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Naloxone Hydrochloride Injection, USP is a sterile, nonpyrogenic solution of naloxone hydrochloide in water for injection. Each milliliter (mL) contains 0.4 mg naloxone hydrochloride and sodium chloride to adjust tonicity in water for injection. May contain hydrochloric acid for pH adjustment; pH 4.0 (3.0 to 6.5). The multiple-dose solution contains, in addition, 1.8 mg/mL methylparaben and 0.2 mg/mL propylparaben added as preservatives. Naloxone Hydrochloride Injection, USP may be administered intravenously, intramuscularly, or subcutaneously. Naloxone, an opioid antagonist, is a synthetic congener of oxymorphone. It differs from oxymorphone in that the methyl group on the nitrogen atom is replaced by an allyl group. Naloxone Hydrochloride, USP is chemically designated 17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride (C19H21NO4 • HCl), a white to slightly off-white powder soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and chloroform. It has a molecular weight of 363.84. It has the following structural formula: structure

Complete or Partial Reversal of Opioid Depression Naloxone prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, Naloxone can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine. Naloxone is an essentially pure opioid antagonist, i.e., it does not possess the "agonistic" or morphine-like properties characteristic of other opioid antagonists. When administered in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity. Naloxone has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on opioids, naloxone will produce withdrawal symptoms. However, in the presence of opioid dependence, opiate withdrawal symptoms may appear within minutes of naloxone administration and will subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the dose of naloxone and to the degree and type of opioid dependence. While the mechanism of action of naloxone is not fully understood, in vitro evidence suggests that naloxone antagonizes opioid effects by competing for the mu, kappa, and sigma opiate receptor sites in the CNS, with the greatest affinity for the mu receptor. When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes; the onset of action is slightly less rapid when it is administered subcutaneously or intramuscularly. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride. Intramuscular administration produces a more prolonged effect than intravenous administration. Since the duration of action of naloxone may be shorter than that of some opiates, the effects of the opiate may return as the effects of naloxone dissipates. The requirement for repeat doses of naloxone, however, will also be dependent upon the amount, type and route of administration of the opioid being antagonized. Adjunctive Use in Septic Shock Naloxone has been shown in some cases of septic shock to produce a rise in blood pressure that may last up to several hours; however this pressor response has not been demonstrated to improve patient survival. In some studies, treatment with naloxone in the setting of septic shock has been associated with adverse effects, including agitation, nausea and vomiting, pulmonary edema, hypotension, cardiac arrhythmias, and seizures. The decision to use naloxone in septic shock should be exercised with caution, particularly in patients who may have underlying pain or have previously received opioid therapy and may have developed opioid tolerance. Because of the limited number of patients who have been treated, optimal dosage and treatment regimens have not been established.

Distribution Following parenteral administration, naloxone is rapidly distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk. Metabolism and Elimination Naloxone is metabolized in the liver primarily by glucuronide conjugation with naloxone-3-glucuronide as the major metabolite. In one study, the serum half-life in adults ranged from 30 to 81 minutes (mean 64 ± 12 minutes). In a neonatal study, the mean plasma half-life was observed to be 3.1 ± 0.5 hours. After an oral or intravenous dose, about 25 to 40% of the drug is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours.

Naloxone Hydrochloride Injection is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids including propoxyphene, methadone, and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclazocine. Naloxone hydrochloride is also indicated for the diagnosis of suspected or known acute opioid overdosage. Naloxone may be useful as an adjunctive agent to increase blood pressure in the management of septic shock (see CLINICAL PHARMACOLOGY; Adjunctive Use in Septic Shock).

Drug Dependence Naloxone hydrochloride injection should be administered cautiously to persons, including newborns of mothers, who are known or suspected to be physically dependent on opioids. In such cases an abrupt and complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The signs and symptoms of opioid withdrawal in a patient physically dependent on opioids may include, but are not limited to, the following: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In the neonate, opioid withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes. Repeat Administration The patient who has satisfactorily responded to naloxone should be kept under continued surveillance and repeated doses of naloxone should be administered, as necessary, since the duration of action of some opioids may exceed that of naloxone. Respiratory Depression Due to Other Drugs Naloxone is not effective against respiratory depression due to non-opioid drugs and in the management of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete or require higher doses of naloxone. If an incomplete response occurs, respirations should be mechanically assisted as clinically indicated.

General In addition to naloxone, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning. Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults, Postoperative Opioid Depression). Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had pre-existing cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone should be used with caution in patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects such as hypotension, ventricular tachycardia or fibrillation and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures. Drug Interactions Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals to assess the carcinogenic potential of naloxone have not been conducted. Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study. Reproduction studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m2), demonstrated no embryotoxic or teratogenic effects due to naloxone. Use in Pregnancy: Teratogenic Effects: Pregnancy Category C Teratology studies conducted in mice and rats at doses 4-times and 8- times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m2), demonstrated no embryotoxic or teratogenic effects due to naloxone. There are, however, no adequate and well controlled studies in pregnant women.

C Teratology studies conducted in mice and rats at doses 4-times and 8- times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m2), demonstrated no embryotoxic or teratogenic effects due to naloxone. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, naloxone hydrochloride should be used during pregnancy only if clearly needed. Non-teratogenic effects: Risk-benefit must be considered before naloxone is administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur. Use in Labor and Delivery It is not known if naloxone hydrochloride injection affects the duration of labor and/or delivery. However, published reports indicated that the administration of naloxone during labor did not adversely affect maternal or neonatal status. Nursing Mothers It is not known whether naloxone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naloxone hydrochloride is administered to a nursing woman. Pediatric Use Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds dramatically to naloxone hydrochloride injection, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized. When naloxone hydrochloride injection is given to the mother shortly before delivery, the duration of its effects lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride injection directly to the neonate if needed after delivery. Naloxone has no apparent benefit as an additional method of resuscitation in the newly born infant with intrauterine asphyxia, which is not related to opioid use. Usage in Pediatric Patients and Neonates for Septic Shock: The safety and effectiveness of naloxone hydrochloride injection in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures. Geriatric Use Clinical studies of naloxone hydrochloride injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, 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. Renal Insufficiency/Failure The safety and effectiveness of Naloxone hydrochloride injection in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when Naloxone is administered to this patient population.

ant disease or other drug therapy. Renal Insufficiency/Failure The safety and effectiveness of Naloxone hydrochloride injection in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when Naloxone is administered to this patient population. Liver Disease The safety and effectiveness of naloxone hydrochloride injection in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when naloxone is administered to patients with liver disease.

Postoperative The following adverse events have been associated with the use of naloxone hydrochloride injection in postoperative patients: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of naloxone in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults, Postoperative Opioid Depression). Opioid Depression Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death (see PRECAUTIONS). Opioid Dependence Abrupt reversal of opioid effects in persons who are physically dependent on opioids may precipitate an acute withdrawal syndrome which may include, but is not limited to the following signs and symptoms: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, and tachycardia. In the neonate, opioid withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes (See WARNINGS). Adverse events associated with the postoperative use of naloxone hydrochloride injection are listed by organ system and in decreasing order of frequency as follows: Cardiac Disorders: pulmonary edema, cardiac arrest or failure, tachycardia, ventricular fibrillation, and ventricular tachycardia. Death, coma, and encephalopathy have been reported as sequelae of these events. Gastrointestinal Disorders: vomiting, nausea Nervous System Disorders: convulsions, paraesthesia, grand mal convulsion Psychiatric Disorders: agitation, hallucination, tremulousness Respiratory, Thoracic, and Mediastinal Disorders: dyspnea, respiratory depression, hypoxia Skin and Subcutaneous Tissue Disorders: nonspecific injection site reactions, sweating Vascular Disorders: hypertension, hypotension, hot flashes or flushing See also PRECAUTIONS and DOSAGE AND ADMINISTRATION; Usage in Adults, Postoperative Opioid Depression.

Naloxone hydrochloride injection is an opioid antagonist. Physical dependence associated with the use of naloxone hydrochloride injection has not been reported. Tolerance to the opioid antagonist effect of naloxone is not known to occur

There is limited clinical experience with naloxone hydrochloride injection overdosage in humans. Adult Patients In one small study, volunteers who received 24 mg/70 kg did not demonstrate toxicity. In another study, 36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/m2/min) of naloxone hydrochloride injection followed immediately by 2 mg/kg/hr for 24 hours. Twenty-three patients experienced adverse events associated with naloxone use, and naloxone was discontinued in seven patients because of adverse effects. The most serious adverse events were: seizures (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3). At doses of 2 mg/kg in normal subjects, cognitive impairment and behavioral symptoms, including irritability, anxiety, tension, suspiciousness, sadness, difficulty concentrating, and lack of appetite have been reported. In addition, somatic symptoms, including dizziness, heaviness, sweating, nausea, and stomachaches were also reported. Although complete information is not available, behavioral symptoms were reported to often persist for 2 to 3 days. Pediatric Patients Up to 11 doses of 0.2 mg naloxone (2.2 mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 2½ year-old child who inadvertently received a dose of 20 mg naloxone for treatment of respiratory depression following overdose with diphenoxylate hydrochloride with atropine sulfate. The child responded well and recovered without adverse sequelae. There is also a report of a 4½ year-old child who received 11 doses during a 12-hour period, with no adverse sequelae. Patient Management Patients who experience a naloxone overdose should be treated symptomatically in a closely supervised environment. Physicians should contact a poison control center for the most up-to-date patient management information.

Naloxone Hydrochloride Injection, may be administered intravenously, intramuscularly, or subcutaneously. The most rapid onset of action is achieved by intravenous administration and it is recommended in emergency situations. Since the duration of action of some opioids may exceed that of naloxone, the patient should be kept under continued surveillance. Repeated doses of naloxone should be administered, as necessary. Intravenous Infusion: Naloxone Hydrochloride Injection, may be diluted for intravenous infusion in 0.9% sodium chloride injection or 5% dextrose injection. The addition of 2 mg of naloxone hydrochloride in 500 mL of either solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24 hours, the remaining unused solution must be discarded. The rate of administration should be titrated in accordance with the patient's response. Naloxone Hydrochloride Injection, should not be mixed with preparations containing bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH. No drug or chemical agent should be added to Naloxone Hydrochloride Injection, unless its effect on the chemical and physical stability of the solution has first been established. General Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Do not administer unless solution is clear and container is undamaged. Usage in Adults: Opioid Overdose—Known or Suspected: An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions are not obtained, it may be repeated at two to three minute intervals. If no response is observed after 10 mg of naloxone hydrochloride have been administered, the diagnosis of opioid-induced or partial opioid-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available Postoperative Opioid Depression: For the partial reversal of opioid depression following the use of opioids during surgery, smaller doses of naloxone hydrochloride are usually sufficient. The dose of naloxone should be titrated according to the patient's response. For the initial reversal of respiratory depression, naloxone hydrochloride should be injected in increments of 0.1 to 0.2 mg intravenously at two to three minute intervals to the desired degree of reversal, i.e., adequate ventilation and alertness without significant pain or discomfort. Larger than necessary dosage of naloxone may result in significant reversal of analgesia and increase in blood pressure. Similarly, too rapid reversal may induce nausea, vomiting, sweating or circulatory stress. Repeat doses of naloxone may be required within one to two hour intervals depending upon the amount, type (i.e., short or long acting) and time interval since last administration of an opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect. Septic Shock: The optimal dosage of Naloxone or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY). Usage in Pediatric Population: Opioid Overdose – Known or Suspected: The usual initial dose in children is 0.01 mg/kg body weight given intravenously.

ck: The optimal dosage of Naloxone or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY). Usage in Pediatric Population: Opioid Overdose – Known or Suspected: The usual initial dose in children is 0.01 mg/kg body weight given intravenously. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be administered. If an intravenous route of administration is not available, naloxone may be administered intramuscularly or subcutaneously in divided doses. If necessary, naloxone hydrochloride injection can be diluted with sterile water for injection. Postoperative Opioid Depression: Follow the recommendations and cautions under Adult Postoperative Opioid Depression. For the initial reversal of respiratory depression naloxone hydrochloride should be injected in increments of 0.005 mg to 0.01 mg intravenously at two to three minute intervals to the desired degree of reversal. Opioid-Induced Depression: The usual initial dose is 0.01 mg/kg body weight administered intravenously, intramuscularly or subcutaneously. This dose may be repeated in accordance with adult administration guidelines for postoperative opioid depression.

