochloride Oral Solution in patients with circulatory shock. ( 5.11 ) Risks of Use in Patients with Increased lntracranial Pressure, Brain Tumors, Head Injury or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of Oxycodone Hydrochloride Oral Solution in patients with impaired consciousness or coma. ( 5.12 ) 5.1 Risk of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with oxycodone hydrochloride solutions of different concentrations, when prescribing, dispensing, and administering Oxycodone Hydrochloride Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately. Instruct patients and caregivers on how to measure and take or administer the correct dose of Oxycodone Hydrochloride Oral Solution and to use extreme caution when measuring the dose. Instruct patients and caregivers to always use the enclosed graduated measuring cup when administering Oxycodone Hydrochloride Oral Solution 5 mg per 5 mL (1 mg/mL) and always use the enclosed graduated oral syringe when administering Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/ mL) to ensure the dose is measured and administered accurately. Instruct them to never use a teaspoon or a tablespoon to measure a dose because household teaspoons or tablespoon are not adequate measuring devices. 5.2 Addiction, Abuse, and Misuse Oxycodone Hydrochloride Oral Solution contains oxycodone, a Schedule II controlled substance. As an opioid, Oxycodone Hydrochloride Oral Solution exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Oxycodone Hydrochloride Oral Solution. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6) ] . Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Oxycodone Hydrochloride Oral Solution, and reassess all patients receiving Oxycodone Hydrochloride Oral Solution for the development of these behaviors and conditions.

patients with long-term opioid use [see Adverse Reactions (6) ] . Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing Oxycodone Hydrochloride Oral Solution, and reassess all patients receiving Oxycodone Hydrochloride Oral Solution for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Oxycodone Hydrochloride Oral Solution but use in such patients necessitates intensive counseling about the risks and proper use of Oxycodone Hydrochloride Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) ]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Oxycodone Hydrochloride Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.3 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents depending on the patient's clinical status [see Overdosage (10) ]. Carbon dioxide (C0 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Oxycodone Hydrochloride Oral Solution, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Oxycodone Hydrochloride Oral Solution are essential [see Dosage and Administration (2) ] . Over estimating the Oxycodone Hydrochloride Oral Solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) is for use in opioid-tolerant patients only. Administration of this formulation may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids. Accidental ingestion of even one dose of Oxycodone Hydrochloride Oral Solution, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion.

and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose . Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5) ]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.2 , 5.4) ] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration (2.2) , Warnings and Precautions (5.2 , 5.4) , Overdosage (10) ]. 5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Oxycodone Hydrochloride Oral Solution with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-­benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7) ]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response.

odiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) , Overdosage (10) ]. Advise both patients and caregivers about the risks of respiratory depression and sedation when Oxycodone Hydrochloride Oral Solution is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) ]. 5.5 Neonatal Opioid Withdrawal Syndrome Use of Oxycodone Hydrochloride Oral Solution for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life­-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1) ]. 5.6 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda/gov/OpioidAnalgesicREMSBlueprint .

tient-prescriber agreements that reinforce patient prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda/gov/OpioidAnalgesicREMSBlueprint . 5.7 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Oxycodone Hydrochloride Oral Solution with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.3) ], particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Oral Solution is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Oxycodone Hydrochloride Oral Solution-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using Oxycodone Hydrochloride Oral Solution with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Oxycodone Hydrochloride Oral Solution-treated patients, evaluate patients at frequent intervals and consider dosage reduction of Oxycodone Hydrochloride Oral Solution until stable drug effects are achieved [see Dosage and Administration (2.1) , Drug Interactions (7) ]. Concomitant use of Oxycodone Hydrochloride Oral Solution with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using Oxycodone Hydrochloride Oral Solution with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Dosage and Administration (2.1) , Drug Interactions (7) ]. 5.8 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3) ]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.5) , Warnings and Precautions (5.15) ]. 5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Oxycodone Hydrochloride Oral Solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated.

fe-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Oxycodone Hydrochloride Oral Solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Oxycodone Hydrochloride Oral Solution-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Oxycodone Hydrochloride Oral Solution [see Warnings and Precautions (5.3) ]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.3) ]. Regularly evaluate patients, particularly when initiating and titrating Oxycodone Hydrochloride Oral Solution and when Oxycodone Hydrochloride Oral Solution is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.3 , 5.4) , Drug Interactions (7) ] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.10 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.11 Severe Hypotension Oxycodone Hydrochloride Oral Solution may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs e.g., phenothiazines or general anesthetics) [see Drug Interactions (7) ]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of Oxycodone Hydrochloride Oral Solution. In patients with circulatory shock, Oxycodone Hydrochloride Oral Solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Oxycodone Hydrochloride Oral Solution in patients with circulatory shock. 5.12 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of C0 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Oxycodone Hydrochloride Oral Solution may reduce respiratory drive, and the resultant C0 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Oxycodone Hydrochloride Oral Solution.

sure or brain tumors), Oxycodone Hydrochloride Oral Solution may reduce respiratory drive, and the resultant C0 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Oxycodone Hydrochloride Oral Solution. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Oxycodone Hydrochloride Oral Solution in patients with impaired consciousness or coma. 5.13 Risks of Gastrointestinal Complications Oxycodone Hydrochloride Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The oxycodone in Oxycodone Hydrochloride Oral Solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2) ] . 5.14 Increased Risk of Seizures in Patients with Seizure Disorders The oxycodone in Oxycodone Hydrochloride Oral Solution may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during Oxycodone Hydrochloride Oral Solution therapy. 5.15 Withdrawal Do not rapidly reduce or abruptly discontinue Oxycodone Hydrochloride Oral Solution in a patient physically dependent on opioids. When discontinuing Oxycodone Hydrochloride Oral Solution in a physically-dependent patient, gradually taper the dosage. Rapid tapering of oxycodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.5) , Drug Abuse and Dependence (9.3) ]. Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) analgesics in patients who are receiving full opioid agonist analgesic, including Oxycodone Hydrochloride Oral Solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7) ]. 5.16 Risks of Driving and Operating Machinery Oxycodone Hydrochloride Oral Solution may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Oxycodone Hydrochloride Oral Solution and know how they will react to the medication.

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.2) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3) ] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.4) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5) ] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8) ] Adrenal Insufficiency [see Warnings and Precautions (5.10) ] Severe Hypotension [ see Warnings and Precautions (5.11) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13) ] Seizures [see Warnings and Precautions (5.14) ] Withdrawal [see Warnings and Precautions (5.15) ] The following adverse reactions associated with the use of oxycodone were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious adverse reactions associated with oxycodone use included: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock. The common adverse reactions seen on initiation of therapy with oxycodone are dose-related and are typical opioid-related adverse reactions. The most frequent adverse events include nausea, constipation, vomiting, headache, and pruritus. The frequency of these reactions depended on several factors, including clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual. In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving another formulation of immediate-release oxycodone, the following adverse events were recorded in oxycodone treated patients with an incidence ≥ 3%. In descending order of frequency, they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. The other less frequently observed adverse reactions from opioid analgesics, including Oxycodone Hydrochloride Oral Solution included: Body as a Whole: abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever, flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis. Cardiovascular: deep thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation, and tachycardia. Digestive: anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, and nausea and vomiting. Hemic and Lymphatic: anemia and leukopenia. Metabolic and Nutritional: edema, gout, hyperglycemia, iron deficiency anemia and peripheral edema. Musculoskeletal: arthralgia, arthritis, bone pain, myalgia and pathological fracture. Nervous: agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation. Respiratory: bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis. Skin and Appendages: herpes simplex, rash, sweating, and urticaria. Special Senses: amblyopia.

hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation. Respiratory: bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis. Skin and Appendages: herpes simplex, rash, sweating, and urticaria. Special Senses: amblyopia. Urogenital : urinary tract infection Serotonin syndrome: Cases of serotonin syndrome, a potentially life threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Oxycodone Hydrochloride Oral Solution. Androgen deficiency: Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2) ]. Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.8) ]. Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.13) ] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2)], respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days' supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database.

east 70 days' supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies. Most common adverse reactions are nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Allucent at 1-866-511-6754 or FDA at 1-800-FDA-1088 or www.fda.gov.medwatch.

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with Oxycodone Hydrochloride Oral Solution. Table 1: Clinically Significant Drug Interactions with Oxycodone Hydrochloride Oral Solution Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of Oxycodone Hydrochloride Oral Solution and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Oxycodone Hydrochloride Oral Solution and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Oral Solution is achieved [see Warnings and Precautions (5.7) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3) ] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. Intervention: If concomitant use is necessary, consider dosage reduction of Oxycodone Hydrochloride Oral Solution until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the Oxycodone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin, azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of Oxycodone Hydrochloride Oral Solution and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.15) ] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3) ] , which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the Oxycodone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal and sedation. If a CYP3A4 inducer is discontinued, consider Oxycodone Hydrochloride Oral Solution dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples Rifampin, carbamazepine, phenytoin Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

e concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing of an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2 , 5.3 , 5.4) ] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently reevaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxycodone Hydrochloride Oral Solution if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.3) ] . Intervention: The use of Oxycodone Hydrochloride Oral Solution is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Oxycodone Hydrochloride Oral Solution and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression that may be greater than otherwise expected, decrease the dosage of Oxycodone Hydrochloride Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2 , Warnings and Precautions (5.3 , 5.4) ] . Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when Oxycodone Hydrochloride Oral Solution is used concomitantly with anticholinergic drugs. Serotonergic Drug s: Concomitant use may result in serotonin syndrome. Discontinue Oxycodone Hydrochloride Oral Solution if serotonin syndrome is suspected. ( 7 ) Monoamine Oxidase Inhibitors (MAOIs ): Can potentiate the effects of oxycodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Oxycodone Hydrochloride Oral Solution because they may reduce analgesic effect of Oxycodone Hydrochloride Oral Solution or precipitate withdrawal symptoms. ( 7 )

<table width="90%"><caption>Table 1: Clinically Significant Drug Interactions with Oxycodone Hydrochloride Oral Solution</caption><col width="20%" align="left" valign="top"/><col width="80%" align="left" valign="top"/><thead><tr><th styleCode="Lrule Rrule" colspan="2">Inhibitors of CYP3A4 and CYP2D6</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">The concomitant use of Oxycodone Hydrochloride Oral Solution and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Oxycodone Hydrochloride Oral Solution and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Oral Solution is achieved <content styleCode="italics">[see <linkHtml href="#S5.7">Warnings and Precautions (5.7)</linkHtml>].</content> After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease <content styleCode="italics">[see <linkHtml href="#S12.3">Clinical Pharmacology (12.3)</linkHtml>]</content>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">If concomitant use is necessary, consider dosage reduction of Oxycodone Hydrochloride Oral Solution until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the Oxycodone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">Macrolide antibiotics (e.g., erythromycin, azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">CYP3A4 Inducers</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">The concomitant use of Oxycodone Hydrochloride Oral Solution and CYP3A4 inducers can decrease the plasma concentration of oxycodone <content styleCode="italics">[see <linkHtml href="#S12.3">Clinical Pharmacology (12.3)</linkHtml>],</content> resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone <content styleCode="italics">[see <linkHtml href="#S5.15">Warnings and Precautions (5.15)</linkHtml>]</content>.

e <linkHtml href="#S12.3">Clinical Pharmacology (12.3)</linkHtml>],</content> resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone <content styleCode="italics">[see <linkHtml href="#S5.15">Warnings and Precautions (5.15)</linkHtml>]</content>. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase <content styleCode="italics">[see <linkHtml href="#S12.3">Clinical Pharmacology (12.3)</linkHtml>]</content>, which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">If concomitant use is necessary, consider increasing the Oxycodone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal and sedation. If a CYP3A4 inducer is discontinued, consider Oxycodone Hydrochloride Oral Solution dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples</content></td><td styleCode="Rrule">Rifampin, carbamazepine, phenytoin</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Benzodiazepines and other Central Nervous System (CNS) Depressants</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing of an opioid overdose reversal agent <content styleCode="italics">[see <linkHtml href="#S2.2">Dosage and Administration (2.2)</linkHtml>, <linkHtml href="#S5.2">Warnings and Precautions (5.2</linkHtml>, <linkHtml href="#S5.3">5.3</linkHtml>, <linkHtml href="#S5.4">5.4)</linkHtml>]</content>.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Serotonergic Drugs</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">If concomitant use is warranted, frequently reevaluate the patient, particularly during treatment initiation and dose adjustment.

smitter system has resulted in serotonin syndrome.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">If concomitant use is warranted, frequently reevaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxycodone Hydrochloride Oral Solution if serotonin syndrome is suspected.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Monoamine Oxidase Inhibitors (MAOIs)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <content styleCode="italics">[see <linkHtml href="#S5.3">Warnings and Precautions (5.3)</linkHtml>]</content>.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">The use of Oxycodone Hydrochloride Oral Solution is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">phenelzine, tranylcypromine, linezolid</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">May reduce the analgesic effect of Oxycodone Hydrochloride Oral Solution and/or precipitate withdrawal symptoms.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Avoid concomitant use.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">butorphanol, nalbuphine, pentazocine, buprenorphine</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Muscle Relaxants</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Because respiratory depression that may be greater than otherwise expected, decrease the dosage of Oxycodone Hydrochloride Oral Solution and/or the muscle relaxant as necessary.

n.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Because respiratory depression that may be greater than otherwise expected, decrease the dosage of Oxycodone Hydrochloride Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent <content styleCode="italics">[see <linkHtml href="#S2.2">Dosage and Administration (2.2</linkHtml>, <linkHtml href="#S5.3">Warnings and Precautions (5.3</linkHtml>, <linkHtml href="#S5.4">5.4)</linkHtml>]</content>.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="right"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">cyclobenzaprine, metaxalone</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Diuretics</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2"><content styleCode="bold">Anticholinergic Drugs</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Evaluate patients for signs of urinary retention or reduced gastric motility when Oxycodone Hydrochloride Oral Solution is used concomitantly with anticholinergic drugs.</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.5) ]. Available data with Oxycodone Hydrochloride Oral Solution are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Animal reproduction studies with oral administrations of oxycodone hydrochloride in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.5) ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Oxycodone Hydrochloride Oral Solution is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Oxycodone Hydrochloride Oral Solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone hydrochloride administered during the period of organogenesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis.

genesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis). 8.2 Lactation Risk Summary Available data from lactation studies indicate that oxycodone is present in breastmilk and that doses of less than 60 mg/day of the immediate-release formulation are unlikely to result in clinically relevant exposures in breastfed infants. A pharmacokinetics study utilizing opportunistic sampling of 76 lactating women receiving oxycodone immediate-release products for postpartum pain management showed that oxycodone concentrates in breastmilk with an average milk to plasma ratio of 3.2. The relative infant dose was low, approximately 1.3% of a weight-adjusted maternal dose ( see Data ) . In the same study, among the 70 infants exposed to oxycodone in breastmilk, no adverse events were attributed to oxycodone. However, based on known adverse effects in adults, infants should be monitored for signs of excess sedation and respiratory depression ( see Clinical Considerations ) . There are no data on the effects of the oxycodone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Oxycodone Hydrochloride Oral Solution and any potential adverse effects on the breastfed infant from Oxycodone Hydrochloride Oral Solution or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to Oxycodone Hydrochloride Oral Solution through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Data Oxycodone concentration data from 76 lactating women receiving immediate-release oxycodone products for postpartum pain management, and 28 infants exposed to oxycodone in breastmilk showed that following a median (range) dose of oxycodone in mothers of 9.2 (5-10) mg/dose or 33.0 (5.4-59.3) mg/day, oxycodone concentrated in breastmilk with a median (range) milk to plasma ratio of 3.2 (1.2-5.3). However, when using maternal breastmilk data to estimate the daily and relative infant dose, the infant dose was 0.006 mg/kg/day, which is 1.3% of a weight-adjusted maternal dose of 10 mg every 6 hours. These estimates based on maternal breastmilk concentrations were corroborated by the observed infant concentrations, of which over 75% (19/25) were below the limit of quantification. Among the 6 infants with quantifiable concentration, the median (range) concentration was 0.2 ng/mL (0.1-0.7). These concentrations are 100 to 1000 times lower than concentrations observed in other studies after infants received oxycodone at 0.1 mg/kg/dose (~20-200 ng/mL). 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6) , Clinical Pharmacology (12.2) ].

200 ng/mL). 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6) , Clinical Pharmacology (12.2) ]. 8.4 Pediatric Use The safety and effectiveness of Oxycodone Hydrochloride Oral Solution have not been established in pediatric patients. The safety and pharmacokinetics of a single-dose of an Oxycodone Hydrochloride Oral Solution were evaluated in an open-label clinical trial in 89 pediatric patients 2 years to less than 17 years of age with postoperative pain. However, definitive conclusions were not possible because of insufficient information. 8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Oxycodone Hydrochloride Oral Solution slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9) ]. Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. 8.6 Hepatic Impairment Since oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Initiate therapy in these patients with a lower than usual dosage of Oxycodone Hydrochloride Oral Solution and titrate carefully. Regularly evaluate for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3) ]. 8.7 Renal Impairment Information from oxycodone tablets indicate that patients with renal impairment had higher plasma concentrations of oxycodone than subjects with normal renal function. Initiate therapy with a lower than usual dosage of Oxycodone Hydrochloride Oral Solution and titrate carefully. Regularly evaluate for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3) ].

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.5) ]. Available data with Oxycodone Hydrochloride Oral Solution are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Animal reproduction studies with oral administrations of oxycodone hydrochloride in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.5) ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Oxycodone Hydrochloride Oral Solution is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Oxycodone Hydrochloride Oral Solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone hydrochloride administered during the period of organogenesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis.

genesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis).

8.4 Pediatric Use The safety and effectiveness of Oxycodone Hydrochloride Oral Solution have not been established in pediatric patients. The safety and pharmacokinetics of a single-dose of an Oxycodone Hydrochloride Oral Solution were evaluated in an open-label clinical trial in 89 pediatric patients 2 years to less than 17 years of age with postoperative pain. However, definitive conclusions were not possible because of insufficient information.

8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Oxycodone Hydrochloride Oral Solution slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.9) ]. Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Oxycodone Hydrochloride Oral Solution contains oxycodone, a Schedule II controlled substance. 9.2 Abuse Oxycodone Hydrochloride Oral Solution contains oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.2) ]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of Oxycodone Hydrochloride Oral Solution increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Oxycodone Hydrochloride Oral Solution with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Oxycodone Hydrochloride Oral Solution abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use Oxycodone Hydrochloride Oral Solution in combination with other abused drugs. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Oxycodone Hydrochloride Oral Solution, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Oral Solution Abuse of Oxycodone Hydrochloride Oral Solution poses a risk of overdose and death.

atient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Oral Solution Abuse of Oxycodone Hydrochloride Oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Oxycodone Hydrochloride Oral Solution with alcohol and/or other CNS depressants. Oxycodone Hydrochloride Oral Solution is approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), missed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not rapidly reduce or abruptly discontinue Oxycodone Hydrochloride Oral Solution in a patient physically dependent on opioids. Rapid tapering of Oxycodone Hydrochloride Oral Solution in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing Oxycodone Hydrochloride Oral Solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Oxycodone Hydrochloride Oral Solution the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5) , Warnings and Precautions (5.15) ]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ].

9.2 Abuse Oxycodone Hydrochloride Oral Solution contains oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.2) ]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of Oxycodone Hydrochloride Oral Solution increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Oxycodone Hydrochloride Oral Solution with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Oxycodone Hydrochloride Oral Solution abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use Oxycodone Hydrochloride Oral Solution in combination with other abused drugs. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Oxycodone Hydrochloride Oral Solution, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Oral Solution Abuse of Oxycodone Hydrochloride Oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Oxycodone Hydrochloride Oral Solution with alcohol and/or other CNS depressants. Oxycodone Hydrochloride Oral Solution is approved for oral use only.

e of Oxycodone Hydrochloride Oral Solution Abuse of Oxycodone Hydrochloride Oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Oxycodone Hydrochloride Oral Solution with alcohol and/or other CNS depressants. Oxycodone Hydrochloride Oral Solution is approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), missed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not rapidly reduce or abruptly discontinue Oxycodone Hydrochloride Oral Solution in a patient physically dependent on opioids. Rapid tapering of Oxycodone Hydrochloride Oral Solution in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing Oxycodone Hydrochloride Oral Solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Oxycodone Hydrochloride Oral Solution the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5) , Warnings and Precautions (5.15) ]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ].

10 OVERDOSAGE Clinical Presentation Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2) ]. Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of oxycodone in Oxycodone Hydrochloride Oral Solution, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.

11. DESCRIPTION Oxycodone Hydrochloride Oral Solution is an agonist, available as a red solution 5 mg/5 mL (1 mg/mL) and a yellow solution 100 mg/5 mL (20 mg/mL) for oral administration. The chemical name is (5R,9R,13S,14S)-4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride. The molecular weight is 351.82. Its molecular formula is C 18 H 21 NO 4 ∙HCl, and it has the following chemical structure: Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. It is soluble in water and slightly soluble in alcohol. The inactive ingredients in Oxycodone Hydrochloride Oral Solution, 5 mg per 5 mL (l mg/mL) include: citric acid anhydrous, FD&C Red #40, natural/artificial berry flavor, purified water, sodium citrate dihydrate, sodium benzoate, saccharin sodium, sorbitol. The inactive ingredients in Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) include: citric acid anhydrous, D&C Yellow #10, natural/artificial berry flavor, purified water, sodium citrate dihydrate, sodium benzoate, saccharin sodium, sorbitol. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. 12.2 Pharmacodynamics Effects of the Central Nervous System (CNS) Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH, cortisol), and luteinizing hormone (LH) in humans [see Adverse Reactions (6) ]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6) ]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in-vitro and Animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

ucted to date [see Adverse Reactions (6) ]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in-vitro and Animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.3 , 2.4) ]. Concentration-Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.3 , 2.4) ]. 12.3 Pharmacokinetics The activity of oxycodone hydrochloride is primarily due to the parent drug oxycodone. Absorption About 60 to 87% of an oral dose reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone. Food Effect When oxycodone capsules are administered with a high-fat meal, mean AUC values are increased by 23% and peak concentrations are decreased by 14%. Food causes a delay in Tmax (1.00 to 3 hours). Similar effects of food are expected with the oral solution. Distribution Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk. Elimination Metabolism Oxycodone hydrochloride is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone < 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone is approximately 4 hours. Specific Populations Age: Geriatric Population: Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.

Apparent elimination half-life of oxycodone following the administration of oxycodone is approximately 4 hours. Specific Populations Age: Geriatric Population: Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65. Hepatic Impairment: Because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic-impaired patients. A dose adjustment is recommended in these patients [see Use in Specific Populations (8.6) ]. Renal Impairment: Because this drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function, a dose reduction is recommended for renal impaired patients [see Use in Specific Populations (8.7) ]. Drug Interaction Studies CYP3A4 Inhibitors CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the co-administration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively. CYP3A4 Inducers A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively. CYP2D6 Inhibitors Oxycodone is metabolized in part to oxymorphone via the cytochrome P450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent.

12.1 Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.

12.2 Pharmacodynamics Effects of the Central Nervous System (CNS) Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH, cortisol), and luteinizing hormone (LH) in humans [see Adverse Reactions (6) ]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6) ]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in-vitro and Animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration-Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.3 , 2.4) ]. Concentration-Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

lgesic tolerance [see Dosage and Administration (2.1 , 2.3 , 2.4) ]. Concentration-Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.3 , 2.4) ].

12.3 Pharmacokinetics The activity of oxycodone hydrochloride is primarily due to the parent drug oxycodone. Absorption About 60 to 87% of an oral dose reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone. Food Effect When oxycodone capsules are administered with a high-fat meal, mean AUC values are increased by 23% and peak concentrations are decreased by 14%. Food causes a delay in Tmax (1.00 to 3 hours). Similar effects of food are expected with the oral solution. Distribution Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk. Elimination Metabolism Oxycodone hydrochloride is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone < 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone is approximately 4 hours. Specific Populations Age: Geriatric Population: Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65. Hepatic Impairment: Because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic-impaired patients. A dose adjustment is recommended in these patients [see Use in Specific Populations (8.6) ]. Renal Impairment: Because this drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function, a dose reduction is recommended for renal impaired patients [see Use in Specific Populations (8.7) ]. Drug Interaction Studies CYP3A4 Inhibitors CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the co-administration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively. CYP3A4 Inducers A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively.

d that the co-administration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively. CYP3A4 Inducers A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively. CYP2D6 Inhibitors Oxycodone is metabolized in part to oxymorphone via the cytochrome P450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of oxycodone have not been conducted. Mutagenesis Oxycodone hydrochloride was genotoxic in an in-vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in-vitro bacterial reverse mutation assay (Salmonella typhimurium and Escherichia coli) and in an assay for chromosomal aberrations (in-vivo mouse bone marrow micronucleus assay). Impairment of Fertility Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of oxycodone have not been conducted. Mutagenesis Oxycodone hydrochloride was genotoxic in an in-vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in-vitro bacterial reverse mutation assay (Salmonella typhimurium and Escherichia coli) and in an assay for chromosomal aberrations (in-vivo mouse bone marrow micronucleus assay). Impairment of Fertility Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

16 HOW SUPPLIED/STORAGE AND HANDLING Oxycodone Hydrochloride Oral Solution 5 mg per 5 mL (1 mg/mL), is a red solution, supplied as: NDC# 64950-354-10: Bottle of 100 mL supplied with a calibrated measuring cup NDC# 64950-354-50: Bottle of 500 mL supplied with a calibrated measuring cup NDC# 64950-354-05: 5 mL unit dose cup NDC# 64950-354-45: Case contains 40 unit dose cups of 5 mL (NDC 64950-354-05), packaged in 4 trays of 10 unit dose cups each NDC# 64950-354-55: Case contains 50 unit dose cups of 5 mL (NDC 64950-354-05), packaged in 5 trays of 10 unit dose cups each Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL), is a yellow solution, supplied as: NDC# 64950-353-03: Bottle of 30 mL supplied with a calibrated oral syringe Store at Controlled Room Temperature, 25°C (77°F); excursions are permitted to 15° - 30°C (59° - 86°F). PROTECT from MOISTURE and LIGHT. Store Oxycodone Hydrochloride Oral Solution securely and dispose of properly .

Store at Controlled Room Temperature, 25°C (77°F); excursions are permitted to 15° - 30°C (59° - 86°F). PROTECT from MOISTURE and LIGHT. Store Oxycodone Hydrochloride Oral Solution securely and dispose of properly .

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal: Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Oxycodone Hydrochloride Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving Oxycodone Hydrochloride Oral Solution unsecured can pose a deadly risk to others in the home ( see Warnings and Precautions (5.2 , 5.3) , Drug Abuse and Dependence (9.2) ]. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Oxycodone Hydrochloride Oral Solution should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Medication Errors Instruct patients and caregivers how to measure and take or administer the correct dose of Oxycodone Hydrochloride Oral Solution and to always use the enclosed graduated measuring cup when administering Oxycodone Hydrochloride Oral Solution 5 mg per 5 mL (1 mg/mL) and to always use the enclosed graduated oral syringe when administering Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) to correctly measure the prescribed amount of medication [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ]. Advise patients and caregivers that Oxycodone Hydrochloride Oral Solution, is available in two concentrations: 5 mg/5 mL and 100 mg/5 mL. Inform patients and caregivers about which concentration they have been prescribed and provide detailed instruction on how to measure and take or administer the correct dose of Oxycodone Hydrochloride Oral Solution, and to always use the enclosed measuring device when administering Oxycodone Hydrochloride Oral Solution, to ensure that the dose is measured and administered accurately. If the prescribed concentration is changed, instruct patients and caregivers on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death. Addiction, Abuse, and Misuse Inform patients that the use of Oxycodone Hydrochloride Oral Solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.2) ] . Instruct patients not to share Oxycodone Hydrochloride Oral Solution with others and to take steps to protect Oxycodone Hydrochloride Oral Solution from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Oxycodone Hydrochloride Oral Solution or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.3) ].

dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.3) ]. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.3) ] . Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if Oxycodone Hydrochloride Oral Solution is used with benzodiazepines or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.4) , Drug Interactions (7) ]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Dosage and Administration (2.2) , Warnings and Precautions (5.4) ] . Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered [see Overdosage (10) ]. Advise patients and caregivers: how to treat with the overdose reversal agent in the event of an opioid overdose to tell family and friends about the opioid reversal agent, and to keep it in a place where family and friends can access it in an emergency to read the Patient Information (or other educational material) that will come with their opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.8) , Adverse Reactions (6) ]. Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications. [see Drug Interactions (7) ] . MAOI Interaction Inform patients to avoid taking Oxycodone Hydrochloride Oral Solution while using any drugs that inhibit monoamine oxidase.

right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications. [see Drug Interactions (7) ] . MAOI Interaction Inform patients to avoid taking Oxycodone Hydrochloride Oral Solution while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Oxycodone Hydrochloride Oral Solution [see Drug Interactions (7) ]. Important Administration Instructions Instruct patients how to properly take Oxycodone Hydrochloride Oral Solution [see Dosage and Administration (2.1) , Warnings and Precautions (5.1) ]. Strongly advise patients and caregivers to always use the enclosed graduated oral syringe or dosing cup when administering Oxycodone Hydrochloride Oral Solution to correctly measure the prescribed amount of medication [see Warnings and Precautions (5.1) ] . Instruct patients and caregivers to never use household teaspoons or tablespoons to measure Oxycodone Hydrochloride Oral Solution. Advise patients and caregivers not to adjust the dose of Oxycodone Hydrochloride Oral Solution without consulting with a physician or other healthcare provider. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Oxycodone Hydrochloride Oral Solution without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5) ]. Driving or Operating Heavy Machinery Inform patients that Oxycodone Hydrochloride Oral Solution may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.16) ]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6) , Clinical Pharmacology (12.2) ]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.10) ]. Hypotension Inform patients that Oxycodone Hydrochloride Oral Solution may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions (5.11) ]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in Oxycodone Hydrochloride Oral Solution. Advise patients how to recognize such a reaction and when to seek medical attention [see Adverse Reactions (6) ]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of Oxycodone Hydrochloride Oral Solution for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.5) , Use in Specific Populations (8.1) ]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that Oxycodone Hydrochloride Oral Solution can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ].

e Warnings and Precautions (5.5) , Use in Specific Populations (8.1) ]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that Oxycodone Hydrochloride Oral Solution can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ]. Lactation Advise breastfeeding women using Oxycodone Hydrochloride Oral Solution to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding women to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2) ]. Infertility Inform patients that chronic use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3) ].

Medication Guide Oxycodone Hydrochloride (ox-ee-CO-dohn) CII Oral Solution Oxycodone Hydrochloride Oral Solution is: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about Oxycodone Hydrochloride Oral Solution: Get emergency help or call 911 right away if you take too much Oxycodone Hydrochloride Oral Solution (overdose). When you first start taking Oxycodone Hydrochloride Oral Solution, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose. Taking Oxycodone Hydrochloride Oral Solution with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your Oxycodone Hydrochloride Oral Solution. They could die from taking it. Selling or giving away Oxycodone Hydrochloride Oral Solution is against the law. Store Oxycodone Hydrochloride Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Do not take Oxycodone Hydrochloride Oral Solution if you have: severe asthma, trouble breathing, or other lung problems. bowel blockage or have narrowing of the stomach or intestines. an allergy to oxycodone or any of the ingredients in Oxycodone Hydrochloride Oral Solution. Before taking Oxycodone Hydrochloride Oral Solution, tell your healthcare provider if you have a history of: head injury, seizures problems urinating abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. liver, kidney, thyroid problems pancreas or gallbladder problems Tell your healthcare provider if you are: noticing your pain getting worse. If your pain gets worse after you take Oxycodone Hydrochloride Oral Solution, do not take more of Oxycodone Hydrochloride Oral Solution without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking Oxycodone Hydrochloride Oral Solution. pregnant or planning to become pregnant. Use of Oxycodone Hydrochloride Oral Solution for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding. Oxycodone Hydrochloride Oral Solution passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. living in a household where there are small children or someone who has abused street or prescription drugs.

n passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Oxycodone Hydrochloride Oral Solution with certain other medicines can cause serious side effects that could lead to death. When taking Oxycodone Hydrochloride Oral Solution: Do not change your dose. Take Oxycodone Hydrochloride Oral Solution exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. For acute (short-term) pain, you may only need to take Oxycodone Hydrochloride Oral Solution for a few days. You may have some Oxycodone Hydrochloride Oral Solution left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused Oxycodone Hydrochloride Oral Solution. See the detailed Instructions for Use for information about how to take Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL). Always use the enclosed graduated measuring cup that comes with Oxycodone Hydrochloride Oral Solution 5 mg per 5 mL and the enclosed graduated oral syringe that comes with Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL) to correctly measure your dose. Never use a household teaspoon or tablespoon to measure Oxycodone Hydrochloride Oral Solution. Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. Call your healthcare provider if the dose you are taking does not control your pain. If you have been taking Oxycodone Hydrochloride Oral Solution regularly, do not stop taking Oxycodone Hydrochloride Oral Solution without talking to your healthcare provider. Dispose of expired, unwanted, or unused Oxycodone Hydrochloride Oral Solution by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking Oxycodone Hydrochloride Oral Solution DO NOT: Drive or operate heavy machinery, until you know how Oxycodone Hydrochloride Oral Solution affects you. Oxycodone Hydrochloride Oral Solution can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Oxycodone Hydrochloride Oral Solution may cause you to overdose and die. The possible side effects of Oxycodone Hydrochloride Oral Solution: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of Oxycodone Hydrochloride Oral Solution. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov Manufactured by and Distributed by: Genus Lifesciences Inc., 514 North 12th Street, Allentown, PA 18102, www.genuslifesciences.com or call 1-866-511-6754.

your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov Manufactured by and Distributed by: Genus Lifesciences Inc., 514 North 12th Street, Allentown, PA 18102, www.genuslifesciences.com or call 1-866-511-6754. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2025

<table width="100%"><col width="2%" align="left" valign="top"/><col width="38%" align="left" valign="top"/><col width="60%" align="left" valign="top"/><thead><tr><th styleCode="Lrule Rrule" colspan="3" align="center">Medication Guide Oxycodone Hydrochloride (ox-ee-CO-dohn) CII Oral Solution</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Oxycodone Hydrochloride Oral Solution is:</content><list listType="unordered" styleCode="disc"><item>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.</item><item>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Important information about Oxycodone Hydrochloride Oral Solution:</content><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Get emergency help or call 911 right away if you take too much Oxycodone Hydrochloride Oral Solution (overdose).</content> When you first start taking Oxycodone Hydrochloride Oral Solution, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose.</item><item>Taking Oxycodone Hydrochloride Oral Solution with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</item><item>Never give anyone else your Oxycodone Hydrochloride Oral Solution. They could die from taking it.

s, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</item><item>Never give anyone else your Oxycodone Hydrochloride Oral Solution. They could die from taking it. Selling or giving away Oxycodone Hydrochloride Oral Solution is against the law.</item><item>Store Oxycodone Hydrochloride Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Do not take Oxycodone Hydrochloride Oral Solution if you have:</content><list listType="unordered" styleCode="disc"><item>severe asthma, trouble breathing, or other lung problems.</item><item>bowel blockage or have narrowing of the stomach or intestines.</item><item>an allergy to oxycodone or any of the ingredients in Oxycodone Hydrochloride Oral Solution.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Before taking Oxycodone Hydrochloride Oral Solution, tell your healthcare provider if you have a history of:</content></td></tr><tr><td styleCode="Lrule"/><td><list listType="unordered" styleCode="disc"><item>head injury, seizures</item><item>problems urinating</item><item>abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.</item></list></td><td styleCode="Rrule"><list listType="unordered" styleCode="disc"><item>liver, kidney, thyroid problems</item><item>pancreas or gallbladder problems</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Tell your healthcare provider if you are:</content><list listType="unordered" styleCode="disc"><item><content styleCode="bold">noticing your pain getting worse.</content> If your pain gets worse after you take Oxycodone Hydrochloride Oral Solution, do not take more of Oxycodone Hydrochloride Oral Solution without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking Oxycodone Hydrochloride Oral Solution.</item><item><content styleCode="bold">pregnant or planning to become pregnant.</content> Use of Oxycodone Hydrochloride Oral Solution for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.</item><item><content styleCode="bold">breastfeeding.</content> Oxycodone Hydrochloride Oral Solution passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.</item><item>living in a household where there are small children or someone who has abused street or prescription drugs.</item><item>taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Oxycodone Hydrochloride Oral Solution with certain other medicines can cause serious side effects that could lead to death.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">When taking Oxycodone Hydrochloride Oral Solution:</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><list listType="unordered" styleCode="disc"><item>Do not change your dose. Take Oxycodone Hydrochloride Oral Solution exactly as prescribed by your healthcare provider.

styleCode="bold">When taking Oxycodone Hydrochloride Oral Solution:</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><list listType="unordered" styleCode="disc"><item>Do not change your dose. Take Oxycodone Hydrochloride Oral Solution exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</item><item>For acute (short-term) pain, you may only need to take Oxycodone Hydrochloride Oral Solution for a few days. You may have some Oxycodone Hydrochloride Oral Solution left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused Oxycodone Hydrochloride Oral Solution.</item><item>See the detailed <linkHtml href="#IFU">Instructions for Use</linkHtml> for information about how to take Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL).</item><item>Always use the enclosed graduated measuring cup that comes with Oxycodone Hydrochloride Oral Solution 5 mg per 5 mL and the enclosed graduated oral syringe that comes with Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL) to correctly measure your dose. Never use a household teaspoon or tablespoon to measure Oxycodone Hydrochloride Oral Solution.</item><item>Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.</item><item>Call your healthcare provider if the dose you are taking does not control your pain.</item><item>If you have been taking Oxycodone Hydrochloride Oral Solution regularly, do not stop taking Oxycodone Hydrochloride Oral Solution without talking to your healthcare provider.</item><item>Dispose of expired, unwanted, or unused Oxycodone Hydrochloride Oral Solution by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">While taking Oxycodone Hydrochloride Oral Solution DO NOT:</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><list listType="unordered" styleCode="disc"><item>Drive or operate heavy machinery, until you know how Oxycodone Hydrochloride Oral Solution affects you. Oxycodone Hydrochloride Oral Solution can make you sleepy, dizzy, or lightheaded.</item><item>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Oxycodone Hydrochloride Oral Solution may cause you to overdose and die.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">The possible side effects of Oxycodone Hydrochloride Oral Solution:</content></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><list listType="unordered" styleCode="disc"><item>constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain.

le Rrule" colspan="3"><content styleCode="bold">The possible side effects of Oxycodone Hydrochloride Oral Solution:</content></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><list listType="unordered" styleCode="disc"><item>constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Get emergency medical help or call 911 right away if you have:</content></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><list listType="unordered" styleCode="disc"><item>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3">These are not all the possible side effects of Oxycodone Hydrochloride Oral Solution. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <content styleCode="bold">For more information go to dailymed.nlm.nih.gov</content> <content styleCode="bold">Manufactured by and Distributed by:</content> Genus Lifesciences Inc., 514 North 12th Street, Allentown, PA 18102, www.genuslifesciences.com or call 1-866-511-6754. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 12/2025</td></tr></tbody></table>

Patient Instructions for Use Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL) Oral Syringe Important information about measuring Oxycodone Hydrochloride Oral Solution Always use the oral syringe provided with your Oxycodone Hydrochloride Oral Solution to make sure you measure the right amount. Measure the dose of medicine from the widest part of the plunger. Do not measure from the narrow tip. See FIGURE 1 . Step 1. Insert the tip of the oral syringe into the medicine bottle. Step 2. Pull back the plunger to the line that matches the dose prescribed by your healthcare provider. Step 3. Remove the oral syringe from the medicine bottle. Step 4. Take your medicine by slowly pushing the plunger until the oral syringe is empty. Figure 1 Figure 1

<table width="100%"><col width="100%" align="left" valign="top"/><tbody><tr><td styleCode="Lrule Rrule" align="center"><content styleCode="bold">Patient Instructions for Use</content></td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL) Oral Syringe Important information about measuring Oxycodone Hydrochloride Oral Solution</content><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Always use the oral syringe provided with your Oxycodone Hydrochloride Oral Solution to make sure you measure the right amount.</content></item><item><content styleCode="bold">Measure the dose of medicine from the widest part of the plunger. Do not measure from the narrow tip. See <linkHtml href="#fig1">FIGURE 1</linkHtml>.</content></item></list></td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold">Step 1.</content> Insert the tip of the oral syringe into the medicine bottle. <content styleCode="bold">Step 2.</content> Pull back the plunger to the line that matches the dose prescribed by your healthcare provider. <content styleCode="bold">Step 3.</content> Remove the oral syringe from the medicine bottle. <content styleCode="bold">Step 4.</content> Take your medicine by slowly pushing the plunger until the oral syringe is empty.</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="bold" ID="fig1">Figure 1</content> <paragraph><renderMultiMedia referencedObject="MM2"/></paragraph></td></tr></tbody></table>

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OXYCODONE HYDROCHLORIDE TABLETS WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OXYCODONE HYDROCHLORIDE TABLETS See full prescribing information for complete boxed warning. Oxycodone hydrochloride tablets expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of oxycodone hydrochloride tablets are essential. ( 5.2 ) Accidental ingestion of oxycodone hydrochloride tablets, especially by children, can result in a fatal overdose of oxycodone. ( 5.2 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation. ( 5.3 , 7 ) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.4 ) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. ( 5.5 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone from oxycodone hydrochloride tablets. ( 5.6 , 7 , 12.3 ) Addiction, Abuse, and Misuse Because the use of oxycodone hydrochloride tablets exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.1) ]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of oxycodone hydrochloride tablets, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of oxycodone hydrochloride tablets are essential [see Warnings and Precautions (5.2) ]. Accidental Ingestion Accidental ingestion of even one dose of oxycodone hydrochloride tablets, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.2) ]. Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death . Reserve concomitant prescribing of oxycodone hydrochloride tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3) , Drug Interactions (7) ].

result in profound sedation, respiratory depression, coma, and death . Reserve concomitant prescribing of oxycodone hydrochloride tablets and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.3) , Drug Interactions (7) ]. Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.4) ]. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.5) ]. Cytochrome P450 3A4 Interaction The concomitant use of oxycodone hydrochloride tablets with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Regularly evaluate patients receiving oxycodone hydrochloride tablets and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.6) , Drug Interactions (7) , Clinical Pharmacology (12.3) ].

