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WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1) , Drug Interactions (7.1) ] . • The use of benzodiazepines, including XANAX, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing XANAX and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2) ] . • The continued use of benzodiazepines, including XANAX, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of XANAX after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX or reduce the dosage [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) ] . WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS See full prescribing information for complete boxed warning. • Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. ( 5.1 , 7.1 ) • The use of benzodiazepines, including XANAX, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing XANAX and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. ( 5.2 ) • Abrupt discontinuation or rapid dosage reduction of XANAX after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX or reduce the dosage. ( 2.2 , 5.3 )

1 INDICATIONS AND USAGE XANAX is indicated for the: • acute treatment of generalized anxiety disorder (GAD) in adults. • treatment of panic disorder (PD), with or without agoraphobia in adults. XANAX is a benzodiazepine indicated for the: • Acute treatment of generalized anxiety disorder in adults. ( 1 ) • Treatment of panic disorder with or without agoraphobia in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION • Generalized Anxiety Disorder : ( 2.1 ) o Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily. o Dosage may be increased, at intervals of every 3 to 4 days, to a maximum recommended daily dose of 4 mg, given in divided doses. o Use the lowest possible effective dose and frequently assess the need for continued treatment. • Panic Disorder : Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. ( 2.2 ) • When tapering, decrease dosage by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction. ( 2.3 , 5.2 ) • See the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. ( 2.4 , 2.5 , 2.6 ) 2.1 Dosage in Generalized Anxiety Disorder The recommended starting oral dosage of XANAX for the acute treatment of patients with GAD is 0.25 mg to 0.5 mg administered three times daily. Depending upon the response, the dosage may be adjusted at intervals of every 3 to 4 days. The maximum recommended dosage is 4 mg daily (in divided doses). Use the lowest possible effective dose and frequently assess the need for continued treatment [see Warnings and Precautions (5.2) ] . 2.2 Dosage in Panic Disorder The recommended starting oral dosage of XANAX for the treatment of PD is 0.5 mg three times daily. Depending on the response, the dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. Controlled trials of XANAX in the treatment of panic disorder included dosages in the range of 1 mg to 10 mg daily. The mean dosage was approximately 5 mg to 6 mg daily. Occasional patients required as much as 10 mg per day. For patients receiving doses greater than 4 mg per day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of XANAX greater than 4 mg per day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. The necessary duration of treatment for PD in patients responding to XANAX is unknown. After a period of extended freedom from panic attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena [see Dosage and Administration (2.3) ] . 2.3 Discontinuation or Dosage Reduction of XANAX To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3) , Drug Abuse and Dependence (9.3) ] . Reduced the dosage by no more than 0.5 mg every 3 days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

ge level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3) , Drug Abuse and Dependence (9.3) ] . Reduced the dosage by no more than 0.5 mg every 3 days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens. In a controlled postmarketing discontinuation study of panic disorder patients which compared the recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. 2.4 Dosage Recommendations in Geriatric Patients In geriatric patients, the recommended starting oral dosage of XANAX is 0.25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. Geriatric patients may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dosage, the dosage may be reduced [see Use in Specific Populations (8.5) , Clinical Pharmacology (12.3) ] . 2.5 Dosage Recommendations in Patients with Hepatic Impairment In patients with hepatic impairment, the recommended starting oral dosage of XANAX is 0.25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. If adverse reactions occur at the recommended starting dose, the dosage may be reduced [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . 2.6 Dosage Modifications for Drug Interactions XANAX should be reduced to half of the recommended dosage when a patient is started on ritonavir and XANAX together, or when ritonavir administered to a patient treated with XANAX. Increase the XANAX dosage to the target dose after 10 to 14 days of dosing ritonavir and XANAX together. It is not necessary to reduce XANAX dose in patients who have been taking ritonavir for more than 10 to 14 days. XANAX is contraindicated with concomitant use of all strong CYP3A inhibitors, except ritonavir [see Contraindications (4) , Warnings and Precautions (5.5) ] .

3 DOSAGE FORMS AND STRENGTHS XANAX tablets are available as: • 0.25 mg: white, oval, scored, imprinted “XANAX 0.25” • 0.5 mg: peach, oval, scored, imprinted “XANAX 0.5” • 1 mg: blue, oval, scored, imprinted “XANAX 1.0” • 2 mg: white, oblong, multi-scored, imprinted “XANAX ” on one side and “2” on the reverse side Tablets: 0.25 mg, 0.5 mg, 1 mg, and 2 mg ( 3 )

4 CONTRAINDICATIONS XANAX is contraindicated in patients: • with known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2) ] . • taking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2.6) , Warnings and Precautions (5.5) , Drug Interactions (7.1) ] • Known hypersensitivity to alprazolam or other benzodiazepines. ( 4 ) • Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. ( 4 , 5.5 , 7.1 )

5 WARNINGS AND PRECAUTIONS • Effects on Driving and Operating Machinery: Patients receiving XANAX should be cautioned against operating machinery or driving a motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. ( 5.4 ) • Patients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. ( 5.6 ) • Neonatal Sedation and Withdrawal Syndrome: XANAX use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.8 , 8.1 ) 5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including XANAX, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe XANAX concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of XANAX than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking XANAX, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when XANAX is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions (7.1) ] . 5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including XANAX, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2) ] . Before prescribing XANAX and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of XANAX, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of XANAX along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

ant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. 5.3 Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX or reduce the dosage (a patient-specific plan should be used to taper the dose) [see Dosage and Administration (2.3) ] . Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines, including XANAX, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of XANAX after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence (9.3) ] . Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3) ] . Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to XANAX. These include a spectrum of withdrawal symptoms; the most important is seizure [see Drug Abuse and Dependence (9.3)] . Even after relatively short-term use at doses of ≤4 mg/day, there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients who received XANAX, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of XANAX greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day. In a controlled clinical trial in which 63 patients were randomized to XANAX and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal. Interdose Symptoms Early morning anxiety and emergence of anxiety symptoms between doses of XANAX have been reported in patients with panic disorder taking prescribed maintenance doses. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of the interdosing interval. 5.4 Effects on Driving and Operating Machinery Because of its CNS depressant effects, patients receiving XANAX should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle.

ntire course of the interdosing interval. 5.4 Effects on Driving and Operating Machinery Because of its CNS depressant effects, patients receiving XANAX should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant use of alcohol and other CNS depressant drugs during treatment with XANAX [see Drug Interactions (7.1) ] . 5.5 Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Strong CYP3A Inhibitors XANAX is contraindicated in patients receiving strong inhibitors of CYP3A (such as azole antifungal agents), except ritonavir [see Contraindications (4) ] . Ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. Dosage adjustment is necessary when XANAX and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of XANAX [see Dosage and Administration (2.6) , Drug Interactions (7.1) ] . Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see Drug Interaction (7.1) , Clinical Pharmacology (12.3) ] . Use caution and consider dose reduction of XANAX, as appropriate, during co-administration with these drugs. 5.6 Patients with Depression Benzodiazepines may worsen depression. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression. 5.7 Mania Episodes of hypomania and mania have been reported in association with the use of XANAX in patients with depression [see Adverse Reactions (6.2) ] . 5.8 Neonatal Sedation and Withdrawal Syndrome Use of XANAX late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see Use in Specific Populations (8.1) ] . Monitor neonates exposed to XANAX during pregnancy or labor for signs of sedation and monitor neonates exposed to XANAX during pregnancy for signs of withdrawal; manage these neonates accordingly. 5.9 Risk in Patients with Impaired Respiratory Function There have been reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with XANAX. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue XANAX.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1) ] • Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2) ] • Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3) ] • Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4) ] • Patients with Depression [see Warnings and Precautions (5.6) ] • Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.8) ] • Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9) ] The most common adverse reactions reported in clinical trials for generalized anxiety disorder and panic disorder (incidence >5% and at least twice that of placebo) include: impaired coordination, hypotension, dysarthria, and increased libido. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in: • 4-week placebo-controlled clinical studies with XANAX dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (Table 1) • Short-term (up to 10 weeks) placebo-controlled clinical studies with XANAX dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2). Table 1: Adverse Reactions Occurring in ≥1% in XANAX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety XANAX n=565 Placebo n=505 Nervous system disorders Drowsiness 41% 22% Light-headedness 21% 19% Dizziness 2% 1% Akathisia 2% 1% Gastrointestinal disorders Dry mouth 15% 13% Increased salivation 4% 2% Cardiovascular disorders Hypotension 5% 2% Skin and subcutaneous tissue disorders Dermatitis/allergy 4% 3% In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.

s: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention. Table 2: Adverse Reactions Occurring in ≥1% in XANAX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder XANAX n=1388 Placebo n=1231 Drowsiness Fatigue and Tiredness Impaired Coordination Irritability Memory Impairment Cognitive Disorder Decreased Libido Dysarthria Confusional state 77% 49% 40% 33% 33% 29% 14% 23% 10% 43% 42% 18% 30% 22% 21% 8% 6% 8% Increased libido 8% 4% Change in libido (not specified) 7% 6% Disinhibition 3% 2% Talkativeness 2% 1% Derealization 2% 1% Gastrointestinal disorders Constipation 26% 15% Increased salivation 6% 4% Skin and subcutaneous tissue disorders Rash 11% 8% Other Increased appetite 33% 23% Decreased appetite 28% 24% Weight gain 27% 18% Weight loss 23% 17% Micturition difficulties 12% 9% Menstrual disorders 11% 9% Sexual dysfunction 7% 4% Incontinence 2% 1% In addition to the reactions (i.e., greater than 1%) enumerated in the table above for patients with panic disorder, the following adverse reactions have been reported in association with the use of XANAX: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice. Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received XANAX, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with XANAX and at a greater rate than the placebo-treated group are shown in Table 3. Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of XANAX-treated Patients and > Placebo-treated Patients n=number of patients. XANAX-treated Patients n=641 Nervous system disorders Insomnia 29.5% Light-headedness 19.3% Abnormal involuntary movement 17.3% Headache 17.0% Muscular twitching 6.9% Impaired coordination 6.6% Muscle tone disorders 5.9% Weakness 5.8% Psychiatric disorders Anxiety 19.2% Fatigue and Tiredness 18.4% Irritability 10.5% Cognitive disorder 10.3% Memory impairment 5.5% Depression 5.1% Confusional state 5.0% Gastrointestinal disorders Nausea/Vomiting 16.5% Diarrhea 13.6% Decreased salivation 10.6% Metabolism and nutrition disorders Weight loss 13.3% Decreased appetite 12.8% Dermatological disorders Sweating 14.4% Cardiovascular disorders Tachycardia 12.2% Special Senses Blurred vision 10.0% There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of XANAX [see Warning and Precautions (5.2) and Drug Abuse and Dependence (9.3) ] . Paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events.

Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of XANAX. 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. Endocrine disorders: Hyperprolactinemia General disorders and administration site conditions: Edema peripheral Hepatobiliary disorders: Hepatitis, hepatic failure Investigations: Liver enzyme elevations Psychiatric disorders: Hypomania, mania Reproductive system and breast disorders: Gynecomastia, galactorrhea Skin and subcutaneous tissue disorders: Photosensitivity reaction, angioedema, Stevens-Johnson syndrome

<table width="100%"><caption>Table 1: Adverse Reactions Occurring in &#x2265;1% in XANAX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety</caption><col width="37%"/><col width="30%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">XANAX</content></paragraph><paragraph><content styleCode="bold">n=565 </content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">n=505 </content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Nervous system disorders </content></paragraph></td><td styleCode="Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td align="justify" styleCode="Rrule Lrule " valign="top"><paragraph> Drowsiness</paragraph></td><td align="center" valign="top"><paragraph>41%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>22%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Light-headedness</paragraph></td><td align="center" valign="top"><paragraph>21%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>19%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Dizziness</paragraph></td><td align="center" valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Akathisia</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td align="justify" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td><td styleCode="Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Dry mouth</paragraph></td><td align="center" valign="top"><paragraph>15%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>13%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Increased salivation</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td align="justify" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cardiovascular disorders</content></paragraph></td><td styleCode="Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph> Hypotension</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Skin and subcutaneous tissue disorders</content></paragraph></td><td styleCode="Toprule

lign="top"><paragraph>5%</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Skin and subcutaneous tissue disorders</content></paragraph></td><td styleCode="Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Dermatitis/allergy</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3%</paragraph></td></tr></tbody></table>

valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Dermatitis/allergy</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>4%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>3%</paragraph></td></tr></tbody></table> <table width="100%"><caption>Table 2: Adverse Reactions Occurring in &#x2265;1% in XANAX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder</caption><col width="38%"/><col width="30%"/><col width="32%"/><thead><tr><th align="left" styleCode="Rrule Botrule Lrule Toprule " valign="top"/><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">XANAX</content> <content styleCode="bold">n=1388 </content></th><th align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><content styleCode="bold">Placebo</content> <content styleCode="bold">n=1231</content></th></tr></thead><tbody><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Drowsiness</paragraph><paragraph> Fatigue and Tiredness</paragraph><paragraph> Impaired Coordination</paragraph><paragraph> Irritability</paragraph><paragraph> Memory Impairment</paragraph><paragraph> Cognitive Disorder</paragraph><paragraph> Decreased Libido</paragraph><paragraph> Dysarthria</paragraph><paragraph> Confusional state</paragraph></td><td align="center" valign="top"><paragraph>77%</paragraph><paragraph>49%</paragraph><paragraph>40%</paragraph><paragraph>33%</paragraph><paragraph>33%</paragraph><paragraph>29%</paragraph><paragraph>14%</paragraph><paragraph>23%</paragraph><paragraph>10%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>43%</paragraph><paragraph>42%</paragraph><paragraph>18%</paragraph><paragraph>30%</paragraph><paragraph>22%</paragraph><paragraph>21%</paragraph><paragraph>8%</paragraph><paragraph>6%</paragraph><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Increased libido</paragraph></td><td align="center" valign="top"><paragraph>8%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Change in libido (not specified)</paragraph></td><td align="center" valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Disinhibition</paragraph></td><td align="center" valign="top"><paragraph>3%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Talkativeness</paragraph></td><td align="center" valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Derealization</paragraph></td><td align="center" valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>1%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td styleCode="Botrule " valign="top"/><td styleCode="Rrule Lrule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td><td valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>15%</paragraph

tent></paragraph></td><td valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Constipation</paragraph></td><td align="center" valign="top"><paragraph>26%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>15%</paragraph ></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Increased salivation</paragraph></td><td align="center" valign="top"><paragraph>6%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">Skin and subcutaneous tissue disorders</content></paragraph></td><td valign="top"/><td styleCode="Rrule Lrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Rash</paragraph></td><td align="center" valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>8%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Other</content></paragraph></td><td styleCode="Toprule " valign="top"/><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Increased appetite</paragraph></td><td align="center" valign="top"><paragraph>33%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>23%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Decreased appetite</paragraph></td><td align="center" valign="top"><paragraph>28%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>24%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Weight gain</paragraph></td><td align="center" valign="top"><paragraph>27%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>18%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Weight loss</paragraph></td><td align="center" valign="top"><paragraph>23%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>17%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Micturition difficulties</paragraph></td><td align="center" valign="top"><paragraph>12%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Menstrual disorders</paragraph></td><td align="center" valign="top"><paragraph>11%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Sexual dysfunction</paragraph></td><td align="center" valign="top"><paragraph>7%</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Incontinence</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1%</paragraph></td></tr></tbody></table>

h>4%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph> Incontinence</paragraph></td><td align="center" styleCode="Botrule " valign="top"><paragraph>2%</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="top"><paragraph>1%</paragraph></td></tr></tbody></table> <table width="100%"><caption>Table 3: Discontinuation-Emergent Symptom Incidence Reported in &#x2265;5% of XANAX-treated Patients and &gt; Placebo-treated Patients</caption><col width="47%"/><col width="53%"/><tfoot><tr><td align="left" colspan="2" valign="top">n=number of patients.</td></tr></tfoot><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">XANAX-treated Patients </content></paragraph><paragraph><content styleCode="bold">n=641</content></paragraph></td></tr><tr><td align="justify" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Nervous system disorders </content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Insomnia</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>29.5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Light-headedness</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>19.3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Abnormal involuntary movement</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>17.3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>17.0%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Muscular twitching</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6.9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Impaired coordination</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>6.6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Muscle tone disorders</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5.9%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Weakness</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5.8%</paragraph></td></tr><tr><td align="justify" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Psychiatric disorders</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Anxiety</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>19.2%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Fatigue and Tiredness</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>18.4%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Irritability</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10.5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Cognitive disorder</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>10.3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Memory impairment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5.5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Depression</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5.1%</paragraph></t

