These highlights do not include all the information needed to use XANAX XR safely and effectively. See full prescribing information for XANAX XR. XANAX® XR (alprazolam) extended release tablets, for oral use, CIV Initial U.S. Approval: 2003

These highlights do not include all the information needed to use XANAX XR safely and effectively. See full prescribing information for XANAX XR. XANAX® XR (alprazolam) extended release tablets, for oral use, CIV Initial U.S. Approval: 2003

Drug Labeling and Warnings

Drug Details

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XANAX  XR- alprazolam tablet, extended release 
Pharmacia and Upjohn Company LLC

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use XANAX XR safely and effectively. See full prescribing information for XANAX XR.

XANAX® XR (alprazolam) extended release tablets, for oral use, CIV
Initial U.S. Approval: 2003

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

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 of these drugs 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)

INDICATIONS AND USAGE

XANAX XR is a benzodiazepine indicated for the treatment of panic disorder, with or without agoraphobia (1)

DOSAGE AND ADMINISTRATION

  • Total daily dose ranges between 3 mg to 6 mg per day taken orally, taken intact and not to be chewed, crushed, or broken. (2.1, 2.2)
  • Initiate with a dose of 0.5 mg to 1 mg once daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Occasional patients required as much as 10 mg per day (2.4, 2.5)

DOSAGE FORMS AND STRENGTHS

Tablets: 0.5 mg, 1mg, 2 mg, and 3 mg (3)

CONTRAINDICATIONS

  • Known sensitivity to alprazolam or other benzodiazepines. (4)
  • Concomitant use with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A). (4)

WARNINGS AND PRECAUTIONS

  • Dependence and Withdrawal Reactions, Including Seizures: physical dependence and withdrawal symptoms, including seizures, multiple seizures and status epilepticus, have been reported. Reduce dose gradually. (5.2)
  • Effects on Driving and Operating Machinery: caution patients against engaging in hazardous activities requiring complete mental alertness such as operating machinery or driving a motor vehicle, and the concomitant use of alcohol and other central nervouse system (CNS) depressant drugs. (5.3)
  • Risk of Fetal Harm: benzodiazepines can cause fetal harm when administered to a pregnant woman. (5.4)
  • Risk of Suicide in Patients with Depression: usual precautions with respect to administration of psychotropic medications and size of the prescription should be taken for severe depression or for those in whom there is reason to expect concealed suicidal ideation or plans. (5.6)

ADVERSE REACTIONS

The most commonly observed adverse events in panic disorder patients treated with XANAX XR (incidence of ≥ 5% and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, and libido decreased (6.1).


To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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. (7.2)
  • Use with Imipramine and Desipramine: increased plasma concentrations of imipramine and desipramine. (7.2)
  • Use with CYP3A Inhibitors: increase the risk of side effects of alprazolam. (4, 5.5, 7.2)
  • Use with CYP3A Inducers: increase the risk of reduced efficacy of alprazolam. (7.2)

USE IN SPECIFIC POPULATIONS

  • Lactation: benzodiazepines are known to be excreted in human milk. Therefore, use of XANAX XR in nursing mothers is not recommended. (8.2)
  • Pediatric Use: safety and effectiveness of alprazolam in individuals below 18 years of age have not been established.

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 6/2018

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Administration Instructions

2.2 Recommended Dose

2.3 Dosing in Special Populations

2.4 Dose Titration

2.5 Dose Maintenance

2.6 Dose Reduction

2.7 Switching from XANAX (immediate-release) Tablets to XANAX XR (extended-release) Tablets

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Risks from Concomitant Use with Opioids

5.2 Dependence and Withdrawal Reactions, Including Seizures

5.3 Effects on Driving and Operating Machinery

5.4 Risk of Fetal Harm

5.5 Alprazolam Interaction With Drugs That Inhibit Metabolism Via Cytochrome P450 3A (CYP3A)

5.6 Risk of Suicide in Patients with Depression

5.7 Mania

5.8 Uricosuric Effect

5.9 Use in Patients with Concomitant Illness

5.10 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Drugs Having Pharmacodynamic Interactions with Alprazolam

7.2 Drugs Having Pharmacokinetic Interactions with XANAX XR

7.3 Drugs Having No Clinically Important Interactions with XANAX XR

7.4 Drug/Laboratory Test Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.3 Dependence

10 OVERDOSAGE

10.1 Clinical Experience

10.2 Management of Overdose

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

  • * Sections or subsections omitted from the full prescribing information are not listed.
  • FULL PRESCRIBING INFORMATION

    WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

    Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death [see Warnings and Precautions (5.1), Drug Interactions (7.1)].

    • Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.
    • Limit dosages and durations to the minimum required.
    • Follow patients for signs and symptoms of respiratory depression and sedation.

    1 INDICATIONS AND USAGE

    XANAX XR tablets are indicated for the treatment of panic disorder, with or without agoraphobia.

    This claim is supported on the basis of 2 positive studies with XANAX XR conducted in patients whose diagnoses corresponded closely to the Diagnostic and Statistical Manual (DSM-III-R/IV) criteria for panic disorder [see Clinical Studies (14)].

    Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes.

    The longer-term efficacy of XANAX XR has not been systematically evaluated. Thus, the physician who elects to use this drug for periods longer than 8 weeks should periodically reassess the usefulness of the drug for the individual patient.

    2 DOSAGE AND ADMINISTRATION

    2.1 Administration Instructions

    XANAX XR tablets may be administered once daily, preferably in the morning. The tablets should be taken intact; they should not be chewed, crushed, or broken.

    2.2 Recommended Dose

    The suggested total daily dose ranges between 3 mg to 6 mg per day. Dosage should be individualized for maximum beneficial effect. While the suggested total daily dosages given will meet the needs of most patients, there will be some patients who require doses greater than 6 mg per day. In such cases, dosage should be increased cautiously to avoid adverse effects.

    2.3 Dosing in Special Populations

    In elderly patients, in patients with advanced liver disease, or in patients with debilitating disease, the usual starting dose of XANAX XR is 0.5 mg once daily. This may be gradually increased if needed and tolerated [see Dosage and Administration (2.4)]. The elderly may be especially sensitive to the effects of benzodiazepines.