<table width="100%" styleCode="Noautorules"><col width="65%" align="left" valign="top"/><col width="35%" align="left" valign="top"/><tbody><tr><td><linkHtml href="#BOX">Boxed Warning</linkHtml></td><td>12/2025</td></tr><tr><td>Indications and Usage (<linkHtml href="#S1">1</linkHtml>)</td><td>12/2025</td></tr><tr><td>Dosage and Administration (<linkHtml href="#S2.2">2.2</linkHtml>, <linkHtml href="#S2.5">2.5</linkHtml>)</td><td>12/2025</td></tr><tr><td>Warnings and Precautions (<linkHtml href="#S5.1">5.1</linkHtml>, <linkHtml href="#S5.2">5.2</linkHtml>, <linkHtml href="#S5.3">5.3</linkHtml>, <linkHtml href="#S5.12">5.12</linkHtml>, <linkHtml href="#S5.14">5.14</linkHtml>)</td><td>12/2025</td></tr></tbody></table>

1 INDICATIONS AND USAGE Oxycodone Hydrochloride Tablets, USP are indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Oxycodone hydrochloride tablets are an opioid agonist indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use: Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including oxycodone hydrochloride tablets for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy [see Warnings and Precautions (5.1) ], reserve opioid analgesics, including Oxycodone Hydrochloride Tablets, USP, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

2 DOSAGE AND ADMINISTRATION Oxycodone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of oxycodone hydrochloride tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) Initiate the dosing regimen for each patient individually, taking into account the patient's underlying case and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with oxycodone hydrochloride tablets. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with oxycodone hydrochloride tablets especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) Initiate treatment with oxycodone hydrochloride tablets in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of oxycodone hydrochloride tablets. ( 2.3 , 2.4 ) Periodically reassess patients receiving oxycodone hydrochloride tablets to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.4 ) Do not rapidly reduce or abruptly discontinue oxycodone hydrochloride tablets in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 , 5.1 ) 2.1 Important Dosage and Administration Instructions Oxycodone hydrochloride tablets should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5) ]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of oxycodone hydrochloride tablets for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic.

oses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.1) ]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with oxycodone hydrochloride tablets. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5) ]. 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1 , 5.2 , 5.3) ] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions (5.2) ] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Initial Dosage Although it is not possible to list every condition that is important to the selection of the initial dose of oxycodone hydrochloride tablets, attention must be given to: 1. the daily dose, potency and characteristics of a full agonist or mixed agonist/antagonist the patient has been taking previously. 2. the reliability of the relative potency estimate to calculate the dose of oxycodone HCl needed. 3. the degree of opioid tolerance. 4. the general condition and medical status of the patient, including the patient's weight and age. 5. the balance between pain management and adverse reactions. 6. the type and severity of the patient's pain. 7. risk factors for abuse or addiction, including a prior history of abuse or addiction. Use of Oxycodone Hydrochloride Tablets as the First Opioid Analgesic Initiate treatment with oxycodone hydrochloride tablets in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of oxycodone hydrochloride tablets. Conversion from Other Opioids to Oxycodone Hydrochloride Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of oxycodone hydrochloride tablets.

l dose of oxycodone hydrochloride tablets. Conversion from Other Opioids to Oxycodone Hydrochloride Tablets There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of oxycodone hydrochloride tablets. It is safer to underestimate a patient's 24-hour oxycodone hydrochloride tablets dosage than to overestimate the 24-hour oxycodone hydrochloride tablets dosage and manage an adverse reaction due to overdose. If a patient has been receiving opioid-containing medications prior to taking oxycodone hydrochloride tablets, the potency of the prior opioid relative to oxycodone should be factored into the selection of the total daily dose (TDD) of oxycodone. In converting patients from other opioids to oxycodone hydrochloride tablets, close observation and adjustment of dosage based upon the patient's response to oxycodone hydrochloride tablets is imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of oxycodone hydrochloride tablets may be necessary, especially in patients who have disease states that are changing rapidly. Conversion from Fixed-Ratio Opioid/Acetaminophen, Opioid/Aspirin, or Opioid/Nonsteroidal Combination Drugs When converting patients from fixed ratio opioid/non-opioid drug regimens, a decision should be made whether or not to continue the non-opioid analgesic. If a decision is made to discontinue the use of non-opioid analgesic, it may be necessary to titrate the dose of oxycodone hydrochloride tablets in response to the level of analgesia and adverse effects afforded by the dosing regimen. If the non-opioid regimen is continued as a separate single entity agent, the starting dose oxycodone hydrochloride tablets should be based upon the most recent dose of opioid as a baseline for further titration of oxycodone. Incremental increases should be gauged according to side effects to an acceptable level of analgesia. Conversion from Oxycodone Hydrochloride Tablets to Extended-Release Oxycodone The relative bioavailability of oxycodone hydrochloride tablets compared to extended-release oxycodone is unknown, so conversion to extended-release oxycodone may lead to increased risk of excessive sedation and respiratory depression. 2.4 Titration and Maintenance of Therapy Individually titrate oxycodone hydrochloride tablets to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving oxycodone hydrochloride tablets to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions (5.1 , 5.14) ]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the oxycodone hydrochloride tablets dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions (5) ] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Oxycodone Hydrochloride Tablets Do not rapidly reduce or abruptly discontinue oxycodone hydrochloride tablets in patients who may be physically dependent on opioids.

just the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Oxycodone Hydrochloride Tablets Do not rapidly reduce or abruptly discontinue oxycodone hydrochloride tablets in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking oxycodone hydrochloride tablets, there are a variety of factors that should be considered, including the total daily dose of opioid (including oxycodone hydrochloride tablets) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on oxycodone hydrochloride tablets who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper.

When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.14) , Drug Abuse and Dependence (9.3) ] .

3 DOSAGE FORMS AND STRENGTHS Immediate-release tablets: 5 mg, 10 mg, 15 mg, 20 mg, 30 mg ( 3 ) Oxycodone Hydrochloride Tablets USP: 5 mg - white to off-white, round, flat faced, beveled edged tablets debossed with "R" above bisect and "P" below on one side and "5" on the other side 10 mg - white to off-white, round, biconvex tablets debossed with "R" above bisect and "P" below on one side and "10" on the other side 15 mg - white to off-white, oval tablets with "R" and "P" (with a center score) on one side and "15" on the other side 20 mg - white to off-white, round, biconvex tablets debossed with "R" above bisect and "P" below on one side and "20" on the other side 30 mg - white to off-white, round, biconvex tablets debossed with "R" above bisect and "P" below on one side and "30" on the other side

<table width="75%" styleCode="Noautorules"><col width="10%" align="right" valign="top"/><col width="90%" align="left" valign="bottom"/><tbody><tr><td><content styleCode="bold italics">5 mg</content> -</td><td>white to off-white, round, flat faced, beveled edged tablets debossed with &quot;R&quot; above bisect and &quot;P&quot; below on one side and &quot;5&quot; on the other side</td></tr><tr><td><content styleCode="bold italics">10 mg</content> -</td><td>white to off-white, round, biconvex tablets debossed with &quot;R&quot; above bisect and &quot;P&quot; below on one side and &quot;10&quot; on the other side</td></tr><tr><td><content styleCode="bold italics">15 mg</content> -</td><td>white to off-white, oval tablets with &quot;R&quot; and &quot;P&quot; (with a center score) on one side and &quot;15&quot; on the other side</td></tr><tr><td><content styleCode="bold italics">20 mg</content> -</td><td>white to off-white, round, biconvex tablets debossed with &quot;R&quot; above bisect and &quot;P&quot; below on one side and &quot;20&quot; on the other side</td></tr><tr><td><content styleCode="bold italics">30 mg</content> -</td><td>white to off-white, round, biconvex tablets debossed with &quot;R&quot; above bisect and &quot;P&quot; below on one side and &quot;30&quot; on the other side</td></tr></tbody></table>

4 CONTRAINDICATIONS Oxycodone hydrochloride tablets are contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions (5.2) ]. Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment or hypercarbia [see Warnings and Precautions (5.8) ]. Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions (5.12) ]. Known hypersensitivity (e.g., anaphylaxis) to oxycodone [see Adverse Reactions (6.2) ]. Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) Hypersensitivity to oxycodone ( 4 )

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.7 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate closely, particularly during initiation and titration. ( 5.8 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9 ) Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of oxycodone hydrochloride tablets in patients with circulatory shock. ( 5.10 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of oxycodone hydrochloride tablets in patients with impaired consciousness or coma. ( 5.11 ) 5.1 Addiction, Abuse, and Misuse Oxycodone hydrochloride tablets contain oxycodone, a Schedule II controlled substance. As an opioid, oxycodone hydrochloride tablets expose users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9) ]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed oxycodone hydrochloride tablets. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions (6.2) ] . Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing oxycodone hydrochloride tablets, and reassess all patients receiving oxycodone hydrochloride tablets for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as oxycodone hydrochloride tablets, but use in such patients necessitates intensive counseling about the risks and proper use of oxycodone hydrochloride tablets along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing oxycodone hydrochloride tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drugs .

use. Consider these risks when prescribing or dispensing oxycodone hydrochloride tablets. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drugs . Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents (e.g., naloxone, nalmefene), depending on the patient's clinical status [see Overdosage (10) ]. Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of oxycodone hydrochloride tablets, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of oxycodone hydrochloride tablets are essential [see Dosage and Administration (2) ]. Overestimating the oxycodone hydrochloride tablets dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of oxycodone hydrochloride tablets, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration (2.5) ] . Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions (5.1 , 5.3) ] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose.

s. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.3) , Overdosage (10) ]. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of oxycodone hydrochloride tablets with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions (7) ]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) , Overdosage (10) ]. Advise both patients and caregivers about the risks of respiratory depression and sedation when oxycodone hydrochloride tablets are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate dangerous machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions (7) ]. 5.4 Neonatal Opioid Withdrawal Syndrome Use of oxycodone hydrochloride tablets for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.

the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations (8.1) ]. 5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com . The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint . 5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of oxycodone hydrochloride tablets with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions (5.3) ], particularly when an inhibitor is added after a stable dose of oxycodone hydrochloride tablets is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in oxycodone hydrochloride tablets-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using oxycodone hydrochloride tablets with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in oxycodone hydrochloride tablets-treated patients, evaluate patients at frequent intervals and consider dosage reduction of oxycodone hydrochloride tablets until stable drug effects are achieved [see Drug Interactions (7) ]. Concomitant use of oxycodone hydrochloride tablets with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone.

Drug Interactions (7) ]. Concomitant use of oxycodone hydrochloride tablets with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using oxycodone hydrochloride tablets with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions (7) ]. 5.7 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence (9.3) ] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration (2.5) , Warnings and Precautions (5.14) ] . 5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of oxycodone hydrochloride tablets in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : Oxycodone hydrochloride tablets-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of oxycodone hydrochloride tablets [see Warnings and Precautions (5.2) ]. Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions (5.2) ]. Regularly evaluate patients, particularly when initiating and titrating oxycodone hydrochloride tablets and when oxycodone hydrochloride tablets are given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2 , 5.3) , Drug Interactions (7) ]. Alternatively, consider the use of non-opioid analgesics in these patients. 5.9 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible.

following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.10 Severe Hypotension Oxycodone hydrochloride tablets may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions (7) ]. Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of oxycodone hydrochloride tablets. In patients with circulatory shock, use of oxycodone hydrochloride tablets may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid use of oxycodone hydrochloride tablets in patients with circulatory shock. 5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), oxycodone hydrochloride tablets may reduce the respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with oxycodone hydrochloride tablets. Opioids may obscure the clinical course in a patient with a head injury. Avoid the use of oxycodone hydrochloride tablets in patients with impaired consciousness or coma. 5.12 Risks of Gastrointestinal Complications Oxycodone hydrochloride tablets are contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. The oxycodone in oxycodone hydrochloride tablets may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology (12.2) ] . 5.13 Increased Risk of Seizures in Patients with Seizure Disorders The oxycodone in oxycodone hydrochloride tablets may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during oxycodone hydrochloride tablets therapy. 5.14 Withdrawal Do not rapidly reduce or abruptly discontinue oxycodone hydrochloride tablets in a patient physically dependent on opioids.

ical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during oxycodone hydrochloride tablets therapy. 5.14 Withdrawal Do not rapidly reduce or abruptly discontinue oxycodone hydrochloride tablets in a patient physically dependent on opioids. When discontinuing oxycodone hydrochloride tablets in a physically dependent patient, gradually taper the dosage. Rapid tapering of oxycodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration (2.4) , Drug Abuse and Dependence (9.3) ]. Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including oxycodone hydrochloride tablets. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions (7) ]. 5.15 Risks of Driving and Operating Machinery Oxycodone hydrochloride tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of oxycodone hydrochloride tablets and know how they will react to the medication [see Patient Counseling Information (17) ].

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4) ] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.7) ] Adrenal Insufficiency [see Warnings and Precautions (5.9) ] Severe Hypotension [see Warnings and Precautions (5.10) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.12) ] Seizures [see Warnings and Precautions (5.13) ] Withdrawal [see Warnings and Precautions (5.14) ] Most common adverse reactions (≥3%) were nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rhodes Pharmaceuticals LLC at 1-888-873-5329; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Oxycodone hydrochloride tablets have been evaluated in open label clinical trials in patients with cancer and nonmalignant pain. Oxycodone hydrochloride tablets are associated with adverse experiences similar to those seen with other opioids. Serious adverse reactions associated with oxycodone hydrochloride tablets use included: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock. The common adverse reactions seen on initiation of therapy with oxycodone hydrochloride tablets are dose related and are typical opioid-related adverse reactions. The most frequent of these included nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. The frequency of these reactions depended on several factors, including clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual. In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving oxycodone hydrochloride tablets, the following adverse events were recorded in oxycodone hydrochloride tablets-treated patients with an incidence ≥ 3%. In descending order of frequency, they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence.

-blind studies involving oxycodone hydrochloride tablets, the following adverse events were recorded in oxycodone hydrochloride tablets-treated patients with an incidence ≥ 3%. In descending order of frequency, they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. Other less frequently observed adverse reactions from opioid analgesics, including oxycodone hydrochloride tablets included: Blood and lymphatic system disorders : anemia, leukopenia Cardiac disorders : cardiac failure, palpitation, tachycardia Gastrointestinal disorders : abdominal pain, dry mouth, diarrhea, dyspepsia, dysphagia, glossitis, nausea, vomiting General disorders and administration site conditions : chills, edema, edema peripheral, pain, pyrexia Immune system disorders : hypersensitivity Infections and infestations : bronchitis, gingivitis, infection, pharyngitis, rhinitis, sepsis, sinusitis, urinary tract infection Injury, poisoning, and procedural complications : injury Metabolism and nutrition disorders : decreased appetite, gout, hyperglycemia Musculoskeletal and connective tissue disorders : arthralgia, arthritis, back pain, bone pain, myalgia, neck pain, pathological fracture Nervous system disorders : hypertonia, hypoesthesia, migraine, neuralgia, tremor, vasodilation Psychiatric disorders : agitation, anxiety, confusional state, nervousness, personality disorder Respiratory, thoracic, and mediastinal disorders : cough, dyspnea, epistaxis, laryngospasm, lung disorder Skin and subcutaneous tissue disorders : photosensitivity reaction, rash, hyperhidrosis, urticaria Vascular disorders : thrombophlebitis, hemorrhage, hypotension, vasodilatation 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of oxycodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General disorders and administrative site disorders : drug withdrawal syndrome neonatal [see Warnings and Precautions (5.4) ] Respiratory, thoracic and mediastinal disorders : pharyngeal edema Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs [see Drug Interactions (7) ]. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use [see Warnings and Precautions (5.9) ]. Anaphylaxis : Anaphylactic reaction has been reported with ingredients contained in oxycodone hydrochloride tablets [see Contraindications (4) ]. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [see Clinical Pharmacology (12.2) ]. Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions (5.7) ] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids . Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions (5.12) ] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021.

, and/or in patients taking opioids longer term [see Warnings and Precautions (5.12) ] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence (9.2)] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days' supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5 to 11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with oxycodone hydrochloride tablets. Table 1: Clinically Significant Drug Interactions with Oxycodone Hydrochloride Tablets Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone hydrochloride tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone hydrochloride tablets is achieved [see Warnings and Precautions (5.3) ]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3) ], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. Intervention: If concomitant use is necessary, consider dosage reduction of oxycodone hydrochloride tablets until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir). CYP3A4 Inducers Clinical Impact: The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3) ], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions (5.6) ]. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3) ], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone hydrochloride tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions (5.3) ] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation) .

concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation) . If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.1 , 5.2 , 5.3) ]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Adverse Reactions (6.2) ]. Intervention: If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone hydrochloride tablets if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions (5.2) ]. Intervention: The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of oxycodone hydrochloride tablets and/or may precipitate withdrawal symptoms. Intervention: Avoid concomitant use Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of oxycodone hydrochloride tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration (2.2) , Warnings and Precautions (5.2 , 5.3) ]. Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of dismissed diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

tients for signs of dismissed diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when oxycodone hydrochloride tablets are used concurrently with anticholinergic drugs. Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue oxycodone hydrochloride tablets if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with oxycodone hydrochloride tablets because they may reduce analgesic effect of oxycodone hydrochloride tablets or precipitate withdrawal symptoms. ( 7 ) Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of morphine. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 )

<table width="95%"><caption>Table 1: Clinically Significant Drug Interactions with Oxycodone Hydrochloride Tablets</caption><col width="25%" align="left" valign="top"/><col width="75%" align="left" valign="top"/><tbody><tr><td styleCode="Lrule Rrule Botrule" colspan="2"><content styleCode="bold">Inhibitors of CYP3A4 and CYP2D6</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of oxycodone hydrochloride tablets and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of oxycodone hydrochloride tablets is achieved <content styleCode="italics">[see <linkHtml href="#S5.3">Warnings and Precautions (5.3)</linkHtml>].</content> After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease <content styleCode="italics">[see <linkHtml href="#S12.3">Clinical Pharmacology (12.3)</linkHtml>],</content> resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">If concomitant use is necessary, consider dosage reduction of oxycodone hydrochloride tablets until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved.

sider dosage reduction of oxycodone hydrochloride tablets until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir).</td></tr><tr><td styleCode="Lrule Rrule Botrule" colspan="2"><content styleCode="bold">CYP3A4 Inducers</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">The concomitant use of oxycodone hydrochloride tablets and CYP3A4 inducers can decrease the plasma concentration of oxycodone <content styleCode="italics">[see <linkHtml href="#S12.3">Clinical Pharmacology (12.3)</linkHtml>],</content> resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone <content styleCode="italics">[see <linkHtml href="#S5.6">Warnings and Precautions (5.6)</linkHtml>].</content> After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase <content styleCode="italics">[see <linkHtml href="#S12.3">Clinical Pharmacology (12.3)</linkHtml>],</content> which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">If concomitant use is necessary, consider increasing the oxycodone hydrochloride tablets dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider oxycodone hydrochloride tablets dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">Rifampin, carbamazepine, phenytoin</td></tr><tr><td styleCode="Lrule Rrule Botrule" colspan="2"><content styleCode="bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <content styleCode="italics">[see <linkHtml href="#S5.3">Warnings and Precautions (5.3)</linkHtml>]</content>.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required.

ent>.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation)<content styleCode="italics">.</content> If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent <content styleCode="italics">[see <linkHtml href="#S2.2">Dosage and Administration (2.2)</linkHtml>, <linkHtml href="#S5.1">Warnings and Precautions (5.1</linkHtml>, <linkHtml href="#S5.2">5.2</linkHtml>, <linkHtml href="#S5.3">5.3)</linkHtml>].</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol.</td></tr><tr><td styleCode="Lrule Rrule Botrule" colspan="2"><content styleCode="bold">Serotonergic Drugs</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <content styleCode="italics">[see <linkHtml href="#S6.2">Adverse Reactions (6.2)</linkHtml>].</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">If concomitant use is warranted, frequently evaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue oxycodone hydrochloride tablets if serotonin syndrome is suspected.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td></tr><tr><td styleCode="Lrule Rrule Botrule" colspan="2"><content styleCode="bold">Monoamine Oxidase Inhibitors (MAOIs)</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <content styleCode="italics">[see <linkHtml href="#S5.2">Warnings and Precautions (5.2)</linkHtml>].</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

s and Precautions (5.2)</linkHtml>].</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">The use of oxycodone hydrochloride tablets is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">Phenelzine, tranylcypromine, linezolid</td></tr><tr><td styleCode="Lrule Rrule Botrule" colspan="2"><content styleCode="bold">Mixed Agonist/Antagonist Opioid Analgesics</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">May reduce the analgesic effect of oxycodone hydrochloride tablets and/or may precipitate withdrawal symptoms.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Avoid concomitant use</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">Butorphanol, nalbuphine, pentazocine, buprenorphine</td></tr><tr><td styleCode="Lrule Rrule Botrule" colspan="2"><content styleCode="bold">Muscle Relaxants</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Because respiratory depression may be greater than otherwise expected, decrease the dosage of oxycodone hydrochloride tablets and/or the muscle relaxant as necessary.

y depression.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Because respiratory depression may be greater than otherwise expected, decrease the dosage of oxycodone hydrochloride tablets and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent <content styleCode="italics">[see <linkHtml href="#S2.2">Dosage and Administration (2.2)</linkHtml>, <linkHtml href="#S5.2">Warnings and Precautions (5.2</linkHtml>, <linkHtml href="#S5.3">5.3)</linkHtml>].</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Examples:</content></td><td styleCode="Rrule">cyclobenzaprine, metaxalone</td></tr><tr><td styleCode="Lrule Rrule Botrule" colspan="2"><content styleCode="bold">Diuretics</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Evaluate patients for signs of dismissed diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td></tr><tr><td styleCode="Lrule Rrule Botrule" colspan="2"><content styleCode="bold">Anticholinergic Drugs</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Rrule">The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td></tr><tr><td styleCode="Lrule Rrule"><content styleCode="italics">Intervention:</content></td><td styleCode="Rrule">Evaluate patients for signs of urinary retention or reduced gastric motility when oxycodone hydrochloride tablets are used concurrently with anticholinergic drugs.</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ]. Available data with oxycodone hydrochloride tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. Animal reproduction studies with oral administrations of oxycodone HCl in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents irritability, hyperactivity, and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid use, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Oxycodone hydrochloride tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including oxycodone hydrochloride tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone HCl administered during the period of organogenesis up to 16 mg/kg/day and up to 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis.

esis up to 16 mg/kg/day and up to 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m 2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis). 8.2 Lactation Risk Summary Available data from lactation studies indicate that oxycodone is present in breastmilk and that doses of less than 60 mg/day of the immediate-release formulation are unlikely to result in clinically relevant exposures in breastfed infants. A pharmacokinetics study utilizing opportunistic sampling of 76 lactating women receiving oxycodone immediate-release products for postpartum pain management showed that oxycodone concentrates in breastmilk with an average milk to plasma ratio of 3.2. The relative infant dose was low, approximately 1.3% of a weight-adjusted maternal dose (see Data ) . In the same study, among the 70 infants exposed to oxycodone in breastmilk, no adverse events were attributed to oxycodone. However, based on known adverse effects in adults, infants should be monitored for signs of excess sedation and respiratory depression (see Clinical Considerations ) . There are no data on the effects of the oxycodone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for oxycodone hydrochloride tablets and any potential adverse effects on the breastfed infant from oxycodone hydrochloride tablets or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to oxycodone hydrochloride tablets through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped or when breastfeeding is stopped. Data Oxycodone concentration data from 76 lactating women receiving immediate-release oxycodone products for postpartum pain management, and 28 infants exposed to oxycodone in breastmilk showed that following a median (range) dose of oxycodone in mothers of 9.2 (5 to 10) mg/dose or 33.0 (5.4 to 59.3) mg/day, oxycodone concentrated in breastmilk with a median (range) milk to plasma ratio of 3.2 (1.2 to 5.3). However, when using maternal breastmilk data to estimate the daily and relative infant dose, the infant dose was 0.006 mg/kg/day, which is 1.3% of a weight-adjusted maternal dose of 10 mg every 6 hours. These estimates based on maternal breastmilk concentrations were corroborated by the observed infant concentrations, of which over 75% (19/25) were below the limit of quantification. Among the 6 infants with quantifiable concentration, the median (range) concentration was 0.2 ng/mL (0.1 to 0.7). These concentrations are 100 to 1000 times lower than concentrations observed in other studies after infants received oxycodone at 0.1 mg/kg/dose (~20 to 200 ng/mL). 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) , Clinical Pharmacology (12.2) ].

0 ng/mL). 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions (6.2) , Clinical Pharmacology (12.2) ]. 8.4 Pediatric Use The safety and efficacy of oxycodone hydrochloride tablets in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the total number of subjects in clinical studies of oxycodone hydrochloride tablets, 20.8% (112/538) were 65 and over, while 7.2% (39/538) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of oxycodone hydrochloride tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2) ]. Oxycodone is known to be substantially excreted by the kidney and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to regularly evaluate renal function. 8.6 Hepatic Impairment Because oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Initiate therapy in these patients with a lower than usual dosage of oxycodone hydrochloride tablets and titrate carefully. Regularly evaluate for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3) ]. 8.7 Renal Impairment Because oxycodone is known to be substantially excreted by the kidney, its clearance may decrease in patients with renal impairment. Initiate therapy with a lower than usual dosage of oxycodone hydrochloride tablets and titrate carefully. Regularly evaluate for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3) ].

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions (5.4) ]. Available data with oxycodone hydrochloride tablets in pregnant women are insufficient to inform a drug-associated risk for major birth defects and miscarriage or adverse maternal outcomes. Animal reproduction studies with oral administrations of oxycodone HCl in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data ]. Based on animal data, advise pregnant women of the potential risk to a fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents irritability, hyperactivity, and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid use, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions (5.4) ]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Oxycodone hydrochloride tablets are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including oxycodone hydrochloride tablets, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone HCl administered during the period of organogenesis up to 16 mg/kg/day and up to 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis.

esis up to 16 mg/kg/day and up to 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m 2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis).

8.5 Geriatric Use Of the total number of subjects in clinical studies of oxycodone hydrochloride tablets, 20.8% (112/538) were 65 and over, while 7.2% (39/538) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of oxycodone hydrochloride tablets slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.2) ]. Oxycodone is known to be substantially excreted by the kidney and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to regularly evaluate renal function.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Oxycodone hydrochloride tablets contain oxycodone, a Schedule II controlled substance. 9.2 Abuse Oxycodone hydrochloride tablets contain oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1) ]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of oxycodone hydrochloride tablets increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of oxycodone hydrochloride tablets with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of oxycodone hydrochloride tablets abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use oxycodone hydrochloride tablets in combination with other abused drugs. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Oxycodone hydrochloride tablets, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Tablets Abuse of oxycodone hydrochloride tablets poses a risk of overdose and death.

ent of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Tablets Abuse of oxycodone hydrochloride tablets poses a risk of overdose and death. The risk is increased with concurrent use of oxycodone hydrochloride tablets with alcohol and/or other CNS depressants. Oxycodone hydrochloride tablets are approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not rapidly reduce or abruptly discontinue oxycodone hydrochloride tablets in a patient physically dependent on opioids. Rapid tapering of oxycodone hydrochloride tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing oxycodone hydrochloride tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of oxycodone hydrochloride tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.4) , Warnings and Precautions (5.14) ]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ].

9.2 Abuse Oxycodone hydrochloride tablets contain oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.1) ]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of oxycodone hydrochloride tablets increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of oxycodone hydrochloride tablets with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of oxycodone hydrochloride tablets abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use oxycodone hydrochloride tablets in combination with other abused drugs. "Drug-seeking" behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated "loss" of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). "Doctor shopping" (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Oxycodone hydrochloride tablets, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Tablets Abuse of oxycodone hydrochloride tablets poses a risk of overdose and death. The risk is increased with concurrent use of oxycodone hydrochloride tablets with alcohol and/or other CNS depressants. Oxycodone hydrochloride tablets are approved for oral use only.

Risks Specific to Abuse of Oxycodone Hydrochloride Tablets Abuse of oxycodone hydrochloride tablets poses a risk of overdose and death. The risk is increased with concurrent use of oxycodone hydrochloride tablets with alcohol and/or other CNS depressants. Oxycodone hydrochloride tablets are approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not rapidly reduce or abruptly discontinue oxycodone hydrochloride tablets in a patient physically dependent on opioids. Rapid tapering of oxycodone hydrochloride tablets in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing oxycodone hydrochloride tablets, gradually taper the dosage using a patient-specific plan that considers the following: the dose of oxycodone hydrochloride tablets the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.4) , Warnings and Precautions (5.14) ]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ].

10 OVERDOSAGE Clinical Presentation Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology (12.2) ]. Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of oxycodone in oxycodone hydrochloride tablets, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.

11 DESCRIPTION Oxycodone Hydrochloride Tablets, USP contain oxycodone, an opioid agonist. Each tablet for oral administration contains 5 mg, 10 mg, 15 mg, 20 mg, or 30 mg of oxycodone hydrochloride, USP. Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is considered slightly soluble in alcohol (octanol water partition coefficient is 0.7). Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride and has the following structural formula: C 18 H 21 NO 4 ∙HCl MW 351.82 The Oxycodone Hydrochloride Tablets, USP contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, crospovidone, and magnesium stearate. The 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg tablets contain the equivalent of 4.5 mg, 9 mg, 13.5 mg, 18 mg, and 27 mg, respectively, of oxycodone free base. Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. 12.2 Pharmacodynamics Effects on Central Nervous System Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on Cardiovascular System Oxycodone produces peripheral vasodilatation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2) ]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2) ]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

ted to date [see Adverse Reactions (6.2) ]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.3) ]. Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.3) ]. 12.3 Pharmacokinetics The activity of oxycodone hydrochloride tablets is primarily due to the parent drug oxycodone. Oxycodone hydrochloride tablets are designed to provide immediate release of oxycodone. Table 2: Pharmacokinetic Parameters (Mean±SD) Dose\Parameters AUC (ng×hr/mL) C max (ng/mL) T max (hr) C min (ng/mL) C avg (ng/mL) Half-Life (hr) Single Dose Pharmacokinetics Oxycodone HCl 5 mg tabs × 3 133.2±33 22.3±8.2 1.8±1.8 N/A N/A 3.73±0.9 Oxycodone HCl 15 mg tab 128.2±35.1 22.2±7.6 1.4±0.7 N/A N/A 3.55±1.0 Oxycodone HCl Liquid Concentrate 15 mg oral solution 130.6±34.7 21.1±6.1 1.9±1.5 N/A N/A 3.71±0.8 Oxycodone HCl 30 mg tab 268.2±60.7 39.3±14.0 2.6±3.0 N/A N/A 3.85±1.3 Food Effect, Single Dose Oxycodone HCl 10 mg/10 mL oral sol'n (fasted) 105±6.2 19.0±3.7 1.25±0.5 N/A N/A 2.9±0.4 Oxycodone HCl 10 mg/10 mL oral sol'n (fed) 133±25.2 17.7±3.0 2.54±1.2 N/A N/A 3.3±0.5 Multiple-Dose Studies AUC (72 to 84) Oxycodone HCl 5 mg tabs q6h × 14 doses 113.3±24.0 15.7±3.2 1.3±0.3 7.4±1.8 9.4±2.0 N/A Oxycodone HCl 3.33 mg (3.33 mL) oral sol'n q4h × 21 doses 99.0±24.8 12.9±3.1 1.0±0.3 7.2±2.3 9.7±2.6 N/A Absorption About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lower presystemic and/or first-pass metabolism of oxycodone. The relative oral bioavailability of oxycodone hydrochloride tablets 15 mg and 30 mg tablets, compared to the 5 mg oxycodone hydrochloride tablet, is 96% and 101%, respectively. Oxycodone hydrochloride tablets, 15 mg and 30 mg tablets, are bioequivalent to the 5 mg oxycodone hydrochloride tablets (see Table 2 for pharmacokinetic parameters). Dose proportionality of oxycodone has been established using the oxycodone hydrochloride tablets 5 mg at doses of 5 mg, 15 mg (three 5 mg tablets) and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) (see Figure 1 ). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride tablets. Figure 1 – Oxycodone Hydrochloride Tablets, USP Dose-Proportionality Study 5mg, 15mg, 30mg (single-dose) Figure 1 Food Effect A single-dose food effect study was conducted in normal volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of oxycodone absorption from the oral solution (see Table 2 ). In addition, food caused a delay in T max (1.25 to 2.54 hour).

ood effect study was conducted in normal volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of oxycodone absorption from the oral solution (see Table 2 ). In addition, food caused a delay in T max (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30 mg tablets. Distribution Following intravenous administration, the volume of distribution (V ss ) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk [see Special Populations (8.2) ]. Elimination Metabolism A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism and is catalyzed by CYP3A4. Oxymorphone is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6 [see Drug Interactions (7) ]. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone hydrochloride tablets was 3.5 to 4 hours. Specific Populations Age: Geriatric Population Population pharmacokinetic studies conducted with oxycodone hydrochloride tablets, indicated that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65. Hepatic Impairment In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased hepatic function were evaluated to study these potential differences. However, because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic impaired patients [see Use in Specific Populations (8.6) ]. Renal Impairment This drug is known to be substantially excreted by the kidney and the risk of adverse reactions to this drug may be greater in patients with impaired renal function [see Use in Specific Populations (8.7) ] .

12.2 Pharmacodynamics Effects on Central Nervous System Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on Cardiovascular System Oxycodone produces peripheral vasodilatation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions (6.2) ]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6.2) ]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.3) ]. Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

of analgesic tolerance [see Dosage and Administration (2.1 , 2.3) ]. Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.3) ].

12.3 Pharmacokinetics The activity of oxycodone hydrochloride tablets is primarily due to the parent drug oxycodone. Oxycodone hydrochloride tablets are designed to provide immediate release of oxycodone. Table 2: Pharmacokinetic Parameters (Mean±SD) Dose\Parameters AUC (ng×hr/mL) C max (ng/mL) T max (hr) C min (ng/mL) C avg (ng/mL) Half-Life (hr) Single Dose Pharmacokinetics Oxycodone HCl 5 mg tabs × 3 133.2±33 22.3±8.2 1.8±1.8 N/A N/A 3.73±0.9 Oxycodone HCl 15 mg tab 128.2±35.1 22.2±7.6 1.4±0.7 N/A N/A 3.55±1.0 Oxycodone HCl Liquid Concentrate 15 mg oral solution 130.6±34.7 21.1±6.1 1.9±1.5 N/A N/A 3.71±0.8 Oxycodone HCl 30 mg tab 268.2±60.7 39.3±14.0 2.6±3.0 N/A N/A 3.85±1.3 Food Effect, Single Dose Oxycodone HCl 10 mg/10 mL oral sol'n (fasted) 105±6.2 19.0±3.7 1.25±0.5 N/A N/A 2.9±0.4 Oxycodone HCl 10 mg/10 mL oral sol'n (fed) 133±25.2 17.7±3.0 2.54±1.2 N/A N/A 3.3±0.5 Multiple-Dose Studies AUC (72 to 84) Oxycodone HCl 5 mg tabs q6h × 14 doses 113.3±24.0 15.7±3.2 1.3±0.3 7.4±1.8 9.4±2.0 N/A Oxycodone HCl 3.33 mg (3.33 mL) oral sol'n q4h × 21 doses 99.0±24.8 12.9±3.1 1.0±0.3 7.2±2.3 9.7±2.6 N/A Absorption About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lower presystemic and/or first-pass metabolism of oxycodone. The relative oral bioavailability of oxycodone hydrochloride tablets 15 mg and 30 mg tablets, compared to the 5 mg oxycodone hydrochloride tablet, is 96% and 101%, respectively. Oxycodone hydrochloride tablets, 15 mg and 30 mg tablets, are bioequivalent to the 5 mg oxycodone hydrochloride tablets (see Table 2 for pharmacokinetic parameters). Dose proportionality of oxycodone has been established using the oxycodone hydrochloride tablets 5 mg at doses of 5 mg, 15 mg (three 5 mg tablets) and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) (see Figure 1 ). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride tablets. Figure 1 – Oxycodone Hydrochloride Tablets, USP Dose-Proportionality Study 5mg, 15mg, 30mg (single-dose) Figure 1 Food Effect A single-dose food effect study was conducted in normal volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of oxycodone absorption from the oral solution (see Table 2 ). In addition, food caused a delay in T max (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30 mg tablets. Distribution Following intravenous administration, the volume of distribution (V ss ) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk [see Special Populations (8.2) ]. Elimination Metabolism A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism and is catalyzed by CYP3A4. Oxymorphone is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6 [see Drug Interactions (7) ]. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations.

ree and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone hydrochloride tablets was 3.5 to 4 hours. Specific Populations Age: Geriatric Population Population pharmacokinetic studies conducted with oxycodone hydrochloride tablets, indicated that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65. Hepatic Impairment In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased hepatic function were evaluated to study these potential differences. However, because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic impaired patients [see Use in Specific Populations (8.6) ]. Renal Impairment This drug is known to be substantially excreted by the kidney and the risk of adverse reactions to this drug may be greater in patients with impaired renal function [see Use in Specific Populations (8.7) ] .