Lrule " valign="top"><paragraph>Memory impairment</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5.5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Depression</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5.1%</paragraph></t d></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Confusional state</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>5.0%</paragraph></td></tr><tr><td align="justify" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Nausea/Vomiting</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>16.5%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>13.6%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Decreased salivation</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10.6%</paragraph></td></tr><tr><td align="justify" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Metabolism and nutrition disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Weight loss</paragraph></td><td align="center" styleCode="Rrule " valign="top"><paragraph>13.3%</paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph>Decreased appetite</paragraph></td><td align="center" styleCode="Rrule Lrule " valign="top"><paragraph>12.8%</paragraph></td></tr><tr><td align="justify" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Dermatological disorders</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Sweating</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>14.4%</paragraph></td></tr><tr><td align="justify" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Cardiovascular disorders</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Tachycardia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12.2%</paragraph></td></tr><tr><td align="justify" styleCode="Rrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Special Senses</content></paragraph></td><td styleCode="Rrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Blurred vision</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>10.0%</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS • Use with Opioids: Increase the risk of respiratory depression. ( 7.1 ) • Use with Other CNS Depressants: Produces additive CNS depressant effects. ( 7.1 ) • Use with Digoxin: Increase the risk of digoxin toxicity. ( 7.1 ) • Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. ( 4 , 5.5 , 7.1 ) • Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. ( 7.1 ) 7.1 Drugs Having Clinically Important Interactions with XANAX Table 4 includes clinically significant drug interactions with XANAX [see Clinical Pharmacology (12.3) ] . Table 4: Clinically Significant Drug Interactions with XANAX Opioids Clinical implication The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma-aminobutyric acid (GABA A ) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid‑related respiratory depression exists. Prevention or management Limit dosage and duration of concomitant use of XANAX and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions (5.1) ] . Examples Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorphanol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol. CNS Depressants Clinical implication The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants. Prevention or management Limit dosage and duration of XANAX during concomitant use with CNS depressants [see Warnings and Precautions (5.3) ] . Examples Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression. Strong Inhibitors of CYP3A (except ritonavir) Clinical implication Concomitant use of XANAX with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see Clinical Pharmacology (12.3) ]. Prevention or management Concomitant use of XANAX with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4) , Warnings and Precautions (5.5) ]. Examples Ketoconazole, itraconazole, clarithromycin Moderate or Weak Inhibitors of CYP3A Clinical implication Concomitant use of XANAX with CYP3A inhibitors may increase the concentrations of XANAX, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology (12.3) ]. Prevention or management Avoid use and consider appropriate dose reduction when XANAX is coadministered with a moderate or weak CYP3A inhibitor [see Warnings and Precautions (5.5) ]. Examples Nefazodone, fluvoxamine, cimetidine, erythromycin CYP3A Inducers Clinical implication Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3) ] . Prevention or management Caution is recommended during coadministration with XANAX. Examples Carbamazepine, phenytoin Ritonavir Clinical implication Interactions involving ritonavir and alprazolam are complex and time dependent.

and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3) ] . Prevention or management Caution is recommended during coadministration with XANAX. Examples Carbamazepine, phenytoin Ritonavir Clinical implication Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (>10 to 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir. Prevention or management Reduce XANAX dosage when ritonavir and XANAX are initiated concomitantly, or when ritonavir is added to a regimen where XANAX is stabilized. Increase XANAX dosage to the target dosage after 10 to 14 days of dosing ritonavir and XANAX concomitantly. No dosage adjustment of XANAX is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration (2.6) ] . Concomitant use of XANAX with a strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications (4) , Warnings and Precautions (5.5) ]. Digoxin Clinical implication Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age). Prevention or management In patients on digoxin therapy, measure serum digoxin concentrations before initiating XANAX. Continue monitoring digoxin serum concentration and toxicity frequently . Reduce the digoxin dose if necessary. 7.2 Drug/Laboratory Test Interactions Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.

<table width="100%"><caption>Table 4: Clinically Significant Drug Interactions with XANAX</caption><col width="30%"/><col width="70%"/><tbody><tr><td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Opioids</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Clinical implication</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma-aminobutyric acid (GABA_A) sites and opioids interact primarily at mu receptors.

top"><paragraph>The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma-aminobutyric acid (GABA_A) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid&#x2011;related respiratory depression exists.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Prevention or management</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Limit dosage and duration of concomitant use of XANAX and opioids, and monitor patients closely for respiratory depression and sedation <content styleCode="italics">[see <linkHtml href="#ID_5d85083f-60a8-42f5-bb49-765d77b8ad77">Warnings and Precautions (5.1)</linkHtml>]</content>.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Examples</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorphanol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">CNS Depressants</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Clinical implication</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Prevention or management</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Limit dosage and duration of XANAX during concomitant use with CNS depressants <content styleCode="italics">[see </content><content styleCode="italics"><linkHtml href="#ID_58258d50-157f-4561-b332-24df0ffea8b3">Warnings and Precautions (5.3)</linkHtml>]</content>.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Examples</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression.</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Strong Inhibitors of CYP3A (except ritonavir)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Clinical implication</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Concomitant use of XANAX with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions <content styleCode="italics">[see <linkHtml href="#ID_5B95325C-EACB-4019-ADA4-9DFF8CB013AC">Clinical Pharmacology (12.3)</linkHtml>].</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Prevention or management</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Concomitant use of XANAX with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated <content styleCode="italics">[see <linkHtml href="#ID_1ABE74ED-72FB-40AD-AD82-02DF8DB1D2D6">Contraindications (4)</linkHtml>, <linkHtml href="#ID_ddfca055-514d-478e-b7c6-48221ff648bd">Warnings and Precautions (5.5)</linkHtml>].</co

mitant use of XANAX with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated <content styleCode="italics">[see <linkHtml href="#ID_1ABE74ED-72FB-40AD-AD82-02DF8DB1D2D6">Contraindications (4)</linkHtml>, <linkHtml href="#ID_ddfca055-514d-478e-b7c6-48221ff648bd">Warnings and Precautions (5.5)</linkHtml>].</co ntent></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Examples</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Ketoconazole, itraconazole, clarithromycin</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Moderate or Weak Inhibitors of CYP3A</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Clinical implication</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Concomitant use of XANAX with CYP3A inhibitors may increase the concentrations of XANAX, resulting in increased risk of adverse reactions of alprazolam <content styleCode="italics">[see <linkHtml href="#ID_5B95325C-EACB-4019-ADA4-9DFF8CB013AC">Clinical Pharmacology (12.3)</linkHtml>].</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Prevention or management</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Avoid use and consider appropriate dose reduction when XANAX is coadministered with a moderate or weak CYP3A inhibitor <content styleCode="italics">[see </content><content styleCode="italics"><linkHtml href="#ID_ddfca055-514d-478e-b7c6-48221ff648bd">Warnings and Precautions (5.5)</linkHtml>].</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Examples</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Nefazodone, fluvoxamine, cimetidine, erythromycin</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">CYP3A Inducers</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Clinical implication</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam <content styleCode="italics">[see <linkHtml href="#ID_5B95325C-EACB-4019-ADA4-9DFF8CB013AC">Clinical Pharmacology (12.3)</linkHtml>]</content>.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Prevention or management</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Caution is recommended during coadministration with XANAX.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Examples</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Carbamazepine, phenytoin</paragraph></td></tr><tr><td colspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Ritonavir</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Clinical implication</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Interactions involving ritonavir and alprazolam are complex and time dependent.

ph><content styleCode="bold">Ritonavir</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Clinical implication</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (&gt;10 to 14 days), CYP3A4 induction offsets this inhibition.</paragraph><paragraph>Alprazolam exposure was not meaningfully affected in the presence of ritonavir.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Prevention or management</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Reduce XANAX dosage when ritonavir and XANAX are initiated concomitantly, or when ritonavir is added to a regimen where XANAX is stabilized.</paragraph><paragraph>Increase XANAX dosage to the target dosage after 10 to 14 days of dosing ritonavir and XANAX concomitantly. No dosage adjustment of XANAX is necessary in patients receiving ritonavir for more than 10 to14 days <content styleCode="italics">[see <linkHtml href="#ID_582d207a-8a01-4aec-9345-ac9c5a18ee9f">Dosage and Administration (2.6)</linkHtml>]</content>.</paragraph><paragraph>Concomitant use of XANAX with a strong CYP3A inhibitor, except ritonavir, is contraindicated <content styleCode="italics">[see <linkHtml href="#ID_1ABE74ED-72FB-40AD-AD82-02DF8DB1D2D6">Contraindications (4)</linkHtml>, <linkHtml href="#ID_ddfca055-514d-478e-b7c6-48221ff648bd">Warnings and Precautions (5.5)</linkHtml>].</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Digoxin</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Clinical implication</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (&gt;65 years of age).</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Prevention or management</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>In patients on digoxin therapy, measure serum digoxin concentrations before initiating XANAX. Continue monitoring digoxin serum concentration and toxicity frequently<content styleCode="italics">. </content>Reduce the digoxin dose if necessary.</paragraph></td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including XANAX, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8) and Clinical Considerations) ] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to XANAX during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to XANAX during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8) ] . Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with XANAX. 8.4 Pediatric Use Safety and effectiveness of XANAX have not been established in pediatric patients. 8.5 Geriatric Use XANAX-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. Therefore, dosage reduction of XANAX is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . 8.6 Hepatic Impairment Patients with alcoholic liver disease exhibit a longer elimination half-life (19.7 hours), compared to healthy subjects (11.4 hours).

the same doses. Therefore, dosage reduction of XANAX is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . 8.6 Hepatic Impairment Patients with alcoholic liver disease exhibit a longer elimination half-life (19.7 hours), compared to healthy subjects (11.4 hours). This may be caused by decreased clearance of alprazolam in patients with alcoholic liver disease. Dosage reduction of XANAX is recommended in patients with hepatic impairment [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including XANAX, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8) and Clinical Considerations) ] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to XANAX during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to XANAX during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8) ] . Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings.

Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8) and Clinical Considerations) ] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Risk Summary Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with XANAX.

8.5 Geriatric Use XANAX-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. Therefore, dosage reduction of XANAX is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] .

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance XANAX contains alprazolam, which is a Schedule IV controlled substance. 9.2 Abuse XANAX is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2) ] . The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol). 9.3 Dependence XANAX may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3) ] . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX or reduce the dosage [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) ] .

her dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3) ] . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX or reduce the dosage [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) ] . Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to XANAX may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of XANAX may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

9.2 Abuse XANAX is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2) ] . The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

9.3 Dependence XANAX may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3) ] . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX or reduce the dosage [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) ] . Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to XANAX may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of XANAX may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

10 OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2) ] . Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help Line (1-800-222-1222), or a medical toxicologist for additional overdosage management recommendations.

11 DESCRIPTION XANAX contains alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds. The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine. The structural formula is: Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH. Each XANAX tablet, for oral administration, contains 0.25 mg, 0.5 mg, 1 mg, or 2 mg of alprazolam. Inactive ingredients: cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide and sodium benzoate. In addition, the 0.5 mg tablet contains FD&C Yellow No. 6 and the 1 mg tablet contains FD&C Blue No. 2. alprazolam structural formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Alprazolam is a 1,4 benzodiazepine. Alprazolam exerts its effect for the acute treatment of generalized anxiety disorder and panic disorder through binding to the benzodiazepine site of gamma‑aminobutyric acid-A (GABA A ) receptors in the brain and enhances GABA-mediated synaptic inhibition. 12.3 Pharmacokinetics Plasma levels of alprazolam increase proportionally to the dose over the range of 0.5 to 3.0 mg. Absorption Following oral administration, peak plasma concentration of alprazolam (C max ) occurs in 1 to 2 hours post dose. Distribution Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding. Elimination The mean plasma elimination half-life (T 1/2 ) of alprazolam is approximately 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults. Metabolism Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to 2 major active metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. The plasma circulation levels of the two active metabolites are less than 4% of the parent. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. Excretion Alprazolam and its metabolites are excreted primarily in the urine. Specific Populations Geriatric Patients The mean T 1/2 of alprazolam was 16.3 hours (range: 9.0 to 26.9 hours) in healthy elderly subjects compared to 11.0 hours (range: 6.3 to -15.8 hours, n=16) in healthy younger adult subjects. Obese Patients The mean T 1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in a group of obese subjects. Patients with Hepatic Impairment The mean T 1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease. Racial or Ethnic Groups Maximal concentrations and T 1/2 of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians. Smoking Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers. Drug Interaction Studies In Vivo Studies Most of the interactions that have been documented with alprazolam are with drugs that modulate CYP3A4 activity. Compounds that are inhibitors or inducers of CYP3A would be expected to increase or decrease plasma alprazolam concentrations, respectively. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.66 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4) , Warnings and Precautions (5.5) , Drug Interactions (7.2) ] . Other studied drugs include: Cimetidine: Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T 1/2 by 16%. Fluoxetine: Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T 1/2 by 17%, and decreased measured psychomotor performance.

asma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T 1/2 by 16%. Fluoxetine: Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T 1/2 by 17%, and decreased measured psychomotor performance. Oral Contraceptives: Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T 1/2 by 29%. Carbamazepine: The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination T 1/2 was shortened (from 17.1±4.9 to 7.7±1.7 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2) ] . However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000-1200 mg per day); the effect at usual carbamazepine doses is unknown. Ritonavir: Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect C max of alprazolam. The elimination T 1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and C max was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T 1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5) ] . Sertraline: A single dose of alprazolam 1 mg and steady state dose of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Imipramine and Desipramine: The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of XANAX in doses up to 4 mg per day. Warfarin: Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. In Vitro Studies Data from in vitro studies of alprazolam suggest a possible drug interaction of alprazolam with paroxetine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined.

12.1 Mechanism of Action Alprazolam is a 1,4 benzodiazepine. Alprazolam exerts its effect for the acute treatment of generalized anxiety disorder and panic disorder through binding to the benzodiazepine site of gamma‑aminobutyric acid-A (GABA A ) receptors in the brain and enhances GABA-mediated synaptic inhibition.

12.3 Pharmacokinetics Plasma levels of alprazolam increase proportionally to the dose over the range of 0.5 to 3.0 mg. Absorption Following oral administration, peak plasma concentration of alprazolam (C max ) occurs in 1 to 2 hours post dose. Distribution Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding. Elimination The mean plasma elimination half-life (T 1/2 ) of alprazolam is approximately 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults. Metabolism Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to 2 major active metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. The plasma circulation levels of the two active metabolites are less than 4% of the parent. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. Excretion Alprazolam and its metabolites are excreted primarily in the urine. Specific Populations Geriatric Patients The mean T 1/2 of alprazolam was 16.3 hours (range: 9.0 to 26.9 hours) in healthy elderly subjects compared to 11.0 hours (range: 6.3 to -15.8 hours, n=16) in healthy younger adult subjects. Obese Patients The mean T 1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in a group of obese subjects. Patients with Hepatic Impairment The mean T 1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease. Racial or Ethnic Groups Maximal concentrations and T 1/2 of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians. Smoking Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers. Drug Interaction Studies In Vivo Studies Most of the interactions that have been documented with alprazolam are with drugs that modulate CYP3A4 activity. Compounds that are inhibitors or inducers of CYP3A would be expected to increase or decrease plasma alprazolam concentrations, respectively. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.66 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4) , Warnings and Precautions (5.5) , Drug Interactions (7.2) ] . Other studied drugs include: Cimetidine: Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T 1/2 by 16%. Fluoxetine: Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T 1/2 by 17%, and decreased measured psychomotor performance. Oral Contraceptives: Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T 1/2 by 29%.

ma concentration of alprazolam by 46%, decreased clearance by 21%, increased T 1/2 by 17%, and decreased measured psychomotor performance. Oral Contraceptives: Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T 1/2 by 29%. Carbamazepine: The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination T 1/2 was shortened (from 17.1±4.9 to 7.7±1.7 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2) ] . However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000-1200 mg per day); the effect at usual carbamazepine doses is unknown. Ritonavir: Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect C max of alprazolam. The elimination T 1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and C max was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T 1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5) ] . Sertraline: A single dose of alprazolam 1 mg and steady state dose of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Imipramine and Desipramine: The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of XANAX in doses up to 4 mg per day. Warfarin: Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. In Vitro Studies Data from in vitro studies of alprazolam suggest a possible drug interaction of alprazolam with paroxetine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No evidence of carcinogenic potential was observed in rats or mice administered alprazolam for 2 years at doses up to 30 and 10 mg/kg day respectively. These doses are 29 times and 4.8 times the maximum recommended human dose of 10 mg/day based on mg/m 2 body surface area, respectively. Mutagenesis Alprazolam was negative in the in vitro Ames bacterial reverse mutation assay and DNA Damage/Alkaline Elution Assay and in vivo rat micronucleus genetic toxicology assays. Impairment of Fertility Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg per day, which is approximately 5 times the maximum recommended human dose of 10 mg per day based on mg/m 2 body surface area. 13.2 Animal Toxicology and/or Pharmacology When rats were treated with alprazolam at oral doses of 3 mg, 10 mg, and 30 mg/kg day (3 to 29 times the maximum recommended human dose based on mg/m 2 body surface area) for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No evidence of carcinogenic potential was observed in rats or mice administered alprazolam for 2 years at doses up to 30 and 10 mg/kg day respectively. These doses are 29 times and 4.8 times the maximum recommended human dose of 10 mg/day based on mg/m 2 body surface area, respectively. Mutagenesis Alprazolam was negative in the in vitro Ames bacterial reverse mutation assay and DNA Damage/Alkaline Elution Assay and in vivo rat micronucleus genetic toxicology assays. Impairment of Fertility Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg per day, which is approximately 5 times the maximum recommended human dose of 10 mg per day based on mg/m 2 body surface area.