Naloxone Hydrochloride Injection USP, 4 mg/10 mL (0.4 mg/mL) is a clear, colorless solution. Naloxone Hydrochloride Injection USP, 4 mg/10 mL (0.4 mg/mL) for intravenous, intramuscular, and subcutaneous administration is available as: NDC 51662-1673-1 - 10 mL vials are Multiple-Dose Vials, packaged as monocarton. Store at 20° to 25°C (68° to 77°F). [see USP Controlled Room Temperature]. Protect from light. Store in the carton until contents have been used. Discard unused portion. For Product Inquiry call 1-800-417-9175. Manufactured for: Somerset Therapeutics, LLC Hollywood, FL 33024 Distributed By: HF Acquisition Co LLC dba HealthFirst 11629 49th Pl W, Mukilteo, WA 98275

Opioid Antagonist Rx Only Hospira Logo PHARMACOKINETICS Distribution Following parenteral administration, naloxone is rapidly distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk. Metabolism and Elimination Naloxone is metabolized in the liver primarily by glucuronide conjugation with naloxone-3-glucuronide as the major metabolite. In one study, the serum half-life in adults ranged from 30 to 81 minutes (mean 64 ± 12 minutes). In a neonatal study, the mean plasma half-life was observed to be 3.1 ± 0.5 hours. After an oral or intravenous dose, about 25-40% of the drug is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.

serum half-life in adults ranged from 30 to 81 minutes (mean 64 ± 12 minutes). In a neonatal study, the mean plasma half-life was observed to be 3.1 ± 0.5 hours. After an oral or intravenous dose, about 25-40% of the drug is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours. USAGE IN ADULTS Opioid Overdose – Known or Suspected : An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions is not obtained, it may be repeated at two to three minute intervals. If no response is observed after 10 mg of naloxone hydrochloride have been administered, the diagnosis of opioid-induced or partial opioid-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available. Postoperative Opioid-Induced Depression: For the partial reversal of opioid depression following the use of opioids during surgery, smaller doses of naloxone hydrochloride are usually sufficient. The dose of naloxone hydrochloride should be titrated according to the patient's response. For the initial reversal of respiratory depression, naloxone hydrochloride should be injected in increments of 0.1 to 0.2 mg intravenously at two to three minute intervals to the desired degree of reversal, i.e., adequate ventilation and alertness without significant pain or discomfort. Larger than necessary dosage of naloxone may result in significant reversal of analgesia and increase in blood pressure. Similarly, too rapid reversal may induce nausea, vomiting, sweating or circulatory stress. Repeat doses of naloxone may be required within one to two hour intervals depending upon the amount, type (i.e., short or long acting) and time interval since last administration of opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect. Septic Shock: The optimal dosage of naloxone hydrochloride or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY ).

val since last administration of opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect. Septic Shock: The optimal dosage of naloxone hydrochloride or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY ). USAGE IN CHILDREN Opioid Overdose – Known or Suspected: The usual initial dose in children is 0.01 mg/kg body weight given intravenously. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be administered. If an intravenous route of administration is not available, naloxone may be administered intramuscularly or subcutaneously in divided doses. If necessary, naloxone hydrochloride injection can be diluted with sterile water for injection. Postoperative Opioid Depression: Follow the recommendations and cautions under Adult Postoperative Opioid Depression . For the initial reversal of respiratory depression naloxone hydrochloride should be injected in increments of 0.005 mg to 0.01 mg intravenously at two to three minute intervals to the desired degree of reversal. USAGE IN NEONATES Opioid-Induced Depression: The usual initial dose is 0.01 mg/kg body weight administered intravenously, intramuscularly or subcutaneously. This dose may be repeated in accordance with adult administration guidelines for postoperative opioid depression.

DESCRIPTION Naloxone hydrochloride, an opioid antagonist, is a synthetic congener of oxymorphone. In structure it differs from oxymorphone in that the methyl group on the nitrogen atom is replaced by an allyl group. It is known chemically as 17-allyl-4,5α-epoxy,3-14-dihydroxymorphinan-6-one hydrochloride. It has a molecular weight of 363.84, and the following structural formula: Naloxone hydrochloride occurs as a white to slightly off-white powder, and is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform. Naloxone hydrochloride injection is available as a sterile solution for intravenous, intramuscular, and subcutaneous administration. Each mL contains 0.4 mg of naloxone hydrochloride. Each mL contains 8.9 mg of sodium chloride. The pH is adjusted between 3.0 to 6.5 with hydrochloric acid or sodium hydroxide. The air in the cartridges has been displaced by nitrogen gas. Naloxone Formula

CLINICAL PHARMACOLOGY Naloxone prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine. Naloxone is an essentially pure opioid antagonist, i.e., it does not possess the "agonistic" or morphine-like properties characteristic of other opioid antagonists. When administered in usual doses in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity. Naloxone has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on opioids, naloxone will produce withdrawal symptoms. However, in the presence of opioid dependence, withdrawal symptoms will appear within minutes of naloxone administration and will subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the dose of naloxone and to the degree and type of dependence. While the mechanism of action of naloxone is not fully understood, in vitro evidence suggests that naloxone antagonizes opioid effects by competing for the mu, kappa, and sigma opiate receptor sites in the CNS, with the greatest affinity for the mu receptor. When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes; the onset of action is slightly less rapid when it is administered subcutaneously or intramuscularly. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride. Intramuscular administration produces a more prolonged effect than intravenous administration. Since the duration of action of naloxone may be shorter than that of some opiates, the effects of the opiate may return as the effects of naloxone dissipate. The requirement for repeat doses of naloxone will also be dependent upon the amount, type and route of administration of the opioid being antagonized. Adjunctive Use in Septic Shock Naloxone has been shown in some cases of septic shock to produce a rise in blood pressure that may last up to several hours; however this pressor response has not been demonstrated to improve patient survival. In some studies, treatment with naloxone in the setting of septic shock has been associated with adverse effects, including agitation, nausea and vomiting, pulmonary edema, hypotension, cardiac arrhythmias, and seizures. The decision to use naloxone in septic shock should be exercised with caution, particularly in patients who may have underlying pain or have previously received opioid therapy and may have developed opioid tolerance. Because of the limited number of patients who have been treated, optimal dosage and treatment regimens have not been established.

INDICATIONS AND USAGE Naloxone hydrochloride injection is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids including propoxyphene, methadone, and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclazocine. Naloxone hydrochloride is also indicated for the diagnosis of suspected or known acute opioid overdosage. Naloxone hydrochloride injection may be useful as an adjunctive agent to increase blood pressure in the management of septic shock (see CLINICAL PHARMACOLOGY : Adjunctive Use in Septic Shock ).

WARNINGS Drug Dependence Naloxone hydrochloride injection should be administered cautiously to persons including newborns of mothers who are known or suspected to be physically dependent on opioids. In such cases, an abrupt and complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The signs and symptoms of opioid withdrawal in a patient physically dependent on opioids may include, but are not limited to, the following: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In the neonate, opioid withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes. Repeat Administration The patient who has satisfactorily responded to naloxone should be kept under continued surveillance and repeated doses of naloxone should be administered, as necessary, since the duration of action of some opioids may exceed that of naloxone. Respiratory Depression Due to Other Drugs Naloxone is not effective against respiratory depression due to non-opioid drugs and in the management of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete or require higher doses of naloxone. If an incomplete response occurs, respirations should be mechanically assisted as clinically indicated.

PRECAUTIONS General In addition to naloxone, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning. Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION : USAGE IN ADULTS , Postoperative Opioid Depression ). Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had pre-existing cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone should be used with caution in patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catacholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures. Drug Interactions Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals to assess the carcinogenic potential of naloxone have not been conducted. Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study. Reproduction studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone. Use in Pregnancy: Teratogenic Effects: Teratology studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone. There are, however, no adequate and well controlled studies in pregnant women.

Teratology studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, naloxone hydrochloride should be used during pregnancy only if clearly needed. Non-teratogenic effects: Risk-benefit must be considered before naloxone is administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur. Use in Labor and Delivery It is not known if naloxone hydrochloride injection affects the duration of labor and/or delivery. However, published reports indicated that the administration of naloxone during labor did not adversely affect maternal or neonatal status. Nursing Mothers It is not known whether naloxone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naloxone hydrochloride is administered to a nursing woman. Pediatric Use Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds dramatically to naloxone hydrochloride injection, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized. When naloxone hydrochloride injection is given to the mother shortly before delivery, the duration of its effects lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride injection directly to the neonate if needed after delivery. Naloxone has no apparent benefit as an additional method of resuscitation in the newly born infant with intrauterine asphyxia, which is not related to opioid use. Usage in Pediatric Patients and Neonates for Septic Shock: The safety and effectiveness of naloxone hydrochloride injection in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures. Geriatric Use Clinical studies of naloxone hydrochloride injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, 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. Renal Insufficiency/Failure The safety and effectiveness of naloxone hydrochloride injection in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when naloxone is administered to this patient population.

ant disease or other drug therapy. Renal Insufficiency/Failure The safety and effectiveness of naloxone hydrochloride injection in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when naloxone is administered to this patient population. Liver Disease The safety and effectiveness of naloxone hydrochloride injection in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when naloxone is administered to patients with liver disease.

ADVERSE REACTIONS Postoperative The following adverse events have been associated with the use of naloxone hydrochloride injection in postoperative patients: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of naloxone in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION : USAGE IN ADULTS , Postoperative Opioid Depression ). Opioid Depression Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death (see PRECAUTIONS ). Opioid Dependence Abrupt reversal of opioid effects in persons who are physically dependent on opioids may precipitate an acute withdrawal syndrome which may include, but is not limited to the following signs and symptoms: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In the neonate, opioid withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes (see WARNINGS ). Adverse events associated with the postoperative use of naloxone hydrochloride injection are listed by organ system and in decreasing order of frequency as follows: Cardiac Disorders : pulmonary edema, cardiac arrest or failure, tachycardia, ventricular fibrillation, and ventricular tachycardia. Death, coma, and encephalopathy have been reported as sequelae of these events. Gastrointestinal Disorders : vomiting, nausea Nervous System Disorders : convulsions, paraesthesia, grand mal convulsion Psychiatric Disorders : agitation, hallucination, tremulousness Respiratory, Thoracic, and Mediastinal Disorders : dyspnea, respiratory depression, hypoxia Skin and Subcutaneous Tissue Disorders : nonspecific injection site reactions, sweating Vascular Disorders : hypertension, hypotension, hot flushes, or flushing See also PRECAUTIONS and DOSAGE AND ADMINISTRATION : USAGE IN ADULTS , Postoperative Opioid Depression.

DRUG ABUSE AND DEPENDENCE Naloxone hydrochloride injection is an opioid antagonist. Physical dependence associated with the use of naloxone hydrochloride injection has not been reported. Tolerance to the opioid antagonist effect of naloxone is not known to occur.

OVERDOSAGE There is limited clinical experience with naloxone hydrochloride injection overdosage in humans. Adult Patients In one small study, volunteers who received 24 mg/70 kg did not demonstrate toxicity. In another study, 36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/m 2 /min) of naloxone hydrochloride injection followed immediately by 2 mg/kg/hr for 24 hours. Twenty-three patients experienced adverse events associated with naloxone use, and naloxone was discontinued in seven patients because of adverse effects. The most serious adverse events were: seizures (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3). At doses of 2 mg/kg in normal subjects, cognitive impairment and behavioral symptoms, including irritability, anxiety, tension, suspiciousness, sadness, difficulty concentrating, and lack of appetite have been reported. In addition, somatic symptoms, including dizziness, heaviness, sweating, nausea, and stomachaches were also reported. Although complete information is not available, behavioral symptoms were reported to often persist for 2 to 3 days. Pediatric Patients Up to 11 doses of 0.2 mg naloxone (2.2 mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 2½ year-old child who inadvertently received a dose of 20 mg naloxone for treatment of respiratory depression following overdose with diphenoxylate hydrochloride with atropine sulfate. The child responded well and recovered without adverse sequelae. There is also a report of a 4½ year-old child who received 11 doses during a 12-hour period, with no adverse sequelae. Patient Management Patients who experience a naloxone overdose should be treated symptomatically in a closely supervised environment. Physicians should contact a poison control center for the most up-to-date patient management information.

DOSAGE AND ADMINISTRATION Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously. The most rapid onset of action is achieved by intravenous administration and it is recommended in emergency situations. Since the duration of action of some opioids may exceed that of naloxone the patient should be kept under continued surveillance. Repeated doses of naloxone should be administered, as necessary. Intravenous Infusion Naloxone hydrochloride injection may be diluted for intravenous infusion in 0.9% sodium chloride or 5% dextrose injection. The addition of 2 mg of naloxone hydrochloride in 500 mL of either solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24 hours, the remaining unused solution must be discarded. The rate of administration should be titrated in accordance with the patient's response. Naloxone hydrochloride injection should not be mixed with preparations containing bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH. No drug or chemical agent should be added to naloxone hydrochloride injection unless its effect on the chemical and physical stability of the solution has first been established. General Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

HOW SUPPLIED Naloxone hydrochloride injection, USP for intravenous, intramuscular, and subcutaneous administration is available as: Unit of Sale Concentration (per total volume) NDC 0409-1782-69 Box of 10 1 mL fill in 2.5 mL Carpuject™ Single-dose cartridge with Luer Lock for the Carpuject™ Syringe System 0.4 mg/mL Instructions for Use of the Syringe Systems Needle not included . Instructions for using the Carpuject Syringe are available with the reusable Carpuject Holder, List 2049-02. Protect from light. Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Distributed by Hospira, Inc., Lake Forest, IL 60045 USA LAB-1215-3.0 Revised: 03/2023 Hospira Logo

<table width="65%"><col width="38%"/><col width="25%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><content styleCode="bold">Unit of Sale</content></th><th align="center" styleCode="Rrule Botrule Toprule " valign="top"><content styleCode="bold">Concentration</content> <content styleCode="bold">(per total volume)</content></th></tr></thead><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">NDC 0409-1782-69</content> Box of 10 1 mL fill in 2.5 mL Carpuject&#x2122; Single-dose cartridge with Luer Lock for the Carpuject&#x2122; Syringe System</paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph>0.4 mg/mL</paragraph></td></tr></tbody></table>

NALOXONE HYDROCHLORIDE INJECTION, USP Opioid Antagonist Rx Only Store at 25˚C (77˚F); excursions permitted to 15˚-30˚C (59˚-86˚F). [See USP Controlled Room Temperature.] Protect from light. Store in carton until contents have been used. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

DESCRIPTION Naloxone hydrochloride, an opioid antagonist, is a synthetic congener of oxymorphone. In structure it differs from oxymorphone in that the methyl group on the nitrogen atom is replaced by an allyl group. NALOXONE HYDROCHLORIDE (-)-17-Allyl-4,5α-epoxy-3,14-dihydroxymorphinan-6-one hydrochloride Naloxone hydrochloride occurs as a white to slightly off-white powder, and is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform. Naloxone Hydrochloride Injection is available as a sterile solution for intravenous, intramuscular and subcutaneous administration in 1 mg/mL concentration. pH is adjusted to 3.5 ± 0.5 with hydrochloric acid. Each mL also contains 8.35 mg of sodium chloride. Naloxone Hydrochloride Injection is preservative-free. structure

CLINICAL PHARMACOLOGY Complete or Partial Reversal of Opioid Depression Naloxone hydrochloride prevents or reverses the effects of opioids including respiratory depression, sedation, and hypotension. Also, it can reverse the psychotomimetic and dysphoric effects of agonist-antagonist such as pentazocine. Naloxone hydrochloride is an essentially pure opioid antagonist, i.e., it does not possess the “agonistic” or morphine-like properties characteristic of other opioid antagonists. When administered in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity. Naloxone hydrochloride has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on opioids, naloxone hydrochloride will produce withdrawal symptoms. However, in the presence of opioid dependence, opiate withdrawal symptoms may appear within minutes of naloxone hydrochloride administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the dose of naloxone hydrochloride and to the degree and type of opioid dependence. While the mechanism of action of naloxone hydrochloride is not fully understood, in vitro evidence suggests that naloxone hydrochloride antagonizes opioid effects by competing for the μ , κ and σ opiate receptor sites in the CNS, with the greatest affinity for the μ receptor. When naloxone hydrochloride is administered intravenously (I.V.), the onset of action is generally apparent within two minutes. The onset of action is slightly less rapid when it is administered subcutaneously (S.C.) or intramuscularly (I.M.). The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride. Intramuscular administration produces a more prolonged effect than intravenous administration. Since the duration of action of naloxone hydrochloride may be shorter than that of some opiates, the effect of the opiate may return as the effects of naloxone hydrochloride dissipates. The requirement for repeat doses of naloxone hydrochloride will also be dependent upon the amount, type and route of administration of the opioid being antagonized. Adjunctive Use in Septic Shock Naloxone hydrochloride has been shown in some cases of septic shock to produce a rise in blood pressure that may last up to several hours; however, this pressor response has not been demonstrated to improve patient survival. In some studies, treatment with naloxone hydrochloride in the setting of septic shock has been associated with adverse effects, including agitation, nausea and vomiting, pulmonary edema, hypotension, cardiac arrhythmias, and seizures. The decision to use naloxone hydrochloride in septic shock should be exercised with caution, particularly in patients who may have underlying pain or have previously received opioid therapy and may have developed opioid tolerance. Because of the limited number of patients who have been treated, optimal dosage and treatment regimens have not been established.