<table width="90%" ID="Tb2"><caption>Table 2: Pharmacokinetic Parameters (Mean&#xB1;SD)</caption><col width="19%" align="center" valign="middle"/><col width="11%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><col width="14%" align="center" valign="middle"/><thead><tr><th styleCode="Lrule Rrule" align="left" valign="top">Dose\Parameters</th><th styleCode="Rrule" valign="top">AUC (ng&#xD7;hr/mL)</th><th styleCode="Rrule" valign="top">C_max (ng/mL)</th><th styleCode="Rrule" valign="top">T_max (hr)</th><th styleCode="Rrule" valign="top">C_min (ng/mL)</th><th styleCode="Rrule" valign="top">C_avg (ng/mL)</th><th styleCode="Rrule" valign="top">Half-Life (hr)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Single Dose Pharmacokinetics</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Oxycodone HCl 5 mg tabs &#xD7; 3</td><td styleCode="Rrule">133.2&#xB1;33</td><td styleCode="Rrule">22.3&#xB1;8.2</td><td styleCode="Rrule">1.8&#xB1;1.8</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">3.73&#xB1;0.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Oxycodone HCl 15 mg tab</td><td styleCode="Rrule">128.2&#xB1;35.1</td><td styleCode="Rrule">22.2&#xB1;7.6</td><td styleCode="Rrule">1.4&#xB1;0.7</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">3.55&#xB1;1.0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Oxycodone HCl Liquid Concentrate 15 mg oral solution</td><td styleCode="Rrule">130.6&#xB1;34.7</td><td styleCode="Rrule">21.1&#xB1;6.1</td><td styleCode="Rrule">1.9&#xB1;1.5</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">3.71&#xB1;0.8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Oxycodone HCl 30 mg tab</td><td styleCode="Rrule">268.2&#xB1;60.7</td><td styleCode="Rrule">39.3&#xB1;14.0</td><td styleCode="Rrule">2.6&#xB1;3.0</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">3.85&#xB1;1.3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Food Effect, Single Dose</content></td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Oxycodone HCl 10 mg/10 mL oral sol&apos;n (fasted)</td><td styleCode="Rrule">105&#xB1;6.2</td><td styleCode="Rrule">19.0&#xB1;3.7</td><td styleCode="Rrule">1.25&#xB1;0.5</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">2.9&#xB1;0.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Oxycodone HCl 10 mg/10 mL oral sol&apos;n (fed)</td><td styleCode="Rrule">133&#xB1;25.2</td><td styleCode="Rrule">17.7&#xB1;3.0</td><td styleCode="Rrule">2.54&#xB1;1.2</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">3.3&#xB1;0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Multiple-Dose Studies</content></td><td styleCode="Rrule">AUC (72 to 84)

"Rrule">17.7&#xB1;3.0</td><td styleCode="Rrule">2.54&#xB1;1.2</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">N/A</td><td styleCode="Rrule">3.3&#xB1;0.5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Multiple-Dose Studies</content></td><td styleCode="Rrule">AUC (72 to 84) </td><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Oxycodone HCl 5 mg tabs q6h &#xD7; 14 doses</td><td styleCode="Rrule">113.3&#xB1;24.0</td><td styleCode="Rrule">15.7&#xB1;3.2</td><td styleCode="Rrule">1.3&#xB1;0.3</td><td styleCode="Rrule">7.4&#xB1;1.8</td><td styleCode="Rrule">9.4&#xB1;2.0</td><td styleCode="Rrule">N/A</td></tr><tr><td styleCode="Lrule Rrule">Oxycodone HCl 3.33 mg (3.33 mL) oral sol&apos;n q4h &#xD7; 21 doses</td><td styleCode="Rrule">99.0&#xB1;24.8</td><td styleCode="Rrule">12.9&#xB1;3.1</td><td styleCode="Rrule">1.0&#xB1;0.3</td><td styleCode="Rrule">7.2&#xB1;2.3</td><td styleCode="Rrule">9.7&#xB1;2.6</td><td styleCode="Rrule">N/A</td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies have not been performed in animals to evaluate the carcinogenic potential of oxycodone hydrochloride tablets or oxycodone. Mutagenesis Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay ( Salmonella typhimurium and Escherichia coli) or in an assay for chromosomal aberrations ( in vivo mouse bone marrow micronucleus assay). Impairment of Fertility Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies have not been performed in animals to evaluate the carcinogenic potential of oxycodone hydrochloride tablets or oxycodone. Mutagenesis Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay ( Salmonella typhimurium and Escherichia coli) or in an assay for chromosomal aberrations ( in vivo mouse bone marrow micronucleus assay). Impairment of Fertility Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

16 HOW SUPPLIED/STORAGE AND HANDLING Oxycodone Hydrochloride Tablets, USP are available as follows: 5 mg – white to off-white, round, flat faced, beveled edged tablets debossed with "R" above bisect and "P" below on one side and "5" on the other side NDC 42858-001-01: Bottles of 100 tablets NDC 42858-001-10: Unit Dose Packages of 100, 10 per Card, 10 cards per shipper 10 mg – white to off-white, round, biconvex tablets debossed with "R" above bisect and "P" below on one side and "10" on the other side NDC 42858-002-01 Bottles of 100 tablets NDC 42858-002-10: Unit Dose Packages of 100, 10 per Card, 10 cards per shipper 15 mg – white to off-white, oval tablets with "R" and "P" (with a center score) on one side and "15" on the other side NDC 42858-003-01: Bottles of 100 tablets 20 mg – white to off-white, round, biconvex tablets debossed with "R" above bisect and "P" below on one side and "20" on the other side NDC 42858-004-01: Bottles of 100 tablets 30 mg – white to off-white, round, biconvex tablets debossed with "R" above bisect and "P" below on one side and "30" on the other side NDC 42858-005-01: Bottles of 100 tablets Dispense in a tight, light-resistant container. Protect from moisture. Store at 25°C (77°F); excursions are permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store oxycodone hydrochloride tablets securely and dispose of properly [see Patient Counseling Information (17) ] .

<table width="75%" styleCode="Noautorules"><col width="10%" align="right" valign="top"/><col width="90%" align="left" valign="top"/><tbody><tr><td><content styleCode="bold italics">5 mg</content><content styleCode="italics"> &#x2013;</content></td><td>white to off-white, round, flat faced, beveled edged tablets debossed with &quot;R&quot; above bisect and &quot;P&quot; below on one side and &quot;5&quot; on the other side</td></tr><tr><td/><td><content styleCode="bold">NDC 42858-001-01: Bottles of 100 tablets NDC 42858-001-10: Unit Dose Packages of 100, 10 per Card, 10 cards per shipper</content></td></tr><tr><td><content styleCode="bold italics">10 mg</content><content styleCode="italics"> &#x2013;</content></td><td>white to off-white, round, biconvex tablets debossed with &quot;R&quot; above bisect and &quot;P&quot; below on one side and &quot;10&quot; on the other side</td></tr><tr><td/><td><content styleCode="bold">NDC 42858-002-01 Bottles of 100 tablets NDC 42858-002-10: Unit Dose Packages of 100, 10 per Card, 10 cards per shipper</content></td></tr><tr><td><content styleCode="bold italics">15 mg</content><content styleCode="italics"> &#x2013;</content></td><td>white to off-white, oval tablets with &quot;R&quot; and &quot;P&quot; (with a center score) on one side and &quot;15&quot; on the other side</td></tr><tr><td/><td><content styleCode="bold">NDC 42858-003-01: Bottles of 100 tablets</content></td></tr><tr><td><content styleCode="bold italics">20 mg &#x2013;</content></td><td>white to off-white, round, biconvex tablets debossed with &quot;R&quot; above bisect and &quot;P&quot; below on one side and &quot;20&quot; on the other side</td></tr><tr><td/><td><content styleCode="bold">NDC 42858-004-01: Bottles of 100 tablets</content></td></tr><tr><td><content styleCode="bold italics">30 mg</content><content styleCode="italics"> &#x2013;</content></td><td>white to off-white, round, biconvex tablets debossed with &quot;R&quot; above bisect and &quot;P&quot; below on one side and &quot;30&quot; on the other side</td></tr><tr><td/><td><content styleCode="bold">NDC 42858-005-01: Bottles of 100 tablets</content></td></tr></tbody></table>

Dispense in a tight, light-resistant container. Protect from moisture. Store at 25°C (77°F); excursions are permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store oxycodone hydrochloride tablets securely and dispose of properly [see Patient Counseling Information (17) ] .

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store oxycodone hydrochloride tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving oxycodone hydrochloride tablets unsecured can pose a deadly risk to others in the home [see Warnings and Precautions (5.1 , 5.3) , Drug Abuse and Dependence (9.2) ] . Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused oxycodone hydrochloride tablets should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of oxycodone hydrochloride tablets, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions (5.1) ]. Instruct patients not to share oxycodone hydrochloride tablets with others and to take steps to protect oxycodone hydrochloride tablets from theft and misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting oxycodone hydrochloride tablets or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions (5.2) , Overdosage (10) ] . Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions (5.2) ]. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if oxycodone hydrochloride tablets are used with benzodiazepines or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.3) , Drug Interactions (7) ]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

ioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) ] . Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered [see Overdosage (10) ]. Advise patients and caregivers: how to treat with the overdose reversal agent in the event of an opioid overdose to tell family and friends about their opioid overdose reversal agent, and to keep it in a place where family and friends can access it in an emergency to read the Patient Information (or other educational material) that will come with their opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions (5.7) , Adverse Reactions (6.2) ] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take, serotonergic medication [see Drug Interactions (7) ]. MAOI Interaction Inform patients to avoid taking oxycodone hydrochloride tablets while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking oxycodone hydrochloride tablets [see Drug Interactions (7) ]. Important Administration Instructions Instruct patients how to properly take oxycodone hydrochloride tablets. Patients should be advised not to adjust the dose of oxycodone hydrochloride tablets without consulting the prescribing healthcare provider [see Dosage and Administration (2) ]. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue oxycodone hydrochloride tablets without first discussing a tapering plan with the prescriber [see Dosage and Administration (2.5) ]. Driving or Operating Machinery Inform patients that oxycodone hydrochloride tablets may impair the ability to perform potentially hazardous activities such as driving a car or operating dangerous machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions (5.15) ]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6) , Clinical Pharmacology (12.1) ]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition.

tion Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6) , Clinical Pharmacology (12.1) ]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.9) ]. Hypotension Inform patients that oxycodone hydrochloride tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from sitting or lying position) [see Warnings and Precautions (5.10) ]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in oxycodone hydrochloride tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4) , Adverse Reactions (6.2) ]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of oxycodone hydrochloride tablets for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that oxycodone hydrochloride tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ]. Lactation Advise breastfeeding women using oxycodone hydrochloride tablets to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding women to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2) ]. Infertility Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3) ]. To request medical information or to report suspected adverse reactions, contact Rhodes Pharmaceuticals LLC at 1-888-873-5329.

Medication Guide Oxycodone Hydrochloride (ox" i koe' done hye" droe klor' ide) Tablets, USP CII This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev.: 05/2026 Oxycodone hydrochloride tablets are: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about oxycodone hydrochloride tablets: Get emergency help or call 911 right away if you take too much oxycodone hydrochloride tablets (overdose). When you first start taking oxycodone hydrochloride tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose. Taking oxycodone hydrochloride tablets with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your oxycodone hydrochloride tablets. They could die from taking it. Selling or giving away oxycodone hydrochloride tablets is against the law. Store oxycodone hydrochloride tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Do not take oxycodone hydrochloride tablets if you have: severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines. allergy to oxycodone. Before taking oxycodone hydrochloride tablets, tell your healthcare provider if you have a history of: head injury, seizures problems urinating abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems liver, kidney, thyroid problems pancreas or gallbladder problems Tell your healthcare provider if you are: noticing your pain getting worse. If your pain gets worse after you take oxycodone hydrochloride tablets, do not take more of oxycodone hydrochloride tablets without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking oxycodone hydrochloride tablets. pregnant or planning to become pregnant. Use of oxycodone hydrochloride tablets for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding. Oxycodone hydrochloride tablets pass into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements.

eased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking oxycodone hydrochloride tablets with certain other medicines can cause serious side effects that could lead to death. When taking oxycodone hydrochloride tablets: Do not change your dose. Take oxycodone hydrochloride tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. For acute (short-term) pain, you may only need to take oxycodone hydrochloride tablets for a few days. You may have some oxycodone hydrochloride tablets left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused oxycodone hydrochloride tablets. Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. Call your healthcare provider if the dose you are taking does not control your pain. If you have been taking oxycodone hydrochloride tablets regularly, do not stop taking oxycodone hydrochloride tablets without talking to your healthcare provider. Dispose of expired, unwanted, or unused oxycodone hydrochloride tablets by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking oxycodone hydrochloride tablets DO NOT: Drive or operate heavy machinery, until you know how oxycodone hydrochloride tablets affect you. Oxycodone hydrochloride tablets can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with oxycodone hydrochloride tablets may cause you to overdose and die. The possible side effects of oxycodone hydrochloride tablets are: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of oxycodone hydrochloride tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information, go to dailymed.nlm.nih.gov Marketed by: Rhodes Pharmaceuticals LLC, Wilson, NC 27893 US, http://rhodespharma.com or call 1-888-873-5329. Manufactured by: Knoa Pharma LLC, Stamford, CT 06901.

<table width="100%"><col width="2%" align="left" valign="top"/><col width="62%" align="left" valign="top"/><col width="36%" align="left" valign="top"/><thead><tr><th colspan="3" styleCode="Lrule Rrule">Medication Guide Oxycodone Hydrochloride (ox&quot; i koe&apos; done hye&quot; droe klor&apos; ide) Tablets, USP CII</th></tr></thead><tfoot><tr><td align="left" colspan="2"><content styleCode="bold">This Medication Guide has been approved by the U.S. Food and Drug Administration.</content></td><td align="right" valign="top">Rev.: 05/2026 </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Oxycodone hydrochloride tablets are:</content><list listType="unordered" styleCode="disc"><item>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.</item><item>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Important information about oxycodone hydrochloride tablets:</content><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Get emergency help or call 911 right away if you take too much oxycodone hydrochloride tablets (overdose).</content> When you first start taking oxycodone hydrochloride tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose.</item><item>Taking oxycodone hydrochloride tablets with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</item><item>Never give anyone else your oxycodone hydrochloride tablets. They could die from taking it.

zepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</item><item>Never give anyone else your oxycodone hydrochloride tablets. They could die from taking it. Selling or giving away oxycodone hydrochloride tablets is against the law.</item><item>Store oxycodone hydrochloride tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Do not take oxycodone hydrochloride tablets if you have:</content><list listType="unordered" styleCode="disc"><item>severe asthma, trouble breathing, or other lung problems.</item><item>a bowel blockage or have narrowing of the stomach or intestines.</item><item>allergy to oxycodone.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Before taking oxycodone hydrochloride tablets, tell your healthcare provider if you have a history of:</content></td></tr><tr><td styleCode="Lrule"/><td><list listType="unordered" styleCode="disc"><item>head injury, seizures</item><item>problems urinating</item><item>abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems</item></list></td><td styleCode="Rrule"><list listType="unordered" styleCode="disc"><item>liver, kidney, thyroid problems</item><item>pancreas or gallbladder problems</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Tell your healthcare provider if you are:</content><list listType="unordered" styleCode="disc"><item><content styleCode="bold">noticing your pain getting worse.</content> If your pain gets worse after you take oxycodone hydrochloride tablets, do not take more of oxycodone hydrochloride tablets without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking oxycodone hydrochloride tablets.</item><item><content styleCode="bold">pregnant or planning to become pregnant.</content> Use of oxycodone hydrochloride tablets for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.</item><item><content styleCode="bold">breastfeeding.</content> Oxycodone hydrochloride tablets pass into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.</item><item>living in a household where there are small children or someone who has abused street or prescription drugs.</item><item>taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking oxycodone hydrochloride tablets with certain other medicines can cause serious side effects that could lead to death.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">When taking oxycodone hydrochloride tablets:</content><list listType="unordered" styleCode="disc"><item>Do not change your dose. Take oxycodone hydrochloride tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</item><item>For acute (short-term) pain, you may only need to take oxycodone hydrochloride tablets for a few days. You may have some oxycodone hydrochloride tablets left over that you did not use.

oride tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</item><item>For acute (short-term) pain, you may only need to take oxycodone hydrochloride tablets for a few days. You may have some oxycodone hydrochloride tablets left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused oxycodone hydrochloride tablets.</item><item>Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.</item><item>Call your healthcare provider if the dose you are taking does not control your pain.</item><item>If you have been taking oxycodone hydrochloride tablets regularly, do not stop taking oxycodone hydrochloride tablets without talking to your healthcare provider.</item><item>Dispose of expired, unwanted, or unused oxycodone hydrochloride tablets by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit <content styleCode="underline">www.fda.gov/drugdisposal</content> for additional information on disposal of unused medicines.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">While taking oxycodone hydrochloride tablets DO NOT:</content><list listType="unordered" styleCode="disc"><item>Drive or operate heavy machinery, until you know how oxycodone hydrochloride tablets affect you. Oxycodone hydrochloride tablets can make you sleepy, dizzy, or lightheaded.</item><item>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with oxycodone hydrochloride tablets may cause you to overdose and die.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">The possible side effects of oxycodone hydrochloride tablets are:</content><list listType="unordered" styleCode="disc"><item>constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Get emergency medical help or call 911 right away if you have:</content><list listType="unordered" styleCode="disc"><item>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3">These are not all the possible side effects of oxycodone hydrochloride tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <content styleCode="bold">For more information, go to dailymed.nlm.nih.gov</content></td></tr><tr><td styleCode="Lrule Rrule" colspan="3">Marketed by: Rhodes Pharmaceuticals LLC, Wilson, NC 27893 US, http://rhodespharma.com or call 1-888-873-5329.</td></tr><tr><td styleCode="Lrule Rrule" colspan="3">Manufactured by: Knoa Pharma LLC, Stamford, CT 06901.</td></tr></tbody></table>

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OXYCODONE HYDROCHLORIDE ORAL SOLUTION WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OXYCODONE HYDROCHLORIDE ORAL SOLUTION See full prescribing information for complete boxed warning. Ensure accuracy when prescribing, dispensing, and administering Oxycodone Hydrochloride Oral Solution. Dosing errors due to confusion between mg and mL, and other oxycodone hydrochloride oral solutions of different concentrations can result in accidental overdose and death ( 2.1 , 5.1 ). Oxycodone Hydrochloride Oral Solution exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and reassess regularly for these behaviors and conditions ( 5.2 ) Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dosage increase. To reduce risk of respiratory depression, proper dosing and titration of Oxycodone Hydrochloride Oral Solution are essential. ( 5.3 ) Accidental ingestion of Oxycodone Hydrochloride Oral Solution, especially by children, can result in a fatal overdose of oxycodone. ( 5.3 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. ( 5.4 , 7 ) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.5 ) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. (5.6) The concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone. ( 5.7 , 7 , 12.3 ) WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OXYCODONE HYDROCHLORIDE ORAL SOLUTION Risk of Medication Errors Ensure accuracy when prescribing, dispensing, and administering Oxycodone Hydrochloride Oral Solution. Dosing errors due to confusion between mg and mL, and other oxycodone hydrochloride oral solutions of different concentrations can result in accidental overdose and death [see Dosage and Administration (2.1), Warnings and Precautions (5.1)]. Addiction, Abuse, and Misuse Because the use of Oxycodone Hydrochloride Oral Solution exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions (5.2)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Oxycodone Hydrochloride Oral Solution, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, especially during initiation or following a dose increase.

Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Oxycodone Hydrochloride Oral Solution, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of Oxycodone Hydrochloride Oral Solution are essential [see Warnings and Precautions (5.3)]. Accidental Ingestion Accidental ingestion of even one dose of Oxycodone Hydrochloride Oral Solution, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions (5.3)]. R i s ks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Oxycodone Hydrochloride Oral Solution and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions (5.4), Drug Interactions (7)]. Neonatal Opioid Withdrawal Syndrome (NOWS) If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of NOWS, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions (5.5)]. Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions (5.6)]. Cytochrome P450 3A4 Interaction The concomitant use of Oxycodone Hydrochloride Oral Solution with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Regularly evaluate patients receiving Oxycodone Hydrochloride Oral Solution and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.7), Drug Interactions (7), Clinical Pharmacology (12.3)]. RECENT MAJOR CHANGES Boxed Warning 12/2023 Indications and Usage (1) 12/2023 Dosage and Administration (2.1, 2.3, 2.4) 12/2023 Warnings and Precautions (5.8) 12/2023

1 INDICATIONS AND USAGE Oxycodone Hydrochloride Oral Solution is an opioid agonist indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. (1) Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) is indicated for the relief of pain in opioid-tolerant adults. Limitations of Use (1) Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration (5.2), reserve Oxycodone Hydrochloride Oral Solution for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or opioid combination products): Have not been tolerated, or are not expected to be tolerated, Have not provided adequate analgesia, or are not expected to provide adequate analgesia Oxycodone Hydrochloride Oral Solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Oxycodone Hydrochloride Oral Solution is indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) is indicated for the relief of pain in opioid-tolerant adults. Limitations of Use Because of the risks of addiction, abuse, and misuse with opioids, which can occur at any dosage or duration [see Warnings and Precautions ( 5.2 )], reserve Oxycodone Hydrochloride Oral Solution for use in patients for whom alternative treatment options [e.g., non-opioid analgesics or opioid combination products]: • Have not been tolerated or are not expected to be tolerated • Have not provided adequate analgesia or are not expected to provide adequate analgesia Oxycodone Hydrochloride Oral Solution should not be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate.

2 DOSAGE AND ADMINISTRATION Oxycodone Hydrochloride Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. (2.1) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Oxycodone Hydrochloride Oral Solution for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. (2.1, 5) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. (2.1) Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse and misuse. (2.1, 5.2) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Oxycodone Hydrochloride Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments. (2.1, 5.3) Discuss availability of naloxone with the patient and caregiver and assess each patient’s need for access to naloxone, both when initiating and renewing treatment with Oxycodone Hydrochloride Oral Solution. Consider prescribing naloxone based on the patient’s risk factors for overdose (2.2, 5.2, 5.3, 5.4). Initiate dosing with a range of 5 to 15 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Oxycodone Hydrochloride Oral Solution. (2.3, 2.4) Do not abruptly discontinue Oxycodone Hydrochloride Oral Solution in a physically dependent patient because rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. (2.5, 5.15) 2.1 Important Dosage and Administration Instructions Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) is for use in only opioid-tolerant patients who have already been receiving opioid therapy. Use this strength only for patients who have already been titrated to a stable analgesic regimen using lower strengths of oxycodone hydrochloride and who can benefit from use of a smaller volume of oral solution. Patients considered to be opioid tolerant are those who are receiving, for one week or longer, at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl per hour, 30 mg oral oxycodone per day, 8 mg oral hydromorphone per day, 25 mg oral oxymorphone per day, 60 mg oral hydrocodone per day, or an equianalgesic dose of another opioid. Ensure accuracy when prescribing, dispensing, and administering Oxycodone Hydrochloride Oral Solution to avoid dosing errors due to confusion between mg and mL, and with other oxycodone hydrochloride solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume.

errors due to confusion between mg and mL, and with other oxycodone hydrochloride solutions of different concentrations, which could result in accidental overdose and death. Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Instruct patients and caregivers on how to accurately measure and take or administer the correct dose of Oxycodone Hydrochloride Oral Solution. Strongly advise patients and caregivers to always use the enclosed graduated measuring cup when administering Oxycodone Hydrochloride Oral Solution 5 mg per 5 mL and always use the enclosed graduated oral syringe when administering Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL) to ensure that the dose is measured and administered accurately. Instruct patients and caregivers to never use household teaspoons or tablespoons to measure Oxycodone Hydrochloride Oral Solution. Oxycodone Hydrocodone Oral Solution should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions (5)]. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Oxycodone Hydrochloride Oral Solution for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions (5.2)]. Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Oxycodone Hydrochloride Oral Solution. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions (5)]. 2.2 Patient Access to Naloxone for the Emergency Treatment Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Oxycodone Hydrochloride Oral Solution [see Warnings and Precautions ( 5.3 )]. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose.

he presence of risk factors for overdose should not prevent the proper management of pain in any given patient [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )]. Consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. 2.3 Initial Dosage Although it is not possible to list every condition that is important to the selection of the initial dose of Oxycodone Hydrochloride Oral Solution, attention must be given to: 1. the daily dose, potency and characteristics of a full agonist or mixed agonist/antagonist the patient has been taking previously 2. the reliability of the relative potency estimate to calculate the dose of oxycodone HCl needed 3. the degree of opioid tolerance 4. the general condition and medical status of the patient, including the patient’s weight and age 5. the balance between pain management and adverse reactions 6. the type and severity of the patient’s pain 7. risk factors for abuse or addiction, including a prior history of abuse or addiction Use of Oxycodone Hydrochloride Oral Solution as the First Opioid Analgesic Do not initiate treatment with Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL) in patients who are opioid naïve. Select an alternate product with lower concentration. Initiate treatment with Oxycodone Hydrochloride Oral Solution in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Oxycodone Hydrochloride Oral Solution. Conversion from Other Opioids to Oxycodone Hydrochloride Oral Solution There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Oxycodone Hydrochloride Oral Solution. It is safer to underestimate a patient’s 24-hour Oxycodone Hydrochloride Oral Solution dosage than to overestimate the 24-hour Oxycodone Hydrochloride Oral Solution dosage and manage an adverse reaction due to overdose. If a patient has been receiving opioid-containing medications prior to taking Oxycodone Hydrochloride Oral Solution, the potency of the prior opioid relative to oxycodone should be factored into the selection of the total daily dose (TDD) of oxycodone. In converting patients from other opioids to Oxycodone Hydrochloride Oral Solution close observation and adjustment of dosage based upon the patient’s response to Oxycodone Hydrochloride Oral Solution is imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of Oxycodone Hydrochloride Oral Solution may be necessary, especially in patients who have disease states that are changing rapidly. Conversion from Oxycodone Hydrochloride Oral Solution to Extended-Release Oxycodone Hydrochloride The relative bioavailability of Oxycodone Hydrochloride Oral Solution compared to extended-release oxycodone is unknown, so conversion to extended-release oxycodone may lead to increased risk of excessive sedation and respiratory depression. 2.4 Titration and Maintenance of Therapy Individually titrate Oxycodone Hydrochloride Oral Solution to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Oxycodone Hydrochloride Oral Solution to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.2 , 5.15 )].

tions. Continually reevaluate patients receiving Oxycodone Hydrochloride Oral Solution to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.2 , 5.15 )]. Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Oxycodone Hydrochloride Oral Solution dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )]. Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Oxycodone Hydrochloride Oral Solution Do not abruptly discontinue Oxycodone Hydrochloride Oral Solution in patients who may be physically dependent on opioids. Rapid discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Oxycodone Hydrochloride Oral Solution, there are a variety of factors that should be considered, including the total daily dose of opioid (including Oxycodone Hydrochloride Oral Solution) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Oxycodone Hydrochloride Oral Solution who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis.

y be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions (5.15), Drug Abuse and Dependence (9.3)]

3 DOSAGE FORMS AND STRENGTHS Oral Solution 100 mg per 5 mL (20 mg/ mL): (3) Oxycodone Hydrochloride Oral Solution, USP 100 mg per 5 mL (20 mg per mL) Strength Oral Solution: Each 5 mL of yellow Oxycodone Hydrochloride Oral Solution, USP contains oxycodone hydrochloride 100 mg. The concentration of this solution is 20 mg per mL.

4 CONTRAINDICATIONS Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting in absence of resuscitative equipment. ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) Hypersensitivity to oxycodone. ( 4 ) Oxycodone Hydrochloride Oral Solution is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.3 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.9 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.13 )] Hypersensitivity to oxycodone (e.g., angioedema) [see Adverse Reactions ( 6 )]

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation. (5.8) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic or Debilitated Patients : Regularly evaluate, particularly during initiation and titration. (5.9) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. (5.10) Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of Oxycodone Hydrochloride Oral Solution in patients with circulatory shock. (5.11) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of Oxycodone Hydrochloride Oral Solution in patients with impaired consciousness or coma. (5.12) 5.1 Risk of Accidental Overdose and Death due to Medication Errors Dosing errors can result in accidental overdose and death. Avoid dosing errors that may result from confusion between mg and mL and confusion with oxycodone hydrochloride solutions of different concentrations, when prescribing, dispensing, and administering Oxycodone Hydrochloride Oral Solution. Ensure that the dose is communicated clearly and dispensed accurately. Instruct patients and caregivers on how to measure and take or administer the correct dose of Oxycodone Hydrochloride Oral Solution and to use extreme caution when measuring the dose. Instruct patients and caregivers to always use the enclosed graduated oral syringe when administering Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/ mL) to ensure the dose is measured and administered accurately. Instruct them to never use a teaspoon or a tablespoon to measure a dose because household teaspoons or tablespoon are not adequate measuring devices. 5.2 Addiction, Abuse, and Misuse Oxycodone Hydrochloride Oral Solution contains oxycodone, a Schedule II controlled substance. As an opioid, Oxycodone Hydrochloride Oral Solution exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9)] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Oxycodone Hydrochloride Oral Solution. Addiction can occur at recommended dosages and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Oxycodone Hydrochloride Oral Solution, and reassess all patients receiving Oxycodone Hydrochloride Oral Solution for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Oxycodone Hydrochloride Oral Solution but use in such patients necessitates intensive counseling about the risks and proper use of Oxycodone Hydrochloride Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse.

given patient. Patients at increased risk may be prescribed opioids such as Oxycodone Hydrochloride Oral Solution but use in such patients necessitates intensive counseling about the risks and proper use of Oxycodone Hydrochloride Oral Solution along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration (2.2), Warnings and Precautions (5.3)]. Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Oxycodone Hydrochloride Oral Solution. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.3 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage ( 10 )] . Carbon dioxide (C02) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Oxycodone Hydrochloride Oral Solution, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Oxycodone Hydrochloride Oral Solution are essential [see Dosage and Administration ( 2 )] . Over estimating the Oxycodone Hydrochloride Oral Solution dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) is for use in opioid-tolerant patients only. Administration of this formulation may cause fatal respiratory depression when administered to patients who are not tolerant to the respiratory depressant effects of opioids. Accidental ingestion of even one dose of Oxycodone Hydrochloride Oral Solution, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.5 )]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Oxycodone Hydrochloride Oral Solution.

cess to Naloxone for the Emergency Treatment of Opioid Overdose Discuss the availability of naloxone for the emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing treatment with Oxycodone Hydrochloride Oral Solution. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program). Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help, even if naloxone is administered. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. The presence of risk factors for overdose should not prevent the proper management of pain in any given patient. Also consider prescribing naloxone if the patient has household members (including children) or other close contacts at risk for accidental ingestion or overdose. If naloxone is prescribed, educate patients and caregivers on how to treat with naloxone. [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.4), Overdosage ( 10 )] . 5.4 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Oxycodone Hydrochloride Oral Solution with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7 )]. If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 ), Overdosage ( 10 )] . Advise both patients and caregivers about the risks of respiratory depression and sedation when Oxycodone Hydrochloride Oral Solution is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined.

depression and sedation when Oxycodone Hydrochloride Oral Solution is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7 )] . 5.5 Neonatal Opioid Withdrawal Syndrome Use of Oxycodone Hydrochloride Oral Solution for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1 )]. 5.6 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda/gov/OpioidAnalgesicREMSBlueprint. 5.7 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Oxycodone Hydrochloride Oral Solution with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions ( 5.3 )] , particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Oral Solution is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Oxycodone Hydrochloride Oral Solution-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions.

is added after a stable dose of Oxycodone Hydrochloride Oral Solution is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Oxycodone Hydrochloride Oral Solution-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using Oxycodone Hydrochloride Oral Solution with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Oxycodone Hydrochloride Oral Solution-treated patients, evaluate patients at frequent intervals and consider dosage reduction of Oxycodone Hydrochloride Oral Solution until stable drug effects are achieved [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7 )] . Concomitant use of Oxycodone Hydrochloride Oral Solution with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using Oxycodone Hydrochloride Oral Solution with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7 )] . 5.8 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence ( 9.3) ]. Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration ( 2.5 ), Warnings and Precautions (5.15)] . 5.9 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Oxycodone Hydrochloride Oral Solution in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: Oxycodone Hydrochloride Oral Solution- treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Oxycodone Hydrochloride Oral Solution [see Warnings and Precautions ( 5.3 )]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions ( 5.3 )].

utions ( 5.3 )]. Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions ( 5.3 )]. Regularly evaluate patients, particularly when initiating and titrating Oxycodone Hydrochloride Oral Solution and when Oxycodone Hydrochloride Oral Solution is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.3 , 5.4 ), Drug Interactions ( 7) ] . Alternatively, consider the use of non-opioid analgesics in these patients 5.10 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non- specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.11 Severe Hypotension Oxycodone Hydrochloride Oral Solution may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions ( 7 )] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of Oxycodone Hydrochloride Oral Solution. In patients with circulatory shock, Oxycodone Hydrochloride Oral Solution may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Oxycodone Hydrochloride Oral Solution in patients with circulatory shock. 5.12 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of C02 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Oxycodone Hydrochloride Oral Solution may reduce respiratory drive, and the resultant C02 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Oxycodone Hydrochloride Oral Solution. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Oxycodone Hydrochloride Oral Solution in patients with impaired consciousness or coma. 5.13 Risks of Use in Patients with Gastrointestinal Conditions Oxycodone Hydrochloride Oral Solution is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The oxycodone in Oxycodone Hydrochloride Oral Solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms.

r suspected gastrointestinal obstruction, including paralytic ileus. The oxycodone in Oxycodone Hydrochloride Oral Solution may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis for worsening symptoms. 5.14 Increased Risk of Seizures in Patients with Seizure Disorders The oxycodone in Oxycodone Hydrochloride Oral Solution may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during Oxycodone Hydrochloride Oral Solution therapy. 5.15 Withdrawal Do not abruptly discontinue Oxycodone Hydrochloride Oral Solution in a patient physically dependent on opioids. When discontinuing Oxycodone Hydrochloride Oral Solution in a physically-dependent patient, gradually taper the dosage. Rapid tapering of oxycodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration ( 2.5 ), Drug Abuse and Dependence ( 9.3 )] . Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) analgesics in patients who are receiving full opioid agonist analgesic, including Oxycodone Hydrochloride Oral Solution. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7 )].

5.16 Risks of Driving and Operating Machinery Oxycodone Hydrochloride Oral Solution may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Oxycodone Hydrochloride Oral Solution and know how they will react to the medication.

6 ADVERSE REACTIONS Most common adverse reactions are nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-866-403-7592 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.2) ] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.3) ] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.4) ] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.5) ] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.8) ] • Adrenal Insufficiency [see Warnings and Precautions (5.10) ] • Severe Hypotension [see Warnings and Precautions (5.11) ] • Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.13) ] • Seizures [see Warnings and Precautions (5.14) ] • Withdrawal [see Warnings and Precautions (5.15) ] The following adverse reactions associated with the use of oxycodone were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious adverse reactions associated with oxycodone use included: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock. The common adverse reactions seen on initiation of therapy with oxycodone are dose-related and are typical opioid-related adverse reactions. The most frequent adverse events include nausea, constipation, vomiting, headache, and pruritus. The frequency of these reactions depended on several factors, including clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual. In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving another formulation of immediate-release oxycodone, the following adverse events were recorded in oxycodone treated patients with an incidence ≥ 3%. In descending order of frequency, they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. The other less frequently observed adverse reactions from opioid analgesics, including Oxycodone Hydrochloride Oral Solution included: Body as a Whole: abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever, flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis. Cardiovascular: deep thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation, and tachycardia. Digestive: anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, and nausea and vomiting. Hemic and Lymphatic: anemia and leukopenia. Metabolic and Nutritional: edema, gout, hyperglycemia, iron deficiency anemia and peripheral edema. Musculoskeletal: arthralgia, arthritis, bone pain, myalgia and pathological fracture. Nervous: agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation.

Nutritional: edema, gout, hyperglycemia, iron deficiency anemia and peripheral edema. Musculoskeletal: arthralgia, arthritis, bone pain, myalgia and pathological fracture. Nervous: agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation. Respiratory: bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis. Skin and Appendages: herpes simplex, rash, sweating, and urticaria. Special Senses: amblyopia. Urogenital: urinary tract infection Serotonin syndrome : Cases of serotonin syndrome, a potentially life threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis : Anaphylaxis has been reported with ingredients contained in Oxycodone Hydrochloride Oral Solution. Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time [ see Clinical Pharmacology (12.2) ] . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [ see Warnings and Precautions (5.8) ] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes).