13.2 Animal Toxicology and/or Pharmacology When rats were treated with alprazolam at oral doses of 3 mg, 10 mg, and 30 mg/kg day (3 to 29 times the maximum recommended human dose based on mg/m 2 body surface area) for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

14 CLINICAL STUDIES 14.1 Generalized Anxiety Disorder XANAX was compared to placebo in double-blind clinical studies (doses up to 4 mg per day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. XANAX was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s Global Impressions, and Self-Rating Symptom Scale. 14.2 Panic Disorder The effectiveness of XANAX in the treatment of panic disorder was studied in 3 short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder. The average dose of XANAX was 5 mg to 6 mg per day in 2 of the studies, and the doses of XANAX were fixed at 2 mg and 6 mg per day in the third study. In all 3 studies, XANAX was superior to placebo on a variable defined as “the number of patients with zero panic attacks” (range, 37% to 83% met this criterion), as well as on a global improvement score. In 2 of the 3 studies, XANAX was superior to placebo on a variable defined as “change from baseline on the number of panic attacks per week” (range, 3.3 to 5.2), and also on a phobia rating scale. A subgroup of patients who improved on XANAX during short-term treatment in 1 of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

16 HOW SUPPLIED/STORAGE AND HANDLING XANAX is supplied in the following strengths and package configurations: XANAX Tablets Package Configuration Tablet Strength (mg) NDC Print Bottles of 100 Reverse Numbered Unit dose (100) Bottles of 500 Bottles of 1000 0.25 mg NDC 0009-0029-01 NDC 0009-0029-46 NDC 0009-0029-02 NDC 0009-0029-14 white, oval, scored, imprinted “XANAX 0.25” Bottles of 100 Reverse Numbered Unit dose (100) Bottles of 500 Bottles of 1000 0.5 mg NDC 0009-0055-01 NDC 0009-0055-46 NDC 0009-0055-03 NDC 0009-0055-15 peach, oval, scored, imprinted “XANAX 0.5” Bottles of 100 Bottles of 500 Bottles of 1000 1 mg NDC 0009-0090-01 NDC 0009-0090-04 NDC 0009-0090-13 blue, oval, scored, imprinted “XANAX 1.0” Bottles of 100 Bottles of 500 2 mg NDC 0009-0094-01 NDC 0009-0094-03 white, oblong, multi-scored, imprinted “XANAX” on one side and “2” on the reverse side Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

<table width="100%"><caption>XANAX Tablets</caption><col width="21%"/><col width="17%"/><col width="22%"/><col width="40%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Package Configuration</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Tablet Strength (mg)</content></paragraph></td><td styleCode="Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">NDC</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Print</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Bottles of 100</paragraph><paragraph>Reverse Numbered</paragraph><paragraph>Unit dose (100)</paragraph><paragraph>Bottles of 500</paragraph><paragraph>Bottles of 1000</paragraph></td><td align="justify" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.25 mg</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>NDC 0009-0029-01</paragraph><paragraph>NDC 0009-0029-46</paragraph><paragraph>NDC 0009-0029-02</paragraph><paragraph>NDC 0009-0029-14</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>white, oval, scored, imprinted &#x201C;XANAX 0.25&#x201D;</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Bottles of 100</paragraph><paragraph>Reverse Numbered</paragraph><paragraph>Unit dose (100)</paragraph><paragraph>Bottles of 500</paragraph><paragraph>Bottles of 1000</paragraph></td><td align="justify" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.5 mg</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>NDC 0009-0055-01</paragraph><paragraph>NDC 0009-0055-46</paragraph><paragraph>NDC 0009-0055-03</paragraph><paragraph>NDC 0009-0055-15</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>peach, oval, scored, imprinted &#x201C;XANAX 0.5&#x201D;</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Bottles of 100</paragraph><paragraph>Bottles of 500</paragraph><paragraph>Bottles of 1000</paragraph></td><td align="justify" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1 mg</paragraph></td><td styleCode="Lrule Toprule Botrule " valign="top"><paragraph>NDC 0009-0090-01</paragraph><paragraph>NDC 0009-0090-04</paragraph><paragraph>NDC 0009-0090-13</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>blue, oval, scored, imprinted &#x201C;XANAX 1.0&#x201D;</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Bottles of 100</paragraph><paragraph>Bottles of 500</paragraph></td><td align="justify" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2 mg</paragraph></td><td styleCode="Botrule Lrule Toprule " valign="top"><paragraph>NDC 0009-0094-01</paragraph><paragraph>NDC 0009-0094-03</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>white, oblong, multi-scored, imprinted &#x201C;XANAX&#x201D; on one side and &#x201C;2&#x201D; on the reverse side</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when XANAX is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Warnings and Precautions (5.1) , Drug Interactions (7.1) ] . Abuse, Misuse, and Addiction Inform patients that the use of XANAX, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) , Drug Abuse and Dependence (9.2) ] . Withdrawal Reactions Inform patients that the continued use of XANAX may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of XANAX may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of XANAX may require a slow taper [see Warnings and Precautions (5.3) , Drug Abuse and Dependence (9.3) ] . Effects on Driving and Operating Machinery Advise patients not to drive a motor vehicle or operate heavy machinery while taking XANAX due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking XANAX [see Warnings and Precautions (5.3) ] . Patients with Depression Advise patients, their families, and caregivers to look for signs of suicidality or worsening depression, and to inform the patient’s healthcare provider immediately [see Warnings and Precautions (5.6) ] . Concomitant Medications Advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medications, vitamins and herbal supplements [see Drug Interactions (7) ] . Pregnancy Advise pregnant females that use of XANAX late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see Warnings and Precautions (5.8) , Use in Specific Populations (8.1) ] . Instruct patients to inform their healthcare provider if they are pregnant. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XANAX during pregnancy [see Use in Specific Populations (8.1) ] . Lactation Advise patients that breastfeeding is not recommended during treatment with XANAX [see Use in Specific Populations (8.2) ] . Distributed by: Viatris Specialty LLC Morgantown, WV 26505 U.S.A. UPJ:XNXT:RX2

Medication Guide XANAX (ZAN-aks) (alprazolam) tablets, C-IV What is the most important information I should know about XANAX? • XANAX is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens: o shallow or slowed breathing o breathing stops (which may lead to the heart stopping) o excessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking XANAX with opioids affects you. • Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines, including XANAX, which can lead to overdose and serious side effects including coma and death. o Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including XANAX. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. o You can develop an addiction even if you take XANAX as prescribed by your healthcare provider. o Take XANAX exactly as your healthcare provider prescribed. o Do not share your XANAX with other people. o Keep XANAX in a safe place and away from children. • Physical dependence and withdrawal reactions. XANAX can cause physical dependence and withdrawal reactions. o Do not suddenly stop taking XANAX. Stopping XANAX suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. o Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months , including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. o Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. • Do not take more XANAX than prescribed or take XANAX for longer than prescribed. What is XANAX? • XANAX is a prescription medicine used: o to treat anxiety disorders o for the short-term relief of the symptoms of anxiety o to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia) • XANAX is a federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence. Keep XANAX in a safe place to prevent misuse and abuse. Selling or giving away XANAX may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.

V) because it contains alprazolam that can be abused or lead to dependence. Keep XANAX in a safe place to prevent misuse and abuse. Selling or giving away XANAX may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. • It is not known if XANAX is safe and effective in children. • Elderly patients are especially susceptible to dose related adverse effects when taking XANAX. • It is not known if XANAX is safe and effective when used to treat anxiety disorder for longer than 4 months. • It is not known if XANAX is safe and effective when used to treat panic disorder for longer than 10 weeks. Do not take XANAX if: • you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in XANAX. See the end of this Medication Guide for a complete list of ingredients in XANAX. • you are taking antifungal medicines including ketoconazole and itraconazole Before you take XANAX, tell your healthcare provider about all of your medical conditions, including if you: • have or have had depression, mood problems, or suicidal thoughts or behavior • have liver or kidney problems • have lung disease or breathing problems • are pregnant or plan to become pregnant. • Taking XANAX late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems). • Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with XANAX. • There is a pregnancy registry for women who take XANAX during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with XANAX, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/. • are breastfeeding or plan to breastfeed. XANAX passes into your breast milk. • Talk to your healthcare provider about the best way to feed your baby if you take XANAX. • Breastfeeding is not recommended during treatment with XANAX. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking XANAX with certain other medicines can cause side effects or affect how well XANAX or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. How should I take XANAX? • See “What is the most important information I should know about XANAX?” • Take XANAX exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much XANAX to take and when to take it. • If you take too much XANAX, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of XANAX? XANAX may cause serious side effects, including: • See “What is the most important information I should know about XANAX?” • Seizures. Stopping XANAX can cause seizures and seizures that will not stop (status epilepticus). • Mania. XANAX may cause an increase in activity and talking (hypomania and mania) in people who have depression. o XANAX can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how XANAX affects you. o Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking XANAX without first talking to your healthcare provider.

ou sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how XANAX affects you. o Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking XANAX without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, XANAX may make your sleepiness or dizziness much worse. The most common side effects of XANAX include: • problems with coordination • hypotension • trouble saying words clearly (dysarthria) • changes in sex drive (libido) These are not all the possible side effects of XANAX. 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 XANAX? • Store XANAX at room temperature between 68°F to 77°F (20°C to 25°C) • Keep XANAX and all medicines out of the reach of children. General information about the safe and effective use of XANAX. • Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. • Do not use XANAX for a condition for which it was not prescribed. • Do not give XANAX to other people, even if they have the same symptoms that you have. It may harm them. • You can ask your pharmacist or healthcare provider for information about XANAX that is written for health professionals. What are the ingredients in XANAX? Active ingredient: alprazolam Inactive ingredients: Cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide and sodium benzoate. In addition, the 0.5 mg tablet contains FD&C Yellow No. 6 and the 1 mg tablet contains FD&C Blue No. 2. XANAX® is a registered trademark of UPJOHN US 2 LLC, a Viatris Company. For more information, call Viatris at 1-877-446-3679 (1-877-4-INFO-RX). Distributed by: Viatris Specialty LLC Morgantown, WV 26505 U.S.A. UPJ:MG:XNXT:RX2 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 1/2023

<table width="100%"><col width="100%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">XANAX (ZAN-aks)</content></paragraph><paragraph><content styleCode="bold">(alprazolam) tablets, C-IV</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph><content styleCode="bold">What is the most important information I should know about XANAX?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">XANAX is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.</content> Get emergency help right away if any of the following happens: <list listType="unordered"><item><caption>o</caption>shallow or slowed breathing </item><item><caption>o</caption>breathing stops (which may lead to the heart stopping)</item><item><caption>o</caption>excessive sleepiness (sedation) </item></list></item></list></td></tr><tr><td styleCode="Rrule Lrule " valign="top"><paragraph> Do not drive or operate heavy machinery until you know how taking XANAX with opioids affects you.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption><content styleCode="bold">Risk of abuse, misuse, and addiction.</content> There is a risk of abuse, misuse, and addiction with benzodiazepines, including XANAX, which can lead to overdose and serious side effects including coma and death. <list listType="unordered"><item><caption>o</caption><content styleCode="bold">Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including XANAX.</content> These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.</content></item><item><caption>o</caption><content styleCode="bold">You can develop an addiction even if you take XANAX as prescribed by your healthcare provider.</content></item><item><caption>o</caption><content styleCode="bold">Take XANAX exactly as your healthcare provider prescribed. </content></item><item><caption>o</caption>Do not share your XANAX with other people.</item><item><caption>o</caption>Keep XANAX in a safe place and away from children.</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">Physical dependence and withdrawal reactions.</content> XANAX can cause physical dependence and withdrawal reactions. <list listType="unordered"><item><caption>o</caption><content styleCode="bold">Do not suddenly stop taking XANAX.</content> Stopping XANAX suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions.

e-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms.</content></item><item><caption>o</caption><content styleCode="bold">Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months</content>, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.</item><item><caption>o</caption>Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. </item></list></item><item><caption>&#x2022;</caption>Do not take more XANAX than prescribed or take XANAX for longer than prescribed.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What is XANAX?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>XANAX is a prescription medicine used:<list listType="unordered"><item><caption>o</caption>to treat anxiety disorders</item><item><caption>o</caption>for the short-term relief of the symptoms of anxiety</item><item><caption>o</caption>to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)</item></list></item><item><caption>&#x2022;</caption><content styleCode="bold">XANAX is a federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence.</content> Keep XANAX in a safe place to prevent misuse and abuse. Selling or giving away XANAX may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.</item><item><caption>&#x2022;</caption>It is not known if XANAX is safe and effective in children.</item><item><caption>&#x2022;</caption>Elderly patients are especially susceptible to dose related adverse effects when taking XANAX.</item><item><caption>&#x2022;</caption>It is not known if XANAX is safe and effective when used to treat anxiety disorder for longer than 4 months.</item><item><caption>&#x2022;</caption>It is not known if XANAX is safe and effective when used to treat panic disorder for longer than 10 weeks.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Do not take XANAX if:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in XANAX.

an 10 weeks.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Do not take XANAX if:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in XANAX. See the end of this Medication Guide for a complete list of ingredients in XANAX.</item><item><caption>&#x2022;</caption>you are taking antifungal medicines including ketoconazole and itraconazole</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Before you take XANAX, tell your healthcare provider about all of your medical conditions, including if you:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>have or have had depression, mood problems, or suicidal thoughts or behavior</item><item><caption>&#x2022;</caption>have liver or kidney problems</item><item><caption>&#x2022;</caption>have lung disease or breathing problems</item><item><caption>&#x2022;</caption>are pregnant or plan to become pregnant. <list listType="unordered"><item><caption>&#x2022;</caption>Taking XANAX late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).</item><item><caption>&#x2022;</caption>Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with XANAX.</item><item><caption>&#x2022;</caption>There is a pregnancy registry for women who take XANAX during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with XANAX, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/.</item></list></item><item><caption>&#x2022;</caption>are breastfeeding or plan to breastfeed. XANAX passes into your breast milk. <list listType="unordered"><item><caption>&#x2022;</caption>Talk to your healthcare provider about the best way to feed your baby if you take XANAX. </item><item><caption>&#x2022;</caption>Breastfeeding is not recommended during treatment with XANAX.</item></list></item></list><paragraph><content styleCode="bold">Tell your healthcare provider about all the medicines you take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements.</paragraph><paragraph>Taking XANAX with certain other medicines can cause side effects or affect how well XANAX or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I take XANAX?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>See &#x201C;What is the most important information I should know about XANAX?&#x201D;</item><item><caption>&#x2022;</caption>Take XANAX exactly as your healthcare provider tells you to take it.