    2.4 Dose Titration

    Treatment with XANAX XR may be initiated with a dose of 0.5 mg to 1 mg once daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels may be advisable to allow full expression of the pharmacodynamic effect of XANAX XR.

    Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response (ie, a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.

    2.5 Dose Maintenance

    In controlled trials conducted to establish the efficacy of XANAX XR tablets in panic disorder, doses in the range of 1 mg to 10 mg per day were used. Most patients showed efficacy in the dose range of 3 mg to 6 mg per day. Occasional patients required as much as 10 mg/day to achieve a successful response.

    The necessary duration of treatment for panic disorder patients responding to XANAX XR is unknown. However, periodic reassessment is advised. After a period of extended freedom from 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.

    2.6 Dose Reduction

    Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided [see Warnings and Precautions (5.2), Drug Abuse and Dependence (9.3)]

    In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction.

    In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be attempted. In a controlled postmarketing discontinuation study of panic disorder patients which compared this 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. It is suggested that the dose be reduced by no more than 0.5 mg every 3 days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

    2.7 Switching from XANAX (immediate-release) Tablets to XANAX XR (extended-release) Tablets

    Patients who are currently being treated with divided doses of XANAX (immediate-release) tablets, for example 3 to 4 times a day, may be switched to XANAX XR tablets at the same total daily dose taken once daily. If the therapeutic response after switching is inadequate, the dosage may be titrated as outlined above.

    3 DOSAGE FORMS AND STRENGTHS

    XANAX XR (extended-release) tablets are available as:

    • 0.5 mg: white, pentagonal shaped tablets debossed with an "X" on one side and "0.5" on the other side
    • 1 mg: yellow, square shaped tablets debossed with an "X" on one side and "1" on the other side
    • 2 mg: blue, round shaped tablets debossed with an "X" on one side and "2" on the other side
    • 3 mg: green, triangular shaped tablets debossed with an "X" on one side and "3" on the other side

    4 CONTRAINDICATIONS

    XANAX XR tablets are contraindicated in the following conditions:

    • Known sensitivity to alprazolam or other benzodiazepines.
    • Concomitant use with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) [see Warnings and Precautions (5.5), Drug Interactions (7.2)]

    5 WARNINGS AND PRECAUTIONS

    5.1 Risks from Concomitant Use with Opioids

    Concomitant use of benzodiazepines, including XANAX XR, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

    Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe XANAX XR 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 XR 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 XR, 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 XR 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 Dependence and Withdrawal Reactions, Including Seizures

    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 per 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 per day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients who received XANAX tablets, 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 tablets greater than 4 mg per day had more difficulty tapering to zero dose than those treated with less than 4 mg per day.

    Relapse or return of illness was defined as a return of symptoms characteristic of panic disorder (primarily panic attacks) to levels approximately equal to those seen at baseline before active treatment was initiated. Rebound refers to a return of symptoms of panic disorder to a level substantially greater in frequency, or more severe in intensity than seen at baseline. Withdrawal symptoms were identified as those which were generally not characteristic of panic disorder and which occurred for the first time more frequently during discontinuation than at baseline.

    The rate of relapse, rebound, and withdrawal in patients with panic disorder who received XANAX XR tablets has not been systematically studied. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder who received XANAX tablets showed a high rate of rebound and withdrawal symptoms compared to placebo-treated patients.

    In a controlled clinical trial in which 63 patients were randomized to XANAX tablets 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.

    In 2 controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 71% to 93% of patients treated with XANAX tablets tapered completely off therapy compared to 89% to 96% of placebo-treated patients. In a controlled postmarketing discontinuation study of panic disorder patients treated with XANAX tablets, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose.

    Seizures were reported for 3 patients in panic disorder clinical trials with XANAX XR. In 2 cases, the patients had completed 6 weeks of treatment with XANAX XR 6 mg per day before experiencing a single seizure. In one case, the patient abruptly discontinued XANAX XR, and in both cases, alcohol intake was implicated. The third case involved multiple seizures after the patient completed treatment with XANAX XR 4 mg per day and missed taking the medication on the first day of taper. All 3 patients recovered without sequelae.

    Seizures have also been observed in association with dose reduction or discontinuation of XANAX tablets, the immediate release form of alprazolam. Seizures attributable to XANAX were seen after drug discontinuance or dose reduction in 8 of 1980 patients with panic disorder or in patients participating in clinical trials where doses of XANAX greater than 4 mg per day for over 3 months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2 mg to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In 1 instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every 3 days from 6 mg daily. In 2 other instances, the relationship to taper is indeterminate; in both of these cases the patients had been receiving doses of 3 mg daily prior to seizure. The duration of use in the above 8 cases ranged from 4 to 22 weeks. There have been occasional voluntary reports of patients developing seizures while apparently tapering gradually from XANAX. The risk of seizure seems to be greatest 24 to 72 hours after discontinuation for recommended tapering and discontinuation schedule [see Dosage and Administration (2.6)].

    Status Epilepticus and its Treatment

    The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of XANAX tablets. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well.

    Interdose Symptoms

    Early morning anxiety and emergence of anxiety symptoms between doses of XANAX tablets 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 [see Dosage and Administration (2.5)].

    Risk of Dose Reduction

    Withdrawal reactions may occur when dosage reduction occurs for any reason. This includes purposeful tapering, but also inadvertent reduction of dose (eg, the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of XANAX XR should be reduced or discontinued gradually [see Dosage and Administration (2.6)].

    5.3 Effects on Driving and Operating Machinery

    Because of its central nervous system (CNS) depressant effects, patients receiving XANAX XR 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 simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with XANAX XR.

    5.4 Risk of Fetal Harm

    Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If alprazolam is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Because of experience with other members of the benzodiazepine class, alprazolam is assumed to be capable of causing an increased risk of congenital abnormalities when administered to a pregnant woman during the first trimester. Because use of these drugs is rarely a matter of urgency, their use during the first trimester should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug [see Use in Specific Populations (8.1)].

    5.5 Alprazolam Interaction With Drugs That Inhibit Metabolism Via Cytochrome P450 3A (CYP3A)

    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. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, alprazolam should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with alprazolam has been quantified with clinical data; for other drugs, interactions are predicted from in vitro data and/or experience with similar drugs in the same pharmacologic class.