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with Oxycodone Hydrochloride Oral Solution. Table 1: Clinically Significant Drug Interactions with Oxycodone Hydrochloride Oral Solution Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of Oxycodone Hydrochloride Oral Solution and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Oxycodone Hydrochloride Oral Solution and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Oral Solution is achieved [see Warnings and Precautions ( 5.7 )]. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone Intervention: If concomitant use is necessary, consider dosage reduction of Oxycodone Hydrochloride Oral Solution until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the Oxycodone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of Oxycodone Hydrochloride Oral Solution and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions ( 5.15 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology (12.3)] , which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the Oxycodone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal and sedation. If a CYP3A4 inducer is discontinued, consider Oxycodone Hydrochloride Oral Solution dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death. Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

e concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.3 , 5.4 )]. Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently reevaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxycodone Hydrochloride Oral Solution if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.3 )]. Intervention: The use of Oxycodone Hydrochloride Oral Solution is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Oxycodone Hydrochloride Oral Solution and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression that may be greater than otherwise expected, decrease the dosage of Oxycodone Hydrochloride Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose [see Dosage and Administration ( 2.2 , Warnings and Precautions ( 5.3 , 5.4 )]. Diuretics Clinical Impact Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention Evaluate patients for signs of urinary retention or reduced gastric motility when Oxycodone Hydrochloride Oral Solution is used concomitantly with anticholinergic drugs.

mitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention Evaluate patients for signs of urinary retention or reduced gastric motility when Oxycodone Hydrochloride Oral Solution is used concomitantly with anticholinergic drugs. Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue Oxycodone Hydrochloride Oral Solution if serotonin syndrome is suspected. ( 7 ) Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of oxycodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics : Avoid use with Oxycodone Hydrochloride Oral Solution because they may reduce analgesic effect of Oxycodone Hydrochloride Oral Solution or precipitate withdrawal symptoms.( 7 )

<table ID="ID3481" width="707px"><colgroup><col width="124"/><col width="583"/></colgroup><tbody><tr><td styleCode="Botrule Lrule Rrule Toprule" colspan="2" align="left"><content styleCode="bold"> Inhibitors of CYP3A4 and CYP2D6</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Rrule" align="left" valign="top">The concomitant use of Oxycodone Hydrochloride Oral Solution and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Oxycodone Hydrochloride Oral Solution and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Oral Solution is achieved <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#L6844d3de-c8dd-4c7e-95f4-0f34e87b15a2">5.7</linkHtml>)].</content> After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology (12.3)], resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Rrule" align="left">If concomitant use is necessary, consider dosage reduction of Oxycodone Hydrochloride Oral Solution until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the Oxycodone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Examples:</content></td><td styleCode="Botrule Rrule" align="left">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="bottom"><content styleCode="bold"> CYP3A4 Inducers</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Rrule" align="left">The concomitant use of Oxycodone Hydrochloride Oral Solution and CYP3A4 inducers can decrease the plasma concentration of oxycodone <content styleCode="italics">[see Clinical Pharmacology (12.3)]</content>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#ID3479">5.15</linkHtml>)]</content>.

e <content styleCode="italics">[see Clinical Pharmacology (12.3)]</content>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#ID3479">5.15</linkHtml>)]</content>. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase <content styleCode="italics">[see Clinical Pharmacology (12.3)]</content>, which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Rrule" align="left">If concomitant use is necessary, consider increasing the Oxycodone Hydrochloride Oral Solution dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal and sedation. If a CYP3A4 inducer is discontinued, consider Oxycodone Hydrochloride Oral Solution dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Examples:</content></td><td styleCode="Botrule Rrule" align="left">Rifampin, carbamazepine, phenytoin</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="bottom"><content styleCode="bold"> Benzodiazepines and other Central Nervous System (CNS) Depressants</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Rrule" align="left">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Rrule" align="left">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation).

e concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider prescribing naloxone for the emergency treatment of opioid overdose <content styleCode="italics">[see Dosage and Administration (<linkHtml href="#L76f77135-5fb9-431d-8810-b5eefac3bdfb">2.2</linkHtml>), Warnings and Precautions (<linkHtml href="#ID3325">5.2</linkHtml>, <linkHtml href="#ID3326">5.3</linkHtml>,<linkHtml href="#Lbffbbb03-ec6b-468c-9851-d59050589cb0">5.4</linkHtml>)].</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Examples:</content></td><td styleCode="Botrule Rrule" align="left">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="bottom"><content styleCode="bold"> Serotonergic Drugs</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Rrule" align="left">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Rrule" align="left">If concomitant use is warranted, frequently reevaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxycodone Hydrochloride Oral Solution if serotonin syndrome is suspected.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Examples:</content></td><td styleCode="Botrule Rrule" align="left">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="bottom"><content styleCode="bold"> Monoamine Oxidase Inhibitors (MAOIs)</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Rrule" align="left">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma)<content styleCode="italics"> [see Warnings and Precautions (<linkHtml href="#ID3326">5.3</linkHtml>)].</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Rrule" align="left">The use of Oxycodone Hydrochloride Oral Solution is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

tent></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Rrule" align="left">The use of Oxycodone Hydrochloride Oral Solution is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Examples:</content></td><td styleCode="Botrule Rrule" align="left">phenelzine, tranylcypromine, linezolid</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="bottom"><content styleCode="bold"> Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Rrule" align="left">May reduce the analgesic effect of Oxycodone Hydrochloride Oral Solution and/or precipitate withdrawal symptoms.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Rrule" align="left">Avoid concomitant use.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Examples:</content></td><td styleCode="Botrule Rrule" align="left">butorphanol, nalbuphine, pentazocine, buprenorphine</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="bottom"><content styleCode="bold"> Muscle Relaxants</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td styleCode="Botrule Rrule" align="left">Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Rrule" align="left">Because respiratory depression that may be greater than otherwise expected, decrease the dosage of Oxycodone Hydrochloride Oral Solution and/or the muscle relaxant as necessary.

ule Lrule Rrule" align="left" valign="top"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Rrule" align="left">Because respiratory depression that may be greater than otherwise expected, decrease the dosage of Oxycodone Hydrochloride Oral Solution and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider prescribing naloxone for the emergency treatment of opioid overdose <content styleCode="italics">[see Dosage and Administration (<linkHtml href="#L76f77135-5fb9-431d-8810-b5eefac3bdfb">2.2</linkHtml>, Warnings and Precautions (<linkHtml href="#ID3326">5.3</linkHtml>, <linkHtml href="#Lbffbbb03-ec6b-468c-9851-d59050589cb0">5.4</linkHtml>)].</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="bottom"><content styleCode="bold"> Diuretics</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom"><content styleCode="italics">Clinical Impact</content></td><td styleCode="Botrule Rrule" align="left">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom"><content styleCode="italics">Intervention:</content></td><td styleCode="Botrule Rrule" align="left">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td></tr><tr><td styleCode="Botrule Lrule Rrule" colspan="2" align="left" valign="bottom"><content styleCode="bold"> Anticholinergic Drugs</content></td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom"><content styleCode="italics">Clinical Impact</content></td><td styleCode="Botrule Rrule" align="left">The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td></tr><tr><td styleCode="Botrule Lrule Rrule" align="left" valign="bottom"><content styleCode="italics">Intervention</content></td><td styleCode="Botrule Rrule" align="left">Evaluate patients for signs of urinary retention or reduced gastric motility when Oxycodone Hydrochloride Oral Solution is used concomitantly with anticholinergic drugs.</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Pregnancy : May cause fetal harm. ( 8.1 ). 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 )] . Available data with Oxycodone Hydrochloride Oral Solution are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Animal reproduction studies with oral administrations of oxycodone hydrochloride in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 )]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Oxycodone Hydrochloride Oral Solution is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Oxycodone Hydrochloride Oral Solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone hydrochloride administered during the period of organogenesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m2 basis.

ogenesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m2 basis). 8.2 Lactation Risk Summary Available data from lactation studies indicate that oxycodone is present in breastmilk and that doses of less than 60 mg/day of the immediate-release formulation are unlikely to result in clinically relevant exposures in breastfed infants. A pharmacokinetics study utilizing opportunistic sampling of 76 lactating women receiving oxycodone immediate-release products for postpartum pain management showed that oxycodone concentrates in breastmilk with an average milk to plasma ratio of 3.2. The relative infant dose was low, approximately 1.3% of a weight-adjusted maternal dose (see Data). In the same study, among the 70 infants exposed to oxycodone in breastmilk, no adverse events were attributed to oxycodone. However, based on known adverse effects in adults, infants should be monitored for signs of excess sedation and respiratory depression (see Clinical Considerations). There are no data on the effects of the oxycodone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Oxycodone Hydrochloride Oral Solution and any potential adverse effects on the breastfed infant from Oxycodone Hydrochloride Oral Solution or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to Oxycodone Hydrochloride Oral Solution through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Data Oxycodone concentration data from 76 lactating women receiving immediate-release oxycodone products for postpartum pain management, and 28 infants exposed to oxycodone in breastmilk showed that following a median (range) dose of oxycodone in mothers of 9.2 (5-10) mg/dose or 33.0 (5.4-59.3) mg/day, oxycodone concentrated in breastmilk with a median (range) milk to plasma ratio of 3.2 (1.2-5.3). However, when using maternal breastmilk data to estimate the daily and relative infant dose, the infant dose was 0.006 mg/kg/day, which is 1.3% of a weight-adjusted maternal dose of 10 mg every 6 hours. These estimates based on maternal breastmilk concentrations were corroborated by the observed infant concentrations, of which over 75% (19/25) were below the limit of quantification. Among the 6 infants with quantifiable concentration, the median (range) concentration was 0.2 ng/mL (0.1-0.7). These concentrations are 100 to 1000 times lower than concentrations observed in other studies after infants received oxycodone at 0.1 mg/kg/dose (~20-200 ng/mL). 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [ see Adverse Reactions (6) , Clinical Pharmacology (12.2) ].

00 ng/mL). 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [ see Adverse Reactions (6) , Clinical Pharmacology (12.2) ]. 8.4 Pediatric Use The safety and effectiveness of Oxycodone Hydrochloride Oral Solution have not been established in pediatric patients. The safety and pharmacokinetics of a single-dose of an Oxycodone Hydrochloride Oral Solution were evaluated in an open-label clinical trial in 89 pediatric patients 2 years to less than 17 years of age with postoperative pain. However definitive conclusions were not possible because of insufficient information. 8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Oxycodone Hydrochloride Oral Solution slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.8)]. Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. 8.6 Hepatic Impairment Since oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Initiate therapy in these patients with a lower than usual dosage of Oxycodone Hydrochloride Oral Solution and titrate carefully. Regularly evaluate closely for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Information from oxycodone tablets indicate that patients with renal impairment had higher plasma concentrations of oxycodone than subjects with normal renal function. Initiate therapy with a lower than usual dosage of Oxycodone Hydrochloride Oral Solution and titrate carefully. Monitor closely for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology (12.3)].

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.5 )] . Available data with Oxycodone Hydrochloride Oral Solution are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Animal reproduction studies with oral administrations of oxycodone hydrochloride in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data]. Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.5 )]. Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid antagonist, such as naloxone, must be available for reversal of opioid-induced respiratory depression in the neonate. Oxycodone Hydrochloride Oral Solution is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Oxycodone Hydrochloride Oral Solution, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone hydrochloride administered during the period of organogenesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m2 basis.

ogenesis up to 16 mg/kg/day and up 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m2 basis).

8.2 Lactation Risk Summary Available data from lactation studies indicate that oxycodone is present in breastmilk and that doses of less than 60 mg/day of the immediate-release formulation are unlikely to result in clinically relevant exposures in breastfed infants. A pharmacokinetics study utilizing opportunistic sampling of 76 lactating women receiving oxycodone immediate-release products for postpartum pain management showed that oxycodone concentrates in breastmilk with an average milk to plasma ratio of 3.2. The relative infant dose was low, approximately 1.3% of a weight-adjusted maternal dose (see Data). In the same study, among the 70 infants exposed to oxycodone in breastmilk, no adverse events were attributed to oxycodone. However, based on known adverse effects in adults, infants should be monitored for signs of excess sedation and respiratory depression (see Clinical Considerations). There are no data on the effects of the oxycodone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Oxycodone Hydrochloride Oral Solution and any potential adverse effects on the breastfed infant from Oxycodone Hydrochloride Oral Solution or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to Oxycodone Hydrochloride Oral Solution through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. Data Oxycodone concentration data from 76 lactating women receiving immediate-release oxycodone products for postpartum pain management, and 28 infants exposed to oxycodone in breastmilk showed that following a median (range) dose of oxycodone in mothers of 9.2 (5-10) mg/dose or 33.0 (5.4-59.3) mg/day, oxycodone concentrated in breastmilk with a median (range) milk to plasma ratio of 3.2 (1.2-5.3). However, when using maternal breastmilk data to estimate the daily and relative infant dose, the infant dose was 0.006 mg/kg/day, which is 1.3% of a weight-adjusted maternal dose of 10 mg every 6 hours. These estimates based on maternal breastmilk concentrations were corroborated by the observed infant concentrations, of which over 75% (19/25) were below the limit of quantification. Among the 6 infants with quantifiable concentration, the median (range) concentration was 0.2 ng/mL (0.1-0.7). These concentrations are 100 to 1000 times lower than concentrations observed in other studies after infants received oxycodone at 0.1 mg/kg/dose (~20-200 ng/mL).

8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [ see Adverse Reactions (6) , Clinical Pharmacology (12.2) ].

8.4 Pediatric Use The safety and effectiveness of Oxycodone Hydrochloride Oral Solution have not been established in pediatric patients. The safety and pharmacokinetics of a single-dose of an Oxycodone Hydrochloride Oral Solution were evaluated in an open-label clinical trial in 89 pediatric patients 2 years to less than 17 years of age with postoperative pain. However definitive conclusions were not possible because of insufficient information.

8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids, and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Oxycodone Hydrochloride Oral Solution slowly in geriatric patients and monitor closely for signs of central nervous system and respiratory depression [see Warnings and Precautions (5.8)]. Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Oxycodone Hydrochloride Oral Solution contain oxycodone, a Schedule II controlled substance. 9.2 Abuse Oxycodone Hydrochloride Oral Solution contains oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.2) ]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of Oxycodone Hydrochloride Oral Solution increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Oxycodone Hydrochloride Oral Solution with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Oxycodone Hydrochloride Oral Solution abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use Oxycodone Hydrochloride Oral Solution in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug- seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Oxycodone Hydrochloride Oral Solution, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Oral Solution Abuse of Oxycodone Hydrochloride oral Solution poses a risk of overdose and death.

atient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Oral Solution Abuse of Oxycodone Hydrochloride oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Oxycodone Hydrochloride Oral Solution with alcohol and/or other CNS depressants. Oxycodone Hydrochloride Oral Solution is approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), missed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not abruptly discontinue Oxycodone Hydrochloride Oral Solution in a patient physically dependent on opioids. Rapid tapering of Oxycodone Hydrochloride Oral Solution in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing Oxycodone Hydrochloride Oral Solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Oxycodone Hydrochloride Oral Solution the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5) , Warnings and Precautions (5.15) ]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ].

9.2 Abuse Oxycodone Hydrochloride Oral Solution contains oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions (5.2) ]. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of Oxycodone Hydrochloride Oral Solution increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Oxycodone Hydrochloride Oral Solution with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Oxycodone Hydrochloride Oral Solution abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use Oxycodone Hydrochloride Oral Solution in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug- seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Oxycodone Hydrochloride Oral Solution, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Oral Solution Abuse of Oxycodone Hydrochloride oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Oxycodone Hydrochloride Oral Solution with alcohol and/or other CNS depressants. Oxycodone Hydrochloride Oral Solution is approved for oral use only.

e of Oxycodone Hydrochloride Oral Solution Abuse of Oxycodone Hydrochloride oral Solution poses a risk of overdose and death. The risk is increased with concurrent use of Oxycodone Hydrochloride Oral Solution with alcohol and/or other CNS depressants. Oxycodone Hydrochloride Oral Solution is approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone), missed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not abruptly discontinue Oxycodone Hydrochloride Oral Solution in a patient physically dependent on opioids. Rapid tapering of Oxycodone Hydrochloride Oral Solution in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing Oxycodone Hydrochloride Oral Solution, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Oxycodone Hydrochloride Oral Solution the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration (2.5) , Warnings and Precautions (5.15) ]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations (8.1) ].

10 OVERDOSAGE Clinical Presentation Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [ see Clinical Pharmacology (12.2) ] . Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. Opioid antagonists, such as naloxone, are specific antidotes to respiratory depression resulting from opioid overdose. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid antagonist. Because the duration of opioid reversal is expected to be less than the duration of action of oxycodone in Oxycodone Hydrochloride Oral Solution, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid antagonist is suboptimal or only brief in nature, administer additional antagonist as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist.

11 DESCRIPTION Oxycodone Hydrochloride is a white odorless crystalline powder derived from the opium alkaloid, thebaine. It is soluble in water and slightly soluble in alcohol. Chemically, oxycodone hydrochloride (5R,9R,13S,14S)-4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride. The molecular weight is 351.82. Its molecular formula is C18H21NO4.HCl, and it has the following chemical Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/ mL): Each 1 mL of oral yellow solution contains 20 mg of oxycodone hydrochloride, USP and the following inactive ingredients: citric acid anhydrous, D&C Yellow #10, natural/artificial mixed berry flavor, purified water, sodium citrate dihydrate, sodium benzoate, saccharin sodium, sorbital solution. structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. 12.2 Pharmacodynamics Effects of the Central Nervous System (CNS) Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH, cortisol), and luteinizing hormone (LH) in humans [ see Adverse Reactions (6) ] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [ see Adverse Reactions (6) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in-vitro and Animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

ted to date [ see Adverse Reactions (6) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in-vitro and Animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [ see Dosage and Administration (2.1) , (2.3) , ( 2.4 )] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [ see Dosage and Administration (2.1) , (2.2) , (2.3) ] . 12.3 Pharmacokinetics The activity of oxycodone hydrochloride is primarily due to the parent drug oxycodone. Absorption About 60 to 87% of an oral dose reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone. Food Effect When oxycodone capsules are administered with a high-fat meal, mean AUC values are increased by 23% and peak concentrations are decreased by 14%. Food causes a delay in Tmax(1.00 to 3 hours). Similar effects of food are expected with the oral solution. Distribution Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk. Elimination Metabolism Oxycodone hydrochloride is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N- demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone < 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone is approximately 4 hours. Specific Populations Age: Geriatric Population: Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over of the age of 65.

parent elimination half-life of oxycodone following the administration of oxycodone is approximately 4 hours. Specific Populations Age: Geriatric Population: Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over of the age of 65. Hepatic Impairment: Because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic- impaired patients. A dose adjustment is recommended in these patients [see Use in Specific Populations (8.6)]. Renal Impairment: Because this drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function, a dose reduction is recommended for renal impaired patients [see Use in Specific Populations (8.7)] . Drug Interaction Studies CYP3A4 Inhibitors CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the co-administration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively. CYP3A4 Inducers A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively. CYP2D6 Inhibitors Oxycodone is metabolized in part to oxymorphone via the cytochrome P450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent.

12.2 Pharmacodynamics Effects of the Central Nervous System (CNS) Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase. Effects on the Cardiovascular System Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes and sweating and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH, cortisol), and luteinizing hormone (LH) in humans [ see Adverse Reactions (6) ] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [ see Adverse Reactions (6) ] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in-vitro and Animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [ see Dosage and Administration (2.1) , (2.3) , ( 2.4 )] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

tolerance [ see Dosage and Administration (2.1) , (2.3) , ( 2.4 )] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [ see Dosage and Administration (2.1) , (2.2) , (2.3) ] .

12.3 Pharmacokinetics The activity of oxycodone hydrochloride is primarily due to the parent drug oxycodone. Absorption About 60 to 87% of an oral dose reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone. Food Effect When oxycodone capsules are administered with a high-fat meal, mean AUC values are increased by 23% and peak concentrations are decreased by 14%. Food causes a delay in Tmax(1.00 to 3 hours). Similar effects of food are expected with the oral solution. Distribution Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk. Elimination Metabolism Oxycodone hydrochloride is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N- demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone < 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone is approximately 4 hours. Specific Populations Age: Geriatric Population: Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over of the age of 65. Hepatic Impairment: Because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic- impaired patients. A dose adjustment is recommended in these patients [see Use in Specific Populations (8.6)]. Renal Impairment: Because this drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function, a dose reduction is recommended for renal impaired patients [see Use in Specific Populations (8.7)] . Drug Interaction Studies CYP3A4 Inhibitors CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the co-administration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and Cmax by 3.6 and 1.7 fold, respectively. CYP3A4 Inducers A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and Cmax values by 86% and 63%, respectively.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of oxycodone have not been conducted. Mutagenesis Oxycodone hydrochloride was genotoxic in an in-vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in-vitro bacterial reverse mutation assay ( Salmonella typhimurium and Escherichia coli ) and in an assay for chromosomal aberrations ( in-vivo mouse bone marrow micronucleus assay). Impairment of Fertility Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

16 HOW SUPPLIED/STORAGE AND HANDLING Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL). is a yellow solution available in one strength as follows: 100 mg per 5 mL (20 mg per mL) oral solution NDC# 43386-920-60: Bottle of 30 mL supplied with a calibrated oral syringe Store at Controlled Room Temperature, 25°C (77°F); excursions are permitted to 15° - 30°C (59° - 86°F). ). PROTECT from MOISTURE and LIGHT. Store Oxycodone Hydrochloride Oral Solution securely and dispose of properly [see Patient Counseling Information (17)].

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal: Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Oxycodone Hydrochloride Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving Oxycodone Hydrochloride Oral Solution unsecured can pose a deadly risk to others in the home [see Warnings and Precautions ( 5.2 , 5.3 ), Drug Abuse and Dependence ( 9.2 )]. Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Oxycodone Hydrochloride Oral Solution should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Medication Errors Instruct patients and caregivers how to measure and take or administer the correct dose of Oxycodone Hydrochloride Oral Solution and to always use the enclosed graduated measuring cup when administering Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg/mL) to correctly measure the prescribed amount of medication [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.1 )]. Advise patients and caregivers that Oxycodone Hydrochloride Oral Solution, is available 100 mg/5 mL. Inform patients and caregivers about which concentration they have been prescribed and provide detailed instruction on how to measure and take or administer the correct dose of Oxycodone Hydrochloride Oral Solution, and to always use the enclosed measuring device when administering Oxycodone Hydrochloride Oral Solution, to ensure that the dose is measured and administered accurately. If the prescribed concentration is changed, instruct patients and caregivers on how to correctly measure the new dose to avoid errors which could result in accidental overdose and death. Addiction, Abuse, and Misuse Inform patients that the use of Oxycodone Hydrochloride Oral Solution, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.2 )]. Instruct patients not to share Oxycodone Hydrochloride Oral Solution with others and to take steps to protect Oxycodone Hydrochloride Oral Solution from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Oxycodone Hydrochloride Oral Solution or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.3 )]. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.3 )].

of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.3 )]. Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.3 )]. Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if Oxycodone Hydrochloride Oral Solution is used with benzodiazepines or other CNS depressants, including alcohol, and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 )]. Patient Access to Naloxone for the Emergency Treatment of Opioid Overdose Discuss with the patient and caregiver the availability of naloxone for the emergency treatment of opioid overdose, both when initiating and renewing treatment with Oxycodone Hydrochloride Oral Solution. Inform patients and caregivers about the various ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (e.g., by prescription, directly from a pharmacist, or as part of a community-based program) [see Dosage and Administrations ( 2.2 ), Warnings and Precautions ( 5.3 )]. Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that naloxone’s effects are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if naloxone is administered [see Overdosage (10)]. If naloxone is prescribed, also advise patients and caregivers: • How to treat with naloxone in the event of an opioid overdose • To tell family and friends about their naloxone and to keep it in a place where family and friends can access it in an emergency • To read the Patient Information (or other educational material) that will come with their naloxone. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions ( 5.8 ), Adverse Reactions ( 6 )]. Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition called serotonin syndrome resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications. [see Drug Interactions ( 7 )]. MAOI Interaction Inform patients to avoid taking Oxycodone Hydrochloride Oral Solution while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Oxycodone Hydrochloride Oral Solution [see Drug Interactions ( 7 )]. Important Administration Instructions Instruct patients how to properly take Oxycodone Hydrochloride Oral Solution [see Dosage and Administration ( 2.1 ), Warnings and Precautions ( 5.1 )] • Strongly advise patients and caregivers to always use the enclosed graduated oral syringe or dosing cup when administering Oxycodone Hydrochloride Oral Solution to correctly measure the prescribed amount of medication [see Warnings and Precautions ( 5.1 )]. • Instruct patients and caregivers to never use household teaspoons or tablespoons to measure Oxycodone Hydrochloride Oral Solution.

duated oral syringe or dosing cup when administering Oxycodone Hydrochloride Oral Solution to correctly measure the prescribed amount of medication [see Warnings and Precautions ( 5.1 )]. • Instruct patients and caregivers to never use household teaspoons or tablespoons to measure Oxycodone Hydrochloride Oral Solution. • Advise patients and caregivers not to adjust the dose of Oxycodone Hydrochloride Oral Solution without consulting with a physician or other healthcare provider. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Oxycodone Hydrochloride Oral Solution without first discussing a tapering plan with the prescriber [see Dosage and Administration ( 2.5 )]. Driving or Operating Heavy Machinery Inform patients that Oxycodone Hydrochloride Oral Solution may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions ( 5.16 )]. Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6), Clinical Pharmacology ( 12.2 )]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life- threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.10) ]. Hypotension Inform patients that Oxycodone Hydrochloride Oral Solution may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions ( 5.11 )]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in Oxycodone Hydrochloride Oral Solution. Advise patients how to recognize such a reaction and when to seek medical attention [see Adverse Reactions ( 6 )]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of Oxycodone Hydrochloride Oral Solution for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.5 ), Use in Specific Populations ( 8.1 )]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that Oxycodone Hydrochloride Oral Solution can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ]. Lactation Advise breastfeeding women using Oxycodone Hydrochloride Oral Solution to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding women to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2) ]. Infertility Inform patients that chronic use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3) ]. Manufactured by: Novel Laboratories, Inc Somerset, NJ 08873 Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, MD 21202 SAP Code: xxxxxx Rev. 09/2024

FDA approved Medication Guide Oxycodone Hydrochloride (ox-ee-CO-dohn) Oral Solution, CII Oxycodone Hydrochloride Oral Solution is: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about Oxycodone Hydrochloride Oral Solution: Get emergency help or call 911 right away if you take too much Oxycodone Hydrochloride Oral Solution (overdose) . When you first start taking Oxycodone Hydrochloride Oral Solution, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Talk to your healthcare provider about naloxone, a medicine for the emergency treatment of an opioid overdose. Taking Oxycodone Hydrochloride Oral Solution with other opioid medicines, benzodiazepines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your Oxycodone Hydrochloride Oral Solution. They could die from taking it. Selling or giving away Oxycodone Hydrochloride Oral Solution is against the law. Store Oxycodone Hydrochloride Oral Solution securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Do not take Oxycodone Hydrochloride Oral Solution if you have: severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines. an allergy to oxycodone or any of the ingredients in Oxycodone Hydrochloride Oral Solution. Before taking Oxycodone Hydrochloride Oral Solution, tell your healthcare provider if you have a history of: head injury, seizures liver, kidney, thyroid problems problems urinating pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Tell your healthcare provider if you are: noticing your pain getting worse. If your pain gets worse after you take Oxycodone Hydrochloride Oral Solution, do not take more of Oxycodone Hydrochloride Oral Solution without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking Oxycodone Hydrochloride Oral Solution. pregnant or planning to become pregnant. Use of Oxycodone Hydrochloride Oral Solution for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding. Oxycodone Hydrochloride Oral Solution passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements.

eased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Oxycodone Hydrochloride Oral Solution with certain other medicines can cause serious side effects that could lead to death. When taking Oxycodone Hydrochloride Oral Solution: Do not change your dose. Take Oxycodone Hydrochloride Oral Solution exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. For acute (short-term) pain, you may only need to take Oxycodone Hydrochloride Oral Solution for a few days. You may have some Oxycodone Hydrochloride Oral Solution left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused Oxycodone Hydrochloride Oral Solution. See the detailed Instructions for Use for information about how to take Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL). Always use the enclosed calibrated measuring cup that comes with Oxycodone Hydrochloride Oral Solution 5 mg per 5 mL and the enclosed calibrated oral syringe that comes with Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL) to correctly measure your dose. Never use a household teaspoon or tablespoon to measure Oxycodone Hydrochloride Oral Solution. Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. Call your healthcare provider if the dose you are taking does not control your pain. If you have been taking Oxycodone Hydrochloride Oral Solution regularly, do not stop taking Oxycodone Hydrochloride Oral Solution without talking to your healthcare provider. Dispose of expired, unwanted, or unused Oxycodone Hydrochloride Oral Solution by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking Oxycodone Hydrochloride Oral Solution DO NOT: Drive or operate heavy machinery, until you know how Oxycodone Hydrochloride Oral Solution affects you. Oxycodone Hydrochloride Oral Solution can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Oxycodone Hydrochloride Oral Solution may cause you to overdose and die. What are the possible side effects of Oxycodone Hydrochloride Oral Solution: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of Oxycodone Hydrochloride Oral Solution. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Novel Laboratories, Inc. Somerset, NJ 08873 Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, MD 21202 SAP Code: xxxxxx Rev.

rt side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Novel Laboratories, Inc. Somerset, NJ 08873 Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, MD 21202 SAP Code: xxxxxx Rev. 09/2024 Patient Instructions for Use Oxycodone Hydrochloride Oral Solution 100 mg per 5 mL (20 mg per mL) Oral Syringe Important information about measuring Oxycodone Hydrochloride Oral Solution Always use the oral syringe provided with your Oxycodone Hydrochloride Oral Solution to make sure you measure the right amount. Measure the dose of medicine from the widest part of the plunger. Do not measure from the narrow tip. See Figure 1. Step 1. Insert the tip of the oral syringe into the medicine bottle. Step 2. Pull back the plunger to the line that matches the dose prescribed by your healthcare provider. Step 3. Remove the oral syringe from the medicine bottle. Step 4. Take your medicine by slowly pushing the plunger until the oral syringe is empty FIGURE 1: figure-1

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1) ] Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2) ] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions (5.3) ] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.4) ] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions (5.7) ] Adrenal Insufficiency [see Warnings and Precautions (5.9) ] Severe Hypotension [see Warnings and Precautions (5.10) ] Gastrointestinal Adverse Reactions [see Warnings and Precautions (5.12) ] Seizures [see Warnings and Precautions (5.13) ] Withdrawal [see Warnings and Precautions (5.14) ] Most common adverse reactions (≥3%) were nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rhodes Pharmaceuticals at 1-888-873-5329; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Oxycodone hydrochloride tablets have been evaluated in open label clinical trials in patients with cancer and nonmalignant pain. Oxycodone hydrochloride tablets are associated with adverse experiences similar to those seen with other opioids. Serious adverse reactions associated with oxycodone hydrochloride tablets use included: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock. The common adverse reactions seen on initiation of therapy with oxycodone hydrochloride tablets are dose related and are typical opioid-related adverse reactions. The most frequent of these included nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. The frequency of these reactions depended on several factors, including clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual. In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving oxycodone hydrochloride tablets, the following adverse events were recorded in oxycodone hydrochloride tablets-treated patients with an incidence ≥ 3%. In descending order of frequency, they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence.

11 DESCRIPTION Oxycodone Hydrochloride Tablets, USP contain oxycodone, an opioid agonist. Each tablet for oral administration contains 5 mg, 10 mg, 15 mg, 20 mg, or 30 mg of oxycodone hydrochloride, USP. Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is considered slightly soluble in alcohol (octanol water partition coefficient is 0.7). Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride and has the following structural formula: C 18 H 21 NO 4 ∙HCl MW 351.82 The Oxycodone Hydrochloride Tablets, USP contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, crospovidone, and magnesium stearate. The 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg tablets contain the equivalent of 4.5 mg, 9 mg, 13.5 mg, 18 mg, and 27 mg, respectively, of oxycodone free base.

ted to date [see Adverse Reactions (6.2) ]. Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration (2.1 , 2.3) ]. Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration (2.1 , 2.3) ]. 12.3 Pharmacokinetics The activity of oxycodone hydrochloride tablets is primarily due to the parent drug oxycodone. Oxycodone hydrochloride tablets are designed to provide immediate release of oxycodone. Table 2: Pharmacokinetic Parameters (Mean±SD) Dose\Parameters AUC (ng×hr/mL) C max (ng/mL) T max (hr) C min (ng/mL) C avg (ng/mL) Half-Life (hr) Single Dose Pharmacokinetics Oxycodone HCl 5 mg tabs × 3 133.2±33 22.3±8.2 1.8±1.8 N/A N/A 3.73±0.9 Oxycodone HCl 15 mg tab 128.2±35.1 22.2±7.6 1.4±0.7 N/A N/A 3.55±1.0 Oxycodone HCl Liquid Concentrate 15 mg oral solution 130.6±34.7 21.1±6.1 1.9±1.5 N/A N/A 3.71±0.8 Oxycodone HCl 30 mg tab 268.2±60.7 39.3±14.0 2.6±3.0 N/A N/A 3.85±1.3 Food Effect, Single Dose Oxycodone HCl 10 mg/10 mL oral sol'n (fasted) 105±6.2 19.0±3.7 1.25±0.5 N/A N/A 2.9±0.4 Oxycodone HCl 10 mg/10 mL oral sol'n (fed) 133±25.2 17.7±3.0 2.54±1.2 N/A N/A 3.3±0.5 Multiple-Dose Studies AUC (72 to 84) Oxycodone HCl 5 mg tabs q6h × 14 doses 113.3±24.0 15.7±3.2 1.3±0.3 7.4±1.8 9.4±2.0 N/A Oxycodone HCl 3.33 mg (3.33 mL) oral sol'n q4h × 21 doses 99.0±24.8 12.9±3.1 1.0±0.3 7.2±2.3 9.7±2.6 N/A Absorption About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lower presystemic and/or first-pass metabolism of oxycodone. The relative oral bioavailability of oxycodone hydrochloride tablets 15 mg and 30 mg tablets, compared to the 5 mg oxycodone hydrochloride tablet, is 96% and 101%, respectively. Oxycodone hydrochloride tablets, 15 mg and 30 mg tablets, are bioequivalent to the 5 mg oxycodone hydrochloride tablets (see Table 2 for pharmacokinetic parameters). Dose proportionality of oxycodone has been established using the oxycodone hydrochloride tablets 5 mg at doses of 5 mg, 15 mg (three 5 mg tablets) and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) (see Figure 1 ). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride tablets. Figure 1 – Oxycodone Hydrochloride Tablets, USP Dose-Proportionality Study 5mg, 15mg, 30mg (single-dose) Food Effect A single-dose food effect study was conducted in normal volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of oxycodone absorption from the oral solution (see Table 2 ). In addition, food caused a delay in T max (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30 mg tablets.

solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of oxycodone absorption from the oral solution (see Table 2 ). In addition, food caused a delay in T max (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30 mg tablets. Distribution Following intravenous administration, the volume of distribution (V ss ) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk [see Special Populations (8.2) ]. Elimination Metabolism A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism and is catalyzed by CYP3A4. Oxymorphone is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6 [see Drug Interactions (7) ]. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone hydrochloride tablets was 3.5 to 4 hours. Specific Populations Age: Geriatric Population Population pharmacokinetic studies conducted with oxycodone hydrochloride tablets, indicated that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65. Hepatic Impairment In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased hepatic function were evaluated to study these potential differences. However, because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic impaired patients [see Use in Specific Populations (8.6) ]. Renal Impairment This drug is known to be substantially excreted by the kidney and the risk of adverse reactions to this drug may be greater in patients with impaired renal function [see Use in Specific Populations (8.7) ] .

12.3 Pharmacokinetics The activity of oxycodone hydrochloride tablets is primarily due to the parent drug oxycodone. Oxycodone hydrochloride tablets are designed to provide immediate release of oxycodone. Table 2: Pharmacokinetic Parameters (Mean±SD) Dose\Parameters AUC (ng×hr/mL) C max (ng/mL) T max (hr) C min (ng/mL) C avg (ng/mL) Half-Life (hr) Single Dose Pharmacokinetics Oxycodone HCl 5 mg tabs × 3 133.2±33 22.3±8.2 1.8±1.8 N/A N/A 3.73±0.9 Oxycodone HCl 15 mg tab 128.2±35.1 22.2±7.6 1.4±0.7 N/A N/A 3.55±1.0 Oxycodone HCl Liquid Concentrate 15 mg oral solution 130.6±34.7 21.1±6.1 1.9±1.5 N/A N/A 3.71±0.8 Oxycodone HCl 30 mg tab 268.2±60.7 39.3±14.0 2.6±3.0 N/A N/A 3.85±1.3 Food Effect, Single Dose Oxycodone HCl 10 mg/10 mL oral sol'n (fasted) 105±6.2 19.0±3.7 1.25±0.5 N/A N/A 2.9±0.4 Oxycodone HCl 10 mg/10 mL oral sol'n (fed) 133±25.2 17.7±3.0 2.54±1.2 N/A N/A 3.3±0.5 Multiple-Dose Studies AUC (72 to 84) Oxycodone HCl 5 mg tabs q6h × 14 doses 113.3±24.0 15.7±3.2 1.3±0.3 7.4±1.8 9.4±2.0 N/A Oxycodone HCl 3.33 mg (3.33 mL) oral sol'n q4h × 21 doses 99.0±24.8 12.9±3.1 1.0±0.3 7.2±2.3 9.7±2.6 N/A Absorption About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lower presystemic and/or first-pass metabolism of oxycodone. The relative oral bioavailability of oxycodone hydrochloride tablets 15 mg and 30 mg tablets, compared to the 5 mg oxycodone hydrochloride tablet, is 96% and 101%, respectively. Oxycodone hydrochloride tablets, 15 mg and 30 mg tablets, are bioequivalent to the 5 mg oxycodone hydrochloride tablets (see Table 2 for pharmacokinetic parameters). Dose proportionality of oxycodone has been established using the oxycodone hydrochloride tablets 5 mg at doses of 5 mg, 15 mg (three 5 mg tablets) and 30 mg (six 5 mg tablets) based on extent of absorption (AUC) (see Figure 1 ). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride tablets. Figure 1 – Oxycodone Hydrochloride Tablets, USP Dose-Proportionality Study 5mg, 15mg, 30mg (single-dose) Food Effect A single-dose food effect study was conducted in normal volunteers using the 5 mg/5 mL solution. The concurrent intake of a high fat meal was shown to enhance the extent (27% increase in AUC), but not the rate of oxycodone absorption from the oral solution (see Table 2 ). In addition, food caused a delay in T max (1.25 to 2.54 hour). Similar effects of food are expected with the 15 mg and 30 mg tablets. Distribution Following intravenous administration, the volume of distribution (V ss ) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk [see Special Populations (8.2) ]. Elimination Metabolism A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism and is catalyzed by CYP3A4. Oxymorphone is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6 [see Drug Interactions (7) ]. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations.

16 HOW SUPPLIED/STORAGE AND HANDLING Oxycodone Hydrochloride Tablets, USP are available as follows: 30 mg – white to off-white, round, biconvex tablets debossed with "R" above bisect and "P" below on one side and "30" on the other side NDC 72162-1337-3: Bottles of 30 Tablets NDC 72162-1337-6: Bottles of 60 Tablets NDC 72162-1337-9: Bottles of 90 Tablets Dispense in a tight, light-resistant container. Protect from moisture. Store at 25°C (77°F); excursions are permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store oxycodone hydrochloride tablets securely and dispose of properly [see PATIENT COUNSELING INFORMATION (17)]. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504

tion Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions (6) , Clinical Pharmacology (12.1) ]. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions (5.9) ]. Hypotension Inform patients that oxycodone hydrochloride tablets may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from sitting or lying position) [see Warnings and Precautions (5.10) ]. Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in oxycodone hydrochloride tablets. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications (4) , Adverse Reactions (6.2) ]. Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of oxycodone hydrochloride tablets for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions (5.4) , Use in Specific Populations (8.1) ]. Embryo-Fetal Toxicity Inform female patients of reproductive potential that oxycodone hydrochloride tablets can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations (8.1) ]. Lactation Advise breastfeeding women using oxycodone hydrochloride tablets to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding women to seek immediate medical care if they notice these signs [see Use in Specific Populations (8.2) ]. Infertility Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations (8.3) ]. To request medical information or to report suspected adverse reactions, contact Rhodes Pharmaceuticals at 1-888-873-5329.