ent styleCode="bold">How should I take XANAX?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>See &#x201C;What is the most important information I should know about XANAX?&#x201D;</item><item><caption>&#x2022;</caption>Take XANAX exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much XANAX to take and when to take it.</item><item><caption>&#x2022;</caption>If you take too much XANAX, call your healthcare provider or go to the nearest hospital emergency room right away.</item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">What are the possible side effects of XANAX?</content></paragraph><paragraph><content styleCode="bold">XANAX may cause serious side effects, including:</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>See &#x201C;What is the most important information I should know about XANAX?&#x201D;</item><item><caption>&#x2022;</caption><content styleCode="bold">Seizures.</content> Stopping XANAX can cause seizures and seizures that will not stop (status epilepticus).</item><item><caption>&#x2022;</caption><content styleCode="bold">Mania.</content> XANAX may cause an increase in activity and talking (hypomania and mania) in people who have depression.<list listType="unordered"><item><caption>o</caption><content styleCode="bold">XANAX can make you sleepy or dizzy and can slow your thinking and motor skills.</content> Do not drive, operate heavy machinery, or do other dangerous activities until you know how XANAX affects you.</item><item><caption>o</caption><content styleCode="bold">Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking XANAX without first talking to your healthcare provider.</content> When taken with alcohol or drugs that cause sleepiness or dizziness, XANAX may make your sleepiness or dizziness much worse.</item></list></item></list><paragraph><content styleCode="bold">The most common side effects of XANAX include: </content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>problems with coordination</item><item><caption>&#x2022;</caption>hypotension</item><item><caption>&#x2022;</caption>trouble saying words clearly (dysarthria)</item><item><caption>&#x2022;</caption>changes in sex drive (libido)</item></list><paragraph>These are not all the possible side effects of XANAX. 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="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">How should I store XANAX?</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Store XANAX at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C)</item><item><caption>&#x2022;</caption><content styleCode="bold">Keep XANAX and all medicines out of the reach of children.</content></item></list></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General information about the safe and effective use of XANAX.</content></paragraph><list listType="unordered"><item><caption>&#x2022;</caption>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. </item><item><caption>&#x2022;</caption>Do not use XANAX for a condition for which it was not prescribed. </item><item><caption>&#x2022;</caption>Do not give XANAX to other people, even if they have the same symptoms that you have. It may harm them.

prescribed for purposes other than those listed in a Medication Guide. </item><item><caption>&#x2022;</caption>Do not use XANAX for a condition for which it was not prescribed. </item><item><caption>&#x2022;</caption>Do not give XANAX to other people, even if they have the same symptoms that you have. It may harm them. </item><item><caption>&#x2022;</caption>You can ask your pharmacist or healthcare provider for information about XANAX that is written for health professionals.</item></list></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">What are the ingredients in XANAX?</content></paragraph><paragraph><content styleCode="bold">Active ingredient:</content> alprazolam</paragraph><paragraph><content styleCode="bold">Inactive ingredients:</content> Cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide and sodium benzoate. In addition, the 0.5 mg tablet contains FD&amp;C Yellow No. 6 and the 1 mg tablet contains FD&amp;C Blue No. 2.</paragraph><paragraph>XANAX&#xAE; is a registered trademark of UPJOHN US 2 LLC, a Viatris Company.</paragraph><paragraph>For more information, call Viatris at 1-877-446-3679 (1-877-4-INFO-RX).</paragraph><paragraph>Distributed by:</paragraph><paragraph>Viatris Specialty LLC</paragraph><paragraph>Morgantown, WV 26505 U.S.A. </paragraph><paragraph>UPJ:MG:XNXT:RX2</paragraph></td></tr></tbody></table>

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1) , Drug Interactions (7.1) ] . The use of benzodiazepines, including alprazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing alprazolam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2) ] . The continued use of benzodiazepines, including alprazolam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.2) , Warnings and Precautions (5.3) ] . WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS See full prescribing information for complete boxed warning. Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation. ( 5.1 , 7.1 ) The use of benzodiazepines, including alprazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing alprazolam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. ( 5.2 ) Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam or reduce the dosage. ( 2.2 , 5.3 )

1 INDICATIONS AND USAGE Alprazolam tablets are indicated for the: acute treatment of generalized anxiety disorder (GAD) in adults. treatment of panic disorder (PD), with or without agoraphobia in adults. Alprazolam is a benzodiazepine indicated for the: Acute treatment of generalized anxiety disorder in adults. ( 1 ) Treatment of panic disorder with or without agoraphobia in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Generalized Anxiety Disorder : ( 2.1 ) Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily. Dosage may be increased, at intervals of every 3 to 4 days, to a maximum recommended daily dose of 4 mg, given in divided doses. Use the lowest possible effective dose and frequently assess the need for continued treatment. Panic Disorder : Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. ( 2.2 ) When tapering, decrease dosage by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction. ( 2.3 , 5.2 ) See the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. ( 2.4 , 2.5 , 2.6 ) 2.1 Dosage in Generalized Anxiety Disorder The recommended starting oral dosage of alprazolam tablets for the acute treatment of patients with GAD is 0.25 mg to 0.5 mg administered three times daily. Depending upon the response, the dosage may be adjusted at intervals of every 3 to 4 days. The maximum recommended dosage is 4 mg daily (in divided doses). Use the lowest possible effective dose and frequently assess the need for continued treatment [see Warnings and Precautions (5.2) ] . 2.2 Dosage in Panic Disorder The recommended starting oral dosage of alprazolam tablets for the treatment of PD is 0.5 mg three times daily. Depending on the response, the dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. Controlled trials of alprazolam tablets in the treatment of panic disorder included dosages in the range of 1 mg to 10 mg daily. The mean dosage was approximately 5 mg to 6 mg daily. Occasional patients required as much as 10 mg per day. For patients receiving doses greater than 4 mg per day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam tablets greater than 4 mg per day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. The necessary duration of treatment for PD in patients responding to alprazolam tablets are unknown. After a period of extended freedom from panic attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena [see Dosage and Administration (2.3) ]. 2.3 Discontinuation or Dosage Reduction of Alprazolam Tablets To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam tablets or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3) , Drug Abuse and Dependence (9.3) ]. Reduced the dosage by no more than 0.5 mg every 3 days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

age level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3) , Drug Abuse and Dependence (9.3) ]. Reduced the dosage by no more than 0.5 mg every 3 days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens. In a controlled postmarketing discontinuation study of panic disorder patients which compared the recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. 2.4 Dosage Recommendations in Geriatric Patients In geriatric patients, the recommended starting oral dosage of alprazolam tablets is 0.25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. Geriatric patients may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dosage, the dosage may be reduced [see Use in Specific Populations (8.5) , Clinical Pharmacology (12.3) ] . 2.5 Dosage Recommendations in Patients with Hepatic Impairment In patients with hepatic impairment, the recommended starting oral dosage of alprazolam tablets is 0.25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. If adverse reactions occur at the recommended starting dose, the dosage may be reduced [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . 2.6 Dosage Modifications for Drug Interactions Alprazolam tablets should be reduced to half of the recommended dosage when a patient is started on ritonavir and alprazolam tablets together, or when ritonavir administered to a patient treated with alprazolam tablets. Increase the alprazolam tablets dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam tablets together. It is not necessary to reduce alprazolam tablets dose in patients who have been taking ritonavir for more than 10 to 14 days. Alprazolam tablets are contraindicated with concomitant use of all strong CYP3A inhibitors, except ritonavir [see Contraindications (4) , Warnings and Precautions (5.5) ] .

3 DOSAGE FORMS AND STRENGTHS Alprazolam tablets, USP are available as: 0.25 mg: white, oval shaped, uncoated tablets with breakline on one side debossed with ‘1’ and ‘8’ on either sides of the breakline and ‘Y’ on the other side. 0.5 mg: peach colored, oval shaped, uncoated tablets with breakline on one side debossed with ‘1’ and ‘9’ on either sides of the breakline and ‘Y’ on the other side. 1 mg: blue colored, oval shaped, uncoated tablets with breakline on one side debossed with ‘2’ and ‘0’ on either sides of the breakline and ‘Y’ on the other side. 2 mg: white, oblong, uncoated tablets with three breaklines on both sides debossed with ‘2’ and ‘1’ on either sides of the center breakline and ‘Y’ on the other side. Tablets: 0.25 mg, 0.5 mg, 1 mg, and 2 mg ( 3 )

4 CONTRAINDICATIONS Alprazolam tablets are contraindicated in patients: with known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2) ] . taking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2.6) , Warnings and Precautions (5.5) , Drug Interactions (7.1) ] Known hypersensitivity to alprazolam or other benzodiazepines. ( 4 ) Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. ( 4 , 5.5 , 7.1 )

5 WARNINGS AND PRECAUTIONS Effects on Driving and Operating Machinery: Patients receiving alprazolam should be cautioned against operating machinery or driving a motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. ( 5.4 ) Patients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. ( 5.6 ) Neonatal Sedation and Withdrawal Syndrome: Alprazolam use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.8 , 8.1 ) 5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including alprazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe alprazolam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of alprazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions (7.1) ] . 5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including alprazolam, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2) ] . Before prescribing alprazolam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of alprazolam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

ant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. 5.3 Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam or reduce the dosage (a patient-specific plan should be used to taper the dose) [see Dosage and Administration (2.3) ] . Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines, including alprazolam, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence (9.3) ] . Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3) ] . Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam. These include a spectrum of withdrawal symptoms; the most important is seizure [see Drug Abuse and Dependence (9.3) ] . Even after relatively short-term use at doses of < 4 mg/day, there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients who received alprazolam, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day. In a controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal. Interdose Symptoms Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses. These symptoms may reflect the development of tolerance or a time interval between doses which is longer than the duration of clinical action of the administered dose. In either case, it is presumed that the prescribed dose is not sufficient to maintain plasma levels above those needed to prevent relapse, rebound, or withdrawal symptoms over the entire course of the interdosing interval. 5.4 Effects on Driving and Operating Machinery Because of its CNS depressant effects, patients receiving alprazolam should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle.

course of the interdosing interval. 5.4 Effects on Driving and Operating Machinery Because of its CNS depressant effects, patients receiving alprazolam should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant use of alcohol and other CNS depressant drugs during treatment with alprazolam [see Drug Interactions (7.1) ] . 5.5 Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Strong CYP3A Inhibitors Alprazolam is contraindicated in patients receiving strong inhibitors of CYP3A (such as azole antifungal agents), except ritonavir [see Contraindications (4) ]. Ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. Dosage adjustment is necessary when alprazolam and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of alprazolam [see Dosage and Administration (2.6) , Drug Interactions (7.1) ]. Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see Drug Interaction (7.1), Clinical Pharmacology (12.3)]. Use caution and consider dose reduction of alprazolam, as appropriate, during co-administration with these drugs. 5.6 Patients with Depression Benzodiazepines may worsen depression. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression. 5.7 Mania Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression [see Adverse Reactions (6.2) ] . 5.8 Neonatal Sedation and Withdrawal Syndrome Use of alprazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see Use in Specific Populations (8.1) ] . Monitor neonates exposedtoalprazolam during pregnancy or labor for signs of sedation and monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal; manage these neonates accordingly. 5.9 Risk in Patients with Impaired Respiratory Function There have been reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue alprazolam.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1) ] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2) ] Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3) ] Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4) ] Patients with Depression [see Warnings and Precautions (5.6) ] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.8) ] Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9) ] The most common adverse reactions reported in clinical trials for generalized anxiety disorder and panic disorder (incidence > 5% and at least twice that of placebo) include: impaired coordination, hypotension, dysarthria, and increased libido. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in: 4-week placebo-controlled clinical studies with alprazolam dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (Table 1) Short-term (up to 10 weeks) placebo-controlled clinical studies with alprazolam dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2). Table 1: Adverse Reactions Occurring in ≥1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety Alprazolam n=565 Placebo n=505 Nervous system disorders Drowsiness Light-headedness Dizziness Akathisia Gastrointestinal disorders Dry mouth Increased salivation 41% 21% 2% 2% 15% 4% 22% 19% 1% 1% 13% 2% Cardiovascular disorders Hypotension Skin and subcutaneous tissue disorders Dermatitis/allergy 5% 4% 2% 3% In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.

s: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention. Table 2: Adverse Reactions Occuring in ≥1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder Alprazolam n=1388 Placebo n=1231 Drowsiness Fatique and Tiredness Impaired Coordination Irritability Memory Impairment Cognitive Disorder Decreased Libido Dysartharia Confusional state Increased libido Change in libido (not specified) Disinhibition Talkativeness Derealization 77% 49% 40% 33% 33% 29% 14% 23% 10% 8% 7% 3% 2% 2% 43% 42% 18% 30% 22% 21% 8% 6% 8% 4% 6% 2% 1% 1% Gastrointestinal disorders Constipation Increased salivation 26% 6% 15% 4% Skin and subcutaneous tissue disorders Rash 11% 8% Other Increased appetite Decreased appetite Weight gain Weight loss Micturition difficulties Menstrual disorders Sexual dysfunction Incontinence 33% 28% 27% 23% 12% 11% 7% 2% 23% 24% 18% 17% 9% 9% 4% 1% In addition to the reactions (i.e., greater than 1%) enumerated in the table above for patients with panic disorder, the following adverse reactions have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice. Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam and at a greater rate than the placebo-treated group are shown in Table 3. Table 3: Discontinuation-Emergent Symptom Incidence Reported in ≥5% of Alprazolam-treated Patients and > Placebo-treated Patients n=number of patients. Alprazolam-treated Patients n=641 Nervous system disorders Insomnia Light-headedness Abnormal involuntary movement Headache Muscular twitching Impaired coordination Muscle tone disorders Weakness 29.5% 19.3% 17.3% 17.0% 6.9% 6.6% 5.9% 5.8% Psychiatric disorders Anxiety Fatigue and Tiredness Irritability Cognitive disorder Memory impairment Depression Confusional state 19.2% 18.4% 10.5% 10.3% 5.5% 5.1% 5.0% Gastrointestinal disorders Nausea/Vomiting Diarrhea Decreased salivation 16.5% 13.6% 10.6% Metabolism and nutrition disorders Weight loss Decreased appetite 13.3% 12.8% Dermatological disorders Sweating 14.4% Cardiovascular disorders Tachycardia 12.2% Special Senses Blurred vision 10.0% There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam [see Warning and Precautions (5.2) and Drug Abuse and Dependence (9.3) ]. Paradoxical reactions such as stimulation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage, irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly and/or were described as having underlying psychiatric conditions. Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events.

Should any of the above events occur, alprazolam should be discontinued. Isolated published reports involving small numbers of patients have suggested that patients who have borderline personality disorder, a prior history of violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam in patients with posttraumatic stress disorder. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of alprazolam. 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. Endocrine disorders: Hyperprolactinemia General disorders and administration site conditions: Edema peripheral Hepatobiliary disorders: Hepatitis, hepatic failure Investigations: Liver enzyme elevations Psychiatric disorders: Hypomania, mania Reproductive system and breast disorders: Gynecomastia, galactorrhea Skin and subcutaneous tissue disorders: Photosensitivity reaction, angioedema, Stevens-Johnson syndrome

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 1: Adverse Reactions Occurring in &#x2265;1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety</caption><col width="36.96%"/><col width="30.96%"/><col width="32.08%"/><tbody><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> </td><td align="center" styleCode="Rrule" valign="middle"><content styleCode="bold">Alprazolam</content> <content styleCode="bold">n=565</content> </td><td align="center" styleCode="Rrule" valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">n=505</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Nervous system disorders</content> Drowsiness Light-headedness Dizziness Akathisia <content styleCode="bold">Gastrointestinal disorders</content> Dry mouth Increased salivation </td><td align="center" styleCode="Rrule" valign="middle"> 41% 21% 2% 2% 15% 4% </td><td align="center" styleCode="Rrule" valign="middle"> 22% 19% 1% 1% 13% 2% </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Cardiovascular disorders</content> Hypotension <content styleCode="bold">Skin and subcutaneous tissue disorders</content> Dermatitis/allergy </td><td align="center" styleCode="Rrule" valign="middle"> 5% 4% </td><td align="center" styleCode="Rrule" valign="middle"> 2% 3% </td></tr></tbody></table>

ntent styleCode="bold">Cardiovascular disorders</content> Hypotension <content styleCode="bold">Skin and subcutaneous tissue disorders</content> Dermatitis/allergy </td><td align="center" styleCode="Rrule" valign="middle"> 5% 4% </td><td align="center" styleCode="Rrule" valign="middle"> 2% 3% </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 2: Adverse Reactions Occuring in &#x2265;1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder</caption><col width="36.92%"/><col width="30.94%"/><col width="32.14%"/><tbody><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold"> </content> </td><td align="center" styleCode="Rrule" valign="middle"><content styleCode="bold">Alprazolam</content> <content styleCode="bold">n=1388</content> </td><td align="center" styleCode="Rrule" valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">n=1231</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> Drowsiness Fatique and Tiredness Impaired Coordination Irritability Memory Impairment Cognitive Disorder Decreased Libido Dysartharia Confusional state Increased libido Change in libido (not specified) Disinhibition Talkativeness Derealization </td><td align="center" styleCode="Rrule" valign="middle">77% 49% 40% 33% 33% 29% 14% 23% 10% 8% 7% 3% 2% 2% </td><td align="center" styleCode="Rrule" valign="middle">43% 42% 18% 30% 22% 21% 8% 6% 8% 4% 6% 2% 1% 1% </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="middle"><content styleCode="bold">Gastrointestinal disorders</content> Constipation Increased salivation </td><td align="center" styleCode="Rrule" valign="middle"> 26% 6% </td><td align="center" styleCode="Rrule" valign="middle"> 15% 4% </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Skin and subcutaneous tissue disorders</content> Rash </td><td align="center" styleCode="Rrule" valign="middle"> 11% </td><td align="center" styleCode="Rrule" valign="middle"> 8% </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Other</content> Increased appetite Decreased appetite Weight gain Weight loss Micturition difficulties Menstrual disorders Sexual dysfunction Incontinence </td><td align="center" styleCode="Rrule" valign="middle"> 33% 28% 27% 23% 12% 11% 7% 2% </td><td align="center" styleCode="Rrule" valign="middle"> 23% 24% 18% 17% 9% 9% 4% 1% </td></tr></tbody></table>