PHARMACOKINETICS Distribution Following parenteral administration, naloxone hydrochloride is rapidly distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk. Metabolism and Elimination Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation with naloxone-3-glucoronide as the major metabolite. In one study the serum half-life in adults ranged from 30 to 81 minutes (mean 64 ± 12 minutes). In a neonatal study the mean plasma half-life was observed to be 3.1 ± 0.5 hours. After an oral or intravenous dose, about 25-40% of the drug is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60-70% in 72 hours.

INDICATIONS AND USAGE Naloxone hydrochloride injection is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids including, propoxyphene, methadone and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine and butorphanol and cyclazocine. Naloxone hydrochloride is also indicated for the diagnosis of suspected or known acute opioid overdosage. Naloxone hydrochloride injection may be useful as an adjunctive agent to increase blood pressure in the management of septic shock. (see CLINICAL PHARMACOLOGY ; Adjunctive Use in Septic Shock ).

WARNINGS Drug Dependence Naloxone hydrochloride should be administered cautiously to persons including newborns of mothers who are known or suspected to be physically dependent on opioids. In such cases an abrupt and complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The signs and symptoms of opioid withdrawal in a patient physically dependent on opioids may include, but are not limited to, the following: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In the neonate, opioid withdrawal may also include: convulsions, excessive crying, and hyperactive reflexes. Repeat Administration The patient who has satisfactorily responded to naloxone hydrochloride should be kept under continued surveillance and repeated doses of naloxone hydrochloride should be administered, as necessary, since the duration of action of some opioids may exceed that of naloxone hydrochloride. Respiratory Depression due to Other Drugs Naloxone hydrochloride is not effective against respiratory depression due to non-opioid drugs and in the management of acute toxicity caused by levopropoxyphene. Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete or require higher doses of naloxone. If an incomplete response occurs, respirations should be mechanically assisted as clinically indicated.

PRECAUTIONS General In addition to naloxone hydrochloride, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning. Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ; Usage in Adults-Postoperative Opioid Depression ). Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had preexisting cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone hydrochloride should be used with caution in patients with preexisting cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone hydrochloride is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures. Drug Interactions Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals to assess the carcinogenic potential of naloxone hydrochloride have not been conducted. Naloxone hydrochloride was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the i n vivo rat bone marrow chromosome aberration study. Reproduction studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. Use in Pregnancy Teratogenic Effects: Pregnancy Category C: Teratology studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women.

udies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, naloxone hydrochloride should be used during pregnancy only if clearly needed. Non-teratogenic Effects: Risk-benefit must be considered before naloxone hydrochloride is administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur. Use in Labor and Delivery It is not known if naloxone hydrochloride affects the duration of labor and/or delivery. However, published reports indicated that administration of naloxone during labor did not adversely affect maternal or neonatal status. Nursing Mothers: It is not known whether naloxone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naloxone is administered to a nursing woman. Pediatric Use Naloxone hydrochloride injection, USP may be administered intravenously, intramuscularly or subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds dramatically to naloxone hydrochloride, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized. When naloxone hydrochloride is given to the mother shortly before delivery, the duration of its effect lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride directly to the neonate if needed after delivery. Naloxone hydrochloride has no apparent benefit as an additional method of resuscitation in the newly born infant with intrauterine asphyxia which is not related to opioid use. Usage in Pediatric Patients and Neonates for Septic Shock: The safety and effectiveness of naloxone hydrochloride in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures. Geriatric Use Clinical studies of naloxone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, 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. Renal Insufficiency/Failure The safety and effectiveness of naloxone hydrochloride in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to this patient population. Liver Disease The safety and effectiveness of naloxone hydrochloride in patients with liver disease have not been established in well-controlled clinical trials.

e not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to this patient population. Liver Disease The safety and effectiveness of naloxone hydrochloride in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to patients with liver disease.

General In addition to naloxone hydrochloride, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning. Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ; Usage in Adults-Postoperative Opioid Depression ). Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had preexisting cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone hydrochloride should be used with caution in patients with preexisting cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone hydrochloride is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures.

Drug Interactions Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts.

Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals to assess the carcinogenic potential of naloxone hydrochloride have not been conducted. Naloxone hydrochloride was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the i n vivo rat bone marrow chromosome aberration study. Reproduction studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride.

Use in Pregnancy Teratogenic Effects: Pregnancy Category C: Teratology studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, naloxone hydrochloride should be used during pregnancy only if clearly needed. Non-teratogenic Effects: Risk-benefit must be considered before naloxone hydrochloride is administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur.

Use in Labor and Delivery It is not known if naloxone hydrochloride affects the duration of labor and/or delivery. However, published reports indicated that administration of naloxone during labor did not adversely affect maternal or neonatal status. Nursing Mothers: It is not known whether naloxone is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naloxone is administered to a nursing woman.

Pediatric Use Naloxone hydrochloride injection, USP may be administered intravenously, intramuscularly or subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds dramatically to naloxone hydrochloride, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized. When naloxone hydrochloride is given to the mother shortly before delivery, the duration of its effect lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride directly to the neonate if needed after delivery. Naloxone hydrochloride has no apparent benefit as an additional method of resuscitation in the newly born infant with intrauterine asphyxia which is not related to opioid use. Usage in Pediatric Patients and Neonates for Septic Shock: The safety and effectiveness of naloxone hydrochloride in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures.

Geriatric Use Clinical studies of naloxone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, 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. Renal Insufficiency/Failure The safety and effectiveness of naloxone hydrochloride in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to this patient population. Liver Disease The safety and effectiveness of naloxone hydrochloride in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to patients with liver disease.

ADVERSE REACTIONS Postoperative The following adverse events have been associated with the use of naloxone hydrochloride in postoperative patients: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of naloxone hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ; Usage in Adults-Postoperative Opioid Depression ). Opioid Depression Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death (see PRECAUTIONS ). Opioid Dependence Abrupt reversal of opioid effects in persons who are physically dependent on opioids may precipitate an acute withdrawal syndrome which may include, but is not limited to, the following signs and symptoms: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In the neonate, opioid withdrawal may also include: convulsions; excessive crying; hyperactive reflexes (see WARNINGS ). Adverse events associated with the postoperative use of naloxone hydrochloride are listed by organ system and in decreasing order of frequency as follows: Cardiac Disorders: pulmonary edema, cardiac arrest or failure, tachycardia, ventricular fibrillation, and ventricular tachycardia. Death, coma, and encephalopathy have been reported as sequelae of these events. Gastrointestinal Disorders: vomiting, nausea Nervous System Disorders: convulsions, paraesthesia, grand mal convulsion Psychiatric Disorders: agitation, hallucination, tremulousness Respiratory, Thoracic and Mediastinal Disorders: dyspnea, respiratory depression, hypoxia Skin and Subcutaneous Tissue Disorders: nonspecific injection site reactions, sweating Vascular Disorders: hypertension, hypotension, hot flushes or flushing. See also PRECAUTIONS and DOSAGE AND ADMINISTRATION ; Usage in Adults; Postoperative Opioid Depression .

DRUG ABUSE AND DEPENDENCE Naloxone hydrochloride is an opioid antagonist. Physical dependence associated with the use of naloxone hydrochloride has not been reported. Tolerance to the opioid antagonist effect of naloxone hydrochloride is not known to occur.

OVERDOSAGE There is limited clinical experience with naloxone hydrochloride overdosage in humans. Adult Patients In one small study, volunteers who received 24 mg/70 kg did not demonstrate toxicity. In another study, 36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/m 2 /min) of naloxone hydrochloride followed immediately by 2 mg/kg/hr for 24 hours. Twenty-three patients experienced adverse events associated with naloxone use, and naloxone was discontinued in seven patients because of adverse effects. The most serious adverse events were: seizures (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3). At doses of 2 mg/kg in normal subjects, cognitive impairment and behavioral symptoms, including irritability, anxiety, tension, suspiciousness, sadness, difficulty concentrating, and lack of appetite have been reported. In addition, somatic symptoms, including dizziness, heaviness, sweating, nausea, and stomachaches were also reported. Although complete information is not available, behavioral symptoms were reported to often persist for 2-3 days. Pediatric Patients Up to 11 doses of 0.2 mg of naloxone (2.2 mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 2-1/2 year-old child who inadvertently received a dose of 20 mg of naloxone for treatment of respiratory depression following overdose with diphenoxylate hydrochloride with atropine sulfate. The child responded well and recovered without adverse sequelae. There is also a report of a 4-1/2 year-old child who received 11 doses during a 12-hour period, with no adverse sequelae. Patient Management Patients who experience a naloxone hydrochloride overdose should be treated symptomatically in a closely supervised environment. Physicians should contact a poison control center for the most up-to-date patient management information.

DOSAGE AND ADMINISTRATION Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously. The most rapid onset of action is achieved by intravenous administration, which is recommended in emergency situations. Since the duration of action of some opioids may exceed that of naloxone, the patient should be kept under continued surveillance. Repeated doses of naloxone should be administered, as necessary. Intravenous Infusion Naloxone hydrochloride injection may be diluted for intravenous infusion in normal saline or 5% dextrose solutions. The addition of 2 mg of naloxone in 500 mL of either solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24 hours, the remaining unused mixture must be discarded. The rate of administration should be titrated in accordance with the patient’s response. Naloxone hydrochloride injection should not be mixed with preparations containing bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH. No drug or chemical agent should be added to naloxone hydrochloride injection unless its effect on the chemical and physical stability of the solution has first been established. General Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Usage in Adults Opioid Overdose—Known or Suspected: An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions are not obtained, it may be repeated at two-to-three-minute intervals. If no response is observed after 10 mg of naloxone hydrochloride have been administered, the diagnosis of opioid-induced or partial opioid-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available. Postoperative Opioid Depression: For the partial reversal of opioid depression following the use of opioids during surgery, smaller doses of naloxone hydrochloride are usually sufficient. The dose of naloxone hydrochloride should be titrated according to the patient’s response. For the initial reversal of respiratory depression, naloxone hydrochloride should be injected in increments of 0.1 to 0.2 mg intravenously at two-to three-minute intervals to the desired degree of reversal—i.e., adequate ventilationand alertness without significant pain or discomfort. Larger than necessary dosage of naloxone may result in significant reversal of analgesia and increase in blood pressure. Similarly, too rapid reversal may induce nausea, vomiting, sweating, or circulatory stress. Repeat doses of naloxone may be required within one- to two-hour intervals depending upon the amount, type (i.e., short or long acting) and time interval since last administration of opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect. Septic Shock: The optimal dosage of naloxone hydrochloride or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY ). Usage in Children Opioid Overdose—Known or Suspected: The usual initial dose in children is 0.01 mg/kg body weight given I.V.

Septic Shock: The optimal dosage of naloxone hydrochloride or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY ). Usage in Children Opioid Overdose—Known or Suspected: The usual initial dose in children is 0.01 mg/kg body weight given I.V. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be administered. If an l.V. route of administration is not available, naloxone may be administered I.M. or S.C. in divided doses. If necessary, naloxone hydrochloride injection can be diluted with sterile water for injection. Postoperative Opioid Depression : Follow the recommendations and cautions under Adult Postoperative Depressio n. For the initial reversal of respiratory depression naloxone hydrochloride should be injected in increments of 0.005 mg to 0.01 mg intravenously at two- to three-minute intervals to the desired degree of reversal. Usage in Neonates Opioid-lnduced Depression: The usual initial dose is 0.01 mg/kg body weight administered I.V., I.M., or S.C. This dose may be repeated in accordance with adult administration guidelines for postoperative opioid depression.