Medication Guide Oxycodone Hydrochloride (ox" i koe' done hye" droe klor' ide) Tablets, USP CII This Medication Guide has been approved by the U.S. Food and Drug Administration. Rev.: 12/2025 Oxycodone hydrochloride tablets are: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about oxycodone hydrochloride tablets: Get emergency help or call 911 right away if you take too much oxycodone hydrochloride tablets (overdose). When you first start taking oxycodone hydrochloride tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose. Taking oxycodone hydrochloride tablets with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your oxycodone hydrochloride tablets. They could die from taking it. Selling or giving away oxycodone hydrochloride tablets is against the law. Store oxycodone hydrochloride tablets securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Do not take oxycodone hydrochloride tablets if you have: severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines. allergy to oxycodone. Before taking oxycodone hydrochloride tablets, tell your healthcare provider if you have a history of: head injury, seizures problems urinating abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems liver, kidney, thyroid problems pancreas or gallbladder problems Tell your healthcare provider if you are: noticing your pain getting worse. If your pain gets worse after you take oxycodone hydrochloride tablets, do not take more of oxycodone hydrochloride tablets without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking oxycodone hydrochloride tablets. pregnant or planning to become pregnant. Use of oxycodone hydrochloride tablets for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding. Oxycodone hydrochloride tablets pass into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements.

eased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking oxycodone hydrochloride tablets with certain other medicines can cause serious side effects that could lead to death. When taking oxycodone hydrochloride tablets: Do not change your dose. Take oxycodone hydrochloride tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. For acute (short-term) pain, you may only need to take oxycodone hydrochloride tablets for a few days. You may have some oxycodone hydrochloride tablets left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused oxycodone hydrochloride tablets. Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. Call your healthcare provider if the dose you are taking does not control your pain. If you have been taking oxycodone hydrochloride tablets regularly, do not stop taking oxycodone hydrochloride tablets without talking to your healthcare provider. Dispose of expired, unwanted, or unused oxycodone hydrochloride tablets by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking oxycodone hydrochloride tablets DO NOT: Drive or operate heavy machinery, until you know how oxycodone hydrochloride tablets affect you. Oxycodone hydrochloride tablets can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with oxycodone hydrochloride tablets may cause you to overdose and die. The possible side effects of oxycodone hydrochloride tablets are: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of oxycodone hydrochloride tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information, go to dailymed.nlm.nih.gov Marketed by: Rhodes Pharmaceuticals, Wilson, NC 27893 US, http://rhodespharma.com or call 1-888-873-5329. Manufactured by: Purdue Pharma L.P., Stamford, CT 06901

<table width="100%"><col width="2%" align="left" valign="top"/><col width="62%" align="left" valign="top"/><col width="36%" align="left" valign="top"/><thead><tr><th colspan="3" styleCode="Lrule Rrule">Medication Guide Oxycodone Hydrochloride (ox&quot; i koe&apos; done hye&quot; droe klor&apos; ide) Tablets, USP CII</th></tr></thead><tfoot><tr><td align="left" colspan="2"><content styleCode="bold">This Medication Guide has been approved by the U.S. Food and Drug Administration.</content></td><td align="right" valign="top">Rev.: 12/2025 </td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Oxycodone hydrochloride tablets are:</content><list listType="unordered" styleCode="disc"><item>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.</item><item>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Important information about oxycodone hydrochloride tablets:</content><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Get emergency help or call 911 right away if you take too much oxycodone hydrochloride tablets (overdose).</content> When you first start taking oxycodone hydrochloride tablets, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose.</item><item>Taking oxycodone hydrochloride tablets with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</item><item>Never give anyone else your oxycodone hydrochloride tablets. They could die from taking it.

oride tablets exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</item><item>For acute (short-term) pain, you may only need to take oxycodone hydrochloride tablets for a few days. You may have some oxycodone hydrochloride tablets left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused oxycodone hydrochloride tablets.</item><item>Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.</item><item>Call your healthcare provider if the dose you are taking does not control your pain.</item><item>If you have been taking oxycodone hydrochloride tablets regularly, do not stop taking oxycodone hydrochloride tablets without talking to your healthcare provider.</item><item>Dispose of expired, unwanted, or unused oxycodone hydrochloride tablets by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit <content styleCode="underline">www.fda.gov/drugdisposal</content> for additional information on disposal of unused medicines.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">While taking oxycodone hydrochloride tablets DO NOT:</content><list listType="unordered" styleCode="disc"><item>Drive or operate heavy machinery, until you know how oxycodone hydrochloride tablets affect you. Oxycodone hydrochloride tablets can make you sleepy, dizzy, or lightheaded.</item><item>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with oxycodone hydrochloride tablets may cause you to overdose and die.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">The possible side effects of oxycodone hydrochloride tablets are:</content><list listType="unordered" styleCode="disc"><item>constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.</item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="3"><content styleCode="bold">Get emergency medical help or call 911 right away if you have:</content><list listType="unordered" styleCode="disc"><item>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</item></list></td></tr><tr><td styleCode="Lrule Rrule" colspan="3">These are not all the possible side effects of oxycodone hydrochloride tablets. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <content styleCode="bold">For more information, go to dailymed.nlm.nih.gov</content></td></tr><tr><td styleCode="Lrule Rrule" colspan="3">Marketed by: Rhodes Pharmaceuticals, Wilson, NC 27893 US, http://rhodespharma.com or call 1-888-873-5329.</td></tr><tr><td styleCode="Lrule Rrule" colspan="3">Manufactured by: Purdue Pharma L.P., Stamford, CT 06901</td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Oxycodone Hydrochloride Tablets, USP are available as follows: 5 mg – white to off-white, round, flat faced, beveled edged tablets debossed with "R" above bisect and "P" below on one side and "5" on the other side NDC: 72162-1334-2: 20 Tablets in a BOTTLE NDC: 72162-1334-3: 30 Tablets in a BOTTLE NDC: 72162-1334-6: 60 Tablets in a BOTTLE NDC: 72162-1334-9: 90 Tablets in a BOTTLE Dispense in a tight, light-resistant container. Protect from moisture. Store at 25°C (77°F); excursions are permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store oxycodone hydrochloride tablets securely and dispose of properly [see PATIENT COUNSELING INFORMATION (17)]. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504

11 DESCRIPTION Oxycodone Hydrochloride Tablets, USP contain oxycodone, an opioid agonist. Each tablet for oral administration contains 5 mg, 10 mg, 15 mg, 20 mg, or 30 mg of oxycodone hydrochloride, USP. Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is considered slightly soluble in alcohol (octanol water partition coefficient is 0.7). Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride and has the following structural formula: C18H21NO4∙HCl MW 351.82 The Oxycodone Hydrochloride Tablets, USP contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, crospovidone, and magnesium stearate. The 5 mg, 10 mg, 15 mg, 20 mg, and 30 mg tablets contain the equivalent of 4.5 mg, 9 mg, 13.5 mg, 18 mg, and 27 mg, respectively, of oxycodone free base.

16 HOW SUPPLIED/STORAGE AND HANDLING Oxycodone Hydrochloride Tablets, USP are available as follows: 10 mg – white to off-white, round, biconvex tablets debossed with "R" above bisect and "P" below on one side and "10" on the other side. NDC 72162-1335-2: Bottles of 120 Tablets NDC 72162-1335-3: Bottles of 30 Tablets NDC 72162-1335-6: Bottles of 60 Tablets NDC 72162-1335-9: Bottles of 90 Tablets Dispense in a tight, light-resistant container. Protect from moisture. Store at 25°C (77°F); excursions are permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store oxycodone hydrochloride tablets securely and dispose of properly [see PATIENT COUNSELING INFORMATION (17)]. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OXYCODONE HYDROCHLORIDE CAPSULES Addiction, Abuse, and Misuse Because the use of Oxycodone Hydrochloride Capsules exposes patients and other users to risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient’s risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of Oxycodone Hydrochloride Capsules, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Oxycodone Hydrochloride Capsules are essential [see Warnings and Precautions ( 5.2 )] . Accidental Ingestion Accidental ingestion of even one dose of Oxycodone Hydrochloride Capsules, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions ( 5.2 )] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of Oxycodone Hydrochloride Capsules and benzodiazepines or other CNS depressants for use in patients for whom alternate treatment options are inadequate [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )] . Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions ( 5.4 )] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions ( 5.5 )] . Cytochrome P450 3A4 Interaction The concomitant use of Oxycodone Hydrochloride Capsules with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Regularly evaluate patients receiving Oxycodone Hydrochloride Capsules and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] . WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF OXYCODONE HYDROCHLORIDE CAPSULES See full prescribing information for complete boxed warning. • Oxycodone Hydrochloride Capsules expose users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and reassess regularly for these behaviors and conditions. ( 5.1 ) • Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dosage increase.

to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient’s risk before prescribing and reassess regularly for these behaviors and conditions. ( 5.1 ) • Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Oxycodone Hydrochloride Capsules are essential. ( 5.2 ) • Accidental ingestion of Oxycodone Hydrochloride Capsules, especially by children, can result in a fatal overdose of oxycodone. ( 5.2 ) • Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. ( 5.3 , 7 ) • Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.4 ) • Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. ( 5.5 ) • Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone. ( 5.6 , 7 , 12.3 )

1 INDICATIONS AND USAGE Oxycodone Hydrochloride Capsules are an opioid agonist indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. • Limitations of Use Because of the risks of addiction, abuse, and misuse, overdose, and death, which can occur at any dosage or duration, and persist over the course of therapy [see Warnings and Precautions ( 5.1 )] , reserve opioid analgesics, including Oxycodone Hydrochloride Capsules, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. Oxycodone Hydrochloride Capsules are an opioid agonist indicated in adults for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including Oxycodone Hydrochloride Capsules for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 )

2 DOSAGE AND ADMINISTRATION • Oxycodone Hydrochloride Capsules should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of Oxycodone Hydrochloride Capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) • Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Oxycodone Hydrochloride Capsules. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) • Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with Oxycodone Hydrochloride Capsules, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.2 , 5.3 , 5.4 ). • Initiate treatment with Oxycodone Hydrochloride Capsules in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Oxycodone Hydrochloride Capsules. ( 2.1 , 2.4 ) • Periodically reassess patients receiving Oxycodone Hydrochloride Capsules to evaluate the continued need for opioid analgesics to maintain pain control, for signs and symptoms of adverse reactions, and for the development of addiction, abuse, and misuse. ( 2.4 ) • Do not rapidly reduce or abruptly discontinue Oxycodone Hydrochloride Capsules in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.5 ) 2.1 Important Dosage and Administration Instructions • Oxycodone Hydrochloride Capsules should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. • Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals [see Warnings and Precautions ( 5 )] . Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of Oxycodone Hydrochloride Capsules for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic.

es are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. • Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. • There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient’s underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, misuse [see Warnings and Precautions ( 5.1 )] . • Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with Oxycodone Hydrochloride Capsules. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5 )]. 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Initial Dosage Although it is not possible to list every condition that is important to the selection of the initial dose of Oxycodone Hydrochloride Capsules, attention must be given to: 1. the daily dose, potency and characteristics of a full agonist or mixed agonist/antagonist the patient has been taking previously 2. the reliability of the relative potency estimate to calculate the dose of oxycodone HCl needed 3. the degree of opioid tolerance 4. the general condition and medical status of the patient, including the patient’s weight and age 5. the balance between pain management and adverse reactions 6. the type and severity of the patient’s pain 7. risk factors for abuse or addiction, including a prior history of abuse or addiction Use of Oxycodone Hydrochloride Capsules as the First Opioid Analgesic Initiate treatment with Oxycodone Hydrochloride Capsules in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient’s response to their initial dose of Oxycodone Hydrochloride Capsules. Conversion from Other Opioids to Oxycodone Hydrochloride Capsules There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Oxycodone Hydrochloride Capsules.

ose of Oxycodone Hydrochloride Capsules. Conversion from Other Opioids to Oxycodone Hydrochloride Capsules There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of Oxycodone Hydrochloride Capsules. It is safer to underestimate a patient’s 24-hour Oxycodone Hydrochloride Capsules dosage than to overestimate the 24-hour Oxycodone Hydrochloride Capsules dosage and manage an adverse reaction due to overdose. If a patient has been receiving opioid-containing medications prior to taking Oxycodone Hydrochloride Capsules, the potency of the prior opioid relative to oxycodone should be factored into the selection of the total daily dose (TDD) of oxycodone. In converting patients from other opioids to Oxycodone Hydrochloride Capsules, close observation and adjustment of dosage based upon the patient’s response to Oxycodone Hydrochloride Capsules is imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the total daily dose of Oxycodone Hydrochloride Capsules may be necessary, especially in patients who have disease states that are changing rapidly. Conversion from Oxycodone Hydrochloride Capsules to Extended-Release Oxycodone The relative bioavailability of Oxycodone Hydrochloride Capsules compared to extended-release oxycodone is unknown, so conversion to extended-release oxycodone may lead to increased risk of excessive sedation and respiratory depression. 2.4 Titration and Maintenance of Therapy Individually titrate Oxycodone Hydrochloride Capsules to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving Oxycodone Hydrochloride Capsules to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as to reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 )] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the Oxycodone Hydrochloride Capsules dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after a dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of Oxycodone Hydrochloride Capsules Do not rapidly reduce or abruptly discontinue Oxycodone Hydrochloride Capsules in patients who may be physically dependent on opioids. Rapid reduction or abrupt discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

n, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking Oxycodone Hydrochloride Capsules, there are a variety of factors that should be considered, including the total daily of opioid (including Oxycodone Hydrochloride Capsules) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with co-morbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on Oxycodone Hydrochloride Capsules who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.14 ), Drug Abuse and Dependence ( 9.3 )] .

3 DOSAGE FORMS AND STRENGTHS Capsules 5 mg: Each capsule has an opaque yellow cap and an opaque white body, imprinted with ‘ANI’ on the cap and ‘167’ on the body in black ink and contains 5 mg of oxycodone hydrochloride USP. Immediate-release capsules: 5 mg ( 3 )

4 CONTRAINDICATIONS Oxycodone Hydrochloride Capsules are contraindicated in patients with: • Significant respiratory depression [see Warnings and Precautions ( 5.2 )] • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment [see Warnings and Precautions ( 5.8 )] • Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.12 )] • Hypersensitivity to oxycodone (e.g., angioedema) [see Adverse Reactions ( 6 )] • Significant respiratory depression. ( 4 ) • Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment. ( 4 ) • Known or suspected gastrointestinal obstruction, including paralytic ileus. ( 4 ) • Hypersensitivity to oxycodone. ( 4 )

5 WARNINGS AND PRECAUTIONS • Opioid-Induced Hyperalgesia and Allodynia: Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.7 ) • Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients: Regularly evaluate closely, particularly during initiation and titration. ( 5.8 ) • Adrenal Insufficiency: If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9 ) • Severe Hypotension: Regularly evaluate during dosage initiation and titration. Avoid use of Oxycodone Hydrochloride Capsules in patients with circulatory shock. ( 5.10 ) • Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness: Monitor for sedation and respiratory depression. Avoid use of Oxycodone Hydrochloride Capsules in patients with impaired consciousness or coma. ( 5.11 ) 5.1 Addiction, Abuse, and Misuse Oxycodone Hydrochloride Capsules contain oxycodone, a Schedule II controlled substance. As an opioid, Oxycodone Hydrochloride Capsules expose users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )]. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed Oxycodone Hydrochloride Capsules. Addiction can occur at recommended dosages and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6 )] . Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing Oxycodone Hydrochloride Capsules, and reassess all patients receiving Oxycodone Hydrochloride Capsules for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as Oxycodone Hydrochloride Capsules but use in such patients necessitates intensive counseling about the risks and proper use of Oxycodone Hydrochloride Capsules along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing Oxycodone Hydrochloride Capsules. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drug.

use. Consider these risks when prescribing or dispensing Oxycodone Hydrochloride Capsules. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drug. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agents, depending on the patient’s clinical status [see Overdosage ( 10 )] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of Oxycodone Hydrochloride Capsules, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of Oxycodone Hydrochloride Capsules are essential [see Dosage and Administration ( 2 )] . Overestimating the Oxycodone Hydrochloride Capsules dosage when converting patients from another opioid product can result in a fatal overdose with the first dose. Accidental ingestion of even one dose of Oxycodone Hydrochloride Capsules, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.5 )]. Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.3 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose.

s. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage ( 10 )]. 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of Oxycodone Hydrochloride Capsules with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7 )] . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ), Overdosage ( 10 )] . Advise both patients and caregivers about the risks of respiratory depression and sedation when Oxycodone Hydrochloride Capsules are used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7 )]. 5.4 Neonatal Opioid Withdrawal Syndrome Use of Oxycodone Hydrochloride Capsules for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly.

the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1 )] . 5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: • Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. • Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. • Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. • Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint. 5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of Oxycodone Hydrochloride Capsules with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions ( 5.2 )] , particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Capsules is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in Oxycodone Hydrochloride Capsules-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using Oxycodone Hydrochloride Capsules with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in Oxycodone Hydrochloride Capsules-treated patients, revaluate patients at frequent intervals and consider dosage reduction of Oxycodone Hydrochloride Capsules until stable drug effects are achieved [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7 )] . Concomitant use of Oxycodone Hydrochloride Capsules with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone.

g Interactions ( 7 )] . Concomitant use of Oxycodone Hydrochloride Capsules with CYP3A4 inducers or discontinuation of an CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using Oxycodone Hydrochloride Capsules with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Dosage and Administration ( 2.1 ), Drug Interactions ( 7 )] . 5.7 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence ( 9.3 )] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.14 )] . 5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of Oxycodone Hydrochloride Capsules in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease: Oxycodone Hydrochloride Capsule-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of Oxycodone Hydrochloride Capsules [see Warnings and Precautions ( 5.2 )] . Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions ( 5.2 )] . Regularly evaluate patients, particularly when initiating and titrating Oxycodone Hydrochloride Capsules and when Oxycodone Hydrochloride Capsules is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 , 5.3 ), Drug Interactions ( 7 )] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.9 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.

. 5.9 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.10 Severe Hypotension Oxycodone Hydrochloride Capsules may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions ( 7 )] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of Oxycodone Hydrochloride Capsules. In patients with circulatory shock, Oxycodone Hydrochloride Capsules may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of Oxycodone Hydrochloride Capsules in patients with circulatory shock. 5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), Oxycodone Hydrochloride Capsules may reduce respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with Oxycodone Hydrochloride Capsules. Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of Oxycodone Hydrochloride Capsules in patients with impaired consciousness or coma. 5.12 Risks of Gastrointestinal Complications Oxycodone Hydrochloride Capsules are contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The oxycodone in Oxycodone Hydrochloride Capsules may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology ( 12.2 )] . 5.13 Increased Risk of Seizures in Patients with Seizure Disorders The oxycodone in Oxycodone Hydrochloride Capsules may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during Oxycodone Hydrochloride Capsules therapy.

les may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during Oxycodone Hydrochloride Capsules therapy. 5.14 Withdrawal Do not rapidly reduce or abruptly discontinue Oxycodone Hydrochloride Capsules in a patient physically dependent on opioids. When discontinuing Oxycodone Hydrochloride Capsules in a physically-dependent patient, gradually taper the dosage. Rapid tapering of oxycodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration ( 2.5 ), Drug Abuse and Dependence ( 9.3 )]. Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including Oxycodone Hydrochloride Capsules. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7 )] . 5.15 Risks of Driving and Operating Machinery Oxycodone Hydrochloride Capsules may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of Oxycodone Hydrochloride Capsules and know how they will react to the medication [see Patient Counseling Information ( 17 )].

6 ADVERSE REACTIONS The following serious adverse reactions are described, or described in greater detail, in other sections: • Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] • Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] • Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] • Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.7 )] • Adrenal Insufficiency [see Warnings and Precautions ( 5.9 )] • Severe Hypotension [see Warnings and Precautions ( 5.10 )] • Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.12 )] • Seizures [see Warnings and Precautions ( 5.13 )] • Withdrawal [see Warnings and Precautions ( 5.14 )] The following adverse reactions associated with the use of oxycodone were identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious adverse reactions associated with oxycodone use included: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock. The common adverse reactions seen on initiation of therapy with oxycodone are dose-related and are typical opioid-related adverse reactions. The most frequent adverse events include nausea, constipation, vomiting, headache, and pruritus. The frequency of these reactions depended on several factors, including clinical setting, the patient’s level of opioid tolerance, and host factors specific to the individual. In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving another formulation of immediate-release oxycodone, the following adverse events were recorded in oxycodone treated patients with an incidence > 3%. In descending order of frequency, they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. The other less frequently observed adverse reactions from opioid analgesics, including Oxycodone Hydrochloride Capsules included: Body as a Whole: abdominal pain, accidental injury, allergic reaction, back pain, chills and fever, fever, flu syndrome, infection, neck pain, pain, photosensitivity reaction, and sepsis. Cardiovascular: deep thrombophlebitis, heart failure, hemorrhage, hypotension, migraine, palpitation, and tachycardia. Digestive: anorexia, diarrhea, dyspepsia, dysphagia, gingivitis, glossitis, and nausea and vomiting. Hemic and Lymphatic: anemia and leukopenia. Metabolic and Nutritional: edema, gout, hyperglycemia, iron deficiency anemia and peripheral edema. Musculoskeletal: arthralgia, arthritis, bone pain, myalgia and pathological fracture. Nervous: agitation, anxiety, confusion, dry mouth, hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation. Respiratory: bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis. Skin and Appendages: herpes simplex, rash, sweating, and urticaria. Special Senses: amblyopia.

hypertonia, hypesthesia, nervousness, neuralgia, personality disorder, tremor, and vasodilation. Respiratory: bronchitis, cough increased, dyspnea, epistaxis, laryngismus, lung disorder, pharyngitis, rhinitis, and sinusitis. Skin and Appendages: herpes simplex, rash, sweating, and urticaria. Special Senses: amblyopia. Urogenital: urinary tract infection Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs. Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Oxycodone Hydrochloride Capsules. Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids for an extended period of time [see Clinical Pharmacology ( 12.2 )] . Hyperalgesia and Allodynia: Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.7 )] . Hypoglycemia: Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED): Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioid, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.12 )] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either, 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: • Approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and • Approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9.2 )] . respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database.

east 70 days’ supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies. Most common adverse reactions are nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with Oxycodone Hydrochloride Capsules. Table 1: Clinically Significant Drug Interactions with Oxycodone Hydrochloride Capsules Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of Oxycodone Hydrochloride Capsules and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Oxycodone Hydrochloride Capsules and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Capsules is achieved [see Warnings and Precautions ( 5.6 )] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. Intervention: If concomitant use is necessary, consider dosage reduction of Oxycodone Hydrochloride Capsules until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation at frequent intervals. If a CYP3A4 inhibitor is discontinued, consider increasing the Oxycodone Hydrochloride Capsules dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of Oxycodone Hydrochloride Capsules and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions ( 5.6 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression. Intervention: If concomitant use is necessary, consider increasing the Oxycodone Hydrochloride Capsule dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Oxycodone Hydrochloride Capsule dosage reduction and reevaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions ( 5.3 )] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs of symptoms of respiratory depression (including sedation).

ve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs of symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin and pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Intervention: If concomitant use is warranted, frequently reevaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxycodone Hydrochloride Capsules if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2 )] . Intervention: The use of Oxycodone Hydrochloride Capsules is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of Oxycodone Hydrochloride Capsules and/or precipitate withdrawal symptoms. Intervention: Avoid concomitant use. Examples: butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression that may be greater than otherwise expected, and decrease the dosage of Oxycodone Hydrochloride Capsules and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.3 )]. Examples: cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when Oxycodone Hydrochloride Capsules is used concomitantly with anticholinergic drugs. • Serotonergic Drugs: Concomitant use may result in serotonin syndrome. Discontinue Oxycodone Hydrochloride Capsules if serotonin syndrome is suspected. ( 7 ) • Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of oxycodone. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 ) • Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with Oxycodone Hydrochloride Capsules because they may reduce analgesic effect of Oxycodone Hydrochloride Capsules or precipitate withdrawal symptoms. ( 7 )

<table styleCode="Noautorules" width="100%"><col width="16%"/><col width="84%"/><tbody><tr><td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Inhibitors of CYP3A4 and CYP2D6</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>The concomitant use of Oxycodone Hydrochloride Capsules and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of Oxycodone Hydrochloride Capsules and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of Oxycodone Hydrochloride Capsules is achieved <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#i4i_section_id_e7615fad-8296-4d5f-8403-42cb7406207d">5.6</linkHtml>)]</content>.</paragraph><paragraph>After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease <content styleCode="italics">[see Clinical Pharmacology (<linkHtml href="#i4i_pharmacokinetics_id_546d522a-963c-4ff5-b996-74714a585eee">12.3</linkHtml>)]</content>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>If concomitant use is necessary, consider dosage reduction of Oxycodone Hydrochloride Capsules until stable drug effects are achieved. </paragraph><paragraph>Evaluate patients at frequent intervals for respiratory depression and sedation at frequent intervals. </paragraph><paragraph>If a CYP3A4 inhibitor is discontinued, consider increasing the Oxycodone Hydrochloride Capsules dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal.

<paragraph>Evaluate patients at frequent intervals for respiratory depression and sedation at frequent intervals. </paragraph><paragraph>If a CYP3A4 inhibitor is discontinued, consider increasing the Oxycodone Hydrochloride Capsules dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Examples:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir)</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">CYP3A4 Inducers</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>The concomitant use of Oxycodone Hydrochloride Capsules and CYP3A4 inducers can decrease the plasma concentration of oxycodone <content styleCode="italics">[see Clinical Pharmacology (<linkHtml href="#i4i_pharmacokinetics_id_546d522a-963c-4ff5-b996-74714a585eee">12.3</linkHtml>)]</content>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone <content styleCode="italics">[see Warnings and Precautions (</content><content styleCode="italics"><linkHtml href="#i4i_section_id_e7615fad-8296-4d5f-8403-42cb7406207d">5.6</linkHtml>)]</content>.</paragraph><paragraph>After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase <content styleCode="italics">[see Clinical Pharmacology (<linkHtml href="#i4i_pharmacokinetics_id_546d522a-963c-4ff5-b996-74714a585eee">12.3</linkHtml>)]</content>, which could increase or prolong both the therapeutic effects and adverse reactions and may cause serious respiratory depression.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>If concomitant use is necessary, consider increasing the Oxycodone Hydrochloride Capsule dosage until stable drug effects are achieved.</paragraph><paragraph>Evaluate patients for signs of opioid withdrawal.

cs">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>If concomitant use is necessary, consider increasing the Oxycodone Hydrochloride Capsule dosage until stable drug effects are achieved.</paragraph><paragraph>Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Oxycodone Hydrochloride Capsule dosage reduction and reevaluate patients at frequent intervals for signs of respiratory depression and sedation.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Examples:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Rifampin, carbamazepine, phenytoin</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Benzodiazepines and other Central Nervous System (CNS) Depressants</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <content styleCode="italics">[see Warnings and Precautions (<linkHtml href="#i4i_section_id_3dc0ffa6-343f-449d-b49a-c97576031625">5.3</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs of symptoms of respiratory depression (including sedation).

ve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs of symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent <content styleCode="italics">[see Dosage and Administration (<linkHtml href="#ID_d90e6e54-210d-4d94-be11-0d1f845248b3">2.2</linkHtml>), Warnings and Precautions (<linkHtml href="#i4i_section_id_648cf004-2880-466f-9fc2-2be7092dd802">5.1</linkHtml>, <linkHtml href="#ID_747eb80d-1572-47d8-a107-26cee37421b0">5.2</linkHtml>, <linkHtml href="#i4i_section_id_3dc0ffa6-343f-449d-b49a-c97576031625">5.3</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Examples:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin and pregabalin), other opioids, alcohol.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Serotonergic Drugs</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>If concomitant use is warranted, frequently reevaluate the patient, particularly during treatment initiation and dose adjustment.

eCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>If concomitant use is warranted, frequently reevaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue Oxycodone Hydrochloride Capsules if serotonin syndrome is suspected.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Examples:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Monoamine Oxidase Inhibitors (MAOIs)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <content styleCode="italics">[see Warnings and Precautions (</content><content styleCode="italics"><linkHtml href="#ID_747eb80d-1572-47d8-a107-26cee37421b0">5.2</linkHtml>)]</content>.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>The use of Oxycodone Hydrochloride Capsules is not recommended for patients taking MAOIs or within 14 days of stopping such treatment.

="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>The use of Oxycodone Hydrochloride Capsules is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. </paragraph><paragraph>If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Examples:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>phenelzine, tranylcypromine, linezolid</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>May reduce the analgesic effect of Oxycodone Hydrochloride Capsules and/or precipitate withdrawal symptoms.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Avoid concomitant use.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Examples:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>butorphanol, nalbuphine, pentazocine, buprenorphine</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Muscle Relaxants</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Because respiratory depression that may be greater than otherwise expected, and decrease the dosage of Oxycodone Hydrochloride Capsules and/or the muscle relaxant as necessary.

graph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Because respiratory depression that may be greater than otherwise expected, and decrease the dosage of Oxycodone Hydrochloride Capsules and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent <content styleCode="italics">[see Dosage and Administration (<linkHtml href="#ID_d90e6e54-210d-4d94-be11-0d1f845248b3">2.2</linkHtml>), Warnings and Precautions (<linkHtml href="#ID_747eb80d-1572-47d8-a107-26cee37421b0">5.2</linkHtml>, <linkHtml href="#i4i_section_id_3dc0ffa6-343f-449d-b49a-c97576031625">5.3</linkHtml>)].</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Examples: </content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>cyclobenzaprine, metaxalone</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Diuretics</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Anticholinergic Drugs</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">Clinical Impact:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="italics">Intervention:</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Evaluate patients for signs of urinary retention or reduced gastric motility when Oxycodone Hydrochloride Capsules is used concomitantly with anticholinergic drugs.</paragraph></td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )] . Available data with Oxycodone Hydrochloride Capsules are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Animal reproduction studies with oral administrations of oxycodone hydrochloride in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Oxycodone Hydrochloride Capsules are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Oxycodone Hydrochloride Capsules, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone hydrochloride administered during the period of organogenesis up to 16 mg/kg/day and 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis.

anogenesis up to 16 mg/kg/day and 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m 2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis). 8.2 Lactation Risk Summary Available data from lactation studies indicate that oxycodone is present in breastmilk and that doses of less than 60 mg/day of the immediate-release formulation are unlikely to result in clinically relevant exposures in breastfed infants. A pharmacokinetics study utilizing opportunistic sampling of 76 lactating women receiving oxycodone immediate-release products for postpartum pain management showed that oxycodone concentrates in breastmilk with an average milk to plasma ratio of 3.2. The relative infant dose was low, approximately 1.3% of a weight-adjusted maternal dose (see Data) . In the same study, among the 70 infants exposed to oxycodone in breastmilk, no adverse events were attributed to oxycodone. However, based on known adverse effects in adults, infants should be monitored for signs of excess sedation and respiratory depression (see Clinical Considerations) . There are no data on the effects of the oxycodone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Oxycodone Hydrochloride Capsules and any potential adverse effects on the breastfed infant from Oxycodone Hydrochloride Capsules or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to Oxycodone Hydrochloride Capsules through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped, or when breastfeeding is stopped. Data Oxycodone concentration data from 76 lactating women receiving immediate-release oxycodone products for postpartum pain management, and 28 infants exposed to oxycodone in breastmilk showed that following a median (range) dose of oxycodone in mothers of 9.2 (5-10) mg/dose or 33.0 (5.4-59.3) mg/day, oxycodone concentrated in breastmilk with a median (range) milk to plasma ratio of 3.2 (1.2-5.3). However, when using maternal breastmilk data to estimate the daily and relative infant dose, the infant dose was 0.006 mg/kg/day, which is 1.3% of a weight-adjusted maternal dose of 10 mg every 6 hours. These estimates based on maternal breastmilk concentrations were corroborated by the observed infant concentrations, of which over 75% (19/25) were below the limit of quantification. Among the 6 infants with quantifiable concentration, the median (range) concentration was 0.2 ng/mL (0.1-0.7). These concentrations are 100 to 1000 times lower than concentrations observed in other studies after infants received oxycodone at 0.1 mg/kg/dose (~20-200 ng/mL). 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.2 )] .

ng/mL). 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.2 )] . 8.4 Pediatric Use The safety and effectiveness of Oxycodone Hydrochloride Capsules have not been established in pediatric patients. The safety and pharmacokinetics of a single-dose of an Oxycodone Hydrochloride Oral Solution were evaluated in an open-label clinical trial in 89 pediatric patients 2 years to less than 17 years of age with postoperative pain. However, definitive conclusions are not possible because of insufficient information. 8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Oxycodone Hydrochloride Capsules slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.2 )] . Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. 8.6 Hepatic Impairment Since oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Initiate therapy in these patients with a lower than usual dosage of Oxycodone Hydrochloride Capsules and titrate carefully. Regularly evaluate for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3 )] . 8.7 Renal Impairment Information from oxycodone tablets indicate that patients with renal impairment had higher plasma concentrations of oxycodone than subjects with normal renal function. Initiate therapy with a lower than usual dosage of Oxycodone Hydrochloride Capsules and titrate carefully. Regularly evaluate for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 )] . Available data with Oxycodone Hydrochloride Capsules are insufficient to inform a drug-associated risk for major birth defects and miscarriage. Animal reproduction studies with oral administrations of oxycodone hydrochloride in rats and rabbits during the period of organogenesis at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data] . Based on animal data, advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. Oxycodone Hydrochloride Capsules are not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including Oxycodone Hydrochloride Capsules, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone hydrochloride administered during the period of organogenesis up to 16 mg/kg/day and 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis.

anogenesis up to 16 mg/kg/day and 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo-fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m 2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis).

8.4 Pediatric Use The safety and effectiveness of Oxycodone Hydrochloride Capsules have not been established in pediatric patients. The safety and pharmacokinetics of a single-dose of an Oxycodone Hydrochloride Oral Solution were evaluated in an open-label clinical trial in 89 pediatric patients 2 years to less than 17 years of age with postoperative pain. However, definitive conclusions are not possible because of insufficient information.

8.5 Geriatric Use Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dose for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of Oxycodone Hydrochloride Capsules slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.2 )] . Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Oxycodone Hydrochloride Capsules contain oxycodone, a Schedule II controlled substance. 9.2 Abuse Oxycodone Hydrochloride Capsules contain oxycodone, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )] . Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority given to drug use than to other activities and obligations), and possible tolerance of physical dependence. Misuse and abuse of Oxycodone Hydrochloride Capsules increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Oxycodone Hydrochloride Capsules with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Oxycodone Hydrochloride Capsules abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use Oxycodone Hydrochloride Capsules in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and among people who abuse drugs and people with substance abuse disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Oxycodone Hydrochloride Capsules, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Capsules Abuse of Oxycodone Hydrochloride Capsules poses a risk of overdose and death.

t of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Capsules Abuse of Oxycodone Hydrochloride Capsules poses a risk of overdose and death. The risk is increased with concurrent use of Oxycodone Hydrochloride Oral Capsules with alcohol and/or other CNS depressants. Oxycodone Hydrochloride Capsules are approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not rapidly reduce or abruptly discontinue Oxycodone Hydrochloride Capsules in a patient physically dependent on opioids. Rapid tapering of Oxycodone Hydrochloride Capsules in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing Oxycodone Hydrochloride Capsules, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Oxycodone Hydrochloride Capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.14 )]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations ( 8.1 )].

9.2 Abuse Oxycodone Hydrochloride Capsules contain oxycodone, a substance with a high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )] . Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority given to drug use than to other activities and obligations), and possible tolerance of physical dependence. Misuse and abuse of Oxycodone Hydrochloride Capsules increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of Oxycodone Hydrochloride Capsules with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of Oxycodone Hydrochloride Capsules abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use Oxycodone Hydrochloride Capsules in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among drug abusers and among people who abuse drugs and people with substance abuse disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. Oxycodone Hydrochloride Capsules, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of Oxycodone Hydrochloride Capsules Abuse of Oxycodone Hydrochloride Capsules poses a risk of overdose and death. The risk is increased with concurrent use of Oxycodone Hydrochloride Oral Capsules with alcohol and/or other CNS depressants. Oxycodone Hydrochloride Capsules are approved for oral use only.

ecific to Abuse of Oxycodone Hydrochloride Capsules Abuse of Oxycodone Hydrochloride Capsules poses a risk of overdose and death. The risk is increased with concurrent use of Oxycodone Hydrochloride Oral Capsules with alcohol and/or other CNS depressants. Oxycodone Hydrochloride Capsules are approved for oral use only. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not rapidly reduce or abruptly discontinue Oxycodone Hydrochloride Capsules in a patient physically dependent on opioids. Rapid tapering of Oxycodone Hydrochloride Capsules in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing Oxycodone Hydrochloride Capsules, gradually taper the dosage using a patient-specific plan that considers the following: the dose of Oxycodone Hydrochloride Capsules the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.14 )]. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Use in Specific Populations ( 8.1 )].

10 OVERDOSAGE Clinical Presentation Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the reestablishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life-support measures. For clinically significant respiratory or circulatory depression secondary to opioid overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of oxycodone in Oxycodone Hydrochloride Capsules, carefully monitor the patient until spontaneous respiration is reliably re-established. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product’s prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.

11 DESCRIPTION Oxycodone Hydrochloride Capsules are an agonist, available as a hard gelatin capsule 5 mg for oral administration. The chemical name is (5R,9R,13S,14S)-4,5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride. The molecular weight is 351.82. Its molecular formula is C 18 H 21 NO 4 ∙HCl, and it has the following chemical structure. Oxycodone hydrochloride is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. It is soluble in water and slightly soluble in alcohol. The inactive ingredients in Oxycodone Hydrochloride Capsules 5 mg include: colloidal silicon dioxide, gelatin, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, FD&C yellow #6, titanium dioxide, yellow iron oxide, shellac glaze, iron oxide black, propylene glycol, and ammonium hydroxide. structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. 12.2 Pharmacodynamics Effects on the Central Nervous System Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

ted to date [see Adverse Reactions ( 6 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonist. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1 , 2.4 )] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.4 )] . 12.3 Pharmacokinetics The activity of oxycodone hydrochloride is primarily due to the parent drug oxycodone. Absorption About 60 to 87% of an oral dose reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone. Food Effect When Oxycodone Hydrochloride Capsules are administered with a high-fat meal, mean AUC values are increased by 23% and peak concentrations are decreased by 14%. Food causes a delay in T max (1.00 to 3 hours). Similar effects of food are expected with the oral solution. Distribution Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk. Elimination Metabolism Oxycodone hydrochloride is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone < 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone is approximately 4 hours. Specific Populations Age: Geriatric Population: Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65.

Apparent elimination half-life of oxycodone following the administration of oxycodone is approximately 4 hours. Specific Populations Age: Geriatric Population: Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65. Hepatic Impairment: Because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic-impaired patients. A dose adjustment is recommended in these patients [see Use in Specific Populations ( 8.6 )] . Renal Impairment: Because this drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function, a dose reduction is recommended for renal impaired patients [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies CYP3A4 Inhibitors CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the co-administration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and C max by 3.6 and 1.7 fold, respectively. CYP3A4 Inducers A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and C max values by 86% and 63%, respectively. CYP2D6 Inhibitors Oxycodone is metabolized in part to oxymorphone via the cytochrome P450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent.

12.2 Pharmacodynamics Effects on the Central Nervous System Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on the Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on the Cardiovascular System Oxycodone produces peripheral vasodilation which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonist. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1 , 2.4 )] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

analgesic tolerance [see Dosage and Administration ( 2.1 , 2.4 )] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.4 )] .