creased appetite Weight gain Weight loss Micturition difficulties Menstrual disorders Sexual dysfunction Incontinence </td><td align="center" styleCode="Rrule" valign="middle"> 33% 28% 27% 23% 12% 11% 7% 2% </td><td align="center" styleCode="Rrule" valign="middle"> 23% 24% 18% 17% 9% 9% 4% 1% </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 3: Discontinuation-Emergent Symptom Incidence Reported in &#x2265;5% of Alprazolam-treated Patients and &gt; Placebo-treated Patients</caption><col width="50%"/><col width="50%"/><tfoot><tr><td colspan="2">n=number of patients.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"> </td><td align="center" styleCode="Rrule" valign="middle"><content styleCode="bold">Alprazolam-treated Patients</content> <content styleCode="bold">n=641</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Nervous system disorders</content> Insomnia Light-headedness Abnormal involuntary movement Headache Muscular twitching Impaired coordination Muscle tone disorders Weakness </td><td align="center" styleCode="Rrule" valign="middle"> 29.5% 19.3% 17.3% 17.0% 6.9% 6.6% 5.9% 5.8% </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Psychiatric disorders</content> Anxiety Fatigue and Tiredness Irritability Cognitive disorder Memory impairment Depression Confusional state </td><td align="center" styleCode="Rrule" valign="middle"> 19.2% 18.4% 10.5% 10.3% 5.5% 5.1% 5.0% </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Gastrointestinal disorders</content> Nausea/Vomiting Diarrhea Decreased salivation </td><td align="center" styleCode="Rrule" valign="middle"> 16.5% 13.6% 10.6% </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Metabolism and nutrition disorders</content> Weight loss Decreased appetite </td><td align="center" styleCode="Rrule" valign="middle"> 13.3% 12.8% </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Dermatological disorders</content> Sweating </td><td align="center" styleCode="Rrule" valign="middle"> 14.4% </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Cardiovascular disorders</content> Tachycardia </td><td align="center" styleCode="Rrule" valign="middle"> 12.2% </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Special Senses</content> Blurred vision </td><td align="center" styleCode="Rrule" valign="middle"> 10.0% </td></tr></tbody></table>

7 DRUG INTERACTIONS Use with Opioids: Increase the risk of respiratory depression. ( 7.1 ) Use with Other CNS Depressants: Produces additive CNS depressant effects. ( 7.1 ) Use with Digoxin: Increase the risk of digoxin toxicity. ( 7.1 ) Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. ( 4 , 5.5 , 7.1 ) Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. ( 7.1 ) 7.1 Drugs Having Clinically Important Interactions with Alprazolam Table 4 includes clinically significant drug interactions with alprazolam [see Clinical Pharmacology (12.3) ] . Table 4: Clinically Significant Drug Interactions with Alprazolam Opioids Clinical implication The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma-aminobutyric acid(GABA A ) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Prevention or management Limit dosage and duration of concomitant use of alprazolam and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions (5.1) ]. Examples Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol. CNS Depressants Clinical implication The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants. Prevention or management Limit dosage and duration of alprazolam during concomitant use with CNS depressants [see Warnings and Precautions (5.3) ] . Examples Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression. Strong Inhibitors of CYP3A (except ritonavir) Clinical implication Concomitant use of alprazolam with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see Clinical Pharmacology (12.3) ]. Prevention or management Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4) , Warnings and Precautions (5.5) ]. Examples Ketoconazole, itraconazole, clarithromycin Moderate or Weak Inhibitors of CYP3A Clinical implication Concomitant use of alprazolam with CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology (12.3) ]. Prevention or management Avoid use and consider appropriate dose reduction when alprazolam is coadministered with a moderate or weak CYP3A inhibitor [see Warnings and Precautions (5.5) ]. Examples Nefazodone, fluvoxamine, cimetidine, erythromycin CYP3A Inducers Clinical implication Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3) ] . Prevention or management Caution is recommended during coadministration with alprazolam.

voxamine, cimetidine, erythromycin CYP3A Inducers Clinical implication Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3) ] . Prevention or management Caution is recommended during coadministration with alprazolam. Examples Carbamazepine, phenytoin Ritonavir Clinical implication Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (>10 to 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir. Prevention or management Reduce alprazolam dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam is stabilized. Increase alprazolam dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam concomitantly. No dosage adjustment of alprazolam is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration (2.6) ] . Concomitant use of alprazolam with a strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications (4) , Warnings and Precautions (5.5) ]. Digoxin Clinical implication Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (>65 years of age). Prevention or management In patients on digoxin therapy, measure serum digoxin concentrations before initiating alprazolam. Continue monitoring digoxin serum concentration and toxicity frequently . Reduce the digoxin dose if necessary. 7.2 Drug/Laboratory Test Interactions Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 4: Clinically Significant Drug Interactions with Alprazolam</caption><col width="30.08%"/><col width="69.92%"/><tbody><tr styleCode="Botrule"><td colspan="2" align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold"> </content><content styleCode="bold">Opioids</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Clinical implication </td><td align="justify" styleCode="Rrule" valign="top">The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma-aminobutyric acid(GABA _A) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Prevention or management </td><td align="justify" styleCode="Rrule" valign="top">Limit dosage and duration of concomitant use of alprazolam and opioids, and monitor patients closely for respiratory depression and sedation <content styleCode="italics">[see <linkHtml href="#Section_5.1">Warnings and Precautions (5.1)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Examples </td><td align="justify" styleCode="Rrule" valign="top">Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol. </td></tr><tr styleCode="Botrule"><td colspan="2" align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">CNS Depressants</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Clinical implication </td><td align="justify" styleCode="Rrule" valign="top">The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants. </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Prevention or management </td><td align="justify" styleCode="Rrule" valign="top">Limit dosage and duration of alprazolam during concomitant use with CNS depressants <content styleCode="italics">[see <linkHtml href="#Section_5.3">Warnings and Precautions (5.3)</linkHtml>] </content>. </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Examples </td><td align="justify" styleCode="Rrule" valign="top">Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression.

cautions (5.3)</linkHtml>] </content>. </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Examples </td><td align="justify" styleCode="Rrule" valign="top">Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression. </td></tr><tr styleCode="Botrule"><td colspan="2" align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Strong Inhibitors of CYP3A (except ritonavir)</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Clinical implication </td><td align="justify" styleCode="Rrule" valign="top">Concomitant use of alprazolam with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions <content styleCode="italics">[see <linkHtml href="#Section_12.3">Clinical Pharmacology (12.3)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Prevention or management </td><td align="justify" styleCode="Rrule" valign="top">Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated <content styleCode="italics">[see <linkHtml href="#Section_4">Contraindications (4)</linkHtml>, <linkHtml href="#Section_5.5">Warnings and Precautions (5.5)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Examples </td><td align="justify" styleCode="Rrule" valign="top">Ketoconazole, itraconazole, clarithromycin </td></tr><tr styleCode="Botrule"><td colspan="2" align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Moderate or Weak Inhibitors of CYP3A</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Clinical implication </td><td align="justify" styleCode="Rrule" valign="top">Concomitant use of alprazolam with CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of adverse reactions of alprazolam <content styleCode="italics">[see <linkHtml href="#Section_12.3">Clinical Pharmacology (12.3)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Prevention or management </td><td align="justify" styleCode="Rrule" valign="top">Avoid use and consider appropriate dose reduction when alprazolam is coadministered with a moderate or weak CYP3A inhibitor <content styleCode="italics">[see <linkHtml href="#Section_5.5">Warnings and Precautions (5.5)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Examples </td><td align="justify" styleCode="Rrule" valign="top">Nefazodone, fluvoxamine, cimetidine, erythromycin </td></tr><tr styleCode="Botrule"><td colspan="2" align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">CYP3A Inducers</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Clinical implication </td><td align="justify" styleCode="Rrule" valign="top">Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam <content styleCode="italics">[see <linkHtml href="#Section_12.3">Clinical Pharmacology (12.3)</linkHtml>] </content>. </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Prevention or management </td><td align="justify" styleCode="Rrule" valign="top">Caution is recommended during coadministration with alprazolam.

<linkHtml href="#Section_12.3">Clinical Pharmacology (12.3)</linkHtml>] </content>. </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Prevention or management </td><td align="justify" styleCode="Rrule" valign="top">Caution is recommended during coadministration with alprazolam. </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Examples </td><td align="justify" styleCode="Rrule" valign="top">Carbamazepine, phenytoin </td></tr><tr styleCode="Botrule"><td colspan="2" align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Ritonavir</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Clinical implication </td><td align="justify" styleCode="Rrule" valign="top">Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (&gt;10 to 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir. </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Prevention or management </td><td align="justify" styleCode="Rrule" valign="top">Reduce alprazolam dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam is stabilized. Increase alprazolam dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam concomitantly. No dosage adjustment of alprazolam is necessary in patients receiving ritonavir for more than 10 to14 days <content styleCode="italics">[see <linkHtml href="#Section_2.6">Dosage and Administration (2.6)</linkHtml>] </content>. Concomitant use of alprazolam with a strong CYP3A inhibitor, except ritonavir, is contraindicated <content styleCode="italics">[see <linkHtml href="#Section_4">Contraindications (4)</linkHtml>, <linkHtml href="#Section_5.5">Warnings and Precautions (5.5)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Digoxin</content> </td><td align="justify" styleCode="Rrule" valign="top"> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top">Clinical implication </td><td align="justify" styleCode="Rrule" valign="top">Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (&gt;65 years of age). </td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top">Prevention or management </td><td align="justify" styleCode="Rrule" valign="top">In patients on digoxin therapy, measure serum digoxin concentrations before initiating alprazolam. Continue monitoring digoxin serum concentration and toxicity frequently <content styleCode="italics">.</content>Reduce the digoxin dose if necessary. </td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Lactation : Breastfeeding not recommended. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including alprazolam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/ . Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8) and Clinical Considerations)]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to alprazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8) ]. Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with alprazolam. 8.4 Pediatric Use Safety and effectiveness of alprazolam have not been established in pediatric patients. 8.5 Geriatric Use Alprazolam-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. Therefore, dosage reduction of alprazolam is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . 8.6 Hepatic Impairment Patients with alcoholic liver disease exhibit a longer elimination half-life (19.7 hours), compared to healthy subjects (11.4 hours).

ame doses. Therefore, dosage reduction of alprazolam is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . 8.6 Hepatic Impairment Patients with alcoholic liver disease exhibit a longer elimination half-life (19.7 hours), compared to healthy subjects (11.4 hours). This may be caused by decreased clearance of alprazolam in patients with alcoholic liver disease. Dosage reduction of alprazolam is recommended in patients with hepatic impairment [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including alprazolam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/ . Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8) and Clinical Considerations)]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to alprazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8) ]. Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings.

8.2 Lactation Risk Summary Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with alprazolam.

8.5 Geriatric Use Alprazolam-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. Therefore, dosage reduction of alprazolam is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] .

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Alprazolam tablets contain alprazolam, which is a Schedule IV controlled substance. 9.2 Abuse Alprazolam is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2) ] . The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol). 9.3 Dependence Alprazolam may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3) ] . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) ] .

osages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3) ] . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) ] . Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to alprazolam may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of alprazolam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

9.2 Abuse Alprazolam is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2) ] . The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

9.3 Dependence Alprazolam may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3) ] . To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) ] . Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to alprazolam may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of alprazolam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

11 DESCRIPTION Alprazolam tablets, USP contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds. The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine. The structural formula is: Alprazolam USP is a white to off-white, crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH. Each alprazolam tablet USP, for oral administration, contains 0.25 mg, 0.5 mg, 1 mg, or 2 mg of alprazolam USP. Inactive ingredients: colloidal silicon dioxide, corn starch, docusate sodium 85% with sodium benzoate 15%, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. In addition, the 0.5 mg tablet contains FD&C Yellow # 6 aluminum lake and the 1 mg tablet contains FD&C Blue No. 2 lake.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Alprazolam is a 1,4 benzodiazepine. Alprazolam exerts its effect for the acute treatment of generalized anxiety disorder and panic disorder through binding to the benzodiazepine site of gamma-aminobutyric acid-A (GABA A ) receptors in the brain and enhances GABA-mediated synaptic inhibition. 12.3 Pharmacokinetics Plasma levels of alprazolam increase proportionally to the dose over the range of 0.5 to 3 mg. Absorption Following oral administration, peak plasma concentration of alprazolam (C max ) occurs in 1 to 2 hours post dose. Distribution Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding. Elimination The mean plasma elimination half-life (T 1/2 ) of alprazolam is approximately 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults. Metabolism Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to 2 major active metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. The plasma circulation levels of the two active metabolites are less than 4% of the parent. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. Excretion Alprazolam and its metabolites are excreted primarily in the urine. Specific Populations Geriatric Patients The mean T 1/2 of alprazolam was 16.3 hours (range: 9.0 to 26.9 hours) in healthy elderly subjects compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy younger adult subjects. Obese Patients The mean T 1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in a group of obese subjects. Patients with Hepatic Impairment The mean T 1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease. Racial or Ethnic Groups Maximal concentrations and T 1/2 of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians. Smoking Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers. Drug Interaction Studies In Vivo Studies Most of the interactions that have been documented with alprazolam are with drugs that modulate CYP3A4 activity. Compounds that are inhibitors or inducers of CYP3A would be expected to increase or decrease plasma alprazolam concentrations, respectively. Drug products that have been studied in vivo , along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.66 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4) , Warnings and Precautions (5.5) , Drug Interactions (7.2) ] . Other studied drugs include: Cimetidine : Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T 1/2 by 16%. Fluoxetine : Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T 1/2 by 17%, and decreased measured psychomotor performance.

sma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T 1/2 by 16%. Fluoxetine : Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T 1/2 by 17%, and decreased measured psychomotor performance. Oral Contraceptives : Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T 1/2 by 29%. Carbamazepine : The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination T 1/2 was shortened (from 17.1±4.9 to 7.7±1.7 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2) ] . However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 to 1200 mg per day); the effect at usual carbamazepine doses is unknown. Ritonavir : Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect C max of alprazolam. The elimination T 1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and C max was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T 1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5) ] . Sertraline : A single dose of alprazolam 1 mg and steady state dose of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Imipramine and Desipramine : The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam in doses up to 4 mg per day. Warfarin : Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. In Vitro Studies Data from in vitro studies of alprazolam suggest a possible drug interaction of alprazolam with paroxetine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined.

12.1 Mechanism of Action Alprazolam is a 1,4 benzodiazepine. Alprazolam exerts its effect for the acute treatment of generalized anxiety disorder and panic disorder through binding to the benzodiazepine site of gamma-aminobutyric acid-A (GABA A ) receptors in the brain and enhances GABA-mediated synaptic inhibition.