    The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP3A.

    Potent CYP3A Inhibitors

    Azole antifungal agents: ketoconazole and itraconazole are potent CYP3A inhibitors and have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.66 fold, respectively. The coadministration of alprazolam with these agents is not recommended. Other azole-type antifungal agents should also be considered potent CYP3A inhibitors and the coadministration of alprazolam with them is not recommended [see Contraindications (4)].

    Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine and cimetidine [see Drug Interaction (7.2), Clinical Pharmacology (12.3)]. Caution and consideration of appropriate alprazolam dose reduction are recommended during co-administration with these drugs.

    HIV Protease Inhibitors

    Interactions involving human immunodeficiency virus (HIV) protease inhibitors (eg, ritonavir) and alprazolam are complex and time dependent. Low doses of ritonavir resulted in a large impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical effects. However, upon extended exposure to ritonavir, CYP3A induction offset this inhibition [see Drug Interaction (7.2), Clinical Pharmacology (12.3)]. This interaction will require a dose-adjustment or discontinuation of alprazolam.

    Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed in the Drug Interactions section [see Drug Interactions (7.2), Clinical Pharmacology (12.3)].

    5.6 Risk of Suicide in Patients with Depression

    As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients.

    5.7 Mania

    Episodes of hypomania and mania have been reported in association with the use of XANAX Tablets in patients with depression.

    5.8 Uricosuric Effect

    Alprazolam has a weak uricosuric effect. Although other medications with weak uricosuric effect have been reported to cause acute renal failure, there have been no reported instances of acute renal failure attributable to therapy with alprazolam.

    5.9 Use in Patients with Concomitant Illness

    It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients [see Dosage and Administration (2.3)]. The usual precautions in treating patients with impaired renal, hepatic, or pulmonary function should be observed. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with XANAX tablets. A decreased systemic alprazolam elimination rate (eg, increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving XANAX Tablets [see Clinical Pharmacology (12.3)]

    5.10 Laboratory Tests

    Laboratory tests are not ordinarily required in otherwise healthy patients. However, when treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable in keeping with good medical practice.

    6 ADVERSE REACTIONS

    The following clinically significant adverse reactions are described elsewhere in the labeling:

    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 information included in the subsection on Adverse Events Observed in Short-Term, Placebo-Controlled Trials with XANAX XR Tablets is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.

    Adverse event reports were elicited either by general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology (version 4.0) was used to classify reported adverse events.

    Adverse Events Observed in Short-Term, Placebo-Controlled Trials of XANAX XR

    Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

    Approximately 17% of the 531 patients who received XANAX XR in placebo-controlled clinical trials for panic disorder had at least 1 adverse event that led to discontinuation compared to 8% of 349 placebo-treated patients. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the patients treated with XANAX XR at a rate at least twice that of placebo) are shown in Table 1.

    Table 1: Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials
    System Organ Class/Adverse EventPercentage of Patients Discontinuing Due to Adverse Events
    XANAX XR
    (n=531)
    Placebo
    (n=349)
    Nervous system disorders
      Sedation7.50.6
      Somnolence3.20.3
      Dysarthria2.10
      Coordination abnormal1.90.3
      Memory impairment1.50.3
    General disorders/administration site conditions
      Fatigue1.70.6
    Psychiatric disorders
      Depression2.51.2

    Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with XANAX XR

    The prescriber should be aware that adverse event incidence cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators. The cited values, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

    The following table shows the incidence of treatment-emergent adverse events that occurred during 6- to 8-week placebo-controlled trials in 1% or more of patients treated with XANAX XR where the incidence in patients treated with XANAX XR was greater than the incidence in placebo-treated patients. The most commonly observed adverse events in panic disorder patients treated with XANAX XR (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased (see Table 2).

    Table 2: Treatment-Emergent Adverse Events: Incidence in Short-Term, Placebo-Controlled Clinical Trials with XANAX XR
    System Organ Class/Adverse EventPercentage of Patients Reporting Adverse Event
    XANAX XR
    (n=531)
    Placebo
    (n=349)
    Nervous system disorders
      Sedation45.222.6
      Somnolence23.06.0
      Memory impairment15.46.9
      Dysarthria10.92.6
      Coordination abnormal9.40.9
      Mental impairment7.25.7
      Ataxia7.23.2
      Disturbance in attention3.20.6
      Balance impaired3.20.6
      Paresthesia2.41.7
      Dyskinesia1.71.4
      Hypoesthesia1.30.3
      Hypersomnia1.30
    General disorders/administration site conditions
      Fatigue13.99.2
      Lethargy1.70.6
    Infections and infestations
      Influenza2.42.3
      Upper respiratory tract infections1.91.7
    Psychiatric disorders
      Depression12.19.2
      Libido decreased6.02.3
      Disorientation1.50
      Confusion1.50.9
      Depressed mood1.30.3
      Anxiety1.10.6
    Metabolism and nutrition disorders
      Appetite decreased7.37.2
      Appetite increased7.06.0
      Anorexia1.50
    Gastrointestinal disorders
      Dry mouth10.29.7
      Constipation8.14.3
      Nausea6.03.2
      Pharyngolaryngeal pain3.22.6
    Investigations
      Weight increased5.14.3
      Weight decreased4.33.7
    Injury, poisoning, and procedural complications
      Road traffic accident1.50
    Reproductive system and breast disorders
      Dysmenorrhea3.62.9
      Sexual dysfunction2.41.1
      Premenstrual syndrome1.70.6
    Musculoskeletal and connective tissue disorders
      Arthralgia2.40.6
      Myalgia1.51.1
      Pain in limb1.10.3
    Vascular disorders
      Hot flushes1.51.4
    Respiratory, thoracic, and mediastinal disorders
      Dyspnea1.50.3
      Rhinitis allergic1.10.6
    Skin and subcutaneous tissue disorders
      Pruritis1.10.9

    Other Adverse Events Observed During the Premarketing Evaluation of XANAX XR Tablets

    Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported by 531 patients with panic disorder treated with XANAX XR. All potentially important reported events are included except those already listed in the above table or elsewhere in labeling, those events for which a drug cause was remote, those event terms that were so general as to be uninformative, and those events that occurred at rates similar to background rates in the general population. It is important to emphasize that, although the events reported occurred during treatment with XANAX XR, they were not necessarily caused by the drug. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least l/l00 patients; infrequent adverse events are those occurring in less than l/100 patients but at least l/1000 patients; rare events are those occurring in fewer than l/1000 patients.