HOW SUPPLIED 1 mg/mL naloxone hydrochloride injection USP, for intravenous, intramuscular and subcutaneous administration. Available as follows: 1 mg/mL 2 mL single dose disposable prefilled syringes, in the MIN-I-JET® system with 21 G. x 11/2” needle. Shrink Wrapped Packages of 10. NDC: 70518-2725-00 NDC: 70518-2725-01 PACKAGING: 10 in 1 BOX PACKAGING: (1) 2 mL in 1 SYRINGE TYPE 2 Store at 25˚C (77˚F); excursions permitted to 15˚-30˚C (59˚-86˚F). [See USP Controlled Room Temperature.] Protect from light. Store in carton until contents have been used. Repackaged and Distributed By: Remedy Repack, Inc. 625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

DESCRIPTION Naloxone hydrochloride injection, USP an opioid antagonist, is a synthetic congener of oxymorphone. In structure it differs from oxymorphone in that the methyl group on the nitrogen atom is replaced by an allyl group. Naloxone hydrochloride, USP occurs as a white to slightly off-white powder, and is soluble in water, in dilute acids, and in strong alkali; slightly soluble in alcohol; practically insoluble in ether and in chloroform. Naloxone hydrochloride injection, USP is available as a sterile, clear, colorless solution for intravenous, intramuscular and subcutaneous administration in concentration: 0.4 mg of naloxone hydrochloride per mL. It has a molecular weight of 363.84. pH is adjusted to 3.0 to 6.5 with hydrochloric acid. The 0.4 mg/mL vial is available in an unpreserved, paraben-free formulation containing 9 mg/mL of sodium chloride. structure

CLINICAL PHARMACOLOGY Complete or Partial Reversal of Opioid Depression Naloxone hydrochloride prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. Also, naloxone hydrochloride can reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine. Naloxone hydrochloride is an essentially pure opioid antagonist, i.e., it does not possess the "agonistic" or morphine-like properties characteristic of other opioid antagonists. When administered in usual doses and in the absence of opioids or agonistic effects of other opioid antagonists, it exhibits essentially no pharmacologic activity. Naloxone hydrochloride has not been shown to produce tolerance or cause physical or psychological dependence. In the presence of physical dependence on opioids, naloxone hydrochloride will produce withdrawal symptoms. However, in the presence of opioid dependence, opiate withdrawal symptoms may appear within minutes of naloxone hydrochloride administration and subside in about 2 hours. The severity and duration of the withdrawal syndrome are related to the dose of naloxone hydrochloride and to the degree and type of opioid dependence. While the mechanism of action of naloxone hydrochloride is not fully understood, in vitro evidence suggests that naloxone hydrochloride antagonizes opioid effects by competing for the µ, ҡ and σ opiate receptor sites in the CNS, with the greatest affinity for the µ receptor. When naloxone hydrochloride is administered intravenously (I.V.), the onset of action is generally apparent within two minutes. The onset of action is slightly less rapid when it is administered subcutaneously (S.C.) or intramuscularly (I.M.). The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride. Intramuscular administration produces a more prolonged effect than intravenous administration. Since the duration of action of naloxone hydrochloride may be shorter than that of some opiates, the effects of the opiate may return as the effects of naloxone hydrochloride dissipates. The requirement for repeat doses of naloxone hydrochloride will also be dependent upon the amount, type and route of administration of the opioid being antagonized. Adjunctive Use in Septic Shock Naloxone hydrochloride has been shown in some cases of septic shock to produce a rise in blood pressure that may last up to several hours; however, this pressor response has not been demonstrated to improve patient survival. In some studies, treatment with naloxone hydrochloride in the setting of septic shock has been associated with adverse effects, including agitation, nausea and vomiting, pulmonary edema, hypotension, cardiac arrhythmias, and seizures. The decision to use naloxone hydrochloride in septic shock should be exercised with caution, particularly in patients who may have underlying pain or have previously received opioid therapy and may have developed opioid tolerance. Because of the limited number of patients who have been treated, optimal dosage and treatment regimens have not been established.

PHARMACOKINETICS Distribution Following parenteral administration, naloxone hydrochloride is rapidly distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk. Metabolism and Elimination Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation with naloxone-3-glucoronide as the major metabolite. In one study the serum half-life in adults ranged from 30 to 81 minutes (mean 64 ± 12 minutes). In a neonatal study the mean plasma half-life was observed to be 3.1 ± 0.5 hours. After an oral or intravenous dose, about 25% to 40% of the drug is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60% to 70% in 72 hours.

INDICATIONS AND USAGE Naloxone hydrochloride injection is indicated for the complete or partial reversal of opioid depression, including respiratory depression, induced by natural and synthetic opioids, including propoxyphene, methadone and certain mixed agonist-antagonist analgesics: nalbuphine, pentazocine, butorphanol, and cyclazocine. Naloxone hydrochloride injection is also indicated for diagnosis of suspected or known acute opioid overdosage. Naloxone hydrochloride injection may be useful as an adjunctive agent to increase blood pressure in the management of septic shock (see CLINICAL PHARMACOLOGY ; Adjunctive Use in Septic Shock ).

CONTRAINDICATIONS Naloxone hydrochloride injection is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients contained in this formulation.

PRECAUTIONS General In addition to naloxone hydrochloride, other resuscitative measures such as maintenance of a free airway, artificial ventilation, cardiac massage, and vasopressor agents should be available and employed when necessary to counteract acute opioid poisoning. Abrupt postoperative reversal of opioid depression may result in nausea, vomiting, sweating, tremulousness, tachycardia, increased blood pressure, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death. Excessive doses of naloxone hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ; Usage in Adults-Postoperative Opioid Depression ). Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest have been reported in postoperative patients. Death, coma, and encephalopathy have been reported as sequelae of these events. These have occurred in patients most of whom had pre-existing cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone hydrochloride should be used with caution in patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects, such as hypotension, ventricular tachycardia or fibrillation, and pulmonary edema. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone hydrochloride is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures. Drug Interactions Large doses of naloxone are required to antagonize buprenorphine since the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor. Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. The barbiturate methohexital appears to block the acute onset of withdrawal symptoms induced by naloxone in opiate addicts. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies in animals to assess the carcinogenic potential of naloxone hydrochloride have not been conducted. Naloxone hydrochloride was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study. Reproduction studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. Use in Pregnancy Teratogenic Effects: Teratology studies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women.

udies conducted in mice and rats at doses 4-times and 8-times, respectively, the dose of a 50 kg human given 10 mg/day (when based on surface area or mg/m 2 ), demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, naloxone hydrochloride should be used during pregnancy only if clearly needed. Non-teratogenic Effects: Risk-benefit must be considered before naloxone hydrochloride is administered to a pregnant woman who is known or suspected to be opioid-dependent since maternal dependence may often be accompanied by fetal dependence. Naloxone crosses the placenta, and may precipitate withdrawal in the fetus as well as in the mother. Patients with mild to moderate hypertension who receive naloxone during labor should be carefully monitored as severe hypertension may occur. Use in Labor and Delivery It is not known if naloxone hydrochloride injection affects the duration of labor and/or delivery. However, published reports indicated that administration of naloxone during labor did not adversely affect maternal or neonatal status. Nursing Mothers It is not known whether naloxone hydrochloride is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when naloxone hydrochloride is administered to a nursing woman. Pediatric Use Naloxone hydrochloride injection may be administered intravenously, intramuscularly or subcutaneously in children and neonates to reverse the effects of opiates. The American Academy of Pediatrics, however, does not endorse subcutaneous or intramuscular administration in opiate intoxication since absorption may be erratic or delayed. Although the opiate-intoxicated child responds dramatically to naloxone hydrochloride, he/she must be carefully monitored for at least 24 hours as a relapse may occur as naloxone is metabolized. When naloxone hydrochloride is given to the mother shortly before delivery, the duration of its effect lasts only for the first two hours of neonatal life. It is preferable to administer naloxone hydrochloride directly to the neonate if needed after delivery. Naloxone hydrochloride has no apparent benefit as an additional method of resuscitation in the newly born infant with intrauterine asphyxia which is not related to opioid use. Usage in Pediatric Patients and Neonates for Septic Shock: The safety and effectiveness of naloxone hydrochloride in the treatment of hypotension in pediatric patients and neonates with septic shock have not been established. One study of two neonates in septic shock reported a positive pressor response; however, one patient subsequently died after intractable seizures. Geriatric Use Clinical studies of naloxone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, 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. Renal Insufficiency/Failure The safety and effectiveness of naloxone hydrochloride in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to this patient population.

disease or other drug therapy. Renal Insufficiency/Failure The safety and effectiveness of naloxone hydrochloride in patients with renal insufficiency/failure have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to this patient population. Liver Disease The safety and effectiveness of naloxone hydrochloride in patients with liver disease have not been established in well-controlled clinical trials. Caution should be exercised when naloxone hydrochloride is administered to patients with liver disease.

ADVERSE REACTIONS Postoperative The following adverse events have been associated with the use of naloxone hydrochloride in postoperative patients: hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of naloxone hydrochloride in postoperative patients may result in significant reversal of analgesia and may cause agitation (see PRECAUTIONS and DOSAGE AND ADMINISTRATION ; Usage in Adults- Postoperative Opioid Depression). Opioid Depression Abrupt reversal of opioid depression may result in nausea, vomiting, sweating, tachycardia, increased blood pressure, tremulousness, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest which may result in death (see PRECAUTIONS ). Opioid Dependence Abrupt reversal of opioid effects in persons who are physically dependent on opioids may precipitate an acute withdrawal syndrome which may include, but is not limited to, the following signs and symptoms: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In the neonate, opioid withdrawal may also include: convulsions; excessive crying; hyperactive reflexes (see WARNINGS ). Adverse events associated with the postoperative use of naloxone hydrochloride are listed by organ system and in decreasing order of frequency as follows: Cardiac Disorders: pulmonary edema, cardiac arrest or failure, tachycardia, ventricular fibrillation, and ventricular tachycardia. Death, coma, and encephalopathy have been reported as sequelae of these events. Gastrointestinal Disorders: vomiting, nausea Nervous System Disorders: convulsions, paraesthesia, grand mal convulsion Psychiatric Disorders: agitation, hallucination, tremulousness Respiratory, Thoracic and Mediastinal Disorders: dyspnea, respiratory depression, hypoxia Skin and Subcutaneous Tissue Disorders: nonspecific injection site reactions, sweating Vascular Disorders: hypertension, hypotension, hot flushes or flushing. See also PRECAUTIONS and DOSAGE AND ADMINISTRATION ; Usage in Adults ; Postoperative Opioid Depression. To report SUSPECTED ADVERSE REACTIONS, contact Lifestar Pharma LLC at 1-888-995-4337 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

OVERDOSAGE There is limited clinical experience with naloxone hydrochloride overdosage in humans. Adult Patients In one small study, volunteers who received 24 mg/70 kg did not demonstrate toxicity. In another study, 36 patients with acute stroke received a loading dose of 4 mg/kg (10 mg/m 2 /min) of naloxone hydrochloride followed immediately by 2 mg/kg/hr for 24 hours. Twenty-three patients experienced adverse events associated with naloxone use, and naloxone was discontinued in seven patients because of adverse effects. The most serious adverse events were: seizures (2 patients), severe hypertension (1), and hypotension and/or bradycardia (3). At doses of 2 mg/kg in normal subjects, cognitive impairment and behavioral symptoms, including irritability, anxiety, tension, suspiciousness, sadness, difficulty concentrating, and lack of appetite have been reported. In addition, somatic symptoms, including dizziness, heaviness, sweating, nausea, and stomachaches were also reported. Although complete information is not available, behavioral symptoms were reported to often persist for 2-3 days. Pediatric Patients Up to 11 doses of 0.2 mg of naloxone (2.2 mg) have been administered to children following overdose of diphenoxylate hydrochloride with atropine sulfate. Pediatric reports include a 2 1 / 2 year-old child who inadvertently received a dose of 20 mg of naloxone for treatment of respiratory depression following overdose with diphenoxylate hydrochloride with atropine sulfate. The child responded well and recovered without adverse sequelae. There is also a report of a 4 1 / 2 year-old child who received 11 doses during a 12-hour period, with no adverse sequelae. Patient Management Patients who experience a naloxone hydrochloride overdose should be treated symptomatically in a closely supervised environment. Physicians should contact a poison control center for the most up-to-date patient management information.

DOSAGE AND ADMINISTRATION Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously. The most rapid onset of action is achieved by intravenous administration, which is recommended in emergency situations. Since the duration of action of some opioids may exceed that of naloxone hydrochloride injection, the patient should be kept under continued surveillance. Repeated doses of naloxone hydrochloride injection should be administered, as necessary. Intravenous Infusion Naloxone hydrochloride injection may be diluted for intravenous infusion in normal saline or 5% dextrose solutions. The addition of 2 mg of naloxone hydrochloride injection in 500 mL of either solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24 hours, the remaining unused mixture must be discarded. The rate of administration should be titrated in accordance with the patient's response. Naloxone hydrochloride injection should not be mixed with preparations containing bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH. No drug or chemical agent should be added to naloxone hydrochloride injection unless its effect on the chemical and physical stability of the solution has first been established. General Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Usage in Adults Opioid Overdose–Known or Suspected: An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride injection may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions are not obtained, it may be repeated at two- to three-minute intervals. If no response is observed after 10 mg of naloxone hydrochloride injection have been administered, the diagnosis of opioid-induced or partial opioid-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available. Postoperative Opioid Depression: For the partial reversal of opioid depression following the use of opioids during surgery, smaller doses of naloxone hydrochloride injection are usually sufficient. The dose of naloxone hydrochloride injection should be titrated according to the patient's response. For the initial reversal of respiratory depression, naloxone hydrochloride injection should be injected in increments of 0.1 to 0.2 mg intravenously at two- to three-minute intervals to the desired degree of reversal, i.e., adequate ventilation and alertness without significant pain or discomfort. Larger than necessary dosage of naloxone hydrochloride injection may result in significant reversal of analgesia and increase in blood pressure. Similarly, too rapid reversal may induce nausea, vomiting, sweating or circulatory stress. Repeat doses of naloxone hydrochloride injection may be required within one- to two-hour intervals depending upon the amount, type (i.e., short or long acting) and time interval since last administration of an opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect. Septic Shock: The optimal dosage of naloxone hydrochloride injection or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY ).

t administration of an opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect. Septic Shock: The optimal dosage of naloxone hydrochloride injection or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY ). Usage in Pediatric Population Opioid Overdose–Known or Suspected: The usual initial dose in pediatric patients is 0.01 mg/kg body weight given I.V. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be administered. If an intravenous (I.V.) route of administration is not available, naloxone hydrochloride injection may be administered intramuscularly (I.M.) or subcutaneously (S.C.) in divided doses. If necessary, naloxone hydrochloride injection can be diluted with sterile water for injection. Postoperative Opioid Depression: Follow the recommendations and cautions under Adult Postoperative Depression . For the initial reversal of respiratory depression, naloxone hydrochloride injection should be injected in increments of 0.005 mg to 0.01 mg intravenously at two- to three-minute intervals to the desired degree of reversal. Usage in Neonates Opioid-induced Depression: The usual initial dose is 0.01 mg/kg body weight administered intravenous (I.V.), intramuscularly (I.M.) or subcutaneously (S.C.). This dose may be repeated in accordance with adult administration guidelines for postoperative opioid depression. Do not administer unless solution is clear and container is undamaged. Discard unused portion.