12.3 Pharmacokinetics Plasma levels of alprazolam increase proportionally to the dose over the range of 0.5 to 3 mg. Absorption Following oral administration, peak plasma concentration of alprazolam (C max ) occurs in 1 to 2 hours post dose. Distribution Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding. Elimination The mean plasma elimination half-life (T 1/2 ) of alprazolam is approximately 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults. Metabolism Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to 2 major active metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. The plasma circulation levels of the two active metabolites are less than 4% of the parent. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and α-hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. Excretion Alprazolam and its metabolites are excreted primarily in the urine. Specific Populations Geriatric Patients The mean T 1/2 of alprazolam was 16.3 hours (range: 9.0 to 26.9 hours) in healthy elderly subjects compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy younger adult subjects. Obese Patients The mean T 1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in a group of obese subjects. Patients with Hepatic Impairment The mean T 1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease. Racial or Ethnic Groups Maximal concentrations and T 1/2 of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians. Smoking Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers. Drug Interaction Studies In Vivo Studies Most of the interactions that have been documented with alprazolam are with drugs that modulate CYP3A4 activity. Compounds that are inhibitors or inducers of CYP3A would be expected to increase or decrease plasma alprazolam concentrations, respectively. Drug products that have been studied in vivo , along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.66 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4) , Warnings and Precautions (5.5) , Drug Interactions (7.2) ] . Other studied drugs include: Cimetidine : Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T 1/2 by 16%. Fluoxetine : Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T 1/2 by 17%, and decreased measured psychomotor performance. Oral Contraceptives : Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T 1/2 by 29%.

a concentration of alprazolam by 46%, decreased clearance by 21%, increased T 1/2 by 17%, and decreased measured psychomotor performance. Oral Contraceptives : Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T 1/2 by 29%. Carbamazepine : The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90±0.21 mL/min/kg to 2.13±0.54 mL/min/kg and the elimination T 1/2 was shortened (from 17.1±4.9 to 7.7±1.7 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2) ] . However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 to 1200 mg per day); the effect at usual carbamazepine doses is unknown. Ritonavir : Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect C max of alprazolam. The elimination T 1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and C max was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T 1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5) ] . Sertraline : A single dose of alprazolam 1 mg and steady state dose of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Imipramine and Desipramine : The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of alprazolam in doses up to 4 mg per day. Warfarin : Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. In Vitro Studies Data from in vitro studies of alprazolam suggest a possible drug interaction of alprazolam with paroxetine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No evidence of carcinogenic potential was observed in rats or mice administered alprazolam for 2-years at doses up to 30 and 10 mg/kg day respectively. These doses are 29 times and 4.8 times the maximum recommended human dose of 10 mg/day based on mg/m 2 body surface area, respectively. Mutagenesis Alprazolam was negative in the in vitro Ames bacterial reverse mutation assay and DNA Damage/Alkaline Elution Assay and in vivo rat micronucleus genetic toxicology assays. Impairment of Fertility Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg per day, which is approximately 5 times the maximum recommended human dose of 10 mg per day based on mg/m 2 body surface area. 13.2 Animal Toxicology and/or Pharmacology When rats were treated with alprazolam at oral doses of 3 mg, 10 mg, and 30 mg/kg day (3 to 29 times the maximum recommended human dose based on mg/m 2 body surface area) for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis No evidence of carcinogenic potential was observed in rats or mice administered alprazolam for 2-years at doses up to 30 and 10 mg/kg day respectively. These doses are 29 times and 4.8 times the maximum recommended human dose of 10 mg/day based on mg/m 2 body surface area, respectively. Mutagenesis Alprazolam was negative in the in vitro Ames bacterial reverse mutation assay and DNA Damage/Alkaline Elution Assay and in vivo rat micronucleus genetic toxicology assays. Impairment of Fertility Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg per day, which is approximately 5 times the maximum recommended human dose of 10 mg per day based on mg/m 2 body surface area.

14 CLINICAL STUDIES 14.1 Generalized Anxiety Disorder Alprazolam was compared to placebo in double-blind clinical studies (doses up to 4 mg per day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s Global Impressions, and Self-Rating Symptom Scale. 14.2 Panic Disorders The effectiveness of alprazolam in the treatment of panic disorder was studied in 3 short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder. The average dose of alprazolam was 5 mg to 6 mg per day in 2 of the studies, and the doses of alprazolam were fixed at 2 mg and 6 mg per day in the third study. In all 3 studies, alprazolam was superior to placebo on a variable defined as “the number of patients with zero panic attacks” (range, 37% to 83% met this criterion), as well as on a global improvement score. In 2 of the 3 studies, alprazolam was superior to placebo on a variable defined as “change from baseline on the number of panic attacks per week” (range, 3.3 to 5.2), and also on a phobia rating scale. A subgroup of patients who improved on alprazolam during short-term treatment in 1 of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.

16 HOW SUPPLIED/STORAGE AND HANDLING Alprazolam Tablets USP are supplied in the following strengths and package configurations: Alprazolam Tablets USP, 0.25 mg are white, oval shaped, uncoated tablets with breakline on one side debossed with ‘1’ and ‘8’ on either sides of the breakline and ‘Y’ on the other side. Bottles of 100 NDC 65862-676-01 Bottles of 500 NDC 65862-676-05 Bottles of 1,000 NDC 65862-676-99 Alprazolam Tablets USP, 0.5 mg are peach colored, oval shaped, uncoated tablets with breakline on one side debossed with ‘1’ and ‘9’ on either sides of the breakline and ‘Y’ on the other side. Bottles of 100 NDC 65862-677-01 Bottles of 500 NDC 65862-677-05 Bottles of 1,000 NDC 65862-677-99 Alprazolam Tablets USP, 1 mg are blue colored, oval shaped, uncoated tablets with breakline on one side debossed with ‘2’ and ‘0’ on either sides of the breakline and ‘Y’ on the other side. Bottles of 100 NDC 65862-678-01 Bottles of 500 NDC 65862-678-05 Bottles of 1,000 NDC 65862-678-99 Alprazolam Tablets USP, 2 mg are white, oblong, uncoated tablets with three breaklines on both sides debossed with ‘2’ and ‘1’ on either sides of the center breakline and ‘Y’ on the other side. Bottles of 100 NDC 65862-679-01 Bottles of 500 NDC 65862-679-05 Bottles of 1,000 NDC 65862-679-99 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Warnings and Precautions (5.1) , Drug Interactions (7.1) ]. Abuse, Misuse, and Addiction Inform patients that the use of alprazolam, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) , Drug Abuse and Dependence (9.2) ] . Withdrawal Reactions Inform patients that the continued use of alprazolam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of alprazolam may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of alprazolam may require a slow taper [see Warnings and Precautions (5.3) , Drug Abuse and Dependence (9.3) ] . Effects on Driving and Operating Machinery Advise patients not to drive a motor vehicle or operate heavy machinery while taking alprazolam due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking alprazolam [see Warnings and Precautions (5.3) ] . Patients with Depression Advise patients, their families, and caregivers to look for signs of suicidality or worsening depression, and to inform the patient’s healthcare provider immediately [see Warnings and Precautions (5.6) ] . Concomitant Medications Advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medications, vitamins and herbal supplements [see Drug Interactions (7) ] . Pregnancy Advise pregnant females that use of alprazolam late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see Warnings and Precautions (5.8) , Use in Specific Populations (8.1)]. Instruct patients to inform their healthcare provider if they are pregnant. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam during pregnancy [see Use in Specific Populations (8.1) ]. Lactation Advise patients that breastfeeding is not recommended during treatment with alprazolam [see Use in Specific Populations (8.2) ] . Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides

MEDICATION GUIDE Alprazolam Tablets, USP C-IV (al pra' zoe lam) What is the most important information I should know about alprazolam tablets? Alprazolam tablets are a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens: shallow or slowed breathing breathing stops (which may lead to the heart stopping) excessive sleepiness (sedation) Do not drive or operate heavy machinery until you know how taking alprazolam tablets with opioids affects you. Risk of abuse, misuse, and addiction. There is a risk of abuse, misuse, and addiction with benzodiazepines, including alprazolam tablets, which can lead to overdose and serious side effects including coma and death. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including alprazolam tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take alprazolam tablets as prescribed by your healthcare provider. Take alprazolam tablets exactly as your healthcare provider prescribed. Do not share your alprazolam tablets with other people. Keep alprazolam tablets in a safe place and away from children. Physical dependence and withdrawal reactions . Alprazolam tablets can cause physical dependence and withdrawal reactions. Do not suddenly stop taking alprazolam tablets . Stopping alprazolam tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months , including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. Do not take more alprazolam tablets than prescribed or take alprazolam tablets for longer than prescribed. What are alprazolam tablets? Alprazolam tablets are a prescription medicine used: to treat anxiety disorders for the short-term relief of the symptoms of anxiety to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia) Alprazolam tablets are a federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence. Keep alprazolam tablets in a safe place to prevent misuse and abuse.

with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia) Alprazolam tablets are a federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence. Keep alprazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. It is not known if alprazolam tablets are safe and effective in children. Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets. It is not known if alprazolam tablets are safe and effective when used to treat anxiety disorder for longer than 4 months. It is not known if alprazolam tablets are safe and effective when used to treat panic disorder for longer than 10 weeks. Do not take alprazolam tablets if: you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam tablets. See the end of this Medication Guide for a complete list of ingredients in alprazolam tablets. you are taking antifungal medicines including ketoconazole and itraconazole Before you take alprazolam tablets, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems, or suicidal thoughts or behavior have liver or kidney problems have lung disease or breathing problems are pregnant or plan to become pregnant. Taking alprazolam tablets late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems). Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with alprazolam tablets. There is a pregnancy registry for women who take alprazolam tablets during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with alprazolam tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting https://womensmentalhealth.org/pregnancyregistry/. are breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you take alprazolam tablets. Breastfeeding is not recommended during treatment with alprazolam tablets. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking alprazolam tablets with certain other medicines can cause side effects or affect how well alprazolam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. How should I take alprazolam tablets? See “What is the most important information I should know about alprazolam tablets?” Take alprazolam tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much alprazolam tablets to take and when to take it. If you take too much alprazolam, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of alprazolam tablets? Alprazolam tablets may cause serious side effects, including: See “What is the most important information I should know about alprazolam tablets?” Seizures. Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus). Mania.

at are the possible side effects of alprazolam tablets? Alprazolam tablets may cause serious side effects, including: See “What is the most important information I should know about alprazolam tablets?” Seizures. Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus). Mania. Alprazolam tablets may cause an increase in activity and talking (hypomania and mania) in people who have depression. Alprazolam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affect you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse. The most common side effects of alprazolam tablets include: problems with coordination hypotension trouble saying words clearly (dysarthria) changes in sex drive (libido) These are not all the possible side effects of alprazolam tablets. 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 alprazolam tablets? Store alprazolam tablets at room temperature between 68°F to 77°F (20°C to 25°C) Keep alprazolam tablets and all medicines out of the reach of children. General information about the safe and effective use of alprazolam tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use alprazolam tablets for a condition for which it was not prescribed. Do not give alprazolam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals. What are the ingredients in alprazolam tablets? Active ingredient: alprazolam Inactive ingredients: colloidal silicon dioxide, corn starch, docusate sodium 85% with sodium benzoate 15%, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. In addition, the 0.5 mg tablet contains FD&C Yellow # 6 aluminum lake and the 1 mg tablet contains FD&C Blue No. 2 lake. Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 03/2023

<table cellspacing="0" cellpadding="0" border="0" width="100%"><col width="100%"/><tbody><tr styleCode="Botrule"><td align="center" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">MEDICATION GUIDE</content> <content styleCode="bold">Alprazolam Tablets, USP C-IV</content> <content styleCode="bold">(al pra&apos; zoe lam)</content> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">What is the most important information I should know about alprazolam tablets?</content> <list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Alprazolam tablets are a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.</content></item></list>Get emergency help right away if any of the following happens: <list listType="unordered" styleCode="Disc"><item>shallow or slowed breathing </item><item>breathing stops (which may lead to the heart stopping)</item><item>excessive sleepiness (sedation) <content styleCode="bold"/> </item></list>Do not drive or operate heavy machinery until you know how taking alprazolam tablets with opioids affects you. <list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Risk of abuse, misuse, and addiction.</content>There is a risk of abuse, misuse, and addiction with benzodiazepines, including alprazolam tablets, which can lead to overdose and serious side effects including coma and death. <content styleCode="bold"> </content><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including alprazolam tablets.</content>These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects.</content></item><item><content styleCode="bold">You can develop an addiction even if you take alprazolam tablets as prescribed by your healthcare provider.</content></item><item><content styleCode="bold">Take alprazolam tablets exactly as your healthcare provider prescribed.</content></item><item>Do not share your alprazolam tablets with other people.</item><item>Keep alprazolam tablets in a safe place and away from children. <content styleCode="bold"/></item></list></item><item><content styleCode="bold">Physical dependence and withdrawal reactions</content>. Alprazolam tablets can cause physical dependence and withdrawal reactions. <content styleCode="bold"> </content><list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Do not suddenly stop taking alprazolam tablets</content>. Stopping alprazolam tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions.

e-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms.</content></item><item><content styleCode="bold">Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months</content>, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. </item><item>Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.</item></list></item><item>Do not take more alprazolam tablets than prescribed or take alprazolam tablets for longer than prescribed.</item></list> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">What are alprazolam tablets?</content> <list listType="unordered" styleCode="Disc"><item>Alprazolam tablets are a prescription medicine used: <list listType="unordered" styleCode="Disc"><item>to treat anxiety disorders</item><item>for the short-term relief of the symptoms of anxiety</item><item>to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)</item><item><content styleCode="bold">Alprazolam tablets are a federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence.</content>Keep alprazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. </item><item>It is not known if alprazolam tablets are safe and effective in children.</item><item>Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets.</item><item>It is not known if alprazolam tablets are safe and effective when used to treat anxiety disorder for longer than 4 months.</item><item>It is not known if alprazolam tablets are safe and effective when used to treat panic disorder for longer than 10 weeks. </item></list></item></list></td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Do not take alprazolam tablets if:</content> <list listType="unordered" styleCode="Disc"><item>you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam tablets. See the end of this Medication Guide for a complete list of ingredients in alprazolam tablets.</item><item>you are taking antifungal medicines including ketoconazole and itraconazole</item></list></td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Before you take alprazolam tablets, tell your healthcare provider about all of your medical conditions, including if you:</content> <list listType="unordered" styleCode="Disc"><item>have or have had depression, mood problems, or suicidal thoughts or behavior</item><item>have liver or kidney problems</item><item>have lung disease or breathing problems</item><item>are pregnant or plan to become pregnant.

edical conditions, including if you:</content> <list listType="unordered" styleCode="Disc"><item>have or have had depression, mood problems, or suicidal thoughts or behavior</item><item>have liver or kidney problems</item><item>have lung disease or breathing problems</item><item>are pregnant or plan to become pregnant. <list listType="unordered" styleCode="Disc"><item>Taking alprazolam tablets late in pregnancy may cause your baby to have symptoms of sedation (breathing problems, sluggishness, low muscle tone), and/or withdrawal symptoms (jitteriness, irritability, restlessness, shaking, excessive crying, feeding problems).</item><item>Tell your healthcare provider right away if you become pregnant or think you are pregnant during treatment with alprazolam tablets.</item><item>There is a pregnancy registry for women who take alprazolam tablets during pregnancy. The purpose of the registry is to collect information about the health of you and your baby. If you become pregnant during treatment with alprazolam tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Psychiatric Medications. You can register by calling 1-866-961-2388 or visiting <content styleCode="underline">https://womensmentalhealth.org/pregnancyregistry/.</content></item></list></item><item>are breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk. <list listType="unordered" styleCode="Disc"><item>Talk to your healthcare provider about the best way to feed your baby if you take alprazolam tablets.</item><item>Breastfeeding is not recommended during treatment with alprazolam tablets.</item></list></item></list><content styleCode="bold">Tell your healthcare provider about all the medicines you take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking alprazolam tablets with certain other medicines can cause side effects or affect how well alprazolam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="bottom"><content styleCode="bold">How should I take alprazolam tablets?</content> <list listType="unordered" styleCode="Disc"><item>See &#x201C;What is the most important information I should know about alprazolam tablets?&#x201D; <content styleCode="bold"/></item><item>Take alprazolam tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much alprazolam tablets to take and when to take it.</item><item>If you take too much alprazolam, call your healthcare provider or go to the nearest hospital emergency room right away.</item></list> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">What are the possible side effects of alprazolam tablets?</content> <content styleCode="bold">Alprazolam tablets may cause serious side effects, including:</content> <list listType="unordered" styleCode="Disc"><item>See &#x201C;What is the most important information I should know about alprazolam tablets?&#x201D; <content styleCode="bold"/></item><item><content styleCode="bold">Seizures.</content>Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus). </item><item><content styleCode="bold">Mania.</content>Alprazolam tablets may cause an increase in activity and talking (hypomania and mania) in people who have depression.