    Cardiac disorders: Frequent: palpitation; Infrequent: sinus tachycardia

    Ear and Labyrinth disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain

    Eye disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia

    Gastrointestinal disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain; Infrequent: dysphagia, salivary hypersecretion

    General disorders and administration site conditions: Frequent: malaise, weakness, chest pains; Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia, feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of legs, rigors

    Musculoskeletal and connective tissue disorders: Frequent: back pain, muscle cramps, muscle twitching

    Nervous system disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia, clumsiness, syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking, stupor

    Psychiatric system disorders: Frequent: irritability, insomnia, nervousness, derealization, libido increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal dreams, apathy, aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination, homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation

    Renal and urinary disorders: Frequent: difficulty in micturition; Infrequent: urinary frequency, urinary incontinence

    Respiratory, thoracic, and mediastinal disorders: Frequent: nasal congestion, hyperventilation; Infrequent: choking sensation, epistaxis, rhinorrhea

    Skin and subcutaneous tissue disorders: Frequent: sweating increased; Infrequent: clamminess, rash, urticaria

    Vascular disorders: Infrequent: hypotension

    The categories of adverse events reported in the clinical development program for XANAX tablets in the treatment of panic disorder differ somewhat from those reported for XANAX XR tablets because the clinical trials with XANAX tablets and XANAX XR tablets used different standard medical nomenclature for reporting the adverse events. Nevertheless, the types of adverse events reported in the clinical trials with XANAX tablets were generally the same as those reported in the clinical trials with XANAX XR tablets.

    Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More Among Patients Treated with XANAX XR

    Table 3 shows the incidence of discontinuation-emergent adverse events that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with XANAX XR where the incidence in patients treated with XANAX XR was 2 times greater than the incidence in placebo-treated patients.

    Table 3: Discontinuation-Emergent Symptoms: Incidence in Short-Term, Placebo-Controlled Trials with XANAX XR
    System Organ Class/Adverse EventPercentage of Patients Reporting Adverse Event
    XANAX XR
    (n=422)
    Placebo
    (n=261)
    Nervous system disorders
      Tremor28.210.7
      Headache26.512.6
      Hypoesthesia7.82.3
      Paraesthesia7.12.7
    Psychiatric disorders
      Insomnia24.29.6
      Nervousness21.88.8
      Depression10.95.0
      Derealization8.03.8
      Anxiety7.82.7
      Depersonalization5.71.9
    Gastrointestinal disorders
      Diarrhea12.13.1
    Respiratory, thoracic and mediastinal disorders
      Hyperventilation8.52.7
    Metabolism and nutrition disorders
      Appetite decreased9.53.8
    Musculosketal and connective tissue disorders
      Muscle twitching7.42.7
    Vascular disorders
      Hot flushes5.92.7

    There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam [see Warning and Precuations (5.2)].

    To discontinue treatment in patients taking XANAX XR tablets, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of XANAX XR tablets be decreased by no more than 0.5 mg every 3 days [see Dosage and Administration (2.6)]. Some patients may benefit from an even slower dosage reduction. In a controlled postmarketing discontinuation study of panic disorder patients which compared this 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.

    As with all benzodiazepines, 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. 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 post approval use of XANAX XR. 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.

    Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, jaundice, hepatic failure, Stevens-Johnson syndrome, photosensitivity reaction, angioedema, peripheral edema, menstruation irregular, hyperprolactinemia, gynecomastia, and galactorrhea

    7 DRUG INTERACTIONS

    7.1 Drugs Having Pharmacodynamic Interactions with Alprazolam

    Opioids
    Clinical impactThe 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 (GABAA) 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.
    InterventionLimit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions (5.1)].
    ExamplesMorphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol.
    CNS Depressants
    Clinical impactThe benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants.
    InterventionCareful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. Limit dosage and duration during concomitant use with CNS depressants.
    ExamplesPsychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression.

    7.2 Drugs Having Pharmacokinetic Interactions with XANAX XR

    Strong Inhibitors of CYP3A
    Clinical impactConcomitant use of XANAX with strong CYP3A inhibitors may have a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of side effects of alprazolam [see Clinical Pharmacology (12.3)].
    InterventionAvoid concomitant use of alprazolam with a strong CYP3A4 inhibitor [see Contraindications (4), Warnings and Precautions (5.5)].
    ExamplesKetoconazole, itraconazole, and other azole-type antifungal agents.
    Other Inhibitors of CYP3A May Require Dose Reduction for XANAX
    Clinical impactConcomitant use of XANAX with these CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of side effects of alprazolam [see Clinical Pharmacology (12.3)].
    InterventionUse with caution and consider appropriate dose reduction of alprazolam when alprazolam is coadministered with the following CYP3A inhibitors [see Warnings and Precautions (5.5)].
    ExamplesNefazodone, fluvoxamine, cimetidine, HIV protease inhibitors
    Other Inhibitors of CYP3A Require Precaution
    Clinical impactConcomitant use of XANAX with these drugs may increase the concentration of alprazolam, resulting in the potential risk of side effects of alprazolam [see Clinical Pharmacology (12.3)].
    InterventionUse with caution during concomitant use with these drugs
    ExamplesFluoxetine, propoxyphene, oral contraceptives, diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, grapefruit juice, sertraline, paroxetine. ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine.
    Digoxin
    Clinical impactIncreased digoxin concentrations have been reported when alprazolam was given, especially in elderly (>65 years of age).
    InterventionMonitor for signs and symptoms related to digoxin toxicity.
    ExampleDigoxin
    Imipramine and Desipramine
    Clinical impactIncreased steady state plasma concentrations of imipramine and desipramine have been reported during concomitant administration of XANAX in doses up to 4 mg per day [see Clinical Pharmacology (12.3)]. The clinical significance of these changes is unknown.
    InterventionCaution is recommended during coadministration with alprazolam.
    ExamplesImipramine, desipramine
    CYP3A Inducers
    Clinical impactConcomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3)].
    InterventionCaution is recommended during coadministration with alprazolam.
    ExampleCarbamazepine

    7.3 Drugs Having No Clinically Important Interactions with XANAX XR

    The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.