HOW SUPPLIED Naloxone hydrochloride injection, USP is a sterile, clear, colorless solution filled in clear glass vial with rubber stopper along with flip-off seal for intravenous, intramuscular, and subcutaneous administration is available as: Preservative-Free Vials 0.4 mg/mL 1 mL single-dose vial, packed in individual carton, NDC 70756-850-82 0.4 mg/mL 1 mL single-dose vial, carton of 10, NDC 70756-850-10 0.4 mg/mL 1 mL single-dose vial, carton of 25, NDC 70756-850-25 Store at 20°C to 25°C (68°F to 77°F) [See USP Controlled Room Temperature]. Protect from light. Discard unused portion. Store in carton until contents have been used. Manufactured for: Lifestar Pharma LLC 1200 MacArthur Blvd. Mahwah, NJ 07430 USA Novaplus is a registered trademark of Vizient, Inc. Product of France Revised: January 2026, V-01 Image

1 INDICATIONS AND USAGE Naloxone hydrochloride nasal spray is indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. Naloxone hydrochloride nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present. Naloxone hydrochloride nasal spray is not a substitute for emergency medical care. Naloxone hydrochloride nasal spray is an opioid antagonist indicated for the emergency treatment of known or suspected opioid overdose, as manifested by respiratory and/or central nervous system depression. ( 1 ) Naloxone hydrochloride nasal spray is intended for immediate administration as emergency therapy in settings where opioids may be present. ( 1 ) Naloxone hydrochloride nasal spray is not a substitute for emergency medical care. ( 1 )

2 DOSAGE AND ADMINISTRATION Naloxone hydrochloride nasal spray is for intranasal use only. ( 2.1 ) Seek emergency medical care immediately after use. ( 2.1 ) Administration of a single spray of naloxone hydrochloride nasal spray intranasally into one nostril. ( 2.2 ) Administer additional doses of naloxone hydrochloride nasal spray, using a new nasal spray with each dose, if the patient does not respond or responds and then relapses into respiratory depression, additional doses of naloxone hydrochloride nasal spray may be given every 2 to 3 minutes until emergency medical assistance arrives. ( 2.2 ) Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. ( 2.2 ) 2.1 Important Administration Instructions Naloxone hydrochloride nasal spray is for intranasal use only. No additional device assembly is required. Because treatment of suspected opioid overdose must be performed by someone other than the patient, instruct the prescription recipient to inform those around them about the presence of naloxone hydrochloride nasal spray and the Instructions for Use . Instruct the patient or caregiver to read the Instructions for Use at the time they receive a prescription for naloxone hydrochloride nasal spray. Emphasize the following instructions to the patient or caregiver: Administer naloxone hydrochloride nasal spray as quickly as possible because prolonged respiratory depression may result in damage to the central nervous system or death. Since the duration of action of most opioids exceeds that of naloxone hydrochloride and the suspected opioid overdose may occur outside of supervised medical settings, seek immediate emergency medical assistance, keep the patient under continued surveillance until emergency personnel arrive, and administer repeated doses of naloxone hydrochloride nasal spray, as necessary. Always seek emergency medical assistance in the event of a suspected, potentially life-threatening opioid emergency after administration of the first dose of naloxone hydrochloride nasal spray. Additional doses of naloxone hydrochloride nasal spray may be required until emergency medical assistance becomes available. Do not attempt to reuse naloxone hydrochloride nasal spray. Each naloxone hydrochloride nasal spray contains a single dose of naloxone and cannot be reused. Re-administer naloxone hydrochloride nasal spray, using a new nasal spray, every 2 to 3 minutes if the patient does not respond or responds and then relapses into respiratory depression. Administer naloxone hydrochloride nasal spray in alternate nostrils with each dose. Administer naloxone hydrochloride nasal spray according to the printed instructions on the device label and the Instructions for Use . Place the patient in the supine position. Prior to administration, be sure the device nozzle is inserted in either nostril of the patient, and provide support to the back of the neck to allow the head to tilt back. Do not prime or test the device prior to administration. To administer the dose press firmly on the device plunger. Remove the device nozzle from the nostril after use. Turn patient on their side as shown in the Instructions for Use and call for emergency medical assistance immediately after administration of the first dose of naloxone hydrochloride nasal spray.

inistration. To administer the dose press firmly on the device plunger. Remove the device nozzle from the nostril after use. Turn patient on their side as shown in the Instructions for Use and call for emergency medical assistance immediately after administration of the first dose of naloxone hydrochloride nasal spray. 2.2 Dosing in Adults and Pediatric Patients Initial Dosing The recommended initial dose of naloxone hydrochloride nasal spray in adults and pediatric patients is one spray delivered by intranasal administration into one nostril. Repeat Dosing Seek emergency medical assistance as soon as possible after administering the first dose of naloxone hydrochloride nasal spray. The requirement for repeat doses of naloxone hydrochloride nasal spray depends upon the amount, type, and route of administration of the opioid being antagonized. Administer naloxone hydrochloride nasal spray in alternate nostrils with each dose. If the patient responds to naloxone hydrochloride nasal spray and relapses back into respiratory depression before emergency assistance arrives, administer an additional dose of naloxone hydrochloride nasal spray using a new naloxone hydrochloride nasal spray and continue surveillance of the patient. If the desired response is not obtained after 2 or 3 minutes, administer an additional dose of naloxone hydrochloride nasal spray using a new naloxone hydrochloride nasal spray. If there is still no response and additional doses are available, administer additional doses of naloxone hydrochloride nasal spray every 2 to 3 minutes using a new naloxone hydrochloride nasal spray with each dose until emergency medical assistance arrives. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. 2.3 Dosing Modifications due to Partial Agonists or Mixed Agonist/Antagonists Reversal of respiratory depression by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and require higher doses of naloxone hydrochloride or repeated administration of naloxone hydrochloride nasal spray using a new nasal spray [see Warnings and Precautions ( 5.2 )] .

3 DOSAGE FORMS AND STRENGTHS Naloxone hydrochloride nasal spray is supplied as a single-dose intranasal spray containing 4 mg of naloxone hydrochloride in 0.1 mL. Nasal spray: 4 mg of naloxone hydrochloride in 0.1 mL. ( 3 )

4 CONTRAINDICATIONS Naloxone hydrochloride nasal spray is contraindicated in patients known to be hypersensitive to naloxone hydrochloride or to any of the other ingredients. Hypersensitivity to naloxone hydrochloride. ( 4 )

5 WARNINGS AND PRECAUTIONS Risk of Recurrent Respiratory and CNS Depression: Due to the duration of action of naloxone relative to the opioid, keep patient under continued surveillance and administer repeat doses of naloxone using a new nasal spray with each dose, as necessary, while awaiting emergency medical assistance. ( 5.1 ) Risk of Limited Efficacy with Partial Agonists or Mixed Agonists/Antagonists: Reversal of respiratory depression caused by partial agonists or mixed agonists/antagonists, such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses may be required. ( 5.2 ) Precipitation of Severe Opioid Withdrawal: Use in patients who are opioid dependent may precipitate opioid withdrawal. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated. Monitor for the development of opioid withdrawal. ( 5.3 ) Risk of Cardiovascular (CV) Effects: Abrupt postoperative reversal of opioid depression may result in adverse CV effects. These events have primarily occurred in patients who had pre­existing CV disorders or received other drugs that may have similar adverse CV effects. Monitor these patients closely in an appropriate healthcare setting after use of naloxone hydrochloride. ( 5.3 ) 5.1 Risk of Recurrent Respiratory and Central Nervous System Depression The duration of action of most opioids may exceed that of naloxone hydrochloride nasal spray resulting in a return of respiratory and/or central nervous system depression after an initial improvement in symptoms. Therefore, it is necessary to seek emergency medical assistance immediately after administration of the first dose of naloxone hydrochloride nasal spray and to keep the patient under continued surveillance. Administer additional doses of naloxone hydrochloride nasal spray if the patient is not adequately responding or responds and then relapses back into respiratory depression, as necessary [see Dosage and Administration ( 2.2 )] . Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance. 5.2 Risk of Limited Efficacy with Partial Agonists or Mixed Agonist/Antagonists Reversal of respiratory depression by partial agonists or mixed agonist/antagonists such as buprenorphine and pentazocine, may be incomplete. Larger or repeat doses of naloxone hydrochloride may be required to antagonize buprenorphine because the latter has a long duration of action due to its slow rate of binding and subsequent slow dissociation from the opioid receptor [see Dosage and Administration ( 2.3 )] . Buprenorphine antagonism is characterized by a gradual onset of the reversal effects and a decreased duration of action of the normally prolonged respiratory depression. 5.3 Precipitation of Severe Opioid Withdrawal The use of naloxone hydrochloride nasal spray in patients who are opioid-dependent may precipitate opioid withdrawal characterized by the following signs and symptoms: body aches, diarrhea, tachycardia, fever, runny nose, sneezing, piloerection, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated and may include the following signs and symptoms: convulsions, excessive crying, and hyperactive reflexes.

usness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness, and increased blood pressure. In neonates, opioid withdrawal may be life-threatening if not recognized and properly treated and may include the following signs and symptoms: convulsions, excessive crying, and hyperactive reflexes. Monitor the patient for the development of the signs and symptoms of opioid withdrawal. Abrupt postoperative reversal of opioid depression after using naloxone hydrochloride may result in nausea, vomiting, sweating, tremulousness, tachycardia, hypotension, hypertension, seizures, ventricular tachycardia and fibrillation, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. These events have primarily occurred in patients who had pre-existing cardiovascular disorders or received other drugs that may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, after use of naloxone hydrochloride, monitor patients with pre-existing cardiac disease or patients who have received medications with potential adverse cardiovascular effects for hypotension, ventricular tachycardia or fibrillation, and pulmonary edema in an appropriate healthcare setting. It has been suggested that the pathogenesis of pulmonary edema associated with the use of naloxone hydrochloride is similar to neurogenic pulmonary edema, i.e., a centrally mediated massive catecholamine response leading to a dramatic shift of blood volume into the pulmonary vascular bed resulting in increased hydrostatic pressures. There may be clinical settings, particularly the postpartum period in neonates with known or suspected exposure to maternal opioid use, where it is preferable to avoid the abrupt precipitation of opioid withdrawal symptoms. In these settings, consider use of an alternative, naloxone-containing product that can be titrated to effect and, where applicable, dosed according to weight [see Use in Specific Populations ( 8.4 )] .

6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: Precipitation of Severe Opioid Withdrawal [see Warnings and Precautions ( 5.3 )] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. The following adverse reactions were observed in a naloxone hydrochloride nasal spray clinical study. In a pharmacokinetic study of 30 healthy adult volunteers exposed to one spray of naloxone hydrochloride nasal spray in one nostril or two sprays of naloxone hydrochloride nasal spray, one in each nostril, the most common adverse reactions were: increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, and xeroderma. The following adverse reactions have been identified primarily during post-approval use of naloxone hydrochloride in the post-operative setting. 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: Hypotension, hypertension, ventricular tachycardia and fibrillation, dyspnea, pulmonary edema, and cardiac arrest. Death, coma, and encephalopathy have been reported as sequelae of these events. Excessive doses of naloxone hydrochloride in post-operative patients have resulted in significant reversal of analgesia, and have caused agitation. Abrupt reversal of opioid effects in persons who were physically dependent on opioids has precipitated an acute withdrawal syndrome. Signs and symptoms have included: body aches, fever, sweating, runny nose, sneezing, piloerection, yawning, weakness, shivering or trembling, nervousness, restlessness or irritability, diarrhea, nausea or vomiting, abdominal cramps, increased blood pressure, tachycardia. In some patients, there may be aggressive behavior upon abrupt reversal of an opioid overdose. In the neonate, opioid withdrawal signs and symptoms also included convulsions, excessive crying, and hyperactive reflexes. The following adverse reactions were observed in a naloxone hydrochloride nasal spray clinical study: increased blood pressure, constipation, toothache, muscle spasms, musculoskeletal pain, headache, nasal dryness, nasal edema, nasal congestion, nasal inflammation, rhinalgia, and xeroderma. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The limited available data on naloxone use in pregnant women are not sufficient to inform a drug-associated risk. However, there are clinical considerations [see Clinical Considerations] . In animal reproduction studies, no embryotoxic or teratogenic effects were observed in mice and rats treated with naloxone hydrochloride during the period of organogenesis at doses equivalent to 6-times and 12-times, respectively, a human dose of 8 mg/day (two naloxone hydrochloride nasal sprays) based on body surface area comparison [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 Naloxone hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus, as well as in the opioid-dependent mother [see Warnings and Precautions ( 5.3 )] . The fetus should be evaluated for signs of distress after naloxone hydrochloride nasal spray is used. Careful monitoring is needed until the fetus and mother are stabilized. Data Animal Data Naloxone hydrochloride was administered during organogenesis to mice and rats at subcutaneous doses up to 10 mg/kg/day (equivalent to 6-times and 12-times, respectively, a human dose of 8 mg (two naloxone hydrochloride nasal sprays) (based on body surface area comparison). These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. Pregnant female rats were administered 2 or 10 mg/kg naloxone subcutaneously from Gestation Day 15 to Postnatal day 21. There were no adverse effects on the offspring (up to 12-times a human dose of 8 mg/day (two naloxone hydrochloride nasal sprays) based on body surface area comparison). 8.2 Lactation Risk Summary There is no information regarding the presence of naloxone in human milk, or the effects of naloxone on the breastfed infant or on milk production. Studies in nursing mothers have shown that naloxone does not affect prolactin or oxytocin hormone levels. Naloxone is minimally orally bioavailable. 8.4 Pediatric Use The safety and effectiveness of naloxone hydrochloride nasal spray have been established in pediatric patients of all ages for known or suspected opioid overdose as manifested by respiratory and/or central nervous system depression. Use of naloxone hydrochloride in all pediatric patients is supported by adult bioequivalence studies coupled with evidence from the safe and effective use of other naloxone hydrochloride drug products. No pediatric studies were conducted for naloxone hydrochloride nasal spray. Absorption of naloxone hydrochloride following intranasal administration in pediatric patients may be erratic or delayed. Even when the opiate-intoxicated pediatric patient responds appropriately to naloxone hydrochloride, he/she must be carefully monitored for at least 24 hours, as a relapse may occur as naloxone hydrochloride is metabolized. In opioid-dependent pediatric patients, (including neonates), administration of naloxone hydrochloride may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome.