12.3 Pharmacokinetics The activity of oxycodone hydrochloride is primarily due to the parent drug oxycodone. Absorption About 60 to 87% of an oral dose reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other opioids) is due to lower pre-systemic and/or first-pass metabolism of oxycodone. Food Effect When Oxycodone Hydrochloride Capsules are administered with a high-fat meal, mean AUC values are increased by 23% and peak concentrations are decreased by 14%. Food causes a delay in T max (1.00 to 3 hours). Similar effects of food are expected with the oral solution. Distribution Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk. Elimination Metabolism Oxycodone hydrochloride is extensively metabolized by multiple metabolic pathways to noroxycodone, oxymorphone, and noroxymorphone, which are subsequently glucuronidated. CYP3A4 mediated N-demethylation to noroxycodone is the primary metabolic pathway of oxycodone with a less contribution from CYP2D6 mediated O-demethylation to oxymorphone. Therefore, the formation of these and related metabolites can, in theory, be affected by other drugs. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Noroxycodone is reported to be a considerably weaker analgesic than oxycodone. Oxymorphone, although possessing analgesic activity, is present in the plasma only in low concentrations. The correlation between oxymorphone concentrations and opioid effects was much less than that seen with oxycodone plasma concentrations. The analgesic activity profile of other metabolites is not known. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone < 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of oxycodone is approximately 4 hours. Specific Populations Age: Geriatric Population: Information obtained from oxycodone tablets indicate that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65. Hepatic Impairment: Because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic-impaired patients. A dose adjustment is recommended in these patients [see Use in Specific Populations ( 8.6 )] . Renal Impairment: Because this drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function, a dose reduction is recommended for renal impaired patients [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies CYP3A4 Inhibitors CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the co-administration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and C max by 3.6 and 1.7 fold, respectively.

red patients [see Use in Specific Populations ( 8.7 )] . Drug Interaction Studies CYP3A4 Inhibitors CYP3A4 is the major enzyme involved in noroxycodone formation. A published study showed that the co-administration of voriconazole, a CYP3A4 inhibitor, increased oxycodone AUC and C max by 3.6 and 1.7 fold, respectively. CYP3A4 Inducers A published study showed that the co-administration of rifampin, a drug metabolizing enzyme inducer, decreased oxycodone AUC and C max values by 86% and 63%, respectively. CYP2D6 Inhibitors Oxycodone is metabolized in part to oxymorphone via the cytochrome P450 isoenzyme CYP2D6. While this pathway may be blocked by a variety of drugs (e.g., certain cardiovascular drugs and antidepressants), such blockade has not yet been shown to be of clinical significance with this agent.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of oxycodone hydrochloride have not been conducted. Mutagenesis Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay ( Salmonella typhimurium and Escherichia coli ) and in an assay for chromosomal aberrations ( in vivo mouse bone marrow micronucleus assay). Impairment of Fertility Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies in animals to evaluate the carcinogenic potential of oxycodone hydrochloride have not been conducted. Mutagenesis Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay ( Salmonella typhimurium and Escherichia coli ) and in an assay for chromosomal aberrations ( in vivo mouse bone marrow micronucleus assay). Impairment of Fertility Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

16 HOW SUPPLIED/STORAGE AND HANDLING Oxycodone Hydrochloride Capsules 5 mg are hard gelatin capsules with an opaque yellow cap and an opaque white body imprinted with ‘ANI’ on the cap and ‘167’ on the body in black ink available as follows: NDC 62559-167-01: Bottle of 100 Capsules Dispense in a tight, light-resistant container. Protect from moisture and light. Store at 20° to 25°C (68° to 77°F); excursions permitted at 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Store Oxycodone Hydrochloride Capsules securely and dispose of properly [see Patient Counseling Information ( 17 )] .

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Storage and Disposal: Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store Oxycodone Hydrochloride Capsules securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving Oxycodone Hydrochloride Capsules unsecured can pose a deadly risk to others in the home [see Warnings and Precautions ( 5.1 , 5.2 ), Drug Abuse and Dependence ( 9.2 )] . Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused Oxycodone Hydrochloride Capsules should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of Oxycodone Hydrochloride Capsules, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1 )] . Instruct patients not to share Oxycodone Hydrochloride Capsules with others and to take steps to protect Oxycodone Hydrochloride Capsules from theft or misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting Oxycodone Hydrochloride Capsules or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.2 )] . Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.2 )] . Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if Oxycodone Hydrochloride Capsules are used with benzodiazepines or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a health care provider [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )] . Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose.

ioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 )] . Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered [see Overdosage ( 10 )] . Advise patients and caregivers: • how to treat with the overdose reversal agent in the event of an opioid overdose • to tell family and friends about the opioid overdose reversal agent, and to keep it in a place where family and friends can access it in emergency • to read the Patient Information (or other educational material) that will come with their opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6 )] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medications [see Drug Interactions ( 7 )] . MAOI Interaction Inform patients to avoid taking Oxycodone Hydrochloride Capsules while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking Oxycodone Capsules [see Drug Interactions ( 7 )] . Important Administration Instructions Instruct patients how to properly take Oxycodone Hydrochloride Capsules. Patients should be advised not to adjust the dose of Oxycodone Hydrochloride Capsules without consulting the prescribing healthcare provider [see Dosage and Administration ( 2 )] . Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue Oxycodone Hydrochloride Capsules without first discussing a tapering plan with the prescriber [see Dosage and Administration ( 2.5 )] . Driving or Operating Heavy Machinery Inform patients that Oxycodone Hydrochloride Capsules may impair the ability to perform potentially hazardous activities such as driving a car or operating heavy machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions ( 5.15 )] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.2 )] . Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition.

n Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions ( 6 ), Clinical Pharmacology ( 12.2 )] . Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.9 )] . Hypotension Inform patients that Oxycodone Hydrochloride Capsules may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from a sitting or lying position) [see Warnings and Precautions ( 5.10 )] . Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in Oxycodone Hydrochloride Capsules. Advise patients how to recognize such a reaction and when to seek medical attention [see Adverse Reactions ( 6 )] . Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of Oxycodone Hydrochloride Capsules for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )] . Embryo-Fetal Toxicity Inform female patients of reproductive potential that Oxycodone Hydrochloride Capsules can cause fetal harm and to inform the healthcare provider of a known or suspected pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Advise breastfeeding women using Oxycodone Hydrochloride Capsules to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding women to seek immediate medical care if they notice these signs [see Use in Specific Populations ( 8.2 )] . Infertility Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3 )] . Manufactured by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 9541 Rev 01/26 ani-logo

Medication Guide Oxycodone Hydrochloride (ox-ee-CO-dohn) Capsules, CII Oxycodone Hydrochloride Capsules are: • A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. • An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about Oxycodone Hydrochloride Capsules: • Get emergency help or call 911 right away if you take too much Oxycodone Hydrochloride Capsules (overdose). When you first start taking Oxycodone Hydrochloride Capsules, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like, naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose. • Taking Oxycodone Hydrochloride Capsules with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. • Never give anyone else your Oxycodone Hydrochloride Capsules. They could die from taking it. Selling or giving away Oxycodone Hydrochloride Capsules is against the law. • Store Oxycodone Hydrochloride Capsules securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Do not take Oxycodone Hydrochloride Capsules if you have: • severe asthma, trouble breathing, or other lung problems. • a bowel blockage or have narrowing of the stomach or intestines. • an allergy to oxycodone or any of the ingredients in Oxycodone Hydrochloride Capsules. Before taking Oxycodone Hydrochloride Capsules, tell your healthcare provider if you have a history of: • head injury, seizures • liver, kidney, thyroid problems • problems urinating • pancreas or gallbladder problems • abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems. Tell your healthcare provider if you are: • noticing your pain getting worse. If your pain gets worse after you take Oxycodone Hydrochloride Capsules, do not take more of Oxycodone Hydrochloride Capsules without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking Oxycodone Hydrochloride Capsules. • pregnant or planning to become pregnant. Use of Oxycodone Hydrochloride Capsules for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. • breastfeeding. Oxycodone Hydrochloride Capsules passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. • living in a household where there are small children or someone who has abused street or prescription drugs. • taking prescription or over-the-counter medicines, vitamins, or herbal supplements.

d sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. • living in a household where there are small children or someone who has abused street or prescription drugs. • taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Oxycodone Hydrochloride Capsules with certain other medicines can cause serious side effects that could lead to death. When taking Oxycodone Hydrochloride Capsules: • Do not change your dose. Take Oxycodone Hydrochloride Capsules exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. • For acute (short-term) pain, you may only need to take Oxycodone Hydrochloride Capsules for a few days. You may have some Oxycodone Hydrochloride Capsules left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused Oxycodone Hydrochloride Capsules. • Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. • Call your healthcare provider if the dose you are taking does not control your pain. • If you have been taking Oxycodone Hydrochloride Capsules regularly, do not stop taking Oxycodone Hydrochloride Capsules without talking to your healthcare provider. • After you stop taking Oxycodone Hydrochloride Capsules, destroy the unused capsules by flushing down the toilet. • Dispose of expired, unwanted, or unused Oxycodone Hydrochloride Capsules by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking Oxycodone Hydrochloride Capsules DO NOT: • Drive or operate heavy machinery, until you know how Oxycodone Hydrochloride Capsules affects you. Oxycodone Hydrochloride Capsules can make you sleepy, dizzy, or lightheaded. • Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Oxycodone Hydrochloride Capsules may cause you to overdose and die. The possible side effects of Oxycodone Hydrochloride Capsules: • constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: • trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of Oxycodone Hydrochloride Capsules. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov Manufactured by: ANI Pharmaceuticals, Inc., Baudette, MN 56623 This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: January 2026 ani.jpg

<table width="100%"><col width="79%"/><col width="21%"/><tbody><tr><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Oxycodone Hydrochloride (ox-ee-CO-dohn) Capsules, CII</content></paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Oxycodone Hydrochloride Capsules are:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.</item><item><caption>&#x2022;</caption>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Important information about Oxycodone Hydrochloride Capsules:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Get emergency help or call 911 right away if you take too much Oxycodone Hydrochloride Capsules (overdose).</content> When you first start taking Oxycodone Hydrochloride Capsules, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like, naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose.</item><item><caption>&#x2022;</caption>Taking Oxycodone Hydrochloride Capsules with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</item><item><caption>&#x2022;</caption>Never give anyone else your Oxycodone Hydrochloride Capsules. They could die from taking it.

apentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</item><item><caption>&#x2022;</caption>Never give anyone else your Oxycodone Hydrochloride Capsules. They could die from taking it. Selling or giving away Oxycodone Hydrochloride Capsules is against the law.</item><item><caption>&#x2022;</caption>Store Oxycodone Hydrochloride Capsules securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Do not take Oxycodone Hydrochloride Capsules if you have:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>severe asthma, trouble breathing, or other lung problems.</item><item><caption>&#x2022;</caption>a bowel blockage or have narrowing of the stomach or intestines.</item><item><caption>&#x2022;</caption>an allergy to oxycodone or any of the ingredients in Oxycodone Hydrochloride Capsules.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Before taking Oxycodone Hydrochloride Capsules, tell your healthcare provider if you have a history of:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>head injury, seizures</item><item><caption>&#x2022;</caption>liver, kidney, thyroid problems</item><item><caption>&#x2022;</caption>problems urinating</item><item><caption>&#x2022;</caption>pancreas or gallbladder problems</item><item><caption>&#x2022;</caption>abuse of street or prescription drugs, alcohol addiction, opioid overdose, or mental health problems.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider if you are:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>noticing your pain getting worse. If your pain gets worse after you take Oxycodone Hydrochloride Capsules, do not take more of Oxycodone Hydrochloride Capsules without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking Oxycodone Hydrochloride Capsules.</item><item><caption>&#x2022;</caption><content styleCode="bold">pregnant or planning to become pregnant.</content> Use of Oxycodone Hydrochloride Capsules for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated.</item><item><caption>&#x2022;</caption><content styleCode="bold">breastfeeding.</content> Oxycodone Hydrochloride Capsules passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs.</item><item><caption>&#x2022;</caption>living in a household where there are small children or someone who has abused street or prescription drugs.</item><item><caption>&#x2022;</caption>taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking Oxycodone Hydrochloride Capsules with certain other medicines can cause serious side effects that could lead to death.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">When taking Oxycodone Hydrochloride Capsules:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Do not change your dose. Take Oxycodone Hydrochloride Capsules exactly as prescribed by your healthcare provider.

leCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">When taking Oxycodone Hydrochloride Capsules:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Do not change your dose. Take Oxycodone Hydrochloride Capsules exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</item><item><caption>&#x2022;</caption>For acute (short-term) pain, you may only need to take Oxycodone Hydrochloride Capsules for a few days. You may have some Oxycodone Hydrochloride Capsules left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused Oxycodone Hydrochloride Capsules.</item><item><caption>&#x2022;</caption>Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.</item><item><caption>&#x2022;</caption>Call your healthcare provider if the dose you are taking does not control your pain.</item><item><caption>&#x2022;</caption>If you have been taking Oxycodone Hydrochloride Capsules regularly, do not stop taking Oxycodone Hydrochloride Capsules without talking to your healthcare provider.</item><item><caption>&#x2022;</caption>After you stop taking Oxycodone Hydrochloride Capsules, destroy the unused capsules by flushing down the toilet.</item><item><caption>&#x2022;</caption>Dispose of expired, unwanted, or unused Oxycodone Hydrochloride Capsules by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">While taking Oxycodone Hydrochloride Capsules DO NOT:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Drive or operate heavy machinery, until you know how Oxycodone Hydrochloride Capsules affects you. Oxycodone Hydrochloride Capsules can make you sleepy, dizzy, or lightheaded.</item><item><caption>&#x2022;</caption>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with Oxycodone Hydrochloride Capsules may cause you to overdose and die.</item></list></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">The possible side effects of Oxycodone Hydrochloride Capsules:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.</item></list><paragraph><content styleCode="bold">Get emergency medical help or call 911 right away if you have:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</item></list><paragraph>These are not all the possible side effects of Oxycodone Hydrochloride Capsules. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</item></list><paragraph>These are not all the possible side effects of Oxycodone Hydrochloride Capsules. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. <content styleCode="bold">For more information go to dailymed.nlm.nih.gov</content></paragraph></td></tr><tr><td styleCode="Lrule Botrule " valign="top"><paragraph>Manufactured by: ANI Pharmaceuticals, Inc., Baudette, MN 56623</paragraph></td><td align="right" styleCode="Rrule Toprule Botrule " valign="top"><renderMultiMedia ID="id1411960713" referencedObject="D7357E60-B996-4009-A6E3-6E40B36FE550"/></td></tr><tr><td valign="top"><paragraph>This Medication Guide has been approved by the U.S. Food and Drug Administration.</paragraph></td><td align="right" valign="top"><paragraph>Issued: January 2026</paragraph></td></tr></tbody></table>

<table width="100%" styleCode="Noautorules"><col width="85.950%" align="left"/><col width="14.050%" align="left"/><tbody><tr><td align="left" valign="top">Boxed Warning</td><td align="right" valign="top">12/2025</td></tr><tr><td align="left" valign="top">Indications and Usage ( <linkHtml href="#s10">1</linkHtml>) </td><td align="right" valign="top">12/2025</td></tr><tr><td align="left" valign="top">Dosage and Administration ( <linkHtml href="#s14">2.2</linkHtml>, <linkHtml href="#s22">2.5</linkHtml>) </td><td align="right" valign="top">12/2025</td></tr><tr><td align="left" valign="top">Warnings and Precautions ( <linkHtml href="#s26">5.1</linkHtml>, <linkHtml href="#s27">5.2</linkHtml>, <linkHtml href="#s29">5.3</linkHtml>, <linkHtml href="#s40">5.12</linkHtml>, <linkHtml href="#s42">5.14</linkHtml>) </td><td align="right" valign="top">12/2025</td></tr></tbody></table>

WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF ROXYBOND WARNING: SERIOUS AND LIFE-THREATENING RISKS FROM USE OF ROXYBOND See full prescribing information for complete boxed warning. ROXYBOND exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess patient's risk before prescribing and reassess regularly for these behaviors and conditions. ( 5.1 ) Serious, life-threatening, or fatal respiratory depression may occur, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of ROXYBOND are essential. ( 5.2 ) Accidental ingestion of ROXYBOND, especially by children, can result in a fatal overdose of oxycodone. ( 5.2 ) Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. ( 5.3 , 7 ) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery. ( 5.4 ) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription. ( 5.5 ) Concomitant use with CYP3A4 inhibitors (or discontinuation of CYP3A4 inducers) can result in a fatal overdose of oxycodone. ( 5.6 , 7 , 12.3 ) Addiction, Abuse, and Misuse Because the use of ROXYBOND exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions [see Warnings and Precautions ( 5.1 )] . Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of ROXYBOND, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of ROXYBOND are essential [see Warnings and Precautions ( 5.2 )] . Accidental Ingestion Accidental ingestion of even one dose of ROXYBOND, especially by children, can result in a fatal overdose of oxycodone [see Warnings and Precautions ( 5.2 )] . Risks From Concomitant Use With Benzodiazepines Or Other CNS Depressants Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of ROXYBOND and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )]. Neonatal Opioid Withdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions ( 5.4 )] .

hdrawal Syndrome (NOWS) Advise pregnant women using opioids for an extended period of time of the risk of Neonatal Opioid Withdrawal Syndrome, which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery [see Warnings and Precautions ( 5.4 )] . Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) Healthcare providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription [see Warnings and Precautions ( 5.5 )] . Cytochrome P450 3A4 Interaction The concomitant use of ROXYBOND with all cytochrome P450 3A4 inhibitors may result in an increase in oxycodone plasma concentrations, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in oxycodone plasma concentration. Regularly evaluate patients receiving ROXYBOND and any CYP3A4 inhibitor or inducer [see Warnings and Precautions ( 5.6 ), Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] .

1 INDICATIONS AND USAGE ROXYBOND is indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ROXYBOND is an opioid agonist indicated for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. ( 1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur at any dosage or duration and persist over the course of therapy, reserve opioid analgesics, including ROXYBOND, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. ( 1 , 5.1 ) Limitations of Use Because of the risks of addiction, abuse, misuse, overdose, and death, which can occur any dosage or duration and persist over the course of therapy, [see Warnings and Precautions ( 5.1 )] , reserve opioid analgesics, including ROXYBOND, for use in patients for whom alternative treatment options are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

2 DOSAGE AND ADMINISTRATION ROXYBOND should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. ( 2.1 ) Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Reserve titration to higher doses of ROXYBOND for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks. ( 2.1 , 5 ) Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. ( 2.1 ) Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse. ( 2.1 , 5.1 ) Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with ROXYBOND. Consider this risk when selecting an initial dose and when making dose adjustments. ( 2.1 , 5.2 ) Discuss opioid overdose reversal agents and options for acquiring them with the patient and/or caregiver, both when initiating and renewing treatment with ROXYBOND, especially if the patient has additional risk factors for overdose, or close contacts at risk for exposure and overdose. ( 2.2 , 5.1 , 5.2 , 5.3 ) Initiate dosing with a range of 5 to 15 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of ROXYBOND. ( 2.3 , 2.4 ) Periodically reassess patients receiving ROXYBOND to evaluate the continued need for opioid analgesics to maintain pain control, for the signs or symptoms of adverse reactions, and for the development of addiction, abuse, or misuse. ( 2.4 , 5.1 , 5.14 , 6 ) Do not rapidly reduce or abruptly discontinue ROXYBOND in a physically dependent patient because rapid reduction or abrupt discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. ( 2.4 , 5.14 , 9.3 ) 2.1 Important Dosage and Administration Instructions ROXYBOND should be prescribed only by healthcare professionals who are knowledgeable about the use of opioids and how to mitigate the associated risks. Use the lowest effective dosage for the shortest duration of time consistent with individual patient treatment goals. Because the risk of overdose increases as opioid doses increase, reserve titration to higher doses of ROXYBOND for patients in whom lower doses are insufficiently effective and in whom the expected benefits of using a higher dose opioid clearly outweigh the substantial risks [see Warnings and Precautions ( 5 )] . Many acute pain conditions (e.g., the pain that occurs with a number of surgical procedures or acute musculoskeletal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors.

letal injuries) require no more than a few days of an opioid analgesic. Clinical guidelines on opioid prescribing for some acute pain conditions are available. There is variability in the opioid analgesic dose and duration needed to adequately manage pain due both to the cause of pain and to individual patient factors. Initiate the dosing regimen for each patient individually, taking into account the patient's underlying cause and severity of pain, prior analgesic treatment and response, and risk factors for addiction, abuse, and misuse [see Warnings and Precautions ( 5.1 )] . Respiratory depression can occur at any time during opioid therapy, especially when initiating and following dosage increases with ROXYBOND. Consider this risk when selecting an initial dose and when making dose adjustments [see Warnings and Precautions ( 5.2 )] . 2.2 Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Warnings and Precautions ( 5.2 )] . There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. 2.3 Initial Dosage Use of ROXYBOND as the First Opioid Analgesic Initiate treatment with ROXYBOND in a dosing range of 5 to 15 mg every 4 to 6 hours as needed for pain, and at the lowest dose necessary to achieve adequate analgesia. Titrate the dose based upon the individual patient's response to their initial dose of ROXYBOND. Although it is not possible to list every condition that is important to the selection of the initial dose of ROXYBOND, attention should be given to: 1) the daily dose, potency, and characteristics of any prior opioid 2) the reliability of any relative potency estimate used to calculate the dose of oxycodone needed, 3) the degree of opioid tolerance, 4) the general condition and medical status of the patient, and 5) the balance between pain control and adverse experiences. Conversion from Other Opioids to ROXYBOND There is inter-patient variability in the potency of opioid drugs and opioid formulations. Therefore, a conservative approach is advised when determining the total daily dosage of ROXYBOND. It is safer to underestimate a patient's 24-hour ROXYBOND dosage than to overestimate the 24-hour ROXYBOND dosage and manage an adverse reaction due to overdose. If a patient has been receiving opioid-containing medications prior to taking ROXYBOND, the potency of the prior opioid relative to oxycodone should be factored into the selection of the total daily dose (TDD) of oxycodone. In converting patients from other opioids to ROXYBOND, close observation and adjustment of dosage based upon the patient's response to ROXYBOND is imperative.

prior to taking ROXYBOND, the potency of the prior opioid relative to oxycodone should be factored into the selection of the total daily dose (TDD) of oxycodone. In converting patients from other opioids to ROXYBOND, close observation and adjustment of dosage based upon the patient's response to ROXYBOND is imperative. Administration of supplemental analgesia for breakthrough or incident pain and titration of the TDD of ROXYBOND may be necessary, especially in patients who have disease states that are changing rapidly. Conversion From Fixed-Ratio Opioid/Acetaminophen, Opioid/Aspirin, or Opioid/Nonsteroidal Combination Drugs When converting patients from fixed ratio opioid/non-opioid drug regimens, a decision should be made whether or not to continue the non-opioid analgesic. If a decision is made to discontinue the use of non-opioid analgesic, it may be necessary to titrate the dose of ROXYBOND in response to the level of analgesia and adverse effects afforded by the dosing regimen. If the non-opioid regimen is continued as a separate single entity agent, the starting dose of ROXYBOND should be based upon the most recent dose of opioid as a baseline for further titration of oxycodone. Incremental increases should be gauged according to side effects to an acceptable level of analgesia. Conversion from ROXYBOND to Extended-Release Oxycodone The relative bioavailability of ROXYBOND compared to extended-release oxycodone products is unknown, so conversion to extended-release oxycodone may lead to increased risk of excessive sedation and respiratory depression. Conversion from Oxycodone Immediate-Release Tablets Oxycodone pharmacokinetics are similar for ROXYBOND and oxycodone immediate-release tablets. Patients can be converted from oxycodone immediate-release to the same dose and dosing regimen of ROXYBOND. 2.4 Titration and Maintenance of Therapy Individually titrate ROXYBOND to a dose that provides adequate analgesia and minimizes adverse reactions. Continually reevaluate patients receiving ROXYBOND to assess the maintenance of pain control, signs and symptoms of opioid withdrawal, and other adverse reactions, as well as reassess for the development of addiction, abuse, or misuse [see Warnings and Precautions ( 5.1 , 5.14 )] . Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the caregiver/family during periods of changing analgesic requirements, including initial titration. If the level of pain increases after dosage stabilization, attempt to identify the source of increased pain before increasing the ROXYBOND dosage. If after increasing the dosage, unacceptable opioid-related adverse reactions are observed (including an increase in pain after dosage increase), consider reducing the dosage [see Warnings and Precautions ( 5 )] . Adjust the dosage to obtain an appropriate balance between management of pain and opioid-related adverse reactions. 2.5 Safe Reduction or Discontinuation of ROXYBOND Do not rapidly reduce or abruptly discontinue ROXYBOND in patients who may be physically dependent on opioids. Rapid reduction or discontinuation of opioid analgesics in patients who are physically dependent on opioids has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances.

n, and suicide. Rapid reduction or abrupt discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. Patients may also attempt to treat their pain or withdrawal symptoms with illicit opioids, such as heroin, and other substances. When a decision has been made to decrease the dose or discontinue therapy in an opioid-dependent patient taking ROXYBOND, there are a variety of factors that should be considered, including the total daily dose of opioid (including ROXYBOND) the patient has been taking, the duration of treatment, the type of pain being treated, and the physical and psychological attributes of the patient. It is important to ensure ongoing care of the patient and to agree on an appropriate tapering schedule and follow-up plan so that patient and provider goals and expectations are clear and realistic. When opioid analgesics are being discontinued due to a suspected substance use disorder, evaluate and treat the patient, or refer for evaluation and treatment of the substance use disorder. Treatment should include evidence-based approaches, such as medication assisted treatment of opioid use disorder. Complex patients with comorbid pain and substance use disorders may benefit from referral to a specialist. There are no standard opioid tapering schedules that are suitable for all patients. Good clinical practice dictates a patient-specific plan to taper the dose of the opioid gradually. For patients on ROXYBOND who are physically opioid-dependent, initiate the taper by a small enough increment (e.g., no greater than 10% to 25% of the total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2 to 4 weeks. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. It may be necessary to provide the patient with lower dosage strengths to accomplish a successful taper. Reassess the patient frequently to manage pain and withdrawal symptoms, should they emerge. Common withdrawal symptoms include restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, and mydriasis. Other signs and symptoms also may develop, including irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. If withdrawal symptoms arise, it may be necessary to pause the taper for a period of time or raise the dose of the opioid analgesic to the previous dose, and then proceed with a slower taper. In addition, evaluate patients for any changes in mood, emergence of suicidal thoughts, or use of other substances. When managing patients taking opioid analgesics, particularly those who have been treated for an extended period of time, and/or with high doses for chronic pain, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic [see Warnings and Precautions ( 5.14 ), Drug Abuse and Dependence ( 9.3 )] .

3 DOSAGE FORMS AND STRENGTHS ROXYBOND (oxycodone hydrochloride) tablets, 5 mg, 10 mg, 15 mg, and 30 mg with the following characteristics: Strength Tablet Shape Tablet Color Ink-Print on Tablet Side 1 Ink-Print on Tablet Side 2 5 mg Round coated tablets White IDT/O 5 None 10 mg Pink IDT/O 10 None 15 mg Green IDT/O 15 None 30 mg Blue IDT/O 30 None Tablets: 5 mg, 10 mg, 15 mg, 30 mg ( 3 )

<table width="100%"><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><col width="20.000%" align="left"/><tbody><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule" valign="middle">Strength</td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle">Tablet Shape</td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle">Tablet Color</td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle">Ink-Print on Tablet Side 1</td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle">Ink-Print on Tablet Side 2</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="middle">5 mg</td><td rowspan="4" align="center" styleCode="Botrule Rrule" valign="middle">Round coated tablets</td><td align="center" styleCode="Botrule Rrule" valign="middle">White</td><td align="center" styleCode="Botrule Rrule" valign="middle">IDT/O 5</td><td align="center" styleCode="Botrule Rrule" valign="middle">None</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="middle">10 mg</td><td align="center" styleCode="Botrule Rrule" valign="middle">Pink</td><td align="center" styleCode="Botrule Rrule" valign="middle">IDT/O 10</td><td align="center" styleCode="Botrule Rrule" valign="middle">None</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="middle">15 mg</td><td align="center" styleCode="Botrule Rrule" valign="middle">Green</td><td align="center" styleCode="Botrule Rrule" valign="middle">IDT/O 15</td><td align="center" styleCode="Botrule Rrule" valign="middle">None</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="middle">30 mg</td><td align="center" styleCode="Botrule Rrule" valign="middle">Blue</td><td align="center" styleCode="Botrule Rrule" valign="middle">IDT/O 30</td><td align="center" styleCode="Botrule Rrule" valign="middle">None</td></tr></tbody></table>

4 CONTRAINDICATIONS ROXYBOND is contraindicated in patients with: Significant respiratory depression [see Warnings and Precautions ( 5.2 )] Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment or hypercarbia [see Warnings and Precautions ( 5.8 )] Known or suspected gastrointestinal obstruction, including paralytic ileus [see Warnings and Precautions ( 5.12 )] Known hypersensitivity (e.g., anaphylaxis) to oxycodone [see Adverse Reactions ( 6.2 )] Significant respiratory depression ( 4 ) Acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment ( 4 ) Known or suspected gastrointestinal obstruction, including paralytic ileus ( 4 ) Hypersensitivity to oxycodone ( 4 )

5 WARNINGS AND PRECAUTIONS Opioid-Induced Hyperalgesia and Allodynia : Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. If OIH is suspected, carefully consider appropriately decreasing the dose of the current opioid analgesic, or opioid rotation. ( 5.7 ) Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients : Regularly evaluate, particularly during initiation and titration. ( 5.8 ) Adrenal Insufficiency : If diagnosed, treat with physiologic replacement of corticosteroids, and wean patient off of the opioid. ( 5.9 ) Severe Hypotension : Regularly evaluate during dosage initiation and titration. Avoid use of ROXYBOND in patients with circulatory shock. ( 5.10 ) Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness : Monitor for sedation and respiratory depression. Avoid use of ROXYBOND in patients with impaired consciousness or coma. ( 5.11 ) 5.1 Addiction, Abuse, and Misuse ROXYBOND contains oxycodone, a Schedule II controlled substance. As an opioid, ROXYBOND exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence ( 9 )] . Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed ROXYBOND. Addiction can occur at recommended dosages, when taken as directed, and if the drug is misused or abused. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. In postmarketing studies, addiction, abuse, misuse, and fatal and non-fatal opioid overdose were observed in patients with long-term opioid use [see Adverse Reactions ( 6.2 )] . Assess each patient's risk for opioid addiction, abuse, or misuse prior to prescribing ROXYBOND, and reassess all patients receiving ROXYBOND for the development of these behaviors and conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the proper management of pain in any given patient. Patients at increased risk may be prescribed opioids such as ROXYBOND but use in such patients necessitates intensive counseling about the risks and proper use of ROXYBOND along with frequent reevaluation for signs of addiction, abuse, and misuse. Consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ), Overdosage ( 10 )] . Opioids are sought for nonmedical use and are subject to diversion from legitimate prescribed use. Consider these risks when prescribing or dispensing ROXYBOND. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drugs. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product.

propriate quantity and advising the patient on careful storage of the drug during the course of treatment and on the proper disposal of unused drugs. Contact local state professional licensing board or state-controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid overdose reversal agent, depending on the patient's clinical status [see Overdosage ( 10 )] . Carbon dioxide (CO 2 ) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of ROXYBOND, the risk is greatest during the initiation of therapy or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of ROXYBOND are essential [see Dosage and Administration ( 2 )] . Overestimating the ROXYBOND dosage when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of ROXYBOND, especially by children, can result in respiratory depression and death due to an overdose of oxycodone. Educate patients and caregivers on how to recognize respiratory depression and emphasize on the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper [see Dosage and Administration ( 2.4 , 2.5 )] . Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. The presence of risk factors for overdose should not prevent the management of pain in any patient [see Warnings and Precautions ( 5.1 , 5.3 )] . Discuss the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program). There are important differences among the opioid overdose reversal agents, such as route of administration, product strength, approved patient age range, and pharmacokinetics. Be familiar with these differences, as outlined in the approved labeling for those products, prior to recommending or prescribing such an agent. Educate patients and caregivers on how to recognize respiratory depression, and how to use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage ( 10 )] .

use an opioid overdose reversal agent for the emergency treatment of opioid overdose. Emphasize the importance of calling 911 or getting emergency medical help, even if an opioid overdose reversal agent is administered [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage ( 10 )] . 5.3 Risks from Concomitant Use with Benzodiazepines or Other CNS Depressants Profound sedation, respiratory depression, coma, and death may result from the concomitant use of ROXYBOND with benzodiazepines and/or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with opioid analgesics [see Drug Interactions ( 7 )] . If the decision is made to prescribe a benzodiazepine or other CNS depressant concomitantly with an opioid analgesic, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of the benzodiazepine or other CNS depressant than indicated in the absence of an opioid, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking a benzodiazepine or other CNS depressant, prescribe a lower initial dose of the opioid analgesic, and titrate based on clinical response. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 ), Overdosage ( 10 )] . Advise both patients and caregivers about the risks of respiratory depression and sedation when ROXYBOND is used with benzodiazepines or other CNS depressants (including alcohol and illicit drugs). Advise patients not to drive or operate dangerous machinery until the effects of concomitant use of the benzodiazepine or other CNS depressant have been determined. Screen patients for risk of substance use disorders, including opioid abuse and misuse, and warn them of the risk for overdose and death associated with the use of additional CNS depressants including alcohol and illicit drugs [see Drug Interactions ( 7 )] . 5.4 Neonatal Opioid Withdrawal Syndrome Use of ROXYBOND for an extended period of time during pregnancy can result in withdrawal in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1 )] .

ogy experts. Observe newborns for signs of neonatal opioid withdrawal syndrome and manage accordingly. Advise pregnant women using opioids for an extended period of time of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Use in Specific Populations ( 8.1 )] . 5.5 Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a Risk Evaluation and Mitigation Strategy (REMS) for these products. Under the requirements of the REMS, drug companies with approved opioid analgesic products must make REMS-compliant education programs available to healthcare providers. Healthcare providers are strongly encouraged to do all of the following: Complete a REMS-compliant education program offered by an accredited provider of continuing education (CE) or another education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain. Discuss the safe use, serious risks, and proper storage and disposal of opioid analgesics with patients and/or their caregivers every time these medicines are prescribed. The Patient Counseling Guide (PCG) can be obtained at this link: www.fda.gov/OpioidAnalgesicREMSPCG. Emphasize to patients and their caregivers the importance of reading the Medication Guide that they will receive from their pharmacist every time an opioid analgesic is dispensed to them. Consider using other tools to improve patient, household, and community safety, such as patient-prescriber agreements that reinforce patient-prescriber responsibilities. To obtain further information on the opioid analgesic REMS and for a list of accredited REMS CME/CE, call 1-800-503-0784, or log on to www.opioidanalgesicrems.com. The FDA Blueprint can be found at www.fda.gov/OpioidAnalgesicREMSBlueprint . 5.6 Risks of Concomitant Use or Discontinuation of Cytochrome P450 3A4 Inhibitors and Inducers Concomitant use of ROXYBOND with a CYP3A4 inhibitor, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may increase plasma concentrations of oxycodone and prolong opioid adverse reactions, which may cause potentially fatal respiratory depression [see Warnings and Precautions ( 5.2 )] , particularly when an inhibitor is added after a stable dose of ROXYBOND is achieved. Similarly, discontinuation of a CYP3A4 inducer, such as rifampin, carbamazepine, and phenytoin, in ROXYBOND-treated patients may increase oxycodone plasma concentrations and prolong opioid adverse reactions. When using ROXYBOND with CYP3A4 inhibitors or discontinuing CYP3A4 inducers in ROXYBOND-treated patients, evaluate patients at frequent intervals and consider dosage reduction of ROXYBOND until stable drugs effects are achieved [see Drug Interactions ( 7 )] . Concomitant use of ROXYBOND with CYP3A4 inducers or discontinuation of a CYP3A4 inhibitor could decrease oxycodone plasma concentrations, decrease opioid efficacy or, possibly, lead to a withdrawal syndrome in a patient who had developed physical dependence to oxycodone. When using ROXYBOND with CYP3A4 inducers or discontinuing CYP3A4 inhibitors, evaluate patients at frequent intervals and consider increasing the opioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions ( 7 )] . 5.7 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain.

pioid dosage if needed to maintain adequate analgesia or if symptoms of opioid withdrawal occur [see Drug Interactions ( 7 )] . 5.7 Opioid-Induced Hyperalgesia and Allodynia Opioid-Induced Hyperalgesia (OIH) occurs when an opioid analgesic paradoxically causes an increase in pain, or an increase in sensitivity to pain. This condition differs from tolerance, which is the need for increasing doses of opioids to maintain a defined effect [see Dependence ( 9.3 )] . Symptoms of OIH include (but may not be limited to) increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily non-painful stimuli (allodynia). These symptoms may suggest OIH only if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Cases of OIH have been reported, both with short-term and longer-term use of opioid analgesics. Though the mechanism of OIH is not fully understood, multiple biochemical pathways have been implicated. Medical literature suggests a strong biologic plausibility between opioid analgesics and OIH and allodynia. If a patient is suspected to be experiencing OIH, carefully consider appropriately decreasing the dose of the current opioid analgesic or opioid rotation (safely switching the patient to a different opioid moiety) [ see Dosage and Administration ( 2.5 ), Warnings and Precautions ( 5.14 ) ]. 5.8 Life-Threatening Respiratory Depression in Patients with Chronic Pulmonary Disease or in Elderly, Cachectic, or Debilitated Patients The use of ROXYBOND in patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment is contraindicated. Patients with Chronic Pulmonary Disease : ROXYBOND-treated patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression are at increased risk of decreased respiratory drive including apnea, even at recommended dosages of ROXYBOND [see Warnings and Precautions ( 5.2 )] . Elderly, Cachectic, or Debilitated Patients : Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients [see Warnings and Precautions ( 5.2 )] . Regularly evaluate patients, particularly when initiating and titrating ROXYBOND and when ROXYBOND is given concomitantly with other drugs that depress respiration [see Warnings and Precautions ( 5.2 , 5.3 )] . Alternatively, consider the use of non-opioid analgesics in these patients. 5.9 Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.10 Severe Hypotension ROXYBOND may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients.

ent opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. 5.10 Severe Hypotension ROXYBOND may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics) [see Drug Interactions ( 7 )] . Regularly evaluate these patients for signs of hypotension after initiating or titrating the dosage of ROXYBOND. In patients with circulatory shock, use of ROXYBOND may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid use of ROXYBOND in patients with circulatory shock. 5.11 Risks of Use in Patients with Increased Intracranial Pressure, Brain Tumors, Head Injury, or Impaired Consciousness In patients who may be susceptible to the intracranial effects of CO 2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), ROXYBOND may reduce the respiratory drive, and the resultant CO 2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with ROXYBOND. Opioids may obscure the clinical course in a patient with a head injury. Avoid the use of ROXYBOND in patients with impaired consciousness or coma. 5.12 Risks of Gastrointestinal Complications ROXYBOND is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. The oxycodone in ROXYBOND may cause spasm of the sphincter of Oddi. Opioids may cause increases in serum amylase. Regularly evaluate patients with biliary tract disease, including acute pancreatitis, for worsening symptoms. Cases of opioid-induced esophageal dysfunction (OIED) have been reported in patients taking opioids. The risk of OIED may increase as the dose and/or duration of opioids increases. Regularly evaluate patients for signs and symptoms of OIED (e.g., dysphagia, regurgitation, non-cardiac chest pain) and, if necessary, adjust opioid therapy as clinically appropriate [see Clinical Pharmacology ( 12.2 )] . 5.13 Increased Risk of Seizures in Patients with Seizure Disorders The oxycodone in ROXYBOND may increase the frequency of seizures in patients with seizure disorders and may increase the risk of seizures occurring in other clinical settings associated with seizures. Regularly evaluate patients with a history of seizure disorders for worsened seizure control during ROXYBOND therapy. 5.14 Withdrawal Do not rapidly reduce or abruptly discontinue ROXYBOND in a patient physically dependent on opioids. When discontinuing ROXYBOND in a physically-dependent patient, gradually taper the dosage. Rapid tapering of oxycodone in a patient physically dependent on opioids may lead to a withdrawal syndrome and return of pain [see Dosage and Administration ( 2.4 , 2.5 ), Drug Abuse and Dependence ( 9.3 )] . Additionally, avoid the use of mixed agonist/antagonist (e.g., pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including ROXYBOND. In these patients, mixed agonist/antagonist and partial agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7 )] . 5.15 Risks of Driving and Operating Machinery ROXYBOND may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery.

al agonist analgesics may reduce the analgesic effect and/or precipitate withdrawal symptoms [see Drug Interactions ( 7 )] . 5.15 Risks of Driving and Operating Machinery ROXYBOND may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of ROXYBOND and know how they will react to the medication.