    7.4 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.

    8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Risk Summary

    Based on animal data, alprazolam may cause fetal harm (see Data). In reproductive toxicity studies, there were no effects on embryo-fetal development following oral administration of alprazolam during organogenesis in rats and rabbits at 9.5 and 19 times the maximum human dose, based on body surface area, respectively. Animal studies with benzodiazepines have shown potential cognitive and behavioral effects following exposure during third trimester of pregnancy of unknown relevance to human use [see Nonclinical Toxicology (13.2)].

    The background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

    Clinical Considerations

    Fetal/Neonatal adverse reactions

    It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.

    Labor or Delivery

    Alprazolam has no established use in labor or delivery.

    Data

    Animal Data

    In oral teratology studies in the rat, alprazolam was administered during the period of organogenesis at doses up to 100 mg/kg/day. At 10 mg/kg/day (9.5 times the maximum human dose, based on body surface area), there was no teratogenicity or embryo-fetal toxicity. Embryo-fetal toxicity (post-implantation loss and decreased fetal weight) and fetal skeletal malformations (vertebral defects) were observed at ≥30 mg/kg/day (29 times the maximum human dose, based on body surface area) in the presence of maternal toxicity. In rabbit teratology studies, alprazolam was orally administered during organogenesis at doses up to 30 mg/kg/day. There was no teratogenicity or embryo-fetal toxicity at 10 mg/kg/day (19 times the maximum human dose, based on body surface area). Fetal skeletal malformations (rib and vertebral defects) and embryo-fetal toxicity (post-implantation loss) was observed at 30 mg/kg/day (57 times the maximum human dose, based on body surface area) in the presence of maternal toxicity.

    Animal studies with benzodiazepines have shown potential cognitive and behavioral effects following exposure during third trimester of pregnancy of unknown relevance to human use [see Nonclinical Toxicology (13.2)].

    8.2 Lactation

    Risk Summary

    As with other benzodiazepines, alprazolam is known to be excreted in human milk in low quantities. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use alprazolam.

    Data

    In a published study, the pharmacokinetics of alprazolam and its two hydroxylated metabolites were evaluated in 8 breast-feeding healthy women (6 to 28 weeks postpartum) following a single 0.5 mg oral dose of alprazolam. As with other benzodiazepines, alprazolam was excreted in human milk with peak concentrations attained around 60 minutes in both serum and breast milk after ingestion. The estimated relative infant dose via breast-feeding was about 3%.

    8.4 Pediatric Use

    Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established.

    8.5 Geriatric Use

    The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation which may be a particular problem in elderly or debilitated patients. [see Clinical Pharmacology (12.3), Dosage and Administration (2.3)].

    9 DRUG ABUSE AND DEPENDENCE

    9.1 Controlled Substance

    Alprazolam is a controlled substance under the Controlled Substance Act by the Drug Enforcement Administration and XANAX XR Tablets have been assigned to Schedule IV

    9.3 Dependence

    Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including alprazolam. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long-term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of alprazolam sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications.

    While it is difficult to distinguish withdrawal and recurrence for certain patients, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation, and will decrease with time. In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late, and they will persist.

    While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam at doses within the recommended range for the treatment of anxiety (eg, 0.75 mg to 4 mg per day). Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal seizures may be increased at doses above 4 mg per day [see Warnings and Precautions (5.2)].

    Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly discontinued from any CNS depressant agent, including alprazolam. It is recommended that all patients on alprazolam who require a dosage reduction be gradually tapered under close supervision [see Warnings and Precautions (5.2), Dosage and Administration (2.6)].

    Psychological dependence is a risk with all benzodiazepines, including alprazolam. The risk of psychological dependence may also be increased at doses greater than 4 mg per day and with longer term use, and this risk is further increased in patients with a history of alcohol or drug abuse. Some patients have experienced considerable difficulty in tapering and discontinuing from alprazolam, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving alprazolam. As with all anxiolytics, repeat prescriptions should be limited to those who are under medical supervision.

    10 OVERDOSAGE

    10.1 Clinical Experience

    Overdosage reports with XANAX Tablets are limited. 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

    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. If hypotension occurs, it may be combated by the use of vasopressors. Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.

    Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used 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 including Contraindications, Warnings and Precautions should be consulted prior to use.

    11 DESCRIPTION

    XANAX XR tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of CNS-active compounds.

    The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine. The molecular formula is C17H13ClN4 which corresponds to a molecular weight of 308.76.

    The structural formula is represented below:

    Chemical Structure

    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 XR extended-release tablet, for oral administration, contains 0.5 mg, 1 mg, 2 mg, or 3 mg of alprazolam. The inactive ingredients are lactose, magnesium stearate, colloidal silicon dioxide, and hypromellose. In addition, the 1 mg and 3 mg tablets contain D & C yellow No. 10 and the 2 mg and 3 mg tablets contain FD&C blue No. 2.

    12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereospecific receptors at several sites within the CNS. Their exact mechanism of action is unknown.

    12.2 Pharmacodynamics

    Clinically, all benzodiazepines cause a dose-related CNS depressant activity varying from mild impairment of task performance to hypnosis.

    12.3 Pharmacokinetics

    Absorption

    Following oral administration of XANAX (immediate-release) Tablets, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportional to the dose given; over the dose range of 0.5 mg to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.

    The mean absolute bioavailability of alprazolam from XANAX XR tablets is approximately 90%, and the relative bioavailability compared to XANAX tablets is 100%. The bioavailability and pharmacokinetics of alprazolam following administration of XANAX XR Tablets are similar to that for XANAX tablets, with the exception of a slower rate of absorption. The slower absorption rate results in a relatively constant concentration that is maintained between 5 and 11 hours after the dosing. The pharmacokinetics of alprazolam and 2 of its major active metabolites (4-hydroxyalprazolam and α-hydroxyalprazolam) are linear, and concentrations are proportional up to the recommended maximum daily dose of 10 mg given once daily. Multiple dose studies indicate that the metabolism and elimination of alprazolam are similar for the immediate-release and the extended-release products.