lly monitored for at least 24 hours, as a relapse may occur as naloxone hydrochloride is metabolized. In opioid-dependent pediatric patients, (including neonates), administration of naloxone hydrochloride may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening, if not recognized, and should be treated according to protocols developed by neonatology experts [see Warnings and Precautions ( 5.3 )] . In settings such as in neonates with known or suspected exposure to maternal opioid use, where it may be preferable to avoid the abrupt precipitation of opioid withdrawal symptoms, consider use of an alternate naloxone-containing product that can be dosed according to weight and titrated to effect. Also, in situations where the primary concern is for infants at risk for opioid overdose, consider whether the availability of alternate naloxone-containing products may be better suited than naloxone hydrochloride nasal spray. 8.5 Geriatric Use Geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Therefore, the systemic exposure of naloxone hydrochloride can be higher in these patients. Clinical studies of naloxone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

8.1 Pregnancy Risk Summary The limited available data on naloxone use in pregnant women are not sufficient to inform a drug-associated risk. However, there are clinical considerations [see Clinical Considerations] . In animal reproduction studies, no embryotoxic or teratogenic effects were observed in mice and rats treated with naloxone hydrochloride during the period of organogenesis at doses equivalent to 6-times and 12-times, respectively, a human dose of 8 mg/day (two naloxone hydrochloride nasal sprays) based on body surface area comparison [see Data] . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. 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 Naloxone hydrochloride crosses the placenta, and may precipitate withdrawal in the fetus, as well as in the opioid-dependent mother [see Warnings and Precautions ( 5.3 )] . The fetus should be evaluated for signs of distress after naloxone hydrochloride nasal spray is used. Careful monitoring is needed until the fetus and mother are stabilized. Data Animal Data Naloxone hydrochloride was administered during organogenesis to mice and rats at subcutaneous doses up to 10 mg/kg/day (equivalent to 6-times and 12-times, respectively, a human dose of 8 mg (two naloxone hydrochloride nasal sprays) (based on body surface area comparison). These studies demonstrated no embryotoxic or teratogenic effects due to naloxone hydrochloride. Pregnant female rats were administered 2 or 10 mg/kg naloxone subcutaneously from Gestation Day 15 to Postnatal day 21. There were no adverse effects on the offspring (up to 12-times a human dose of 8 mg/day (two naloxone hydrochloride nasal sprays) based on body surface area comparison).

8.4 Pediatric Use The safety and effectiveness of naloxone hydrochloride nasal spray have been established in pediatric patients of all ages for known or suspected opioid overdose as manifested by respiratory and/or central nervous system depression. Use of naloxone hydrochloride in all pediatric patients is supported by adult bioequivalence studies coupled with evidence from the safe and effective use of other naloxone hydrochloride drug products. No pediatric studies were conducted for naloxone hydrochloride nasal spray. Absorption of naloxone hydrochloride following intranasal administration in pediatric patients may be erratic or delayed. Even when the opiate-intoxicated pediatric patient responds appropriately to naloxone hydrochloride, he/she must be carefully monitored for at least 24 hours, as a relapse may occur as naloxone hydrochloride is metabolized. In opioid-dependent pediatric patients, (including neonates), administration of naloxone hydrochloride may result in an abrupt and complete reversal of opioid effects, precipitating an acute opioid withdrawal syndrome. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening, if not recognized, and should be treated according to protocols developed by neonatology experts [see Warnings and Precautions ( 5.3 )] . In settings such as in neonates with known or suspected exposure to maternal opioid use, where it may be preferable to avoid the abrupt precipitation of opioid withdrawal symptoms, consider use of an alternate naloxone-containing product that can be dosed according to weight and titrated to effect. Also, in situations where the primary concern is for infants at risk for opioid overdose, consider whether the availability of alternate naloxone-containing products may be better suited than naloxone hydrochloride nasal spray.

8.5 Geriatric Use Geriatric patients have a greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. Therefore, the systemic exposure of naloxone hydrochloride can be higher in these patients. Clinical studies of naloxone hydrochloride did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

11 DESCRIPTION Naloxone hydrochloride nasal spray is a pre-filled, single dose intranasal spray. Chemically, naloxone hydrochloride dihydrate is the hydrochloride salt of (5R,9R,13S,14S)-17-Allyl-3,14-dihydroxy-4,5-epoxymorphinan-6-on hydrochloride dihydrate with the following structure: C 19 H 22 NO 4 Cl•2H 2 O M.W. 399.87 Naloxone hydrochloride, USP an opioid antagonist, occurs as a white to slightly off-white powder, and is freely soluble in water, soluble in ethanol (96%) and practically insoluble in toluene. Each naloxone hydrochloride nasal spray contains a 4 mg single dose of naloxone hydrochloride, USP (equivalent to 3.6 mg of naloxone) in a 0.1 mL (100 microliter) aqueous solution. Inactive ingredients include benzalkonium chloride (preservative), edetate disodium (stabilizer), sodium chloride, sodium hydroxide/hydrochloric acid to adjust pH, and purified water. The pH range is 3.5 to 5.5. Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites. Naloxone hydrochloride reverses the effects of opioids, including respiratory depression, sedation, and hypotension. It can also reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine. 12.2 Pharmacodynamics When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes. The time to onset of action is shorter for intravenous compared to subcutaneous or intramuscular routes of administration. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride. 12.3 Pharmacokinetics In a pharmacokinetic study in 30 healthy adult subjects, the relative bioavailability (BA) of one nasal spray in one nostril, (4 mg total dose, 0.1 mL of 40 mg/mL naloxone hydrochloride solution), and two nasal sprays administered as one nasal spray in each nostril (8 mg total dose, 0.1 mL of 40 mg/mL naloxone hydrochloride solution in each nostril) was compared to a single dose of 0.4 mg naloxone hydrochloride intramuscular injection. For intranasal administration, the subjects were instructed not to breathe through the nose during administration of the nasal spray, and remained fully supine for approximately one hour post-dose. For intramuscular administration, naloxone was administered as a single injection in the gluteus maximus muscle. The pharmacokinetic parameters obtained in the study are shown in Table 1. Table 1 Mean Pharmacokinetic Parameters (CV%) for Naloxone Following Naloxone HCl Nasal Spray and Intramuscular Injection of Naloxone HCl to Healthy Subjects Parameter 4 mg – One Nasal Spray in one nostril 40 mg/ml (N=29) 8 mg – Two Nasal Sprays, one in each nostril 40 mg/ml (N=29) 0.4 mg Intramuscular Injection (N=29) t max (h) † 0.50 (0.17, 1.00) 0.33 (0.17, 1.00) 0.38 (0.08, 2.05) C max (ng/mL) 4.83 (43) 9.70 (36) 0.88 (31) AUC t (hr . ng/mL) 7.87 (37) 15.3 (23) 1.75 (23) AUC 0-inf (h*ng/mL) 7.95 (37) 15.5 (23) 1.79 (23) t 1/2 (h) 2.08 (30) 2.10 (32) 1.24 (26) Dose normalized Relative BA (%) vs. IM 44.2 (31) †† 43.1 (24) 100 † t max reported as median (minimum, maximum) †† N=28 for Relative BA. Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0 to 6 h and (b) 0 to 1h Following Intranasal Administration and Intramuscular Injection The median naloxone t max after intranasal administration of naloxone hydrochloride nasal spray (one nasal spray in one nostril or two nasal sprays as one spray in each nostril was not significantly different compared to the 0.4 mg dose of naloxone hydrochloride intramuscular injection (Table 1). The dose normalized relative bioavailability of one dose (4 mg) or two doses (8 mg) of naloxone hydrochloride nasal spray as compared to the 0.4 mg dose of naloxone hydrochloride administered by intramuscular injection was 44% and 43%, respectively. Distribution Following parenteral administration, naloxone is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent, but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk.

one is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent, but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk. Elimination Following a single intranasal administration of naloxone hydrochloride nasal spray (4 mg dose of naloxone hydrochloride), the mean plasma half-life of naloxone in healthy adults was approximately 2.08 (30% CV) hours; respectively, which was longer than that observed after administrations of a 0.4 mg naloxone hydrochloride intramuscular injection, where the half-life was 1.24 hours (26% CV). In a neonatal study of naloxone hydrochloride injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours. Metabolism Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucoronide as the major metabolite. Excretion After an oral or intravenous dose, about 25 to 40% of naloxone is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours. Figure 1

12.1 Mechanism of Action Naloxone hydrochloride is an opioid antagonist that antagonizes opioid effects by competing for the same receptor sites. Naloxone hydrochloride reverses the effects of opioids, including respiratory depression, sedation, and hypotension. It can also reverse the psychotomimetic and dysphoric effects of agonist-antagonists such as pentazocine.

12.2 Pharmacodynamics When naloxone hydrochloride is administered intravenously, the onset of action is generally apparent within two minutes. The time to onset of action is shorter for intravenous compared to subcutaneous or intramuscular routes of administration. The duration of action is dependent upon the dose and route of administration of naloxone hydrochloride.

12.3 Pharmacokinetics In a pharmacokinetic study in 30 healthy adult subjects, the relative bioavailability (BA) of one nasal spray in one nostril, (4 mg total dose, 0.1 mL of 40 mg/mL naloxone hydrochloride solution), and two nasal sprays administered as one nasal spray in each nostril (8 mg total dose, 0.1 mL of 40 mg/mL naloxone hydrochloride solution in each nostril) was compared to a single dose of 0.4 mg naloxone hydrochloride intramuscular injection. For intranasal administration, the subjects were instructed not to breathe through the nose during administration of the nasal spray, and remained fully supine for approximately one hour post-dose. For intramuscular administration, naloxone was administered as a single injection in the gluteus maximus muscle. The pharmacokinetic parameters obtained in the study are shown in Table 1. Table 1 Mean Pharmacokinetic Parameters (CV%) for Naloxone Following Naloxone HCl Nasal Spray and Intramuscular Injection of Naloxone HCl to Healthy Subjects Parameter 4 mg – One Nasal Spray in one nostril 40 mg/ml (N=29) 8 mg – Two Nasal Sprays, one in each nostril 40 mg/ml (N=29) 0.4 mg Intramuscular Injection (N=29) t max (h) † 0.50 (0.17, 1.00) 0.33 (0.17, 1.00) 0.38 (0.08, 2.05) C max (ng/mL) 4.83 (43) 9.70 (36) 0.88 (31) AUC t (hr . ng/mL) 7.87 (37) 15.3 (23) 1.75 (23) AUC 0-inf (h*ng/mL) 7.95 (37) 15.5 (23) 1.79 (23) t 1/2 (h) 2.08 (30) 2.10 (32) 1.24 (26) Dose normalized Relative BA (%) vs. IM 44.2 (31) †† 43.1 (24) 100 † t max reported as median (minimum, maximum) †† N=28 for Relative BA. Figure 1 Mean ± SD Plasma Concentration of Naloxone, (a) 0 to 6 h and (b) 0 to 1h Following Intranasal Administration and Intramuscular Injection The median naloxone t max after intranasal administration of naloxone hydrochloride nasal spray (one nasal spray in one nostril or two nasal sprays as one spray in each nostril was not significantly different compared to the 0.4 mg dose of naloxone hydrochloride intramuscular injection (Table 1). The dose normalized relative bioavailability of one dose (4 mg) or two doses (8 mg) of naloxone hydrochloride nasal spray as compared to the 0.4 mg dose of naloxone hydrochloride administered by intramuscular injection was 44% and 43%, respectively. Distribution Following parenteral administration, naloxone is distributed in the body and readily crosses the placenta. Plasma protein binding occurs but is relatively weak. Plasma albumin is the major binding constituent, but significant binding of naloxone also occurs to plasma constituents other than albumin. It is not known whether naloxone is excreted into human milk. Elimination Following a single intranasal administration of naloxone hydrochloride nasal spray (4 mg dose of naloxone hydrochloride), the mean plasma half-life of naloxone in healthy adults was approximately 2.08 (30% CV) hours; respectively, which was longer than that observed after administrations of a 0.4 mg naloxone hydrochloride intramuscular injection, where the half-life was 1.24 hours (26% CV). In a neonatal study of naloxone hydrochloride injection, the mean (± SD) plasma half-life was observed to be 3.1 (± 0.5) hours. Metabolism Naloxone hydrochloride is metabolized in the liver, primarily by glucuronide conjugation, with naloxone-3-glucoronide as the major metabolite. Excretion After an oral or intravenous dose, about 25 to 40% of naloxone is excreted as metabolites in urine within 6 hours, about 50% in 24 hours, and 60 to 70% in 72 hours. Figure 1