m><content styleCode="bold">Seizures.</content>Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus). </item><item><content styleCode="bold">Mania.</content>Alprazolam tablets may cause an increase in activity and talking (hypomania and mania) in people who have depression. <list listType="unordered" styleCode="Disc"><item><content styleCode="bold">Alprazolam tablets can make you sleepy or dizzy and can slow your thinking and motor skills.</content>Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affect you. </item><item><content styleCode="bold">Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider.</content>When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse. </item></list></item></list><content styleCode="bold">The most common side effects of alprazolam tablets include:</content> <list listType="unordered" styleCode="Disc"><item>problems with coordination</item><item>hypotension</item><item>trouble saying words clearly (dysarthria)</item><item>changes in sex drive (libido)</item></list>These are not all the possible side effects of alprazolam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">How should I store</content><content styleCode="bold">alprazolam tablets?</content><content styleCode="bold"/> <list listType="unordered" styleCode="Disc"><item>Store alprazolam tablets at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C)</item><item><content styleCode="bold">Keep alprazolam tablets and all medicines out of the reach of children.</content></item></list> </td></tr><tr styleCode="Botrule"><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">General information about the safe and effective use of alprazolam tablets.</content> <list listType="unordered" styleCode="Disc"><item>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.</item><item>Do not use alprazolam tablets for a condition for which it was not prescribed.</item><item>Do not give alprazolam tablets to other people, even if they have the same symptoms that you have. It may harm them.</item><item>You can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals.</item></list></td></tr><tr><td align="justify" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">What are the ingredients in alprazolam tablets?</content> <content styleCode="bold">Active ingredient:</content>alprazolam <content styleCode="bold">Inactive ingredients:</content>colloidal silicon dioxide, corn starch, docusate sodium 85% with sodium benzoate 15%, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. In addition, the 0.5 mg tablet contains FD&amp;C Yellow # 6 aluminum lake and the 1 mg tablet contains FD&amp;C Blue No. 2 lake. <content styleCode="bold">Dispense with Medication Guide available at: <content styleCode="underline">www.aurobindousa.com/medication-guides</content></content> <content styleCode="bold"> </content> For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876. Distributed by: <content styleCode="bold">Aurobindo Pharma USA, Inc.</content> 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: <content styleCode="bold">Aurobindo Pharma Limited</content> Hyderabad-500 032, India </td></tr></tbody></table>

2 DOSAGE AND ADMINISTRATION Generalized Anxiety Disorder : ( 2.1 ) Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily. Dosage may be increased, at intervals of every 3 to 4 days, to a maximum recommended daily dose of 4 mg, given in divided doses. Use the lowest possible effective dose and frequently assess the need for continued treatment. Panic Disorder : Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. ( 2.2 ) When tapering, decrease dosage by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction. ( 2.3 , 5.2 ) See the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. ( 2.4 , 2.5 , 2.6 ) 2.1 Dosage in Generalized Anxiety Disorder The recommended starting oral dosage of alprazolam tablets for the acute treatment of patients with GAD is 0.25 mg to 0.5 mg administered three times daily. Depending upon the response, the dosage may be adjusted at intervals of every 3 to 4 days. The maximum recommended dosage is 4 mg daily (in divided doses). Use the lowest possible effective dose and frequently assess the need for continued treatment [see Warnings and Precautions (5.2) ] . 2.2 Dosage in Panic Disorder The recommended starting oral dosage of alprazolam tablets for the treatment of PD is 0.5 mg three times daily. Depending on the response, the dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. Controlled trials of alprazolam tablets in the treatment of panic disorder included dosages in the range of 1 mg to 10 mg daily. The mean dosage was approximately 5 mg to 6 mg daily. Occasional patients required as much as 10 mg per day. For patients receiving doses greater than 4 mg per day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam tablets greater than 4 mg per day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. The necessary duration of treatment for PD in patients responding to alprazolam tablets are unknown. After a period of extended freedom from panic attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena [see Dosage and Administration (2.3) ]. 2.3 Discontinuation or Dosage Reduction of Alprazolam Tablets To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam tablets or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level . Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3) , Drug Abuse and Dependence (9.3) ]. Reduced the dosage by no more than 0.5 mg every 3 days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

ge level . Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3) , Drug Abuse and Dependence (9.3) ]. Reduced the dosage by no more than 0.5 mg every 3 days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens. In a controlled postmarketing discontinuation study of panic disorder patients which compared the recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. 2.4 Dosage Recommendations in Geriatric Patients In geriatric patients, the recommended starting oral dosage of alprazolam tablets is 0.25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. Geriatric patients may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dosage, the dosage may be reduced [see Use in Specific Populations (8.5) , Clinical Pharmacology (12.3) ] . 2.5 Dosage Recommendations in Patients with Hepatic Impairment In patients with hepatic impairment, the recommended starting oral dosage of alprazolam tablets is 0.25 mg, given 2 or 3 times daily. This may be gradually increased if needed and tolerated. If adverse reactions occur at the recommended starting dose, the dosage may be reduced [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . 2.6 Dosage Modifications for Drug Interactions Alprazolam tablets should be reduced to half of the recommended dosage when a patient is started on ritonavir and alprazolam tablets together, or when ritonavir administered to a patient treated with alprazolam tablets. Increase the alprazolam tablets dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam tablets together. It is not necessary to reduce alprazolam tablets dose in patients who have been taking ritonavir for more than 10 to 14 days. Alprazolam tablets are contraindicated with concomitant use of all strong CYP3A inhibitors, except ritonavir [see Contraindications (4) , Warnings and Precautions (5.5) ] .

5 WARNINGS AND PRECAUTIONS Effects on Driving and Operating Machinery: Patients receiving alprazolam should be cautioned against operating machinery or driving a motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. ( 5.4 ) Neonatal Sedation and Withdrawal Syndrome (NOWS): Use of alprazolam during pregnancy can result in neonatal sedation and neonatal withdrawal syndrome. ( 5.5 , 8.1 ) Patients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. ( 5.7 ) 5.1 Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including alprazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe alprazolam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of alprazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions (7.1) ] . 5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including alprazolam, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2) ] . Before prescribing alprazolam and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of alprazolam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

course of the interdosing interval. 5.4 Effects on Driving and Operating Machinery Because of its CNS depressant effects, patients receiving alprazolam should be cautioned against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be cautioned about the concomitant use of alcohol and other CNS depressant drugs during treatment with alprazolam [see Drug Interactions (7.1) ] . 5.5 Neonatal Sedation and Withdrawal Syndrome Use of alprazolam during later stages of pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Observe newborns for signs of sedation and neonatal withdrawal syndrome and manage accordingly [see Use in Specific Populations (8.1) ] . 5.6 Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. Strong CYP3A Inhibitors Alprazolam is contraindicated in patients receiving strong inhibitors of CYP3A (such as azole antifungal agents), except ritonavir [see Contraindications (4) ]. Ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. Dosage adjustment is necessary when alprazolam and ritonavir are initiated concomitantly or when ritonavir is added to a stable dosage of alprazolam [see Dosage and Administration (2.6) , Drug Interactions (7.1) ]. Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see Drug Interaction (7.1) , Clinical Pharmacology (12.3) ]. Use caution and consider dose reduction of alprazolam, as appropriate, during co-administration with these drugs. 5.7 Patients with Depression Benzodiazepines may worsen depression. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression. 5.8 Mania Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression [see Adverse Reactions (6.2) ] . 5.9 Risk in Patients with Impaired Respiratory Function There have been reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue alprazolam.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1) ] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2) ] Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3) ] Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4) ] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.5) ] Patients with Depression [see Warnings and Precautions (5.7) ] Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9) ] The most common adverse reactions reported in clinical trials for generalized anxiety disorder and panic disorder (incidence > 5% and at least twice that of placebo) include: impaired coordination, hypotension, dysarthria, and increased libido. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in: 4-week placebo-controlled clinical studies with alprazolam dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (Table 1) Short-term (up to 10 weeks) placebo-controlled clinical studies with alprazolam dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2). Table 1: Adverse Reactions Occurring in ≥1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety Alprazolam n=565 Placebo n=505 Nervous system disorders Drowsiness Light-headedness Dizziness Akathisia Gastrointestinal disorders Dry mouth Increased salivation 41% 21% 2% 2% 15% 4% 22% 19% 1% 1% 13% 2% Cardiovascular disorders Hypotension Skin and subcutaneous tissue disorders Dermatitis/allergy 5% 4% 2% 3% In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, the following adverse reactions have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 1: Adverse Reactions Occurring in &#x2265;1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety </caption><colgroup><col width="36.96%"/><col width="30.96%"/><col width="32.08%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Alprazolam</content> <content styleCode="bold">n=565</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">n=505</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Nervous system disorders </content> Drowsiness Light-headedness Dizziness Akathisia <content styleCode="bold">Gastrointestinal disorders</content> Dry mouth Increased salivation </td><td styleCode="Rrule" align="center" valign="middle"> 41% 21% 2% 2% 15% 4% </td><td styleCode="Rrule" align="center" valign="middle"> 22% 19% 1% 1% 13% 2% </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Cardiovascular disorders </content> Hypotension <content styleCode="bold">Skin and subcutaneous tissue disorders</content> Dermatitis/allergy </td><td styleCode="Rrule" align="center" valign="middle"> 5% 4% </td><td styleCode="Rrule" align="center" valign="middle"> 2% 3% </td></tr></tbody></table>

tent styleCode="bold">Cardiovascular disorders </content> Hypotension <content styleCode="bold">Skin and subcutaneous tissue disorders</content> Dermatitis/allergy </td><td styleCode="Rrule" align="center" valign="middle"> 5% 4% </td><td styleCode="Rrule" align="center" valign="middle"> 2% 3% </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 2: Adverse Reactions Occuring in &#x2265;1% in Alprazolam-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder </caption><colgroup><col width="36.92%"/><col width="30.94%"/><col width="32.14%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold"/> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Alprazolam</content> <content styleCode="bold">n=1388</content> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Placebo</content> <content styleCode="bold">n=1231</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> Drowsiness Fatique and Tiredness Impaired Coordination Irritability Memory Impairment Cognitive Disorder Decreased Libido Dysartharia Confusional state Increased libido Change in libido (not specified) Disinhibition Talkativeness Derealization </td><td styleCode="Rrule" align="center" valign="middle">77% 49% 40% 33% 33% 29% 14% 23% 10% 8% 7% 3% 2% 2% </td><td styleCode="Rrule" align="center" valign="middle">43% 42% 18% 30% 22% 21% 8% 6% 8% 4% 6% 2% 1% 1% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="middle"><content styleCode="bold">Gastrointestinal disorders </content> Constipation Increased salivation </td><td styleCode="Rrule" align="center" valign="middle"> 26% 6% </td><td styleCode="Rrule" align="center" valign="middle"> 15% 4% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Skin and subcutaneous tissue disorders</content> Rash </td><td styleCode="Rrule" align="center" valign="middle"> 11% </td><td styleCode="Rrule" align="center" valign="middle"> 8% </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Other </content> Increased appetite Decreased appetite Weight gain Weight loss Micturition difficulties Menstrual disorders Sexual dysfunction Incontinence </td><td styleCode="Rrule" align="center" valign="middle"> 33% 28% 27% 23% 12% 11% 7% 2% </td><td styleCode="Rrule" align="center" valign="middle"> 23% 24% 18% 17% 9% 9% 4% 1% </td></tr></tbody></table>

creased appetite Weight gain Weight loss Micturition difficulties Menstrual disorders Sexual dysfunction Incontinence </td><td styleCode="Rrule" align="center" valign="middle"> 33% 28% 27% 23% 12% 11% 7% 2% </td><td styleCode="Rrule" align="center" valign="middle"> 23% 24% 18% 17% 9% 9% 4% 1% </td></tr></tbody></table> <table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 3: Discontinuation-Emergent Symptom Incidence Reported in &#x2265;5% of Alprazolam-treated Patients and &gt; Placebo-treated Patients </caption><colgroup><col width="50%"/><col width="50%"/></colgroup><tfoot><tr><td colspan="2">n=number of patients.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"> </td><td styleCode="Rrule" align="center" valign="middle"><content styleCode="bold">Alprazolam-treated Patients</content> <content styleCode="bold">n=641</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Nervous system disorders</content> Insomnia Light-headedness Abnormal involuntary movement Headache Muscular twitching Impaired coordination Muscle tone disorders Weakness </td><td styleCode="Rrule" align="center" valign="middle"> 29.5% 19.3% 17.3% 17.0% 6.9% 6.6% 5.9% 5.8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Psychiatric disorders</content> Anxiety Fatigue and Tiredness Irritability Cognitive disorder Memory impairment Depression Confusional state </td><td styleCode="Rrule" align="center" valign="middle"> 19.2% 18.4% 10.5% 10.3% 5.5% 5.1% 5.0% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Gastrointestinal disorders</content> Nausea/Vomiting Diarrhea Decreased salivation </td><td styleCode="Rrule" align="center" valign="middle"> 16.5% 13.6% 10.6% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Metabolism and nutrition disorders</content> Weight loss Decreased appetite </td><td styleCode="Rrule" align="center" valign="middle"> 13.3% 12.8% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Dermatological disorders</content> Sweating </td><td styleCode="Rrule" align="center" valign="middle"> 14.4% </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Cardiovascular disorders</content> Tachycardia </td><td styleCode="Rrule" align="center" valign="middle"> 12.2% </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Special Senses</content> Blurred vision </td><td styleCode="Rrule" align="center" valign="middle"> 10.0% </td></tr></tbody></table>

7 DRUG INTERACTIONS Use with Opioids: Increase the risk of respiratory depression. ( 7.1 ) Use with Other CNS Depressants: Produces additive CNS depressant effects. ( 7.1 ) Use with Digoxin: Increase the risk of digoxin toxicity. ( 7.1 ) Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. ( 4 , 5.6 , 7.1 ) Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. ( 7.1 ) 7.1 Drugs Having Clinically Important Interactions with Alprazolam Table 4 includes clinically significant drug interactions with alprazolam [see Clinical Pharmacology (12.3) ] . Table 4: Clinically Significant Drug Interactions with Alprazolam Opioids Clinical implication The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma-aminobutyric acid(GABA A ) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Prevention or management Limit dosage and duration of concomitant use of alprazolam and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions (5.1) ]. Examples Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol. CNS Depressants Clinical implication The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants. Prevention or management Limit dosage and duration of alprazolam during concomitant use with CNS depressants [see Warnings and Precautions (5.3) ] . Examples Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression. Strong Inhibitors of CYP3A (except ritonavir) Clinical implication Concomitant use of alprazolam with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see Clinical Pharmacology (12.3) ]. Prevention or management Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4) , Warnings and Precautions (5.5) ]. Examples Ketoconazole, itraconazole, clarithromycin Moderate or Weak Inhibitors of CYP3A Clinical implication Concomitant use of alprazolam with CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology (12.3) ]. Prevention or management Avoid use and consider appropriate dose reduction when alprazolam is coadministered with a moderate or weak CYP3A inhibitor [see Warnings and Precautions (5.5) ]. Examples Nefazodone, fluvoxamine, cimetidine, erythromycin CYP3A Inducers Clinical implication Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3) ] . Prevention or management Caution is recommended during coadministration with alprazolam.