    Food has a significant influence on the bioavailability of XANAX XR Tablets. A high-fat meal given up to 2 hours before dosing with XANAX XR Tablets increased the mean Cmax by about 25%. The effect of this meal on Tmax depended on the timing of the meal, with a reduction in Tmax by about 1/3 for subjects eating immediately before dosing and an increase in Tmax by about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure (AUC) and elimination half-life (t½) were not affected by eating.

    There were significant differences in absorption rate for the XANAX XR Tablet, depending on the time of day administered, with the Cmax increased by 30% and the Tmax decreased by an hour following dosing at night, compared to morning dosing.

    Distribution

    The apparent volume of distribution of alprazolam is similar for XANAX XR and XANAX tablets. In vitro, alprazolam is bound (80%) to human serum protein. Serum albumin accounts for the majority of the binding.

    Elimination

    Metabolism

    Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to 2 major metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and α-hydroxyalprazolam) were similar for XANAX and XANAX XR tablets, indicating that the metabolism of alprazolam is not affected by absorption rate. The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged alprazolam concentration after both XANAX XR and XANAX Tablets were always less than 10% and 4%, respectively. 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. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.

    Excretion

    Alprazolam and its metabolites are excreted primarily in the urine. The mean plasma elimination half-life of alprazolam following administration of XANAX XR tablet ranges from 10.7 to 15.8 hours in healthy adults.

    Specific Populations

    While pharmacokinetic studies have not been performed in special populations with XANAX XR tablets, the factors (such as age, gender, hepatic or renal impairment) that would affect the pharmacokinetics of alprazolam after the administration of XANAX tablets would not be expected to be different with the administration of XANAX XR tablets.

    Changes in the absorption, distribution, metabolism, and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function, and impaired renal function.

    Age: Geriatric Population

    Changes in the pharmacokinetics of alprazolam have been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0 to 26.9 hours, n=16) compared to 11.0 hours (range: 6.3 to 15.8 hours, n=16) in healthy adult subjects.

    Age: Pediatric Population

    The pharmacokinetics of alprazolam after administration of the XANAX XR tablet in pediatric patients have not been studied.

    Sex

    Gender has no effect on the pharmacokinetics of alprazolam.

    Race/Ethnicity

    Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians.

    Hepatic Impairment

    In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean: 11.4 hours, n=17) in healthy subjects.

    Cigarette Smoking

    Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.

    Obesity

    In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean: 21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean: 10.6 hours, n=12) in healthy subjects.

    Drug Interaction Studies

    Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.

    Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. 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)].

    Nefazodone

    Coadministration of nefazodone increased alprazolam concentration two-fold.

    Fluvoxamine

    Coadministration of fluvoxamine approximately doubled the maximum plasma concentration of alprazolam, decreased clearance by 49%, increased half-life by 71%, and decreased measured psychomotor performance.

    Cimetidine

    Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased half-life by 16%.

    Fluoxetine

    Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.

    Propoxyphene

    Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%.

    Oral Contraceptives

    Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%.

    Other Drugs

    Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state doses of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine.

    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 tablets in doses up to 4 mg per day.

    Carbamazepine

    CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo.

    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 t½ was shortened (from 17.1±4.9 to 7.7±1.7 h) 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 mg to 1200 mg per day); the effect at usual carbamazepine doses is unknown.

    HIV Protease Inhibitors

    Interactions involving HIV protease inhibitors (eg, ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) reduced alprazolam clearance to 41% of control values, prolonged its elimination half-life (mean values, 30 hours versus 13 hours) and enhanced clinical effects. However, upon extended exposure to ritonavir (500 mg, twice daily), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir [see Warnings and Precautions (5.5)].

    Warfarin

    The ability of alprazolam to induce or inhibit human hepatic enzyme systems has not been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.

    13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Carcinogenesis

    No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg per day (29 times the maximum recommended daily human dose of 10 mg per day based on body surface area) and in mice at doses up to 10 mg/kg per day (4.8 times the maximum recommended daily human dose based on body surface area).

    Mutagenesis

    Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 95 times the maximum recommended daily human dose of 10 mg per day based on body surface area. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.

    Impairment of Fertility

    Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg per day, which is 4.7 times the maximum recommended daily human dose of 10 mg per day based on body surface area.

    13.2 Animal Toxicology and/or Pharmacology

    When rats were treated with alprazolam at 3 mg/kg, 10 mg/kg, and 30 mg/kg per day (3 to 29 times the maximum recommended human dose) orally 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.

    Effect of anesthetic and sedative drugs

    Nonclinical research has shown that administration of anesthetic and sedation drugs that block N-methyl-D-aspartate (NMDA) receptors and/or potentiate gamma-aminobutyric acid (GABA) activity can increase neuronal cell death in the brain and result in long term deficits in cognition and behavior of juvenile animals when administered during the period of peak brain development. Based on comparisons across nonclinical species, the window of vulnerability of the brain to these effects is believed to correlate with human exposures in the third trimester of pregnancy through the first year of life, but may extend to approximately 3 years of age. While there is limited information of this effect with alprazolam, since the mechanism of action includes potentiation of GABA activity, a similar effect may occur. The relevance of these nonclinical findings to human use is unknown.

    14 CLINICAL STUDIES

    The efficacy of XANAX XR tablets in the treatment of panic disorder was established in two 6-week, placebo-controlled studies of XANAX XR in patients with panic disorder.

    In two 6-week, flexible-dose, placebo-controlled studies in patients meeting DSM-III criteria for panic disorder, patients were treated with XANAX XR in a dose range of 1 mg to 10 mg per day, on a once-a-day basis. The effectiveness of XANAX XR was assessed on the basis of changes in various measures of panic attack frequency, on various measures of the Clinical Global Impression, and on the Overall Phobia Scale. In all, there were 7 primary efficacy measures in these studies, and XANAX XR was superior to placebo on all 7 outcomes in both studies. The mean dose of XANAX XR at the last treatment visit was 4.2 mg per day in the first study and 4.6 mg per day in the second.

    In addition, there were two 8-week, fixed-dose, placebo-controlled studies of XANAX XR in patients with panic disorder, involving fixed XANAX XR doses of 4 mg and 6 mg per day, on a once-a-day basis, that did not show a benefit for either dose of XANAX XR.