<table cellspacing="0" cellpadding="0" border="1"><col width="522.9pt"/><col/><col/><col/><tbody><tr><td colspan="4"><paragraph><content styleCode="bold">Table 1</content><content styleCode="bold">Mean Pharmacokinetic Parameters (CV%) for Naloxone Following Naloxone HCl Nasal Spray and Intramuscular Injection of Naloxone HCl to Healthy Subjects</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Parameter</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold"> </content></paragraph><paragraph><content styleCode="bold">4 mg &#x2013; One Nasal Spray in one nostril </content><content styleCode="bold">40 mg/ml </content><content styleCode="bold">(N=29)</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">8 mg &#x2013; Two Nasal Sprays, one in each nostril </content><content styleCode="bold">40 mg/ml </content><content styleCode="bold">(N=29)</content></paragraph></td><td align="center" styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">0.4 mg </content><content styleCode="bold">Intramuscular Injection </content><content styleCode="bold">(N=29)</content></paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">t _max(h) </content>^&#x2020;</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.50 (0.17, 1.00)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.33 (0.17, 1.00)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.38 (0.08, 2.05)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">C _max(ng/mL) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>4.83 (43)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>9.70 (36)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>0.88 (31)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">AUC _t(hr <content styleCode="bold">.</content>ng/mL) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7.87 (37)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15.3 (23)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.75 (23)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">AUC _0-inf(h*ng/mL) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>7.95 (37)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>15.5 (23)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.79 (23)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">t _1/2(h) </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.08 (30)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.10 (32)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.24 (26)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Dose normalized Relative BA (%) vs.

aph>2.08 (30)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>2.10 (32)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>1.24 (26)</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph><content styleCode="bold">Dose normalized Relative BA (%) vs. IM </content></paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>44.2 (31) ^{&#x2020;&#x2020;}</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>43.1 (24)</paragraph></td><td styleCode=" Botrule Toprule Lrule Rrule"><paragraph>100</paragraph></td></tr><tr><td colspan="4"><paragraph>^&#x2020;t _maxreported as median (minimum, maximum) ^{&#x2020;&#x2020;} N=28 for Relative BA. </paragraph></td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed. Mutagenesis Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study. Impairment of Fertility Male rats were treated with 2 or 10 mg/kg naloxone for 60 days prior to mating. Female rats treated for 14-days prior to mating and throughout gestation with the same doses of naloxone (up to 12-times a human dose of 8 mg/day (two naloxone hydrochloride nasal sprays) based on body surface area comparison). There was no adverse effect on fertility.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Long-term animal studies to evaluate the carcinogenic potential of naloxone have not been completed. Mutagenesis Naloxone was weakly positive in the Ames mutagenicity and in the in vitro human lymphocyte chromosome aberration test but was negative in the in vitro Chinese hamster V79 cell HGPRT mutagenicity assay and in the in vivo rat bone marrow chromosome aberration study. Impairment of Fertility Male rats were treated with 2 or 10 mg/kg naloxone for 60 days prior to mating. Female rats treated for 14-days prior to mating and throughout gestation with the same doses of naloxone (up to 12-times a human dose of 8 mg/day (two naloxone hydrochloride nasal sprays) based on body surface area comparison). There was no adverse effect on fertility.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Naloxone hydrochloride nasal spray 4 mg is supplied as a carton containing two blister packages (NDC 0093-2165-68) each with a single spray device. Naloxone hydrochloride nasal spray is not made with natural rubber latex. 16.2 Storage and Handling Store naloxone hydrochloride nasal spray in the blister and cartons provided. Store below 77°F (25°C). Excursions permitted up to 104°F (40°C). Do not freeze or expose to excessive heat above 104°F (40°C). Protect from light. Naloxone hydrochloride nasal spray freezes at temperatures below 5°F (-15°C). If this happens, the device will not spray. If naloxone hydrochloride nasal spray is frozen and is needed in an emergency, do NOT wait for naloxone hydrochloride nasal spray to thaw. Get emergency medical help right away. However, naloxone hydrochloride nasal spray may be thawed by allowing it to sit at room temperature for 15 minutes, and it may still be used if it has been thawed after being previously frozen.

17 PATIENT COUNSELING INFORMATION Advise the patient and family members or caregivers to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ). Recognition of Opioid Overdose Inform patients and their family members or caregivers about how to recognize the signs and symptoms of an opioid overdose such as the following: Extreme somnolence - inability to awaken a patient verbally or upon a firm sternal rub. Respiratory depression - this can range from slow or shallow respiration to no respiration in a patient who is unarousable. Other signs and symptoms that may accompany somnolence and respiratory depression include the following: Miosis. Bradycardia and/or hypotension. Risk of Recurrent Respiratory and Central Nervous System Depression Instruct patients and their family members or caregivers that, since the duration of action of most opioids may exceed that of naloxone hydrochloride nasal spray, they must seek immediate emergency medical assistance after the first dose of naloxone hydrochloride nasal spray and keep the patient under continued surveillance [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.3 )] . Limited Efficacy for/with Partial Agonists or Mixed Agonist/Antagonists Instruct patients and their family members or caregivers that the reversal of respiratory depression caused by partial agonists or mixed agonist/antagonists, such as buprenorphine and pentazocine, may be incomplete and may require higher doses of naloxone hydrochloride or repeated administration of naloxone hydrochloride nasal spray, using a new nasal spray each time [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.2 )] . Precipitation of Severe Opioid Withdrawal Instruct patients and their family members or caregivers that the use of naloxone hydrochloride nasal spray in patients who are opioid dependent may precipitate opioid withdrawal [see Warnings and Precautions ( 5.3 ), Adverse Reactions ( 6 )] . Administration Instructions Instruct patients and their family members or caregivers to: Ensure naloxone hydrochloride nasal spray is present whenever persons may be intentionally or accidentally exposed to an opioid overdose (i.e., opioid emergencies). Administer naloxone hydrochloride nasal spray as quickly as possible if a patient is unresponsive and an opioid overdose is suspected, even when in doubt, because prolonged respiratory depression may result in damage to the central nervous system or death. Naloxone hydrochloride nasal spray is not a substitute for emergency medical care [see Dosage and Administration ( 2.1 )] . Lay the patient on their back and administer naloxone hydrochloride nasal spray into one nostril while providing support to the back of the neck to allow the head to tilt back [see Dosage and Administration ( 2.1 )] . Use each nasal spray only one time [see Dosage and Administration ( 2.1 )] . Turn patient on their side as shown in the Instructions for Use and call for emergency medical assistance immediately after administration of the first dose of naloxone hydrochloride nasal spray. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration ( 2.1 )] .

s shown in the Instructions for Use and call for emergency medical assistance immediately after administration of the first dose of naloxone hydrochloride nasal spray. Additional supportive and/or resuscitative measures may be helpful while awaiting emergency medical assistance [see Dosage and Administration ( 2.1 )] . Monitor patients and re-administer naloxone hydrochloride nasal spray using a new naloxone hydrochloride nasal spray every 2 to 3 minutes, if the patient is not responding or responds and then relapses back into respiratory depression. Administer naloxone hydrochloride nasal spray in alternate nostrils with each dose [see Dosage and Administration ( 2.1 )] . Replace naloxone hydrochloride nasal spray before its expiration date. Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Rev. F 3/2023

PATIENT INFORMATION Naloxone Hydrochloride (nal ox’ one hye” droe klor’ ide) Nasal Spray You and your family members or caregivers should read this Patient Information leaflet before an opioid emergency happens. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is the most important information I should know about naloxone hydrochloride nasal spray? Naloxone hydrochloride nasal spray is used to temporarily reverse the effects of opioid medicines. The medicine in naloxone hydrochloride nasal spray has no effect in people who are not taking opioid medicines. Always carry naloxone hydrochloride nasal spray with you in case of an opioid emergency. 1. Use naloxone hydrochloride nasal spray right away if you or your caregiver think signs or symptoms of an opioid emergency are present, even if you are not sure, because an opioid emergency can cause severe injury or death. Signs and symptoms of an opioid emergency may include: unusual sleepiness and you are not able to awaken the person with a loud voice or by rubbing firmly on the middle of their chest (sternum) breathing problems including slow or shallow breathing in someone difficult to awaken or who looks like they are not breathing the black circle in the center of the colored part of the eye (pupil) is very small, sometimes called “pinpoint pupils,” in someone difficult to awaken 2. Family members, caregivers, or other people who may have to use naloxone hydrochloride nasal spray in an opioid emergency should know where naloxone hydrochloride nasal spray is stored and how to give naloxone hydrochloride before an opioid emergency happens. 3. Get emergency medical help right away after giving the first dose of naloxone hydrochloride nasal spray. Rescue breathing or CPR (cardiopulmonary resuscitation) may be given while waiting for emergency medical help. 4. The signs and symptoms of an opioid emergency can return after naloxone hydrochloride nasal spray is given. If this happens, give another dose after 2 to 3 minutes using a new naloxone hydrochloride nasal spray and watch the person closely until emergency help is received. What is naloxone hydrochloride nasal spray? Naloxone hydrochloride nasal spray is a prescription medicine used for the treatment of an opioid emergency such as an overdose or a possible opioid overdose with signs of breathing problems and severe sleepiness or not being able to respond. Naloxone hydrochloride nasal spray is to be given right away and does not take the place of emergency medical care. Get emergency medical help right away after giving the first dose of naloxone hydrochloride nasal spray, even if the person wakes up. Naloxone hydrochloride nasal spray is safe and effective in children for known or suspected opioid overdose. Who should not use naloxone hydrochloride nasal spray? Do not use naloxone hydrochloride nasal spray if you are allergic to naloxone hydrochloride or any of the ingredients in naloxone hydrochloride nasal spray. See the end of this leaflet for a complete list of ingredients in naloxone hydrochloride nasal spray. What should I tell my healthcare provider before using naloxone hydrochloride nasal spray? Before using naloxone hydrochloride nasal spray, tell your healthcare provider about all of your medical conditions, including if you: have heart problems are pregnant or plan to become pregnant.

loxone hydrochloride nasal spray. What should I tell my healthcare provider before using naloxone hydrochloride nasal spray? Before using naloxone hydrochloride nasal spray, tell your healthcare provider about all of your medical conditions, including if you: have heart problems are pregnant or plan to become pregnant. Use of naloxone hydrochloride nasal spray may cause withdrawal symptoms in your unborn baby. Your unborn baby should be examined by a healthcare provider right away after you use naloxone hydrochloride nasal spray. are breastfeeding or plan to breastfeed. It is not known if naloxone hydrochloride passes into your breast milk. Tell your healthcare provider about the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. How should I use naloxone hydrochloride nasal spray? Read the “Instructions for Use” at the end of this Patient Information leaflet for detailed information about the right way to use naloxone hydrochloride nasal spray. Use naloxone hydrochloride nasal spray exactly as prescribed by your healthcare provider. Each naloxone hydrochloride nasal spray contains only 1 dose of medicine and cannot be reused. Lay the person on their back. Support their neck with your hand and allow the head to tilt back before giving naloxone hydrochloride nasal spray. Naloxone hydrochloride nasal spray should be given into one nostril. If additional doses are needed, give naloxone hydrochloride nasal spray in the other nostril. What are the possible side effects of naloxone hydrochloride nasal spray? Naloxone hydrochloride nasal spray may cause serious side effects, including: Sudden opioid withdrawal symptoms. In someone who has been using opioids regularly, opioid withdrawal symptoms can happen suddenly after receiving naloxone hydrochloride nasal spray and may include: ○ body aches ○ sneezing ○ nervousness ○ diarrhea ○ goose bumps ○ restlessness or irritability ○ increased heart rate ○ sweating ○ shivering or trembling ○ fever ○ yawning ○ stomach cramping ○ runny nose ○ nausea or vomiting ○ weakness ○ increased blood pressure In infants under 4 weeks old who have been receiving opioids regularly, sudden opioid withdrawal may be life-threatening if not treated the right way. Signs and symptoms include: seizures, crying more than usual, and increased reflexes. These are not all of the possible side effects of naloxone hydrochloride nasal spray. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store naloxone hydrochloride nasal spray? Store below 77°F (25°C). Excursions permitted up to 104°F (40°C). Do not freeze or expose to excessive heat above 104°F (40°C). Keep naloxone hydrochloride nasal spray in its box until ready to use. Protect from light. Replace naloxone hydrochloride nasal spray before the expiration date on the box. Keep naloxone hydrochloride nasal spray and all medicines out of the reach of children. General information about the safe and effective use of naloxone hydrochloride nasal spray. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use naloxone hydrochloride nasal spray for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about naloxone hydrochloride nasal spray that is written for health professionals. What are the ingredients in naloxone hydrochloride nasal spray? Active ingredient: naloxone hydrochloride Inactive ingredients: benzalkonium chloride (preservative), edetate disodium (stabilizer), sodium chloride, sodium hydroxide/hydrochloric acid to adjust pH, and purified water Naloxone hydrochloride nasal spray is not made with natural rubber latex.