6 ADVERSE REACTIONS The following serious adverse reactions are described or are described in greater detail, in other sections: Addiction, Abuse, and Misuse [see Warnings and Precautions ( 5.1 )] Life-Threatening Respiratory Depression [see Warnings and Precautions ( 5.2 )] Interactions with Benzodiazepines or Other CNS Depressants [see Warnings and Precautions ( 5.3 )] Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions ( 5.4 )] Opioid-Induced Hyperalgesia and Allodynia [see Warnings and Precautions ( 5.7 )] Adrenal Insufficiency [see Warnings and Precautions ( 5.9 )] Severe Hypotension [see Warnings and Precautions ( 5.10 )] Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.12 )] Seizures [see Warnings and Precautions ( 5.13 )] Withdrawal [see Warnings and Precautions ( 5.14 )] Most common adverse reactions (≥3%): nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Protega Pharmaceuticals Inc. at 1-844-798-3610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Oxycodone hydrochloride tablets have been evaluated in open label clinical trials in patients with cancer and nonmalignant pain. Oxycodone hydrochloride tablets are associated with adverse experiences similar to those seen with other opioids. Serious adverse reactions that may be associated with ROXYBOND therapy include: respiratory depression, respiratory arrest, circulatory depression, cardiac arrest, hypotension, and/or shock. The common adverse reactions seen on initiation of therapy with oxycodone hydrochloride tablets are dose related and are opioid-related adverse reactions. The most frequent of these included nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. The frequency of these reactions depended on several factors, including clinical setting, the patient's level of opioid tolerance, and host factors specific to the individual. In all patients for whom dosing information was available (n=191) from the open-label and double-blind studies involving oxycodone hydrochloride tablets, the following adverse events were recorded in oxycodone hydrochloride treated patients with an incidence ≥ 3%. In descending order of frequency, they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence.

d double-blind studies involving oxycodone hydrochloride tablets, the following adverse events were recorded in oxycodone hydrochloride treated patients with an incidence ≥ 3%. In descending order of frequency, they were: nausea, constipation, vomiting, headache, pruritus, insomnia, dizziness, asthenia, and somnolence. Other less frequently observed adverse reactions from opioid analgesics, including oxycodone hydrochloride tablets included: Blood and lymphatic system disorders : anemia, leukopenia Cardiac disorders : cardiac failure, palpitation, tachycardia Gastrointestinal disorders : abdominal pain, dry mouth, diarrhea, dyspepsia, dysphagia, glossitis, nausea, vomiting General disorders and administration site conditions : chills, edema, edema peripheral, pain, pyrexia Immune system disorders : hypersensitivity Infections and infestations : bronchitis, gingivitis, infection, pharyngitis, rhinitis, sepsis, sinusitis, urinary tract infection Injury, poisoning, and procedural complications : injury Metabolism and nutritional disorders : decreased appetite, gout, hyperglycemia Musculoskeletal and connective tissue disorders : arthralgia, arthritis, back pain, bone pain, myalgia, neck pain, pathological fracture Nervous system disorders : hypertonia, hypoesthesia, migraine, neuralgia, tremor, vasodilation Psychiatric disorders : agitation, anxiety, confusional state, nervousness, personality disorder Respiratory, thoracic, and mediastinal disorders : cough, dyspnea, epistaxis, laryngospasm, lung disorder Skin and subcutaneous tissue disorders : photosensitivity reaction, rash, hyperhidrosis, urticaria Vascular disorders : thrombophlebitis, hemorrhage, hypotension, vasodilation 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oxycodone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. General disorders and administrative site disorders : drug withdrawal syndrome neonatal [see Warnings and Precautions ( 5.4 )] Respiratory, thoracic, and mediastinal disorders : pharyngeal edema Serotonin syndrome : Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs [see Drug Interactions ( 7 )] . Adrenal insufficiency : Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use [see Warnings and Precautions ( 5.9 )] . Anaphylaxis : Anaphylactic reaction has been reported with ingredients contained in ROXYBOND [see Contraindications ( 4 )] . Androgen deficiency : Cases of androgen deficiency have occurred with use of opioids for an extended period of time. [see Clinical Pharmacology ( 12.2 )] . Hyperalgesia and Allodynia : Cases of hyperalgesia and allodynia have been reported with opioid therapy of any duration [see Warnings and Precautions ( 5.7 )] . Hypoglycemia : Cases of hypoglycemia have been reported in patients taking opioids. Most reports were in patients with at least one predisposing risk factor (e.g., diabetes). Opioid-induced esophageal dysfunction (OIED) : Cases of OIED have been reported in patients taking opioids and may occur more frequently in patients taking higher doses of opioids, and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.12 )] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021.

and/or in patients taking opioids longer term [see Warnings and Precautions ( 5.12 )] . Adverse Reactions from Observational Studies A prospective, observational cohort study estimated the risks of addiction, abuse, and misuse in patients initiating long-term use of Schedule II opioid analgesics between 2017 and 2021. Study participants included in one or more analyses had been enrolled in selected insurance plans or health systems for at least one year, were free of at least one outcome at baseline, completed a minimum number of follow-up assessments, and either: 1) filled multiple extended-release/long-acting opioid analgesic prescriptions during a 90-day period (n=978); or 2) filled any Schedule II opioid analgesic prescriptions covering at least 70 of 90 days (n=1,244). Those included also had no dispensing of the qualifying opioids in the previous 6 months. Over 12 months: approximately 1% to 6% of participants across the two cohorts newly met criteria for addiction, as assessed with two validated interview-based measures of moderate-to-severe opioid use disorder based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, and approximately 9% and 22% of participants across the two cohorts newly met criteria for prescription opioid abuse and misuse [defined in Drug Abuse and Dependence ( 9 ) ] , respectively, as measured with a validated self-reported instrument. A retrospective, observational cohort study estimated the risk of opioid-involved overdose or opioid overdose-related death in patients with new long-term use of Schedule II opioid analgesics from 2006 through 2016 (n=220,249). Included patients had been enrolled in either one of two commercial insurance programs, one managed care program, or one Medicaid program for at least 9 months. New long-term use was defined as having Schedule II opioid analgesic prescriptions covering at least 70 days' supply over the 3 months prior to study entry and none during the preceding 6 months. Patients were excluded if they had an opioid-involved overdose in the 9 months prior to study entry. Overdose was measured using a validated medical code-based algorithm with linkage to the National Death Index database. The 5-year cumulative incidence estimates for opioid-involved overdose or opioid overdose-related death ranged from approximately 1.5% to 4% across study sites, counting only the first event during follow-up. Approximately 17% of first opioid overdoses observed over the entire study period (5-11 years, depending on the study site) were fatal. Higher baseline opioid dose was the strongest and most consistent predictor of opioid-involved overdose or opioid overdose-related death. Study exclusion criteria may have selected patients at lower risk of overdose, and substantial loss to follow-up (approximately 80%) also may have biased estimates. The risk estimates from the studies described above may not be generalizable to all patients receiving opioid analgesics, such as those with exposures shorter or longer than the duration evaluated in the studies.

7 DRUG INTERACTIONS Table 1 includes clinically significant drug interactions with ROXYBOND. Table 1. Clinically Significant Drug Interactions with ROXYBOND Inhibitors of CYP3A4 and CYP2D6 Clinical Impact: The concomitant use of ROXYBOND and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of ROXYBOND and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of ROXYBOND is achieved [see Warnings and Precautions ( 5.6 )] . After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease [see Clinical Pharmacology ( 12.3 )] , resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. Intervention: If concomitant use is necessary, consider dosage reduction of ROXYBOND until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the ROXYBOND dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir). CYP3A4 Inducers Clinical Impact: The concomitant use of ROXYBOND and CYP3A4 inducers can decrease the plasma concentration of oxycodone [see Clinical Pharmacology ( 12.3 )] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone [see Warnings and Precautions ( 5.6 , 5.14 )] . After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase [see Clinical Pharmacology ( 12.3 )] , which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. Intervention If concomitant use is necessary, consider increasing the ROXYBOND dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider ROXYBOND dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation. Examples: Rifampin, carbamazepine, phenytoin Benzodiazepines and Other Central Nervous System (CNS) Depressants Clinical Impact: Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death [see Warnings and Precautions ( 5.3 )] . Intervention: Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] .

egivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.2 , 5.3 )] . Examples: Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol. Serotonergic Drugs Clinical Impact: The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome [see Adverse Reactions ( 6.2 )] . Intervention: If concomitant use is warranted, frequently reevaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue ROXYBOND if serotonin syndrome is suspected. Examples: Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) [see Warnings and Precautions ( 5.2 )] . Intervention: The use of ROXYBOND is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. Examples: Phenelzine, tranylcypromine, linezolid Mixed Agonist/Antagonist Opioid Analgesics Clinical Impact: May reduce the analgesic effect of ROXYBOND and/or may precipitate withdrawal symptoms. Intervention: Avoid concomitant use Examples: Butorphanol, nalbuphine, pentazocine, buprenorphine Muscle Relaxants Clinical Impact: Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Intervention: Because respiratory depression may be greater than otherwise expected, decrease the dosage of ROXYBOND and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.2 , 5.3 )] . Examples: Cyclobenzaprine, metaxalone Diuretics Clinical Impact: Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone. Intervention: Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed. Anticholinergic Drugs Clinical Impact: The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when ROXYBOND is used concurrently with anticholinergic drugs. Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue ROXYBOND if serotonin syndrome is suspected.

on, which may lead to paralytic ileus. Intervention: Evaluate patients for signs of urinary retention or reduced gastric motility when ROXYBOND is used concurrently with anticholinergic drugs. Serotonergic Drugs : Concomitant use may result in serotonin syndrome. Discontinue ROXYBOND if serotonin syndrome is suspected. ( 7 ) Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: Avoid use with ROXYBOND because they may reduce analgesic effect of ROXYBOND or precipitate withdrawal symptoms. ( 7 ) Monoamine Oxidase Inhibitors (MAOIs): Can potentiate the effects of morphine. Avoid concomitant use in patients receiving MAOIs or within 14 days of stopping treatment with an MAOI. ( 7 )

<table ID="t1" width="100%"><caption>Table 1. Clinically Significant Drug Interactions with ROXYBOND</caption><col width="17.500%" align="left"/><col width="82.500%" align="left"/><tbody><tr><td colspan="2" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Inhibitors of CYP3A4 and CYP2D6</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">The concomitant use of ROXYBOND and CYP3A4 inhibitors can increase the plasma concentration of oxycodone, resulting in increased or prolonged opioid effects. These effects could be more pronounced with concomitant use of ROXYBOND and CYP2D6 and CYP3A4 inhibitors, particularly when an inhibitor is added after a stable dose of ROXYBOND is achieved <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s32">5.6</linkHtml>)] </content>. After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the oxycodone plasma concentration will decrease <content styleCode="italics">[see Clinical Pharmacology ( <linkHtml href="#s89">12.3</linkHtml>)] </content>, resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependence to oxycodone. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">If concomitant use is necessary, consider dosage reduction of ROXYBOND until stable drug effects are achieved. Evaluate patients at frequent intervals for respiratory depression and sedation. If a CYP3A4 inhibitor is discontinued, consider increasing the ROXYBOND dosage until stable drug effects are achieved. Evaluate for signs of opioid withdrawal. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Examples:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir).</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">CYP3A4 Inducers</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">The concomitant use of ROXYBOND and CYP3A4 inducers can decrease the plasma concentration of oxycodone <content styleCode="italics">[see Clinical Pharmacology ( <linkHtml href="#s89">12.3</linkHtml>)] </content>, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to oxycodone <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s32">5.6</linkHtml>, <linkHtml href="#s42">5.14</linkHtml>)] </content>. After stopping a CYP3A4 inducer, as the effects of the inducer decline, the oxycodone plasma concentration will increase <content styleCode="italics">[see Clinical Pharmacology ( <linkHtml href="#s89">12.3</linkHtml>)] </content>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression.

effects of the inducer decline, the oxycodone plasma concentration will increase <content styleCode="italics">[see Clinical Pharmacology ( <linkHtml href="#s89">12.3</linkHtml>)] </content>, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention</content></td><td align="left" styleCode="Botrule Rrule" valign="top">If concomitant use is necessary, consider increasing the ROXYBOND dosage until stable drug effects are achieved. Evaluate patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider ROXYBOND dosage reduction and evaluate patients at frequent intervals for signs of respiratory depression and sedation.</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Examples:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Rifampin, carbamazepine, phenytoin</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Benzodiazepines and Other Central Nervous System (CNS) Depressants</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s29">5.3</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Inform patients and caregivers of this potential interaction and educate them on the signs and symptoms of respiratory depression (including sedation). If concomitant use is warranted, consider recommending or prescribing an opioid overdose reversal agent <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s14">2.2</linkHtml>), Warnings and Precautions ( <linkHtml href="#s42">5.1</linkHtml>, <linkHtml href="#s27">5.2</linkHtml></content>, <linkHtml href="#s29">5.3</linkHtml><content styleCode="italics">)]</content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Examples:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids (gabapentin or pregabalin), other opioids, alcohol.</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Serotonergic Drugs</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <content styleCode="italics">[see Adverse Reactions ( <linkHtml href="#s46">6.2</linkHtml>)] </content>.

l Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome <content styleCode="italics">[see Adverse Reactions ( <linkHtml href="#s46">6.2</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">If concomitant use is warranted, frequently reevaluate the patient, particularly during treatment initiation and dose adjustment. Discontinue ROXYBOND if serotonin syndrome is suspected.</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Examples:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), certain muscle relaxants (i.e., cyclobenzaprine, metaxalone), monoamine oxidase inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Monoamine Oxidase Inhibitors (MAOIs)</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma) <content styleCode="italics">[see Warnings and Precautions ( <linkHtml href="#s27">5.2</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">The use of ROXYBOND is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression.

op">The use of ROXYBOND is not recommended for patients taking MAOIs or within 14 days of stopping such treatment. If urgent use of an opioid is necessary, use test doses and frequent titration of small doses to treat pain while closely monitoring blood pressure and signs and symptoms of CNS and respiratory depression. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Examples:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Phenelzine, tranylcypromine, linezolid</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Mixed Agonist/Antagonist Opioid Analgesics</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">May reduce the analgesic effect of ROXYBOND and/or may precipitate withdrawal symptoms.</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Avoid concomitant use</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Examples:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Butorphanol, nalbuphine, pentazocine, buprenorphine</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Muscle Relaxants</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Oxycodone may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Because respiratory depression may be greater than otherwise expected, decrease the dosage of ROXYBOND and/or the muscle relaxant as necessary. Due to the risk of respiratory depression with concomitant use of skeletal muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s14">2.2</linkHtml>), Warnings and Precautions ( <linkHtml href="#s27">5.2</linkHtml>, <linkHtml href="#s29">5.3</linkHtml>)] </content>.

al muscle relaxants and opioids, consider recommending or prescribing an opioid overdose reversal agent <content styleCode="italics">[see Dosage and Administration ( <linkHtml href="#s14">2.2</linkHtml>), Warnings and Precautions ( <linkHtml href="#s27">5.2</linkHtml>, <linkHtml href="#s29">5.3</linkHtml>)] </content>. </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Examples:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Cyclobenzaprine, metaxalone</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Diuretics</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Evaluate patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed.</td></tr><tr><td colspan="2" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Anticholinergic Drugs</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Clinical Impact:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">The concomitant risk of anticholinergic drugs may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="italics">Intervention:</content></td><td align="left" styleCode="Botrule Rrule" valign="top">Evaluate patients for signs of urinary retention or reduced gastric motility when ROXYBOND is used concurrently with anticholinergic drugs.</td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Pregnancy: May cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 ), Clinical Considerations )] . There are reports of respiratory depression when oxycodone is used during labor and delivery [see Clinical Considerations ] . There are no available data with ROXYBOND in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Animal reproduction studies with oral administrations of oxycodone hydrochloride in rats and rabbits during the period of organogenesis, at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data )] . Based on animal data, advise pregnant women of the potential risk to a fetus. The risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity, and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. ROXYBOND is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ROXYBOND, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data Limited published data from case-control and observational studies on oxycodone use during pregnancy are inconsistent in their findings. Although some studies reported an increased risk of congenital malformations, there was no consistent pattern of malformations noted. In addition, multiple similar studies reported no association.

shed data from case-control and observational studies on oxycodone use during pregnancy are inconsistent in their findings. Although some studies reported an increased risk of congenital malformations, there was no consistent pattern of malformations noted. In addition, multiple similar studies reported no association. Methodological limitations of these studies, including small sample size, recall bias, lack of information regarding dose and timing of exposure and concomitant use of other medications, preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of oxycodone in pregnancy. Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone hydrochloride administered during the period of organogenesis up to 16 mg/kg/day and up to 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m 2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis). 8.2 Lactation Risk Summary Available data from lactation studies indicate that oxycodone is present in breastmilk and that doses of less than 60 mg/day of the immediate-release formulation are unlikely to result in clinically relevant exposures in breastfed infants. A pharmacokinetics study utilizing opportunistic sampling of 76 lactating women receiving oxycodone immediate-release products for postpartum pain management showed that oxycodone concentrates in breastmilk with an average milk to plasma ratio of 3.2. The relative infant dose was low, approximately 1.3% of a weight-adjusted maternal dose [see Data )] . In the same study, among the 70 infants exposed to oxycodone in breastmilk, no adverse events were attributed to oxycodone. However, based on known adverse effects in adults, infants should be monitored for signs of excess sedation and respiratory depression [see Clinical Considerations )] . There are no data on the effects of the oxycodone on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ROXYBOND and any potential adverse effects on the breastfed infant from ROXYBOND or from the underlying maternal condition. Clinical Considerations Monitor infants exposed to ROXYBOND through breast milk for excess sedation and respiratory depression. Withdrawal symptoms can occur in breastfed infants when maternal administration of an opioid analgesic is stopped or when breast-feeding is stopped. Data Oxycodone concentration data from 76 lactating women receiving immediate-release oxycodone products for postpartum pain management, and 28 infants exposed to oxycodone in breastmilk showed that following a median (range) dose of oxycodone in mothers of 9.2 (5-10) mg/dose or 33.0 (5.4-59.3) mg/day, oxycodone concentrated in breastmilk with a median (range) milk to plasma ratio of 3.2 (1.2-5.3). However, when using maternal breastmilk data to estimate the daily and relative infant dose, the infant dose was 0.006 mg/kg/day, which is 1.3% of a weight-adjusted maternal dose of 10 mg every 6 hours.

(5.4-59.3) mg/day, oxycodone concentrated in breastmilk with a median (range) milk to plasma ratio of 3.2 (1.2-5.3). However, when using maternal breastmilk data to estimate the daily and relative infant dose, the infant dose was 0.006 mg/kg/day, which is 1.3% of a weight-adjusted maternal dose of 10 mg every 6 hours. These estimates based on maternal breastmilk concentrations were corroborated by the observed infant concentrations, of which over 75% (19/25) were below the limit of quantification. Among the 6 infants with quantifiable concentration, the median (range) concentration was 0.2 ng/mL (0.1-0.7). These concentrations are 100 to 1000 times lower than concentrations observed in other studies after infants received oxycodone at 0.1 mg/kg/dose (~20-200 ng/mL). 8.3 Females and Males of Reproductive Potential Infertility Use of opioids for an extended period of time may cause reduced fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible [see Clinical Pharmacology ( 12.2 ), and Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and efficacy of ROXYBOND in pediatric patients have not been evaluated. 8.5 Geriatric Use Of the total number of subjects in clinical studies of oxycodone hydrochloride, 20.8% (112/538) were 65 and over, while 7.2% (39/538) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of ROXYBOND slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.8 )] . Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function. 8.6 Hepatic Impairment Because oxycodone is extensively metabolized in the liver, its clearance may decrease in patients with hepatic impairment. Initiate therapy in these patients with a lower than usual dosage of ROXYBOND and titrate carefully. Regularly evaluate for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3 )] . 8.7 Renal Impairment Because oxycodone is known to be substantially excreted by the kidney, its clearance may decrease in patients with renal impairment. Initiate therapy with a lower than usual dosage of ROXYBOND and titrate carefully. Regularly evaluate for adverse events such as respiratory depression, sedation, and hypotension [see Clinical Pharmacology ( 12.3 )] .

8.1 Pregnancy Risk Summary Use of opioid analgesics for an extended period of time during pregnancy may cause neonatal opioid withdrawal syndrome [see Warnings and Precautions ( 5.4 ), Clinical Considerations )] . There are reports of respiratory depression when oxycodone is used during labor and delivery [see Clinical Considerations ] . There are no available data with ROXYBOND in pregnant women to inform a drug-associated risk for adverse developmental outcomes. Animal reproduction studies with oral administrations of oxycodone hydrochloride in rats and rabbits during the period of organogenesis, at doses 2.6 and 8.1 times, respectively, the human dose of 60 mg/day did not reveal evidence of teratogenicity or embryo-fetal toxicity. In several published studies, treatment of pregnant rats with oxycodone at clinically relevant doses and below, resulted in neurobehavioral effects in offspring [see Data )] . Based on animal data, advise pregnant women of the potential risk to a fetus. The risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Use of opioid analgesics for an extended period of time during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity, and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. Observe newborns for symptoms of neonatal opioid withdrawal syndrome and manage accordingly [see Warnings and Precautions ( 5.4 )] . Labor or Delivery Opioids cross the placenta and may produce respiratory depression and psycho-physiologic effects in neonates. An opioid overdose reversal agent, such as naloxone or nalmefene, must be available for reversal of opioid-induced respiratory depression in the neonate. ROXYBOND is not recommended for use in pregnant women during or immediately prior to labor, when other analgesic techniques are more appropriate. Opioid analgesics, including ROXYBOND, can prolong labor through actions which temporarily reduce the strength, duration, and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilation, which tends to shorten labor. Monitor neonates exposed to opioid analgesics during labor for signs of excess sedation and respiratory depression. Data Human Data Limited published data from case-control and observational studies on oxycodone use during pregnancy are inconsistent in their findings. Although some studies reported an increased risk of congenital malformations, there was no consistent pattern of malformations noted. In addition, multiple similar studies reported no association.

shed data from case-control and observational studies on oxycodone use during pregnancy are inconsistent in their findings. Although some studies reported an increased risk of congenital malformations, there was no consistent pattern of malformations noted. In addition, multiple similar studies reported no association. Methodological limitations of these studies, including small sample size, recall bias, lack of information regarding dose and timing of exposure and concomitant use of other medications, preclude a reliable evaluation of the potential risk of adverse fetal outcomes with the use of oxycodone in pregnancy. Animal Data In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of oxycodone hydrochloride administered during the period of organogenesis up to 16 mg/kg/day and up to 25 mg/kg/day, respectively. These studies revealed no evidence of teratogenicity or embryo fetal toxicity due to oxycodone. The highest doses tested in rats and rabbits were equivalent to approximately 2.6 and 8.1 times an adult human dose of 60 mg/day, respectively, on a mg/m 2 basis. In published studies, offspring of pregnant rats administered oxycodone during gestation have been reported to exhibit neurobehavioral effects including altered stress responses, increased anxiety-like behavior (2 mg/kg/day IV from Gestation Day 8 to 21 and Postnatal Day 1, 3, and 5; 0.3-times an adult human dose of 60 mg/day, on a mg/m 2 basis) and altered learning and memory (15 mg/kg/day orally from breeding through parturition; 2.4 times an adult human dose of 60 mg/day, on a mg/m 2 basis).

8.5 Geriatric Use Of the total number of subjects in clinical studies of oxycodone hydrochloride, 20.8% (112/538) were 65 and over, while 7.2% (39/538) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients (aged 65 years or older) may have increased sensitivity to oxycodone. In general, use caution when selecting a dosage for an elderly patient, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Respiratory depression is the chief risk for elderly patients treated with opioids and has occurred after large initial doses were administered to patients who were not opioid-tolerant or when opioids were co-administered with other agents that depress respiration. Titrate the dosage of ROXYBOND slowly in geriatric patients and frequently reevaluate the patient for signs of central nervous system and respiratory depression [see Warnings and Precautions ( 5.8 )] . Oxycodone is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to regularly evaluate renal function.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance ROXYBOND contains oxycodone, a Schedule II controlled substance. 9.2 Abuse ROXYBOND contains oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )] . Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of ROXYBOND increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of ROXYBOND with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of ROXYBOND abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use ROXYBOND in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. ROXYBOND, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of ROXYBOND Abuse of ROXYBOND poses a risk of overdose and death. This risk is increased with concurrent use of ROXYBOND with alcohol and/or other CNS depressants. ROXYBOND is for oral use only. Parenteral abuse of ROXYBOND can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury.

dose and death. This risk is increased with concurrent use of ROXYBOND with alcohol and/or other CNS depressants. ROXYBOND is for oral use only. Parenteral abuse of ROXYBOND can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Injection of excipients included in the ROXYBOND formulation, intended to provide abuse-deterrent properties, may be associated with additional unknown serious risks. Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV. Abuse Deterrence Studies ROXYBOND is formulated with inactive ingredients that make the tablet more difficult to manipulate for misuse and abuse even if the tablet is subjected to physical manipulation and/or chemical extraction. To evaluate the ability of the abuse-deterrent technology to reduce the potential for abuse of ROXYBOND, a series of in vitro laboratory manipulation, extraction, and syringe ability studies were conducted. An in vivo intranasal clinical abuse potential study was also conducted. In Vitro Testing ROXYBOND has been tested in vitro using methods of manipulation that drug abusers commonly use for preparation of opioids for administration by various routes, including oral consumption, intranasal insufflation, and injection. Abusers may manipulate prescription opioids in order to prepare the tablets for oral, intranasal, or intravenous administration. The laboratory test data demonstrated that, relative to oxycodone immediate-release tablets, ROXYBOND has increased resistance to cutting, crushing, grinding, or breaking using selected tools. In addition, the intact and manipulated tablets resisted extraction in selected household and laboratory solvents under various conditions, including selected pre-treatments. Relative to oxycodone immediate-release tablets, the formulation forms a viscous material that resists passage through a needle; it was also more difficult to prepare solutions suitable for intravenous injection. Clinical Abuse Potential Studies A randomized, double-blind, double-dummy, placebo-controlled, single-dose four-way crossover study in 29 non-dependent recreational opioid users with a history of intranasal drug abuse was performed to determine the relative bioavailability and abuse potential of crushed intranasal ROXYBOND 30 mg tablets compared with crushed intranasal 30 mg oxycodone immediate-release tablets and intact orally administered ROXYBOND 30 mg tablets. Intact oral ROXYBOND tablets were included as a reference for evaluating abuse potential after manipulation and administration via an unintended route. Drug liking was measured on a 100-mm bipolar visual analog scale (VAS) where 50 represents a neutral response of neither liking nor disliking, 0 represents maximum disliking, and 100 represents maximum liking. Response to whether the subject would be willing to take the study drug again was also measured on a bipolar 0 to 100 VAS where 50 represents a neutral response, 0 represents the strongest negative response (“definitely would not take drug again”) and 100 represents the strongest positive response (“definitely would take drug again”). The pharmacokinetic profiles of oxycodone were also determined in this study ( Table 2 ). When crushed and insufflated, ROXYBOND showed a lower peak oxycodone plasma concentration (C max ~28% reduction) and a 35% longer time to peak plasma concentration (T max ) relative to crushed and insufflated oxycodone immediate-release tablets. Similar results were demonstrated when crushed and insufflated ROXYBOND was compared to intact oral ROXYBOND with a reduction in C max and a longer time to T max .

(C max ~28% reduction) and a 35% longer time to peak plasma concentration (T max ) relative to crushed and insufflated oxycodone immediate-release tablets. Similar results were demonstrated when crushed and insufflated ROXYBOND was compared to intact oral ROXYBOND with a reduction in C max and a longer time to T max . Intact oral ROXYBOND resulted in a C max of oxycodone similar to that of crushed and insufflated oxycodone immediate-release tablets, with a similar T max . Table 2 Summary of Plasma Oxycodone Pharmacokinetic Parameters From the Intranasal Abuse Potential Study (n=31) AUC 0-t = Area under the plasma concentration vs time curve from 0 to last measurable concentration. Treatment or Comparison C max (ng/mL) LS Mean AUC 0-t (ng*hr/mL) LS Mean T max (hr) Median Crushed, Insufflated oxycodone immediate-release tablets 30 mg 55.56 330.77 1.7 Crushed, Insufflated ROXYBOND 30 mg 40.04 309.21 2.3 Intact, oral ROXYBOND 56.97 265.38 1.3 Compared to crushed intranasal oxycodone immediate-release tablets, intranasal administration of crushed ROXYBOND was associated with statistically significantly lower drug liking (E max ) and take drug again (E max ) scores, as summarized in Table 3 . Similar reductions in drug liking and willingness to take the drug again were reported for crushed intranasal ROXYBOND relative to intact oral ROXYBOND. These data are consistent with the slowing of the intended immediate-release properties of ROXYBOND when manipulated then insufflated compared to taking ROXYBOND orally intact. No statistically significant differences in E max of Drug Liking or Take Drug Again were observed between crushed intranasal oxycodone immediate-release tablets and intact oral ROXYBOND. Table 3. Summary of Maximum Drug Liking (E max ), and Take Drug Again (E max ), Following Administration of ROXYBOND, Oxycodone Immediate-release Tablets, and Placebo in Recreational Opioid Users (N=29) VAS Crushed Intranasal ROXYBOND 30 mg Crushed Intranasal Oxycodone immediate- release tablets 30 mg Intact Oral ROXYBOND 30 mg Placebo Drug Liking (E max ) Mean (SD) 71.1 (12.01) 82.9 (11.55) 81.5 (11.49) 53.4 (6.34) Median (Range) 71 (50 to 100) 82 (50 to 100) 82.00 (56 to 100) 51.0 (50 to 77) Take Drug Again (E max ) Mean (SD) 62.2 (24.51) 82.1 (16.44) 77.3 (18.11) 41.9 (20.09) Median (Range) 62.0 (3 to 99) 86.0 (37 to 100) 81.0 (13 to 100) 50.0 (0.0 to 78) Figure 1. Mean Drug Liking VAS Scores Over Time (N=29) The majority of subjects (86%; n=25) experienced some reduction in E max of Drug Liking VAS with crushed intranasal ROXYBOND compared with crushed intranasal oxycodone immediate-release tablets, whereas 59% (n=17) experienced at least a 30% reduction in E max of drug liking and 21% (n=6) experienced at least a 50% reduction in E max of drug liking. Figure 1 Summary The in vitro data demonstrate that ROXYBOND has physicochemical properties expected to make abuse via injection difficult. The data from the clinical study, along with support from in vitro data, also indicate that ROXYBOND has physicochemical properties that are expected to reduce abuse by the intranasal route of administration. However, abuse by the intranasal, oral, and intravenous route is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of ROXYBOND on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose).

e. 9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not rapidly reduce or abruptly discontinue ROXYBOND in a patient physically dependent on opioids. Rapid tapering of ROXYBOND in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing ROXYBOND, gradually taper the dosage using a patient-specific plan that considers the following: the dose of ROXYBOND the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.4 , 2.5 ), and Warnings and Precautions ( 5.14 )] . Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )] .

<table ID="t2" width="100%"><caption>Table 2 Summary of Plasma Oxycodone Pharmacokinetic Parameters From the Intranasal Abuse Potential Study (n=31)</caption><col width="37.725%" align="left"/><col width="20.750%" align="left"/><col width="20.750%" align="left"/><col width="20.775%" align="left"/><tfoot><tr><td colspan="4" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><paragraph styleCode="footnote">AUC <content styleCode="bold">_0-t</content>= Area under the plasma concentration vs time curve from 0 to last measurable concentration. </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="bottom"><content styleCode="bold">Treatment or Comparison</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">C</content><content styleCode="bold">_max</content><content styleCode="bold">(ng/mL) LS Mean </content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">AUC</content><content styleCode="bold">_0-t</content><content styleCode="bold"> (ng*hr/mL) LS Mean </content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">T</content><content styleCode="bold">_max</content><content styleCode="bold">(hr) Median </content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Crushed, Insufflated oxycodone immediate-release tablets 30 mg</td><td align="center" styleCode="Botrule Rrule" valign="top">55.56</td><td align="center" styleCode="Botrule Rrule" valign="top">330.77</td><td align="center" styleCode="Botrule Rrule" valign="top">1.7</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Crushed, Insufflated ROXYBOND 30 mg</td><td align="center" styleCode="Botrule Rrule" valign="top">40.04</td><td align="center" styleCode="Botrule Rrule" valign="top">309.21</td><td align="center" styleCode="Botrule Rrule" valign="top">2.3</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Intact, oral ROXYBOND</td><td align="center" styleCode="Botrule Rrule" valign="top">56.97</td><td align="center" styleCode="Botrule Rrule" valign="top">265.38</td><td align="center" styleCode="Botrule Rrule" valign="top">1.3</td></tr></tbody></table>

/tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">Intact, oral ROXYBOND</td><td align="center" styleCode="Botrule Rrule" valign="top">56.97</td><td align="center" styleCode="Botrule Rrule" valign="top">265.38</td><td align="center" styleCode="Botrule Rrule" valign="top">1.3</td></tr></tbody></table> <table ID="t3" width="100%"><caption>Table 3. Summary of Maximum Drug Liking (E _max), and Take Drug Again (E _max), Following Administration of ROXYBOND, Oxycodone Immediate-release Tablets, and Placebo in Recreational Opioid Users (N=29) </caption><col width="16.650%" align="left"/><col width="16.667%" align="left"/><col width="16.667%" align="left"/><col width="16.667%" align="left"/><col width="16.683%" align="left"/><col width="16.667%" align="left"/><tbody><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule" valign="bottom">VAS</td><td align="left" styleCode="Toprule Botrule Rrule" valign="bottom"/><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom">Crushed Intranasal ROXYBOND 30 mg </td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom">Crushed Intranasal Oxycodone immediate- release tablets 30 mg </td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom">Intact Oral ROXYBOND 30 mg </td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom">Placebo</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="middle">Drug Liking (E _max) </td><td align="center" styleCode="Botrule Rrule" valign="top">Mean (SD) </td><td align="center" styleCode="Botrule Rrule" valign="top">71.1 (12.01) </td><td align="center" styleCode="Botrule Rrule" valign="top">82.9 (11.55) </td><td align="center" styleCode="Botrule Rrule" valign="top">81.5 (11.49) </td><td align="center" styleCode="Botrule Rrule" valign="top">53.4 (6.34) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"/><td align="center" styleCode="Botrule Rrule" valign="top">Median (Range) </td><td align="center" styleCode="Botrule Rrule" valign="top">71 (50 to 100) </td><td align="center" styleCode="Botrule Rrule" valign="top">82 (50 to 100) </td><td align="center" styleCode="Botrule Rrule" valign="top">82.00 (56 to 100) </td><td align="center" styleCode="Botrule Rrule" valign="top">51.0 (50 to 77) </td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="middle">Take Drug Again (E _max) </td><td align="center" styleCode="Botrule Rrule" valign="top">Mean (SD) </td><td align="center" styleCode="Botrule Rrule" valign="top">62.2 (24.51) </td><td align="center" styleCode="Botrule Rrule" valign="top">82.1 (16.44) </td><td align="center" styleCode="Botrule Rrule" valign="top">77.3 (18.11) </td><td align="center" styleCode="Botrule Rrule" valign="top">41.9 (20.09) </td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top"/><td align="center" styleCode="Botrule Rrule" valign="top">Median (Range) </td><td align="center" styleCode="Botrule Rrule" valign="top">62.0 (3 to 99) </td><td align="center" styleCode="Botrule Rrule" valign="top">86.0 (37 to 100) </td><td align="center" styleCode="Botrule Rrule" valign="top">81.0 (13 to 100) </td><td align="center" styleCode="Botrule Rrule" valign="top">50.0 (0.0 to 78) </td></tr></tbody></table>

9.2 Abuse ROXYBOND contains oxycodone, a substance with high potential for misuse and abuse, which can lead to the development of substance use disorder, including addiction [see Warnings and Precautions ( 5.1 )] . Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a healthcare provider or for whom it was not prescribed. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Misuse and abuse of ROXYBOND increases risk of overdose, which may lead to central nervous system and respiratory depression, hypotension, seizures, and death. The risk is increased with concurrent abuse of ROXYBOND with alcohol and/or other CNS depressants. Abuse of and addiction to opioids in some individuals may not be accompanied by concurrent tolerance and symptoms of physical dependence. In addition, abuse of opioids can occur in the absence of addiction. All patients treated with opioids require careful and frequent reevaluation for signs of misuse, abuse, and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Patients at high risk of ROXYBOND abuse include those with a history of prolonged use of any opioid, including products containing oxycodone, those with a history of drug or alcohol abuse, or those who use ROXYBOND in combination with other abused drugs. “Drug-seeking” behavior is very common in persons with substance use disorders. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing, or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating healthcare provider(s). “Doctor shopping” (visiting multiple prescribers to obtain additional prescriptions) is common among people who abuse drugs and people with substance use disorder. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with inadequate pain control. ROXYBOND, like other opioids, can be diverted for nonmedical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic reevaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Risks Specific to Abuse of ROXYBOND Abuse of ROXYBOND poses a risk of overdose and death. This risk is increased with concurrent use of ROXYBOND with alcohol and/or other CNS depressants. ROXYBOND is for oral use only. Parenteral abuse of ROXYBOND can be expected to result in local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury.