    The longer-term efficacy of XANAX XR in panic disorder has not been systematically evaluated.

    Analyses of the relationship between treatment outcome and gender did not suggest any differential responsiveness on the basis of gender.

    16 HOW SUPPLIED/STORAGE AND HANDLING

    XANAX XR is supplied in the following strengths and package configurations:

    XANAX XR Tablets
    Package ConfigurationTablet Strength (mg)NDCPrint
    Bottles of 60 0.5 mgNDC: 0009-0057-07 white, pentagonal shaped tablets debossed with an "X" on one side and "0.5" on the other side
    Bottles of 601 mgNDC: 0009-0059-07yellow, square shaped tablets debossed with an "X" on one side and "1" on the other side
    Bottles of 602 mg NDC: 0009-0066-07blue, round shaped tablets debossed with an "X" on one side and "2" on the other side
    Bottles of 603 mgNDC: 0009-0068-07green, triangular shaped tablets debossed with an "X" on one side and "3" on the other side

    Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°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 XANAX XR is used with opioids and not to use such drugs concomitantly unless supervised by a health care 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)].

    Dependence and Withdrawal Reactions

    Advise patients not to stop taking this medication abruptly or decrease the dose without consulting their physician, since withdrawal symptoms can occur. Advise patients not to increase the dose even if they think the medication "does not work anymore" without consulting their physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence. Some patients may find it very difficult to discontinue treatment with XANAX XR due to severe emotional and physical dependence. Discontinuation symptoms, including possible seizures, may occur following discontinuation from any dose, but the risk may be increased with extended use at doses greater than 4 mg per day, especially if discontinuation is too abrupt. It is important that you seek advice from your physician to discontinue treatment in a careful and safe manner. Proper discontinuation will help to decrease the possibility of withdrawal reactions that can range from mild reactions to severe reactions such as seizure [see Warnings and Precautions (5.2)].

    Effects on Driving and Operating Machinery

    Advise patients not to drive a motor vehicle or operate heavy machinery while taking XANAX XR due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking XANAX XR [see Warnings and Precautions (5.3)]. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.

    Alcohol

    Inform your physician about any alcohol consumption. Alcohol should generally not be used during treatment with benzodiazepines [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)].

    Patients with Depression

    Advise patients, their families and caregivers to look out for any signs of suicidality, and to inform the patient's prescriber or healthcare provider immediately [see Warnings and Precautions (5.6)].

    Concomitant Medications

    Advise patients to inform their healthcare provider of all medicines they take, including medications that may be bought without a prescription [see Drug Interactions (7)].

    Pregnancy

    XANAX XR is not recommended for use in pregnancy. Instruct patients to inform their healthcare provider if they are pregnant, become pregnant or intend to become pregnant during treatment with XANAX XR [see Warnings and Precautions (5.4), Use in Specific Populations (8.1)].

    Lactation

    Advise nursing mothers that breast-feeding should be avoided while on XANAX XR [see Use in Specific Populations (8.2)].

    This product's label may have been updated. For full prescribing information, please visit www.pfizer.com.

    Logo

    LAB-0006-8.1

    MEDICATION GUIDE
    XANAX XR (ZAN-aks XR)
    (alprazolam) Tablets, C-IV
    This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised Month 2018
    What is the most important information I should know about XANAX XR?
    • XANAX XR is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.
    • XANAX XR 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 XR affects you.
      • Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking XANAX XR without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, XANAX XR may make your sleepiness or dizziness much worse.
    • Do not take more XANAX XR than prescribed.
    What is XANAX XR?
    • XANAX XR is a prescription medicine used to treat panic disorder, with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)
    • XANAX XR is a federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep XANAX XR in a safe place to prevent misuse and abuse. Selling or giving away XANAX XR 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 XR is safe and effective in children.
    • Elderly patients are especially susceptible to dose related adverse effects when taking XANAX XR.
    • It is not known if XANAX XR is safe and effective in the treatment of panic disorder for use longer than 8 weeks.
    Do not take XANAX XR if:
    • you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in XANAX XR. See the end of this Medication Guide for a complete list of ingredients in XANAX XR.
    • you are taking antifungal medicines including ketoconazole and itraconazole
    Before you take XANAX XR, 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. XANAX XR may harm your unborn baby. You and your healthcare provider should decide if you should take XANAX XR while you are pregnant.
    • are breastfeeding or plan to breastfeed. XANAX XR 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 XANAX XR. You should not breastfeed while taking XANAX XR.
    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
    Taking XANAX XR with certain other medicines can cause side effects or affect how well XANAX XR or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.
    How should I take XANAX XR?
    • See "What is the most important information I should know about XANAX XR?"
    • Take XANAX XR exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much XANAX XR to take and when to take it.
    • If you take too much XANAX XR, call your healthcare provider or go to the nearest hospital emergency room right away.
    • Swallow XANAX XR tablets whole. Do not crush, chew or break XANAX XR
    What should I avoid while taking XANAX XR?
    • XANAX XR can cause you to be drowsy. Do not drive a car or operate heavy machinery until you know how XANAX XR affects you.
    • You should not drink alcohol while taking XANAX XR. Drinking alcohol can increase your chances of having serious side effects.
    What are the possible side effects of XANAX XR?
    XANAX XR may cause serious side effects, including:
    • See "What is the most important information I should know about XANAX XR?"
    • Abuse and dependence. Taking XANAX XR can cause physical and psychological dependence. Physical and psychological dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction.
    • Withdrawal symptoms. You may have withdrawal symptoms if you stop taking XANAX XR suddenly. Withdrawal symptoms can be serious and include seizures. Mild withdrawal symptoms include a depressed mood and trouble sleeping. Talk to your healthcare provider about slowly stopping XANAX XR to avoid withdrawal symptoms.
    • Seizures. Stopping XANAX XR can cause seizures and seizures that will not stop (status epilepticus).
    • Mania. XANAX XR may cause an increase in activity and talking (hypomania and mania) in people who have depression.
    The most common side effects of XANAX XR include:
    • sedation
    • difficult or unclear ability to talk
    • problems with coordination
    • tiredness
    • drowsiness
    • depression
    • memory problems
    These are not all the possible side effects of XANAX XR. 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 XR?
    • Store XANAX XR between 59°F to 86°F (15°C to 30°C)
    • Keep XANAX XR and all medicines out of the reach of children.
    General information about the safe and effective use of XANAX XR.
    • Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
    • Do not use XANAX XR for a condition for which it was not prescribed.
    • Do not give XANAX XR 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 XR that is written for health professionals.
    What are the ingredients in XANAX XR?
    Active ingredient: alprazolam
    Inactive ingredients: lactose, magnesium stearate, colloidal silicon dioxide, and hypromellose. In addition, the 1 mg and 3 mg tablets contain D & C yellow No. 10 and the 2 mg and 3 mg tablets contain FD&C blue No. 2.
    XANAX® XR is a registered trademark of Pharmacia & Upjohn Company LLC.
    This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com.