e hydrochloride nasal spray? Active ingredient: naloxone hydrochloride Inactive ingredients: benzalkonium chloride (preservative), edetate disodium (stabilizer), sodium chloride, sodium hydroxide/hydrochloric acid to adjust pH, and purified water Naloxone hydrochloride nasal spray is not made with natural rubber latex. Teva Pharmaceuticals USA, Inc., North Wales, PA 19454 For more information, go to www.tevagenerics.com or call 1-888-TEVAUSA (1-888-838-2872). This Patient Information has been approved by the U.S. Food and Drug Administration. Rev. E 6/2022 INSTRUCTIONS FOR USE Naloxone Hydrochloride (nal ox’ one hye” droe klor’ ide) Nasal Spray You and your family members or caregivers should read the Instructions for Use that comes with naloxone hydrochloride nasal spray before using it. Talk to your healthcare provider if you and your family members or caregivers have any questions about the use of naloxone hydrochloride nasal spray. Use naloxone hydrochloride nasal spray for known or suspected opioid overdose in adults and children. Important: For use in the nose only. Do not remove or test the naloxone hydrochloride nasal spray until ready to use. Each naloxone hydrochloride nasal spray has 1 dose and cannot be reused. You do not need to prime naloxone hydrochloride nasal spray. How to use naloxone hydrochloride nasal spray: Step 1. Lay the person on their back to receive a dose of naloxone hydrochloride nasal spray. Step 2. Remove naloxone hydrochloride nasal spray from the box. Peel back the tab with the circle to open the naloxone hydrochloride nasal spray. Note: Naloxone hydrochloride nasal spray freezes at temperatures below 5°F (-15°C). If this happens, the device will not spray. Get emergency medical help right away if this happens. Do not wait for naloxone hydrochloride nasal spray to thaw. Naloxone hydrochloride nasal spray may still be used if it has been thawed after being previously frozen. Step 3. Hold the naloxone hydrochloride nasal spray with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle. Step 4. Tilt the person’s head back and provide support under the neck with your hand. Gently insert the tip of the nozzle into one nostril until your fingers on either side of the nozzle are against the bottom of the person’s nose. Step 5. Press the plunger firmly to give the dose of naloxone hydrochloride nasal spray. Step 6. Remove the naloxone hydrochloride nasal spray from the nostril after giving the dose. What to do after naloxone hydrochloride nasal spray has been used: Step 7. Get emergency medical help right away. Move the person on their side (recovery position) after giving naloxone hydrochloride nasal spray. Watch the person closely. If the person does not respond by waking up, to voice or touch, or breathing normally another dose may be given. Naloxone hydrochloride nasal spray may be dosed every 2 to 3 minutes, if available. Repeat Steps 2 through 6 using a new naloxone hydrochloride nasal spray to give another dose in the other nostril. If additional naloxone hydrochloride nasal sprays are available, Steps 2 through 6 may be repeated every 2 to 3 minutes until the person responds or emergency medical help is received. Step 8. Put the used naloxone hydrochloride nasal spray back into its box. Step 9. Throw away (dispose of) the used naloxone hydrochloride nasal spray in a place that is away from children. How should I store naloxone hydrochloride nasal spray? Store below 77°F (25°C). Excursions permitted up to 104°F (40°C). Do not freeze or expose to excessive heat above 104°F (40°C). Keep naloxone hydrochloride nasal spray in the box until ready to use. Protect from light. Replace naloxone hydrochloride nasal spray before the expiration date on the box.

loride nasal spray? Store below 77°F (25°C). Excursions permitted up to 104°F (40°C). Do not freeze or expose to excessive heat above 104°F (40°C). Keep naloxone hydrochloride nasal spray in the box until ready to use. Protect from light. Replace naloxone hydrochloride nasal spray before the expiration date on the box. Keep naloxone hydrochloride nasal spray and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. For more information, go to www.tevagenerics.com or call 1-888-TEVAUSA (1-888-838-2872). Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Rev. E 6/2022 Naloxone Hydrochloride Nasal Spray QUICK START GUIDE Opioid Overdose Response Instructions Use naloxone hydrochloride nasal spray for known or suspected opioid overdose in adults and children. Important: For use in the nose only. Do not remove or test the naloxone hydrochloride nasal spray until ready to use. 1 Identify Opioid Overdose and Check for Response Ask person if he or she is okay and shout name. Shake shoulders and firmly rub the middle of their chest. Check for signs of opioid overdose: Will not wake up or respond to your voice or touch Breathing is very slow, irregular, or has stopped Center part of their eye is very small, sometimes called “pinpoint pupils” Lay the person on their back to receive a dose of naloxone hydrochloride nasal spray. 2 Give naloxone hydrochloride nasal spray Remove naloxone hydrochloride nasal spray from the box. Peel back the tab with the circle to open the naloxone hydrochloride nasal spray. Note: Naloxone hydrochloride nasal spray freezes at temperatures below 5°F (-15°C). If this happens, the device will not spray. Get emergency medical help right away if this happens. Do not wait for naloxone hydrochloride nasal spray to thaw. Naloxone hydrochloride nasal spray may still be used if it has been thawed after being previously frozen. Hold the naloxone hydrochloride nasal spray with your thumb on the bottom of the plunger and your first and middle fingers on either side of the nozzle. Gently insert the tip of the nozzle into either nostril. Tilt the person’s head back and provide support under the neck with your hand. Gently insert the tip of the nozzle into one nostril , until your fingers on either side of the nozzle are against the bottom of the person’s nose. Press the plunger firmly to give the dose of naloxone hydrochloride nasal spray. Remove the naloxone hydrochloride nasal spray from the nostril after giving the dose. 3 Call for emergency medical help, Evaluate, and Support Get emergency medical help right away. Move the person on their side (recovery position) after giving naloxone hydrochloride nasal spray. Watch the person closely. If the person does not respond by waking up, to voice or touch, or breathing normally another dose may be given. Naloxone hydrochloride nasal spray may be dosed every 2 to 3 minutes, if available. Repeat Step 2 using a new naloxone hydrochloride nasal spray to give another dose in the other nostril. If additional Naloxone hydrochloride nasal sprays are available, repeat step 2 every 2 to 3 minutes until the person responds or emergency medical help is received. For more information go to www.tevagenerics.com or call 1-888-TEVAUSA (1-888-838-2872). You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 Rev. E 6/2022 blister image opening blister Plunger-1 Insert Nozzle 1 Press Plunger 1 Recovery Position 1 Check for Response blister image opening blister Plunger-1 Insert Plunger 2 Insert Nozzle 2 Recovery Position 2

<table><col width="100%"/><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">PATIENT INFORMATION</content></paragraph><paragraph><content styleCode="bold">Naloxone Hydrochloride (nal ox&#x2019; one hye&#x201D; droe klor&#x2019; ide)</content></paragraph><paragraph><content styleCode="bold">Nasal Spray</content></paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>You and your family members or caregivers should read this Patient Information leaflet before an opioid emergency happens. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment.</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about naloxone hydrochloride nasal spray?</content></paragraph><paragraph>Naloxone hydrochloride nasal spray is used to temporarily reverse the effects of opioid medicines. The medicine in naloxone hydrochloride nasal spray has no effect in people who are not taking opioid medicines. Always carry naloxone hydrochloride nasal spray with you in case of an opioid emergency.</paragraph><paragraph>1. Use naloxone hydrochloride nasal spray right away if you or your caregiver think signs or symptoms of an opioid emergency are present, even if you are not sure, because an opioid emergency can cause severe injury or death. Signs and symptoms of an opioid emergency may include:</paragraph><list listType="unordered"><item>unusual sleepiness and you are not able to awaken the person with a loud voice or by rubbing firmly on the middle of their chest (sternum)</item><item>breathing problems including slow or shallow breathing in someone difficult to awaken or who looks like they are not breathing</item><item>the black circle in the center of the colored part of the eye (pupil) is very small, sometimes called &#x201C;pinpoint pupils,&#x201D; in someone difficult to awaken</item></list><paragraph>2. Family members, caregivers, or other people who may have to use naloxone hydrochloride nasal spray in an opioid emergency should know where naloxone hydrochloride nasal spray is stored and how to give naloxone hydrochloride before an opioid emergency happens.</paragraph><paragraph>3. <content styleCode="bold">Get emergency medical help right away after giving the first dose of naloxone hydrochloride nasal spray.</content>Rescue breathing or CPR (cardiopulmonary resuscitation) may be given while waiting for emergency medical help. </paragraph><paragraph>4. The signs and symptoms of an opioid emergency can return after naloxone hydrochloride nasal spray is given.

after giving the first dose of naloxone hydrochloride nasal spray.</content>Rescue breathing or CPR (cardiopulmonary resuscitation) may be given while waiting for emergency medical help. </paragraph><paragraph>4. The signs and symptoms of an opioid emergency can return after naloxone hydrochloride nasal spray is given. If this happens, give another dose after 2 to 3 minutes using a new naloxone hydrochloride nasal spray and watch the person closely until emergency help is received.</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">What is naloxone hydrochloride nasal spray?</content></paragraph><list listType="unordered" styleCode="Disc"><item>Naloxone hydrochloride nasal spray is a prescription medicine used for the treatment of an opioid emergency such as an overdose or a possible opioid overdose with signs of breathing problems and severe sleepiness or not being able to respond.</item><item>Naloxone hydrochloride nasal spray is to be given right away and does not take the place of emergency medical care. Get emergency medical help right away after giving the first dose of naloxone hydrochloride nasal spray, even if the person wakes up. </item><item>Naloxone hydrochloride nasal spray is safe and effective in children for known or suspected opioid overdose.</item></list></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Who should not use naloxone hydrochloride nasal spray?</content></paragraph><paragraph><content styleCode="bold"><content styleCode="bold">Do not use naloxone hydrochloride nasal spray </content></content>if you are allergic to naloxone hydrochloride or any of the ingredients in naloxone hydrochloride nasal spray. See the end of this leaflet for a complete list of ingredients in naloxone hydrochloride nasal spray. <content styleCode="bold"> </content></paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">What should I tell my healthcare provider before using naloxone hydrochloride nasal spray?</content></paragraph><paragraph>Before using naloxone hydrochloride nasal spray, tell your healthcare provider about all of your medical conditions, including if you:</paragraph><list listType="unordered" styleCode="Disc"><item>have heart problems</item><item>are pregnant or plan to become pregnant. Use of naloxone hydrochloride nasal spray may cause withdrawal symptoms in your unborn baby. Your unborn baby should be examined by a healthcare provider right away after you use naloxone hydrochloride nasal spray.</item><item>are breastfeeding or plan to breastfeed. It is not known if naloxone hydrochloride passes into your breast milk.</item></list><paragraph><content styleCode="bold">Tell your healthcare provider about the medicines you take,</content>including prescription and over-the-counter medicines, vitamins, and herbal supplements. </paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">How should I use naloxone hydrochloride nasal spray?</content></paragraph><paragraph><content styleCode="bold">Read the &#x201C;Instructions for Use&#x201D; at the end of this Patient Information leaflet for detailed information about the right way to use naloxone hydrochloride nasal spray.</content></paragraph><list listType="unordered"><item>Use naloxone hydrochloride nasal spray exactly as prescribed by your healthcare provider.</item><item>Each naloxone hydrochloride nasal spray contains only 1 dose of medicine and cannot be reused.</item><item>Lay the person on their back.

hydrochloride nasal spray.</content></paragraph><list listType="unordered"><item>Use naloxone hydrochloride nasal spray exactly as prescribed by your healthcare provider.</item><item>Each naloxone hydrochloride nasal spray contains only 1 dose of medicine and cannot be reused.</item><item>Lay the person on their back. Support their neck with your hand and allow the head to tilt back before giving naloxone hydrochloride nasal spray.</item><item>Naloxone hydrochloride nasal spray should be given into one nostril. </item><item>If additional doses are needed, give naloxone hydrochloride nasal spray in the other nostril.</item></list></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">What are the possible side effects of naloxone hydrochloride nasal spray?</content></paragraph><paragraph><content styleCode="bold">Naloxone hydrochloride nasal spray may cause serious side effects, including:</content></paragraph><list listType="unordered"><item><content styleCode="bold">Sudden opioid withdrawal symptoms.</content>In someone who has been using opioids regularly, opioid withdrawal symptoms can happen suddenly after receiving naloxone hydrochloride nasal spray and may include: </item></list><paragraph>&#x25CB; body aches &#x25CB; sneezing &#x25CB; nervousness</paragraph><paragraph>&#x25CB; diarrhea &#x25CB; goose bumps &#x25CB; restlessness or irritability</paragraph><paragraph>&#x25CB; increased heart rate &#x25CB; sweating &#x25CB; shivering or trembling</paragraph><paragraph>&#x25CB; fever &#x25CB; yawning &#x25CB; stomach cramping</paragraph><paragraph>&#x25CB; runny nose &#x25CB; nausea or vomiting &#x25CB; weakness</paragraph><paragraph>&#x25CB; increased blood pressure</paragraph><paragraph>In infants under 4 weeks old who have been receiving opioids regularly, sudden opioid withdrawal may be life-threatening if not treated the right way. Signs and symptoms include: seizures, crying more than usual, and increased reflexes.</paragraph><paragraph>These are not all of the possible side effects of naloxone hydrochloride nasal spray. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">How should I store naloxone hydrochloride nasal spray?</content></paragraph><list listType="unordered"><item>Store below 77&#xB0;F (25&#xB0;C).</item><item>Excursions permitted up to 104&#xB0;F (40&#xB0;C).</item><item>Do not freeze or expose to excessive heat above 104&#xB0;F (40&#xB0;C).</item><item>Keep naloxone hydrochloride nasal spray in its box until ready to use. Protect from light.</item><item>Replace naloxone hydrochloride nasal spray before the expiration date on the box.</item></list><paragraph><content styleCode="bold">Keep naloxone hydrochloride nasal spray and all medicines out of the reach of children.</content></paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of naloxone hydrochloride nasal spray.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use naloxone hydrochloride nasal spray for a condition for which it was not prescribed.

ral information about the safe and effective use of naloxone hydrochloride nasal spray.</content></paragraph><paragraph>Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use naloxone hydrochloride nasal spray for a condition for which it was not prescribed. You can ask your pharmacist or healthcare provider for information about naloxone hydrochloride nasal spray that is written for health professionals.</paragraph></td></tr><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">What are the ingredients in naloxone hydrochloride nasal spray?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content>naloxone hydrochloride </paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content>benzalkonium chloride (preservative), edetate disodium (stabilizer), sodium chloride, sodium hydroxide/hydrochloric acid to adjust pH, and purified water </paragraph><paragraph>Naloxone hydrochloride nasal spray is not made with natural rubber latex.</paragraph><paragraph><content styleCode="bold">Teva Pharmaceuticals USA, Inc.,</content>North Wales, PA 19454 </paragraph><paragraph>For more information, go to www.tevagenerics.com or call 1-888-TEVAUSA (1-888-838-2872).</paragraph></td></tr></tbody></table>