<table cellspacing="0" cellpadding="0" border="0" width="100%"><caption>Table 4: Clinically Significant Drug Interactions with Alprazolam </caption><colgroup><col width="30.08%"/><col width="69.92%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold"/><content styleCode="bold">Opioids </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Clinical implication </td><td styleCode="Rrule" align="justify" valign="top">The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at gamma-aminobutyric acid(GABA_A) sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Prevention or management </td><td styleCode="Rrule" align="justify" valign="top">Limit dosage and duration of concomitant use of alprazolam and opioids, and monitor patients closely for respiratory depression and sedation<content styleCode="italics"> [see <linkHtml href="#Section_5.1">Warnings and Precautions (5.1)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Examples </td><td styleCode="Rrule" align="justify" valign="top">Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">CNS Depressants </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Clinical implication </td><td styleCode="Rrule" align="justify" valign="top">The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Prevention or management </td><td styleCode="Rrule" align="justify" valign="top">Limit dosage and duration of alprazolam during concomitant use with CNS depressants <content styleCode="italics">[see <linkHtml href="#Section_5.3">Warnings and Precautions (5.3)</linkHtml>]</content>. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Examples </td><td styleCode="Rrule" align="justify" valign="top">Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression.

ecautions (5.3)</linkHtml>]</content>. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Examples </td><td styleCode="Rrule" align="justify" valign="top">Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">Strong Inhibitors of CYP3A (except ritonavir) </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Clinical implication </td><td styleCode="Rrule" align="justify" valign="top">Concomitant use of alprazolam with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions <content styleCode="italics">[see <linkHtml href="#Section_12.3">Clinical Pharmacology (12.3)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Prevention or management </td><td styleCode="Rrule" align="justify" valign="top">Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated <content styleCode="italics">[see <linkHtml href="#Section_4">Contraindications (4)</linkHtml>, <linkHtml href="#Section_5.5">Warnings and Precautions (5.5)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Examples </td><td styleCode="Rrule" align="justify" valign="top">Ketoconazole, itraconazole, clarithromycin </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">Moderate or Weak Inhibitors of CYP3A </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Clinical implication </td><td styleCode="Rrule" align="justify" valign="top">Concomitant use of alprazolam with CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of adverse reactions of alprazolam <content styleCode="italics">[see <linkHtml href="#Section_12.3">Clinical Pharmacology (12.3)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Prevention or management </td><td styleCode="Rrule" align="justify" valign="top">Avoid use and consider appropriate dose reduction when alprazolam is coadministered with a moderate or weak CYP3A inhibitor <content styleCode="italics">[see <linkHtml href="#Section_5.5">Warnings and Precautions (5.5)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Examples </td><td styleCode="Rrule" align="justify" valign="top">Nefazodone, fluvoxamine, cimetidine, erythromycin </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">CYP3A Inducers </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Clinical implication </td><td styleCode="Rrule" align="justify" valign="top">Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam <content styleCode="italics">[see <linkHtml href="#Section_12.3">Clinical Pharmacology (12.3)</linkHtml>]</content>. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Prevention or management </td><td styleCode="Rrule" align="justify" valign="top">Caution is recommended during coadministration with alprazolam.

e <linkHtml href="#Section_12.3">Clinical Pharmacology (12.3)</linkHtml>]</content>. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Prevention or management </td><td styleCode="Rrule" align="justify" valign="top">Caution is recommended during coadministration with alprazolam. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Examples </td><td styleCode="Rrule" align="justify" valign="top">Carbamazepine, phenytoin </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" colspan="2" align="justify" valign="top"><content styleCode="bold">Ritonavir </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Clinical implication </td><td styleCode="Rrule" align="justify" valign="top">Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (&gt;10 to 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Prevention or management </td><td styleCode="Rrule" align="justify" valign="top">Reduce alprazolam dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to a regimen where alprazolam is stabilized. Increase alprazolam dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam concomitantly. No dosage adjustment of alprazolam is necessary in patients receiving ritonavir for more than 10 to14 days <content styleCode="italics">[see <linkHtml href="#Section_2.6">Dosage and Administration (2.6)</linkHtml>]</content>. Concomitant use of alprazolam with a strong CYP3A inhibitor, except ritonavir, is contraindicated <content styleCode="italics">[see <linkHtml href="#Section_4">Contraindications (4)</linkHtml>, <linkHtml href="#Section_5.5">Warnings and Precautions (5.5)</linkHtml>]. </content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Digoxin </content> </td><td styleCode="Rrule" align="justify" valign="top"> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top">Clinical implication </td><td styleCode="Rrule" align="justify" valign="top">Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients (&gt;65 years of age). </td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top">Prevention or management </td><td styleCode="Rrule" align="justify" valign="top">In patients on digoxin therapy, measure serum digoxin concentrations before initiating alprazolam. Continue monitoring digoxin serum concentration and toxicity frequently<content styleCode="italics">. </content>Reduce the digoxin dose if necessary. </td></tr></tbody></table>

8 USE IN SPECIFIC POPULATIONS Lactation : Breastfeeding not recommended. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Other Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/. Risk Summary Neonates born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal [see Warnings and Precautions (5.4) , Clinical Considerations)]. Overall available data from published observational studies of pregnant women exposed to alprazolam have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to benzodiazepines during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly [see Warnings and Precautions (5.4) ]. Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. At this time, there is no clear evidence that alprazolam exposure in early pregnancy can cause major birth defects. Neonates exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation and neonatal withdrawal symptoms. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation and withdrawal symptoms in breastfed neonates and infants exposed to alprazolam. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with alprazolam. 8.4 Pediatric Use Safety and effectiveness of alprazolam have not been established in pediatric patients. 8.5 Geriatric Use Alprazolam-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses.

atment with alprazolam. 8.4 Pediatric Use Safety and effectiveness of alprazolam have not been established in pediatric patients. 8.5 Geriatric Use Alprazolam-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. Therefore, dosage reduction of alprazolam is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] . 8.6 Hepatic Impairment Patients with alcoholic liver disease exhibit a longer elimination half-life (19.7 hours), compared to healthy subjects (11.4 hours). This may be caused by decreased clearance of alprazolam in patients with alcoholic liver disease. Dosage reduction of alprazolam is recommended in patients with hepatic impairment [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Other Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/. Risk Summary Neonates born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal [see Warnings and Precautions (5.4) , Clinical Considerations)]. Overall available data from published observational studies of pregnant women exposed to alprazolam have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to benzodiazepines during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly [see Warnings and Precautions (5.4) ]. Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. At this time, there is no clear evidence that alprazolam exposure in early pregnancy can cause major birth defects. Neonates exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation and neonatal withdrawal symptoms.

8.2 Lactation Risk Summary Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation and withdrawal symptoms in breastfed neonates and infants exposed to alprazolam. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with alprazolam.

10 OVERDOSAGE 10.1 Clinical Experience Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes, and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality. 10.2 Management of Overdose In case of an overdosage, consult a Certified Poison Control Center at 1-800-222-1222 for latest recommendations. As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested. Flumazenil may be useful in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert should be consulted prior to use.

16 HOW SUPPLIED/STORAGE AND HANDLING Alprazolam Tablets USP, 2 mg are white, oblong, uncoated tablets with three breaklines on both sides debossed with ‘2’ and ‘1’ on either sides of the center breakline and ‘Y’ on the other side. NDC: 71335-1894-1: 30 Tablets in a BOTTLE NDC: 71335-1894-2: 60 Tablets in a BOTTLE NDC: 71335-1894-3: 90 Tablets in a BOTTLE NDC: 71335-1894-4: 100 Tablets in a BOTTLE NDC: 71335-1894-5: 10 Tablets in a BOTTLE NDC: 71335-1894-6: 120 Tablets in a BOTTLE NDC: 71335-1894-7: 40 Tablets in a BOTTLE Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Risks from Concomitant Use with Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Warnings and Precautions (5.1) , Drug Interactions (7.1) ]. Abuse, Misuse, and Addiction Inform patients that the use of alprazolam, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) , Drug Abuse and Dependence (9.2) ] . Withdrawal Reactions Inform patients that the continued use of alprazolam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of alprazolam may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of alprazolam may require a slow taper [see Warnings and Precautions (5.3) , Drug Abuse and Dependence (9.3) ] . Effects on Driving and Operating Machinery Advise patients not to drive a motor vehicle or operate heavy machinery while taking alprazolam due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking alprazolam [see Warnings and Precautions (5.3) ] . Patients with Depression Advise patients, their families, and caregivers to look for signs of suicidality or worsening depression, and to inform the patient’s healthcare provider immediately [see Warnings and Precautions (5.6) ] . Concomitant Medications Advise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medications, vitamins and herbal supplements [see Drug Interactions (7) ] . Pregnancy Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Advise mothers using alprazolam to monitor neonates for signs of sedation, respiratory depression, withdrawal symptoms, and feeding problems. Instruct patients to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with alprazolam [see Warnings and Precautions (5.4) . Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam during pregnancy [see Use in Specific Populations (8.1) ]. Lactation Advise women not to breastfeed during treatment with alprazolam [see Use in Specific Populations (8.2) ] . Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides

with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia) Alprazolam tablets are a federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence. Keep alprazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs. It is not known if alprazolam tablets are safe and effective in children. Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets. It is not known if alprazolam tablets are safe and effective when used to treat anxiety disorder for longer than 4 months. It is not known if alprazolam tablets are safe and effective when used to treat panic disorder for longer than 10 weeks. Do not take alprazolam tablets if: you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam tablets. See the end of this Medication Guide for a complete list of ingredients in alprazolam tablets. you are taking antifungal medicines including ketoconazole and itraconazole Before you take alprazolam tablets, tell your healthcare provider about all of your medical conditions, including if you: have or have had depression, mood problems, or suicidal thoughts or behavior have liver or kidney problems have lung disease or breathing problems are pregnant or plan to become pregnant. Alprazolam tablets may harm your unborn baby. You and your healthcare provider should decide if you should take alprazolam tablets while you are pregnant. are breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take alprazolam tablets. You should not breastfeed while taking alprazolam tablets. Tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking alprazolam tablets with certain other medicines can cause side effects or affect how well alprazolam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. How should I take alprazolam tablets? See “What is the most important information I should know about alprazolam tablets?” Take alprazolam tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much alprazolam tablets to take and when to take it. If you take too much alprazolam, call your healthcare provider or go to the nearest hospital emergency room right away. What are the possible side effects of alprazolam tablets? Alprazolam tablets may cause serious side effects, including: See “What is the most important information I should know about alprazolam tablets?” Seizures. Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus). Mania. Alprazolam tablets may cause an increase in activity and talking (hypomania and mania) in people who have depression. Alprazolam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affect you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse.

olam tablets affect you. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse. The most common side effects of alprazolam tablets include: problems with coordination hypotension trouble saying words clearly (dysarthria) changes in sex drive (libido) These are not all the possible side effects of alprazolam tablets. 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 alprazolam tablets? Store alprazolam tablets at room temperature between 68°F to 77°F (20°C to 25°C) Keep alprazolam tablets and all medicines out of the reach of children. General information about the safe and effective use of alprazolam tablets. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use alprazolam tablets for a condition for which it was not prescribed. Do not give alprazolam tablets to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals. What are the ingredients in alprazolam tablets? Active ingredient: alprazolam Inactive ingredients: colloidal silicon dioxide, corn starch, docusate sodium 85% with sodium benzoate 15%, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. In addition, the 0.5 mg tablet contains FD&C Yellow # 6 aluminum lake and the 1 mg tablet contains FD&C Blue No. 2 lake. Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 038, India This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2021

<table cellspacing="0" cellpadding="0" border="0" width="100%"><colgroup><col width="100%"/></colgroup><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="center" valign="top"><content styleCode="bold">MEDICATION GUIDE</content> <content styleCode="bold">Alprazolam Tablets, USP C-IV</content> <content styleCode="bold">(al pra&apos; zoe lam)</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">What is the most important information I should know about alprazolam tablets? </content> <list listType="unordered" styleCode="disc"><item><content styleCode="bold">Alprazolam tablets are a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.</content></item></list>Get emergency help right away if any of the following happens: <list listType="unordered" styleCode="disc"><item>shallow or slowed breathing </item><item>breathing stops (which may lead to the heart stopping) </item><item>excessive sleepiness (sedation)<content styleCode="bold"/></item></list>Do not drive or operate heavy machinery until you know how taking alprazolam tablets with opioids affects you. <list listType="unordered" styleCode="disc"><item><content styleCode="bold">Risk of abuse, misuse, and addiction. </content>There is a risk of abuse, misuse, and addiction with benzodiazepines, including alprazolam tablets, which can lead to overdose and serious side effects including coma and death. <content styleCode="bold"/><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including alprazolam tablets. </content>These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. </content></item><item><content styleCode="bold">You can develop an addiction even if you take alprazolam tablets as prescribed by your healthcare provider.</content></item><item><content styleCode="bold">Take alprazolam tablets exactly as your healthcare provider prescribed.</content></item><item>Do not share your alprazolam tablets with other people. </item><item>Keep alprazolam tablets in a safe place and away from children.<content styleCode="bold"/></item></list></item><item><content styleCode="bold">Physical dependence and withdrawal reactions</content>. Alprazolam tablets can cause physical dependence and withdrawal reactions. <content styleCode="bold"/><list listType="unordered" styleCode="disc"><item><content styleCode="bold">Do not suddenly stop taking alprazolam tablets</content>. Stopping alprazolam tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions.

e-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. <content styleCode="bold">Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms.</content></item><item><content styleCode="bold">Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months</content>, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears. </item><item>Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction. </item></list></item><item>Do not take more alprazolam tablets than prescribed or take alprazolam tablets for longer than prescribed. </item></list> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">What are alprazolam tablets? </content> <list listType="unordered" styleCode="disc"><item>Alprazolam tablets are a prescription medicine used: <list listType="unordered" styleCode="disc"><item>to treat anxiety disorders </item><item>for the short-term relief of the symptoms of anxiety </item><item>to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)</item><item><content styleCode="bold">Alprazolam tablets are a federal controlled substance (C-IV) because it contains alprazolam that can be abused or lead to dependence. </content>Keep alprazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.</item><item>It is not known if alprazolam tablets are safe and effective in children. </item><item>Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets. </item><item>It is not known if alprazolam tablets are safe and effective when used to treat anxiety disorder for longer than 4 months. </item><item>It is not known if alprazolam tablets are safe and effective when used to treat panic disorder for longer than 10 weeks. </item></list></item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Do not take alprazolam tablets if: </content> <list listType="unordered" styleCode="disc"><item>you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam tablets. See the end of this Medication Guide for a complete list of ingredients in alprazolam tablets. </item><item>you are taking antifungal medicines including ketoconazole and itraconazole </item></list></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">Before you take alprazolam tablets, tell your healthcare provider about all of your medical conditions, including if you: </content> <list listType="unordered" styleCode="disc"><item>have or have had depression, mood problems, or suicidal thoughts or behavior </item><item>have liver or kidney problems </item><item>have lung disease or breathing problems </item><item>are pregnant or plan to become pregnant.

al conditions, including if you: </content> <list listType="unordered" styleCode="disc"><item>have or have had depression, mood problems, or suicidal thoughts or behavior </item><item>have liver or kidney problems </item><item>have lung disease or breathing problems </item><item>are pregnant or plan to become pregnant. Alprazolam tablets may harm your unborn baby. You and your healthcare provider should decide if you should take alprazolam tablets while you are pregnant. </item><item>are breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take alprazolam tablets. You should not breastfeed while taking alprazolam tablets. </item></list><content styleCode="bold">Tell your healthcare provider about all the medicines you take</content>, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking alprazolam tablets with certain other medicines can cause side effects or affect how well alprazolam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="bottom"><content styleCode="bold">How should I take alprazolam tablets? </content> <list listType="unordered" styleCode="disc"><item>See &#x201C;What is the most important information I should know about alprazolam tablets?&#x201D;<content styleCode="bold"/></item><item>Take alprazolam tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much alprazolam tablets to take and when to take it. </item><item>If you take too much alprazolam, call your healthcare provider or go to the nearest hospital emergency room right away. </item></list> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">What are the possible side effects of alprazolam tablets? </content> <content styleCode="bold">Alprazolam tablets may cause serious side effects, including: </content> <list listType="unordered" styleCode="disc"><item>See &#x201C;What is the most important information I should know about alprazolam tablets?&#x201D;<content styleCode="bold"/></item><item><content styleCode="bold">Seizures. </content>Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus). </item><item><content styleCode="bold">Mania. </content>Alprazolam tablets may cause an increase in activity and talking (hypomania and mania) in people who have depression. <list listType="unordered" styleCode="disc"><item><content styleCode="bold">Alprazolam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. </content>Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affect you. </item><item><content styleCode="bold">Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider.</content> When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse. </item></list></item></list><content styleCode="bold">The most common side effects of alprazolam tablets include: </content> <list listType="unordered" styleCode="disc"><item>problems with coordination </item><item>hypotension </item><item>trouble saying words clearly (dysarthria) </item><item>changes in sex drive (libido) </item></list>These are not all the possible side effects of alprazolam tablets. Call your doctor for medical advice about side effects.

unordered" styleCode="disc"><item>problems with coordination </item><item>hypotension </item><item>trouble saying words clearly (dysarthria) </item><item>changes in sex drive (libido) </item></list>These are not all the possible side effects of alprazolam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">How should I store </content><content styleCode="bold">alprazolam tablets?</content><content styleCode="bold"/> <list listType="unordered" styleCode="disc"><item>Store alprazolam tablets at room temperature between 68&#xB0;F to 77&#xB0;F (20&#xB0;C to 25&#xB0;C) </item><item><content styleCode="bold">Keep alprazolam tablets and all medicines out of the reach of children.</content></item></list> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">General information about the safe and effective use of alprazolam tablets.</content> <list listType="unordered" styleCode="disc"><item>Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. </item><item>Do not use alprazolam tablets for a condition for which it was not prescribed. </item><item>Do not give alprazolam tablets to other people, even if they have the same symptoms that you have. It may harm them.</item><item>You can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals. </item></list></td></tr><tr><td styleCode="Lrule Rrule" align="justify" valign="top"><content styleCode="bold">What are the ingredients in alprazolam tablets?</content> <content styleCode="bold">Active ingredient: </content>alprazolam <content styleCode="bold">Inactive ingredients: </content>colloidal silicon dioxide, corn starch, docusate sodium 85% with sodium benzoate 15%, lactose monohydrate, magnesium stearate, and microcrystalline cellulose. In addition, the 0.5 mg tablet contains FD&amp;C Yellow # 6 aluminum lake and the 1 mg tablet contains FD&amp;C Blue No. 2 lake. <content styleCode="bold">Dispense with Medication Guide available at: <content styleCode="underline">www.aurobindousa.com/medication-guides</content></content> <content styleCode="bold"/> For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876. Distributed by: <content styleCode="bold">Aurobindo Pharma USA, Inc.</content> 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: <content styleCode="bold">Aurobindo Pharma Limited </content> Hyderabad-500 038, India </td></tr></tbody></table>