    Logo


    LAB-0824-1.1

    PRINCIPAL DISPLAY PANEL - 0.5 mg Tablet Bottle Label

    ALWAYS DISPENSE WITH MEDICATION GUIDE
    NDC: 0009-0057-07
    Pfizer

    Xanax XR®
    CIV

    alprazolam
    extended-release tablets

    0.5 mg

    60 Tablets
    Rx only

    PRINCIPAL DISPLAY PANEL - 0.5 mg Tablet Bottle Label

    PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label

    ALWAYS DISPENSE WITH MEDICATION GUIDE
    NDC: 0009-0059-07
    Pfizer

    Xanax XR®
    CIV

    alprazolam
    extended-release tablets

    1 mg

    60 Tablets
    Rx only

    PRINCIPAL DISPLAY PANEL - 1 mg Tablet Bottle Label

    PRINCIPAL DISPLAY PANEL - 2 mg Tablet Bottle Label

    ALWAYS DISPENSE WITH MEDICATION GUIDE
    NDC: 0009-0066-07
    Pfizer

    Xanax XR®
    CIV

    alprazolam
    extended-release tablets

    2 mg

    60 Tablets
    Rx only

    PRINCIPAL DISPLAY PANEL - 2 mg Tablet Bottle Label

    PRINCIPAL DISPLAY PANEL - 3 mg Tablet Bottle Label

    ALWAYS DISPENSE WITH MEDICATION GUIDE
    NDC: 0009-0068-07
    Pfizer

    Xanax XR®
    CIV

    alprazolam
    extended-release tablets

    3 mg

    60 Tablets
    Rx only

    PRINCIPAL DISPLAY PANEL - 3 mg Tablet Bottle Label
    XANAX   XR
    alprazolam tablet, extended release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0009-0057
    Route of AdministrationORALDEA ScheduleCIV    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM0.5 mg
    Inactive Ingredients
    Ingredient NameStrength
    LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    Product Characteristics
    ColorWHITEScoreno score
    ShapePENTAGON (5 SIDED) (pentagon) Size9mm
    FlavorImprint Code X;0;5
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0009-0057-0760 in 1 BOTTLE; Type 0: Not a Combination Product01/17/2003
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02143401/17/2003
    XANAX   XR
    alprazolam tablet, extended release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0009-0059
    Route of AdministrationORALDEA ScheduleCIV    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM1 mg
    Inactive Ingredients
    Ingredient NameStrength
    LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
    Product Characteristics
    ColorYELLOWScoreno score
    ShapeSQUARESize8mm
    FlavorImprint Code X;1
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0009-0059-0760 in 1 BOTTLE; Type 0: Not a Combination Product01/17/2003
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02143401/17/2003
    XANAX   XR
    alprazolam tablet, extended release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0009-0066
    Route of AdministrationORALDEA ScheduleCIV    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM2 mg
    Inactive Ingredients
    Ingredient NameStrength
    LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    Product Characteristics
    ColorBLUEScoreno score
    ShapeROUNDSize10mm
    FlavorImprint Code X;2
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0009-0066-0760 in 1 BOTTLE; Type 0: Not a Combination Product01/17/2003
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02143401/17/2003
    XANAX   XR
    alprazolam tablet, extended release
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 0009-0068
    Route of AdministrationORALDEA ScheduleCIV    
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY) ALPRAZOLAM3 mg
    Inactive Ingredients
    Ingredient NameStrength
    LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G)  
    MAGNESIUM STEARATE (UNII: 70097M6I30)  
    SILICON DIOXIDE (UNII: ETJ7Z6XBU4)  
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)  
    FD&C BLUE NO. 2 (UNII: L06K8R7DQK)  
    Product Characteristics
    ColorGREENScoreno score
    ShapeTRIANGLESize10mm
    FlavorImprint Code X;3
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 0009-0068-0760 in 1 BOTTLE; Type 0: Not a Combination Product01/17/2003
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA02143401/17/2003
    Labeler - Pharmacia and Upjohn Company LLC (618054084)
    Establishment
    NameAddressID/FEIBusiness Operations
    Pfizer Pharmaceuticals LLC829084545ANALYSIS(0009-0057, 0009-0059, 0009-0066, 0009-0068) , MANUFACTURE(0009-0057, 0009-0059, 0009-0066, 0009-0068)
    Establishment
    NameAddressID/FEIBusiness Operations
    Pharmacia and Upjohn Company LLC618054084API MANUFACTURE(0009-0057, 0009-0059, 0009-0066, 0009-0068)
    Establishment
    NameAddressID/FEIBusiness Operations
    Pfizer Italia S.r.l.458521908ANALYSIS(0009-0057, 0009-0059, 0009-0066, 0009-0068) , MANUFACTURE(0009-0057, 0009-0059, 0009-0066, 0009-0068) , PACK(0009-0057, 0009-0059, 0009-0066, 0009-0068)
    Establishment
    NameAddressID/FEIBusiness Operations
    Pfizer Pharmaceuticals LLC829084552PACK(0009-0057, 0009-0059, 0009-0066, 0009-0068)
    Establishment
    NameAddressID/FEIBusiness Operations
    Pfizer Ireland Pharmaceuticals986019327ANALYSIS(0009-0057, 0009-0059, 0009-0066, 0009-0068) , MANUFACTURE(0009-0057, 0009-0059, 0009-0066, 0009-0068)

    Revised: 3/2020
     
    Pharmacia and Upjohn Company LLC


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