(C max ~28% reduction) and a 35% longer time to peak plasma concentration (T max ) relative to crushed and insufflated oxycodone immediate-release tablets. Similar results were demonstrated when crushed and insufflated ROXYBOND was compared to intact oral ROXYBOND with a reduction in C max and a longer time to T max . Intact oral ROXYBOND resulted in a C max of oxycodone similar to that of crushed and insufflated oxycodone immediate-release tablets, with a similar T max . Table 2 Summary of Plasma Oxycodone Pharmacokinetic Parameters From the Intranasal Abuse Potential Study (n=31) AUC 0-t = Area under the plasma concentration vs time curve from 0 to last measurable concentration. Treatment or Comparison C max (ng/mL) LS Mean AUC 0-t (ng*hr/mL) LS Mean T max (hr) Median Crushed, Insufflated oxycodone immediate-release tablets 30 mg 55.56 330.77 1.7 Crushed, Insufflated ROXYBOND 30 mg 40.04 309.21 2.3 Intact, oral ROXYBOND 56.97 265.38 1.3 Compared to crushed intranasal oxycodone immediate-release tablets, intranasal administration of crushed ROXYBOND was associated with statistically significantly lower drug liking (E max ) and take drug again (E max ) scores, as summarized in Table 3 . Similar reductions in drug liking and willingness to take the drug again were reported for crushed intranasal ROXYBOND relative to intact oral ROXYBOND. These data are consistent with the slowing of the intended immediate-release properties of ROXYBOND when manipulated then insufflated compared to taking ROXYBOND orally intact. No statistically significant differences in E max of Drug Liking or Take Drug Again were observed between crushed intranasal oxycodone immediate-release tablets and intact oral ROXYBOND. Table 3. Summary of Maximum Drug Liking (E max ), and Take Drug Again (E max ), Following Administration of ROXYBOND, Oxycodone Immediate-release Tablets, and Placebo in Recreational Opioid Users (N=29) VAS Crushed Intranasal ROXYBOND 30 mg Crushed Intranasal Oxycodone immediate- release tablets 30 mg Intact Oral ROXYBOND 30 mg Placebo Drug Liking (E max ) Mean (SD) 71.1 (12.01) 82.9 (11.55) 81.5 (11.49) 53.4 (6.34) Median (Range) 71 (50 to 100) 82 (50 to 100) 82.00 (56 to 100) 51.0 (50 to 77) Take Drug Again (E max ) Mean (SD) 62.2 (24.51) 82.1 (16.44) 77.3 (18.11) 41.9 (20.09) Median (Range) 62.0 (3 to 99) 86.0 (37 to 100) 81.0 (13 to 100) 50.0 (0.0 to 78) Figure 1. Mean Drug Liking VAS Scores Over Time (N=29) The majority of subjects (86%; n=25) experienced some reduction in E max of Drug Liking VAS with crushed intranasal ROXYBOND compared with crushed intranasal oxycodone immediate-release tablets, whereas 59% (n=17) experienced at least a 30% reduction in E max of drug liking and 21% (n=6) experienced at least a 50% reduction in E max of drug liking. Figure 1 Summary The in vitro data demonstrate that ROXYBOND has physicochemical properties expected to make abuse via injection difficult. The data from the clinical study, along with support from in vitro data, also indicate that ROXYBOND has physicochemical properties that are expected to reduce abuse by the intranasal route of administration. However, abuse by the intranasal, oral, and intravenous route is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of the current formulation of ROXYBOND on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate.

9.3 Dependence Both tolerance and physical dependence can develop during use of opioid therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Physical dependence is a state that develops as a result of a physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued use. Do not rapidly reduce or abruptly discontinue ROXYBOND in a patient physically dependent on opioids. Rapid tapering of ROXYBOND in a patient physically dependent on opioids may lead to serious withdrawal symptoms, uncontrolled pain, and suicide. Rapid discontinuation has also been associated with attempts to find other sources of opioid analgesics, which may be confused with drug-seeking for abuse. When discontinuing ROXYBOND, gradually taper the dosage using a patient-specific plan that considers the following: the dose of ROXYBOND the patient has been taking, the duration of treatment, and the physical and psychological attributes of the patient. To improve the likelihood of a successful taper and minimize withdrawal symptoms, it is important that the opioid tapering schedule is agreed upon by the patient. In patients taking opioids for an extended period of time at high doses, ensure that a multimodal approach to pain management, including mental health support (if needed), is in place prior to initiating an opioid analgesic taper [see Dosage and Administration ( 2.4 , 2.5 ), and Warnings and Precautions ( 5.14 )] . Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )] .

10 OVERDOSAGE Clinical Presentation Acute overdose with oxycodone can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, in some cases, pulmonary edema, bradycardia, hypotension, hypoglycemia, partial or complete airway obstruction, atypical snoring, and death. Marked mydriasis rather than miosis may be seen with hypoxia in overdose situations [see Clinical Pharmacology ( 12.2 )] . Toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication. Treatment of Overdose In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation, if needed. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advance life-support measures. For clinically significant respiratory or circulatory depression secondary to oxycodone overdose, administer an opioid overdose reversal agent such as naloxone or nalmefene. Because the duration of opioid reversal is expected to be less than the duration of action of oxycodone in ROXYBOND, carefully monitor the patient until spontaneous respiration is reliably reestablished. If the response to an opioid overdose reversal agent is suboptimal or only brief in nature, administer additional reversal agent as directed by the product's prescribing information. In an individual physically dependent on opioids, administration of the recommended usual dosage of the opioid overdose reversal agent will precipitate an acute withdrawal syndrome. The severity of the withdrawal symptoms experienced will depend on the degree of physical dependence and the dose of the reversal agent administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the reversal agent should be initiated with care and by titration with smaller than usual doses of the reversal agent.

11 DESCRIPTION ROXYBOND (oxycodone hydrochloride) tablets for oral administration are available in 5 mg, 10 mg, 15 mg, and 30 mg strengths, each containing an equivalent of 4.5 mg, 9.0 mg, 13.5 mg, and 27 mg of oxycodone free base, respectively. Oxycodone hydrochloride is an opioid agonist. It is a white, odorless crystalline powder derived from the opium alkaloid, thebaine. Oxycodone hydrochloride dissolves in water (1 g in 6 to 7 mL) and is considered slightly soluble in alcohol (octanol water partition coefficient is 0.7). Chemically, oxycodone hydrochloride is 4, 5α-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride and has the following structural formula: Each ROXYBOND tablet contains the following inactive ingredients common to all strengths: alginic acid, ammonium hydroxide, colloidal silicon dioxide, dibutyl sebacate, dimethylaminoethyl methacrylate copolymer, ethyl acrylate and methyl methacrylate copolymer dispersion, ethylcellulose, hypromellose, iron oxide black, isopropyl alcohol, lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, n-butyl alcohol, polyethylene glycol, polysorbate 80, polyvinyl alcohol, propylene glycol, shellac in ethanol, sodium alginate, talc, titanium dioxide, and xanthan gum. The 10 mg ROXYBOND tablets also contain: FD&C Red No. 40, D&C Red No. 30, and D&C Yellow No. 10. The 15 mg ROXYBOND tablets also contain: FD&C Blue No. 2 and iron oxide yellow. The 30 mg ROXYBOND tablets also contain: FD&C Blue No. 2. Structural Formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Oxycodone is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of oxycodone is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with oxycodone. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression. The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug. 12.2 Pharmacodynamics Effects on the Central Nervous System Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum, stomach, and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on Cardiovascular System Oxycodone produces peripheral vasodilatation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.

d to date [see Adverse Reactions ( 6.2 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1 , 2.4 ), Warnings and Precautions ( 5.7 )] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.2 , 2.3 ), Warnings and Precautions ( 5.7 )] . 12.3 Pharmacokinetics The activity of ROXYBOND tablets is primarily due to the parent drug oxycodone. ROXYBOND tablets are designed to provide immediate-release of oxycodone. Oxycodone pharmacokinetics are similar for ROXYBOND and oxycodone immediate-release tablets. In the fasted state, the extent of absorption (AUC) is equivalent, the rate of absorption (C max ) is similar, and median T max is slightly longer (1.0 to 1.8 h). Table 4. Pharmacokinetic Parameters (Mean ± SD) a Median (range) Dose\Parameters AUC 0-t (ng∙hr/mL) AUC 0-inf (ng∙hr/mL) C max (ng/mL) T max (hr) Half Life (hr) Single Dose Pharmacokinetics Study ROXYBOND 5 mg tab (fasted) 45.5±15.4 49.0±16.1 8.3±2.1 1.5 a (0.7 to 5.0) 3.9±1.2 ROXYBOND 15 mg tab (fasted) 127.5±38.1 131.6±39.0 22.0±5.8 1.7 a (1.0 to 12.0) 4.1±0.8 ROXYBOND 30 mg tab (fasted) 277.0±89.6 285.8±94.1 48.5±15.9 1.5 a (1.0 to 8.0) 4.3±1.0 Single Dose Food-Effect Study ROXYBOND 30 mg tab (fasted) 287.4±65.8 292.7±67.4 57.8±18.0 1.8 a (0.8 to 5.0) 3.8±0.7 ROXYBOND 30 mg tab (fed) 354.2±82.5 361.9±86.7 68.0±20.1 2.0 a (1.0 to 6.1) 3.9±0.6 Absorption About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lower presystemic and/or first-pass metabolism of oxycodone. Dose proportionality of oxycodone has been established using the ROXYBOND 5 mg, 15 mg, and 30 mg tablets based on maximum plasma concentration (C max ) and extent of absorption (AUC) ( Figure 2 ). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride. Figure 2. Mean Oxycodone Pharmacokinetic Profiles of 5-, 15-, 30-mg ROXYBOND Tablets (n=51) Figure 2 Food Effect A single-dose food effect study was conducted in normal volunteers using the 30-mg tablet. The concurrent intake of a high fat meal was shown to enhance the extent (23% increase in AUC), and the rate (18% increase in C max ) of oxycodone absorption from the 30-mg tablet ( Table 4 ). In addition, food caused a slight delay in T max (1.8 to 2 hours). Similar effects of food are expected with the 5-mg and 15-mg tablets. Distribution Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk [see Use in Specific Populations ( 8.2 )] .

ood are expected with the 5-mg and 15-mg tablets. Distribution Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk [see Use in Specific Populations ( 8.2 )] . Elimination Metabolism A high proportion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism, and is catalyzed by CYP3A4. Oxymorphone is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6 [see Drug Interactions ( 7 )] . Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of ROXYBOND was 3.8 to 4.3 hours. Specific Populations Age: Geriatric Patients Population pharmacokinetic studies conducted with oxycodone hydrochloride, indicated that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65 [see Use in Specific Populations ( 8.5 )] . Hepatic Impairment In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased hepatic function were evaluated to study these potential differences. However, because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic impaired patients [see Use in Specific Populations ( 8.6 )] . Renal Impairment This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function [see Use in Specific Populations ( 8.7 )] .

12.2 Pharmacodynamics Effects on the Central Nervous System Oxycodone produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation. Oxycodone causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations. Effects on Gastrointestinal Tract and Other Smooth Muscle Oxycodone causes a reduction in motility associated with an increase in smooth muscle tone in the antrum, stomach, and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, transient elevations in serum amylase, and opioid-induced esophageal dysfunction (OIED). Effects on Cardiovascular System Oxycodone produces peripheral vasodilatation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilatation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [see Adverse Reactions ( 6.2 )] . They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Use of opioids for an extended period of time may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions ( 6.2 )] . Effects on the Immune System Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive. Concentration–Efficacy Relationships The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with opioid agonists. The minimum effective analgesic concentration of oxycodone for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [see Dosage and Administration ( 2.1 , 2.4 ), Warnings and Precautions ( 5.7 )] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression.

nd Administration ( 2.1 , 2.4 ), Warnings and Precautions ( 5.7 )] . Concentration–Adverse Reaction Relationships There is a relationship between increasing oxycodone plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [see Dosage and Administration ( 2.1 , 2.2 , 2.3 ), Warnings and Precautions ( 5.7 )] .

12.3 Pharmacokinetics The activity of ROXYBOND tablets is primarily due to the parent drug oxycodone. ROXYBOND tablets are designed to provide immediate-release of oxycodone. Oxycodone pharmacokinetics are similar for ROXYBOND and oxycodone immediate-release tablets. In the fasted state, the extent of absorption (AUC) is equivalent, the rate of absorption (C max ) is similar, and median T max is slightly longer (1.0 to 1.8 h). Table 4. Pharmacokinetic Parameters (Mean ± SD) a Median (range) Dose\Parameters AUC 0-t (ng∙hr/mL) AUC 0-inf (ng∙hr/mL) C max (ng/mL) T max (hr) Half Life (hr) Single Dose Pharmacokinetics Study ROXYBOND 5 mg tab (fasted) 45.5±15.4 49.0±16.1 8.3±2.1 1.5 a (0.7 to 5.0) 3.9±1.2 ROXYBOND 15 mg tab (fasted) 127.5±38.1 131.6±39.0 22.0±5.8 1.7 a (1.0 to 12.0) 4.1±0.8 ROXYBOND 30 mg tab (fasted) 277.0±89.6 285.8±94.1 48.5±15.9 1.5 a (1.0 to 8.0) 4.3±1.0 Single Dose Food-Effect Study ROXYBOND 30 mg tab (fasted) 287.4±65.8 292.7±67.4 57.8±18.0 1.8 a (0.8 to 5.0) 3.8±0.7 ROXYBOND 30 mg tab (fed) 354.2±82.5 361.9±86.7 68.0±20.1 2.0 a (1.0 to 6.1) 3.9±0.6 Absorption About 60% to 87% of an oral dose of oxycodone reaches the systemic circulation in comparison to a parenteral dose. This high oral bioavailability (compared to other oral opioids) is due to lower presystemic and/or first-pass metabolism of oxycodone. Dose proportionality of oxycodone has been established using the ROXYBOND 5 mg, 15 mg, and 30 mg tablets based on maximum plasma concentration (C max ) and extent of absorption (AUC) ( Figure 2 ). It takes approximately 18 to 24 hours to reach steady-state plasma concentrations of oxycodone with oxycodone hydrochloride. Figure 2. Mean Oxycodone Pharmacokinetic Profiles of 5-, 15-, 30-mg ROXYBOND Tablets (n=51) Figure 2 Food Effect A single-dose food effect study was conducted in normal volunteers using the 30-mg tablet. The concurrent intake of a high fat meal was shown to enhance the extent (23% increase in AUC), and the rate (18% increase in C max ) of oxycodone absorption from the 30-mg tablet ( Table 4 ). In addition, food caused a slight delay in T max (1.8 to 2 hours). Similar effects of food are expected with the 5-mg and 15-mg tablets. Distribution Following intravenous administration, the volume of distribution (Vss) for oxycodone was 2.6 L/kg. Plasma protein binding of oxycodone at 37°C and a pH of 7.4 was about 45%. Oxycodone has been found in breast milk [see Use in Specific Populations ( 8.2 )] . Elimination Metabolism A high proportion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism, and is catalyzed by CYP3A4. Oxymorphone is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6 [see Drug Interactions ( 7 )] . Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. The major circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present. Excretion Oxycodone and its metabolites are excreted primarily via the kidney.

ajor circulating metabolite is noroxycodone with an AUC ratio of 0.6 relative to that of oxycodone. Oxymorphone is present in the plasma only in low concentrations. The analgesic activity profile of other metabolites is not known at present. Excretion Oxycodone and its metabolites are excreted primarily via the kidney. The amounts measured in the urine have been reported as follows: free oxycodone up to 19%; conjugated oxycodone up to 50%; free oxymorphone 0%; conjugated oxymorphone ≤ 14%; both free and conjugated noroxycodone have been found in the urine but not quantified. The total plasma clearance was 0.8 L/min for adults. Apparent elimination half-life of oxycodone following the administration of ROXYBOND was 3.8 to 4.3 hours. Specific Populations Age: Geriatric Patients Population pharmacokinetic studies conducted with oxycodone hydrochloride, indicated that the plasma concentrations of oxycodone did not appear to be increased in patients over the age of 65 [see Use in Specific Populations ( 8.5 )] . Hepatic Impairment In a clinical trial supporting the development of oxycodone hydrochloride tablets, too few patients with decreased hepatic function were evaluated to study these potential differences. However, because oxycodone is extensively metabolized in the liver, its clearance may decrease in hepatic impaired patients [see Use in Specific Populations ( 8.6 )] . Renal Impairment This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function [see Use in Specific Populations ( 8.7 )] .

<table ID="t4" width="100%"><caption>Table 4. Pharmacokinetic Parameters (Mean &#xB1; SD)</caption><col width="22.220%" align="left"/><col width="15.369%" align="left"/><col width="15.353%" align="left"/><col width="15.369%" align="left"/><col width="15.836%" align="left"/><col width="15.853%" align="left"/><tfoot><tr><td colspan="6" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><paragraph styleCode="footnote">^aMedian (range) </paragraph></td></tr></tfoot><tbody><tr><td align="left" styleCode="Toprule Botrule Lrule Rrule" valign="bottom"><content styleCode="bold">Dose\Parameters</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">AUC</content><content styleCode="bold">_0-t</content> <content styleCode="bold">(ng&#x2219;hr/mL)</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">AUC</content><content styleCode="bold">_0-inf</content><sub/><content styleCode="bold">(ng&#x2219;hr/mL)</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">C</content><content styleCode="bold">_max</content> <content styleCode="bold">(ng/mL)</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">T</content><content styleCode="bold">_max</content> <content styleCode="bold">(hr)</content></td><td align="center" styleCode="Toprule Botrule Rrule" valign="bottom"><content styleCode="bold">Half Life</content> <content styleCode="bold">(hr)</content></td></tr><tr><td colspan="6" align="center" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Single Dose Pharmacokinetics Study</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">ROXYBOND 5 mg tab (fasted) </td><td align="center" styleCode="Botrule Rrule" valign="top">45.5&#xB1;15.4</td><td align="center" styleCode="Botrule Rrule" valign="top">49.0&#xB1;16.1</td><td align="center" styleCode="Botrule Rrule" valign="top">8.3&#xB1;2.1</td><td align="center" styleCode="Botrule Rrule" valign="top">1.5 ^a (0.7 to 5.0) </td><td align="center" styleCode="Botrule Rrule" valign="top">3.9&#xB1;1.2</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">ROXYBOND 15 mg tab (fasted) </td><td align="center" styleCode="Botrule Rrule" valign="top">127.5&#xB1;38.1</td><td align="center" styleCode="Botrule Rrule" valign="top">131.6&#xB1;39.0</td><td align="center" styleCode="Botrule Rrule" valign="top">22.0&#xB1;5.8</td><td align="center" styleCode="Botrule Rrule" valign="top">1.7 ^a (1.0 to 12.0) </td><td align="center" styleCode="Botrule Rrule" valign="top">4.1&#xB1;0.8</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">ROXYBOND 30 mg tab (fasted) </td><td align="center" styleCode="Botrule Rrule" valign="top">277.0&#xB1;89.6</td><td align="center" styleCode="Botrule Rrule" valign="top">285.8&#xB1;94.1</td><td align="center" styleCode="Botrule Rrule" valign="top">48.5&#xB1;15.9</td><td align="center" styleCode="Botrule Rrule" valign="top">1.5 ^a (1.0 to 8.0) </td><td align="center" styleCode="Botrule Rrule" valign="top">4.3&#xB1;1.0</td></tr><tr><td colspan="6" align="center" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Single Dose Food-Effect Study</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">ROXYBOND 30

0) </td><td align="center" styleCode="Botrule Rrule" valign="top">4.3&#xB1;1.0</td></tr><tr><td colspan="6" align="center" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Single Dose Food-Effect Study</content></td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">ROXYBOND 30 mg tab (fasted) </td><td align="center" styleCode="Botrule Rrule" valign="top">287.4&#xB1;65.8</td><td align="center" styleCode="Botrule Rrule" valign="top">292.7&#xB1;67.4</td><td align="center" styleCode="Botrule Rrule" valign="top">57.8&#xB1;18.0</td><td align="center" styleCode="Botrule Rrule" valign="top">1.8 ^a (0.8 to 5.0) </td><td align="center" styleCode="Botrule Rrule" valign="top">3.8&#xB1;0.7</td></tr><tr><td align="left" styleCode="Botrule Lrule Rrule" valign="top">ROXYBOND 30 mg tab (fed) </td><td align="center" styleCode="Botrule Rrule" valign="top">354.2&#xB1;82.5</td><td align="center" styleCode="Botrule Rrule" valign="top">361.9&#xB1;86.7</td><td align="center" styleCode="Botrule Rrule" valign="top">68.0&#xB1;20.1</td><td align="center" styleCode="Botrule Rrule" valign="top">2.0 ^a (1.0 to 6.1) </td><td align="center" styleCode="Botrule Rrule" valign="top">3.9&#xB1;0.6</td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies have not been performed in animals to evaluate the carcinogenic potential of oxycodone. Mutagenesis Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay ( Salmonella typhimurium and Escherichia coli ) or in an assay for chromosomal aberrations ( in vivo mouse bone marrow micronucleus assay). Impairment of Fertility Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term studies have not been performed in animals to evaluate the carcinogenic potential of oxycodone. Mutagenesis Oxycodone hydrochloride was genotoxic in an in vitro mouse lymphoma assay in the presence of metabolic activation. There was no evidence of genotoxic potential in an in vitro bacterial reverse mutation assay ( Salmonella typhimurium and Escherichia coli ) or in an assay for chromosomal aberrations ( in vivo mouse bone marrow micronucleus assay). Impairment of Fertility Studies in animals to evaluate the potential impact of oxycodone on fertility have not been conducted.

16 HOW SUPPLIED/STORAGE AND HANDLING ROXYBOND (oxycodone hydrochloride) tablets are supplied as 5 mg, 10 mg, 15 mg, and 30 mg strength round and color coated tablets with ink-prints on one side. The tablets are packaged in 100 tablet opaque HDPE bottles. NDC Strength Tablet Shape Tablet Color Ink-Print on Tablet Side 1 Ink-Print on Tablet Side 2 81140-101-10 5 mg Round coated tablets White IDT/O 5 None 81140-104-10 10 mg Pink IDT/O 10 None 81140-102-10 15 mg Green IDT/O 15 None 81140-103-10 30 mg Blue IDT/O 30 None Dispense in a tight, light-resistant container, with a child-resistant closure. Protect from moisture. Store at controlled room temperature, 20°C to 25°C (68°F to 77°F), with excursions to 15°C to 30°C (59°F to 86°F). Store ROXYBOND securely and dispose of properly.

<table width="100%"><col width="18.964%" align="left"/><col width="14.364%" align="left"/><col width="16.664%" align="left"/><col width="16.664%" align="left"/><col width="16.681%" align="left"/><col width="16.664%" align="left"/><tbody><tr><td align="center" styleCode="Toprule Botrule Lrule Rrule" valign="top">NDC</td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle">Strength</td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle">Tablet Shape</td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle">Tablet Color </td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle">Ink-Print on Tablet Side 1 </td><td align="center" styleCode="Toprule Botrule Rrule" valign="middle">Ink-Print on Tablet Side 2 </td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">81140-101-10</td><td align="center" styleCode="Botrule Rrule" valign="middle">5 mg</td><td rowspan="4" align="center" styleCode="Botrule Rrule" valign="middle">Round coated tablets </td><td align="center" styleCode="Botrule Rrule" valign="middle">White</td><td align="center" styleCode="Botrule Rrule" valign="middle">IDT/O 5</td><td align="center" styleCode="Botrule Rrule" valign="middle">None</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">81140-104-10</td><td align="center" styleCode="Botrule Rrule" valign="middle">10 mg</td><td align="center" styleCode="Botrule Rrule" valign="middle">Pink</td><td align="center" styleCode="Botrule Rrule" valign="middle">IDT/O 10</td><td align="center" styleCode="Botrule Rrule" valign="middle">None</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">81140-102-10</td><td align="center" styleCode="Botrule Rrule" valign="middle">15 mg</td><td align="center" styleCode="Botrule Rrule" valign="middle">Green</td><td align="center" styleCode="Botrule Rrule" valign="middle">IDT/O 15</td><td align="center" styleCode="Botrule Rrule" valign="middle">None</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top">81140-103-10</td><td align="center" styleCode="Botrule Rrule" valign="middle">30 mg</td><td align="center" styleCode="Botrule Rrule" valign="middle">Blue</td><td align="center" styleCode="Botrule Rrule" valign="middle">IDT/O 30</td><td align="center" styleCode="Botrule Rrule" valign="middle">None</td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Storage and Disposal: Because of the risks associated with accidental ingestion, misuse, and abuse, advise patients to store ROXYBOND securely, out of sight and reach of children, and in a location not accessible by others, including visitors to the home. Inform patients that leaving ROXYBOND unsecured can pose a deadly risk to others in the home [see Warnings and Precautions ( 5.1 , 5.2 ), Drug Abuse and Dependence ( 9.2 )] . Advise patients and caregivers that when medicines are no longer needed, they should be disposed of promptly. Expired, unwanted, or unused ROXYBOND should be disposed of by flushing the unused medication down the toilet if a drug take-back option is not readily available. Inform patients that they can visit www.fda.gov/drugdisposal for a complete list of medicines recommended for disposal by flushing, as well as additional information on disposal of unused medicines. Addiction, Abuse, and Misuse Inform patients that the use of ROXYBOND, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdose and death [see Warnings and Precautions ( 5.1 ), Drug Abuse and Dependence ( 9.2 )] . Instruct patients not to share ROXYBOND with others and to take steps to protect ROXYBOND from theft and misuse. Life-Threatening Respiratory Depression Inform patients of the risk of life-threatening respiratory depression, including information that the risk is greatest when starting ROXYBOND or when the dosage is increased, and that it can occur even at recommended dosages. Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose [see Warnings and Precautions ( 5.2 ), Overdosage ( 10 )] . Accidental Ingestion Inform patients that accidental ingestion, especially by children, may result in respiratory depression or death [see Warnings and Precautions ( 5.2 )] . Interactions with Benzodiazepines and Other CNS Depressants Inform patients and caregivers that potentially fatal additive effects may occur if ROXYBOND is used with benzodiazepines or other CNS depressants, including alcohol (e.g., non-benzodiazepine sedative/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, gabapentinoids [gabapentin or pregabalin], and other opioids), and not to use these concomitantly unless supervised by a healthcare provider [see Warnings and Precautions ( 5.3 ), Drug Interactions ( 7 )] . Patient Access to an Opioid Overdose Reversal Agent for the Emergency Treatment of Opioid Overdose Inform patients and caregivers about opioid overdose reversal agents (e.g., naloxone, nalmefene). Discuss the importance of having access to an opioid overdose reversal agent, especially if the patient has risk factors for overdose (e.g., concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose) or if there are household members (including children) or other close contacts at risk for accidental ingestion or opioid overdose. Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage ( 10 )] .

s at risk for accidental ingestion or opioid overdose. Discuss with the patient the options for obtaining an opioid overdose reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program) [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.1 , 5.3 ), Overdosage ( 10 )] . Educate patients and caregivers on how to recognize the signs and symptoms of an overdose. Explain to patients and caregivers that effects of opioid overdose reversal agents like naloxone and nalmefene are temporary, and that they must call 911 or get emergency medical help right away in all cases of known or suspected opioid overdose, even if an opioid overdose reversal agent is administered [see Overdosage ( 10 )] . Advise patients and caregivers: how to treat with the overdose reversal agent in the event of an opioid overdose. to tell family and friends about their opioid overdose reversal agent, and to keep it in a place where family and friends can access it in an emergency. to read the Patient Information (or other educational material) that will come with their opioid overdose reversal agent. Emphasize the importance of doing this before an opioid emergency happens, so the patient and caregiver will know what to do. Hyperalgesia and Allodynia Inform patients and caregivers not to increase opioid dosage without first consulting a clinician. Advise patients to seek medical attention if they experience symptoms of hyperalgesia, including worsening pain, increased sensitivity to pain, or new pain [see Warnings and Precautions ( 5.7 ), Adverse Reactions ( 6.2 )] . Serotonin Syndrome Inform patients that opioids could cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs. Warn patients of the symptoms of serotonin syndrome and to seek medical attention right away if symptoms develop. Instruct patients to inform their healthcare providers if they are taking, or plan to take serotonergic medication [see Drug Interactions ( 7 )] . MAOI Interaction Inform patients to avoid taking ROXYBOND while using any drugs that inhibit monoamine oxidase. Patients should not start MAOIs while taking ROXYBOND [see Drug Interactions ( 7 )] . Important Administration Instructions Instruct patients how to properly take ROXYBOND. Patients should be advised not to adjust the dose of ROXYBOND without consulting the prescribing healthcare provider [see Dosage and Administration ( 2 ), Warnings and Precautions ( 5.14 )] . Inform patients taking ROXYBOND that the medicine is absorbed by the body and the part of the tablet that contains inactive ingredients is eliminated from the body; patients may notice something that looks like a tablet in their stool. Important Discontinuation Instructions In order to avoid developing withdrawal symptoms, instruct patients not to discontinue ROXYBOND without first discussing a tapering plan with the prescriber [see Dosage and Administration ( 2.5 )] . Driving or Operating Machinery Inform patients that ROXYBOND may impair the ability to perform potentially hazardous activities such as driving a car or operating dangerous machinery. Advise patients not to perform such tasks until they know how they will react to the medication [see Warnings and Precautions ( 5.15 )] . Constipation Advise patients of the potential for severe constipation, including management instructions and when to seek medical attention [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.2 )] . Healthcare professionals can telephone Protega Pharmaceuticals Inc. (1-844-798-3610) for information on this product. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition.

ttention [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.2 )] . Healthcare professionals can telephone Protega Pharmaceuticals Inc. (1-844-798-3610) for information on this product. Adrenal Insufficiency Inform patients that opioids could cause adrenal insufficiency, a potentially life-threatening condition. Adrenal insufficiency may present with non-specific symptoms and signs such as nausea, vomiting, anorexia, fatigue, weakness, dizziness and low blood pressure. Advise patients to seek medical attention if they experience a constellation of these symptoms [see Warnings and Precautions ( 5.9 )] . Hypotension Inform patients that ROXYBOND may cause orthostatic hypotension and syncope. Instruct patients how to recognize symptoms of low blood pressure and how to reduce the risk of serious consequences should hypotension occur (e.g., sit or lie down, carefully rise from sitting or lying position) [see Warnings and Precautions ( 5.10 )] . Anaphylaxis Inform patients that anaphylaxis has been reported with ingredients contained in ROXYBOND. Advise patients how to recognize such a reaction and when to seek medical attention [see Contraindications ( 4 ), Adverse Reactions ( 6.2 )] . Pregnancy Neonatal Opioid Withdrawal Syndrome Inform female patients of reproductive potential that use of ROXYBOND for an extended period of time during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated [see Warnings and Precautions ( 5.4 ), Use in Specific Populations ( 8.1 )] . Embryo-Fetal Toxicity Inform female patients of reproductive potential that ROXYBOND can cause fetal harm and to inform their healthcare provider of a known or suspected pregnancy [see Use in Specific Populations ( 8.1 )] . Lactation Advise breastfeeding women using ROXYBOND to carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Instruct breastfeeding women to seek immediate medical care if they notice these signs [see Use in Specific Populations ( 8.2 )] . Infertility Inform patients that use of opioids for an extended period of time may cause reduced fertility. It is not known whether these effects on fertility are reversible [see Use in Specific Populations ( 8.3 )] . Manufactured for: Protega Pharmaceuticals Inc. Princeton, NJ 08540 (C) 2025, Protega Pharmaceuticals Inc. GK-425

This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: December 2025 GK-426 Medication Guide ROXYBOND (\'räk-sē- ‘bänd\) (oxycodone hydrochloride) tablets USP, CII ROXYBOND is: A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them. An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death. Important information about ROXYBOND: Get emergency help or call 911 right away if you take too much ROXYBOND (overdose). When you first start taking ROXYBOND, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose. Taking ROXYBOND with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death. Never give anyone else your ROXYBOND. They could die from taking it. Selling or giving away ROXYBOND is against the law. Store ROXYBOND securely, out of sight and reach of children and in a location not accessible by others, including visitors to the home. Do not take ROXYBOND if you have: severe asthma, trouble breathing, or other lung problems. a bowel blockage or have narrowing of the stomach or intestines. allergy to oxycodone. Before taking ROXYBOND, tell your healthcare provider if you have a history of: head injury, seizures problems urinating liver, kidney, thyroid problems pancreas or gallbladder problems abuse of street or prescription drugs, alcohol addiction, opioid overdose or mental health problems. Tell your healthcare provider if you are: noticing your pain getting worse. If your pain gets worse after you take ROXYBOND, do not take more of ROXYBOND without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking ROXYBOND. pregnant or planning to become pregnant. Use of ROXYBOND for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. breastfeeding. ROXYBOND passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. Living in a household where there are small children or someone who has abused street or prescription drugs. taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking ROXYBOND with certain other medicines can cause serious side effects that could lead to death. When taking ROXYBOND: Do not change your dose. Take ROXYBOND exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. For acute (short-term) pain, you may only need to take ROXYBOND for a few days.

er medicines can cause serious side effects that could lead to death. When taking ROXYBOND: Do not change your dose. Take ROXYBOND exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed. For acute (short-term) pain, you may only need to take ROXYBOND for a few days. You may have some ROXYBOND left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused ROXYBOND. Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time. Call your healthcare provider if the dose you are taking does not control your pain. If you have been taking ROXYBOND regularly, do not stop taking ROXYBOND without talking to your healthcare provider. Dispose of expired, unwanted, or unused ROXYBOND by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines. While taking ROXYBOND DO NOT: Drive or operate heavy machinery, until you know how ROXYBOND affects you. ROXYBOND can make you sleepy, dizzy, or lightheaded. Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with ROXYBOND may cause you to overdose and die. The possible side effects of ROXYBOND are: constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe. Get emergency medical help or call 911 right away if you have: trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion. These are not all the possible side effects of ROXYBOND. Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov Manufactured for: Protega Pharmaceuticals Inc.

<table width="100%"><col width="30.000%" align="left"/><col width="49.000%" align="left"/><col width="21.000%" align="left"/><tfoot><tr><td colspan="2" align="left" valign="top"><paragraph styleCode="footnote">This Medication Guide has been approved by the U.S. Food and Drug Administration.</paragraph></td><td align="right" valign="top"><paragraph styleCode="footnote">Issued: December 2025</paragraph></td></tr><tr><td colspan="3" align="left" valign="top"><paragraph styleCode="footnote">GK-426</paragraph></td></tr></tfoot><tbody><tr><td colspan="3" align="left" styleCode="Toprule Botrule Lrule Rrule" valign="top"><content styleCode="bold">Medication Guide</content> <content styleCode="bold">ROXYBOND (\&apos;r&#xE4;k-s&#x113;- &#x2018;b&#xE4;nd\)</content> <content styleCode="bold">(oxycodone hydrochloride) tablets USP, CII</content></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">ROXYBOND is:</content> <list listType="unordered" styleCode="Disc"><item>A strong prescription pain medicine that contains an opioid (narcotic) that is used to manage pain severe enough to require an opioid pain medicine, when other pain treatments such as non-opioid pain medicines do not treat your pain well enough or you cannot tolerate them.</item><item>An opioid pain medicine that can put you at risk for overdose and death. Even if you take your dose correctly as prescribed you are at risk for opioid addiction, abuse, and misuse that can lead to death.</item></list></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Important information about ROXYBOND:</content> <list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Get emergency help or call 911 right away if you take too much ROXYBOND (overdose).</content>When you first start taking ROXYBOND, when your dose is changed, or if you take too much (overdose), serious or life-threatening breathing problems that can lead to death may occur. Ask your healthcare provider about medicines like naloxone or nalmefene that can be used in an emergency to reverse an opioid overdose. </item><item>Taking ROXYBOND with other opioid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</item><item>Never give anyone else your ROXYBOND. They could die from taking it.

oid medicines, benzodiazepines, gabapentinoids (gabapentin or pregabalin), alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, decreased awareness, breathing problems, coma, and death.</item><item>Never give anyone else your ROXYBOND. They could die from taking it. Selling or giving away ROXYBOND is against the law.</item><item>Store ROXYBOND securely, out of sight and reach of children and in a location not accessible by others, including visitors to the home.</item></list></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Do not take ROXYBOND if you have:</content> <list listType="unordered" styleCode="Disc"><item>severe asthma, trouble breathing, or other lung problems.</item><item>a bowel blockage or have narrowing of the stomach or intestines.</item><item>allergy to oxycodone.</item></list></td></tr><tr><td colspan="3" align="left" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Before taking ROXYBOND, tell your healthcare provider if you have a history of:</content></td></tr><tr><td align="left" styleCode="Lrule" valign="top"><list listType="unordered" styleCode="Disc"><item>head injury, seizures</item><item>problems urinating </item></list></td><td align="left" valign="top"><list listType="unordered" styleCode="Disc"><item>liver, kidney, thyroid problems</item><item>pancreas or gallbladder problems</item></list></td><td align="left" styleCode="Rrule" valign="top"/></tr><tr><td colspan="3" align="left" styleCode="Lrule Rrule" valign="top"><list listType="unordered" styleCode="Disc"><item>abuse of street or prescription drugs, alcohol addiction, opioid overdose or mental health problems.</item></list></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">Tell your healthcare provider if you are:</content> <list listType="unordered" styleCode="Disc"><item><content styleCode="bold">noticing your pain getting worse.</content>If your pain gets worse after you take ROXYBOND, do not take more of ROXYBOND without first talking to your healthcare provider. Talk to your healthcare provider if the pain that you have increases, if you feel more sensitive to pain, or if you have new pain after taking ROXYBOND. </item><item><content styleCode="bold">pregnant or planning to become pregnant.</content>Use of ROXYBOND for an extended period of time during pregnancy can cause withdrawal symptoms in your newborn baby that could be life-threatening if not recognized and treated. </item><item><content styleCode="bold">breastfeeding.</content>ROXYBOND passes into breast milk and may harm your baby. Carefully observe infants for increased sleepiness (more than usual), breathing difficulties, or limpness. Seek immediate medical care if you notice these signs. </item><item>Living in a household where there are small children or someone who has abused street or prescription drugs.</item><item>taking prescription or over-the-counter medicines, vitamins, or herbal supplements. Taking ROXYBOND with certain other medicines can cause serious side effects that could lead to death.</item></list></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">When taking ROXYBOND:</content> <list listType="unordered" styleCode="Disc"><item>Do not change your dose. Take ROXYBOND exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</item><item>For acute (short-term) pain, you may only need to take ROXYBOND for a few days. You may have some ROXYBOND left over that you did not use.

yleCode="Disc"><item>Do not change your dose. Take ROXYBOND exactly as prescribed by your healthcare provider. Use the lowest dose possible for the shortest time needed.</item><item>For acute (short-term) pain, you may only need to take ROXYBOND for a few days. You may have some ROXYBOND left over that you did not use. See disposal information at the bottom of this section for directions on how to safely throw away (dispose of) your unused ROXYBOND.</item><item>Take your prescribed dose every 4 to 6 hours as needed for pain. Do not take more than your prescribed dose. If you miss a dose, take your next dose at your usual time.</item><item>Call your healthcare provider if the dose you are taking does not control your pain.</item><item>If you have been taking ROXYBOND regularly, do not stop taking ROXYBOND without talking to your healthcare provider.</item><item>Dispose of expired, unwanted, or unused ROXYBOND by promptly flushing down the toilet, if a drug take-back option is not readily available. Visit www.fda.gov/drugdisposal for additional information on disposal of unused medicines.</item></list></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top"><content styleCode="bold">While taking ROXYBOND DO NOT:</content> <list listType="unordered" styleCode="Disc"><item>Drive or operate heavy machinery, until you know how ROXYBOND affects you. ROXYBOND can make you sleepy, dizzy, or lightheaded.</item><item>Drink alcohol or use prescription or over-the-counter medicines that contain alcohol. Using products containing alcohol during treatment with ROXYBOND may cause you to overdose and die.</item></list></td></tr><tr><td colspan="3" align="left" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">The possible side effects of ROXYBOND are:</content> <list listType="unordered" styleCode="Disc"><item>constipation, nausea, sleepiness, vomiting, tiredness, headache, dizziness, abdominal pain. Call your healthcare provider if you have any of these symptoms and they are severe.</item></list></td></tr><tr><td colspan="3" align="left" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Get emergency medical help or call 911 right away if you have:</content> <list listType="unordered" styleCode="Disc"><item>trouble breathing, shortness of breath, fast heartbeat, chest pain, swelling of your face, tongue, or throat, extreme drowsiness, light-headedness when changing positions, feeling faint, agitation, high body temperature, trouble walking, stiff muscles, or mental changes such as confusion.</item></list></td></tr><tr><td colspan="3" align="left" styleCode="Botrule Lrule Rrule" valign="top">These are not all the possible side effects of ROXYBOND. Call your healthcare provider for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088. For more information go to dailymed.nlm.nih.gov Manufactured for: Protega Pharmaceuticals Inc. </td></tr></tbody></table>