Alprazolam .5 mg Tablet, Extended Release, 60-count

WARNINGS 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 ). 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 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 alprazolam tablets greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/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 alprazolam extended-release tablets has not been systematically studied. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder who received alprazolam 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 alprazolam 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 two 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 alprazolam 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 alprazolam 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 three patients in panic disorder clinical trials with alprazolam extended-release. In two cases, the patients had completed 6 weeks of treatment with alprazolam extended-release 6 mg/day before experiencing a single seizure. In one case, the patient abruptly discontinued alprazolam extended-release, and in both cases, alcohol intake was implicated.

The third case involved multiple seizures after the patient completed treatment with alprazolam extended-release 4 mg/day and missed taking the medication on the first day of taper. All three patients recovered without sequelae. Seizures have also been observed in association with dose reduction or discontinuation of alprazolam tablets, the immediate release form of alprazolam.

Seizures attributable to alprazolam 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 alprazo…

ADVERSE REACTIONS The information included in the subsection on Adverse Events Observed in Short-Term, Placebo-Controlled Trials with alprazolam extended-release 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 Alprazolam Extended-Release Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Approximately 17% of the 531 patients who received alprazolam extended-release in placebo-controlled clinical trials for panic disorder had at least one 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 (i.e., leading to discontinuation in at least 1% of the patients treated with alprazolam extended-release at a rate at least twice that of placebo) are shown in the following table. Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials System Organ Class/ Adverse Event Percentage of Patients Discontinuing Due to Adverse Events Alprazolam Extended-Release (n=531) Placebo (n=349) Nervous system disorders Sedation Somnolence Dysarthria Coordination abnormal Memory impairment 7.5 3.2 2.1 1.9 1.5 0.6 0.3 0 0.3

0.3General disorders/administration site conditions Fatigue 1.7

0.6Psychiatric disorders Depression 2.5

1.2Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam Extended-Release 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 alprazolam extended-release where the incidence in patients treated with alprazolam extended-release was greater than the incidence in placebo-treated patients.

The most commonly observed adverse events in panic disorder patients treated with alprazolam extended-release (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). Treatment-Emergent Adverse Events: Incidence in Short-Term, Placebo-Controlled Clinical Trials with Alprazolam Extended-Release System Organ Class/Adverse Event Percentage of Patients Reporting Adverse Event Alprazolam Extended Release (n=531) Placebo (n=349) Nervous system disorders Sedation Somnolence Memory impairment Dysarthria Coordination abnormal Mental impairment Ataxia Disturbance in attention Balance impaired Paresthesia Dyskinesia Hypoesthesia Hypersomnia 45.2 23 15.4 10.9 9.4 7.2 7.2 3.2 3.2 2.4 1.7 1.3 1.3 22.6 6 6.9 2.6 0.…

Drug Interactions Use with Other CNS Depressants If alprazolam extended-release tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.

Use with 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 tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown. Drugs that inhibit alprazolam metabolism via cytochrome P450 3A The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A).

Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type). Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during coadministration with alprazolam) 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%. Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during coadministration with alprazolam) 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 to 150 mg/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.

Caution is recommended during the coadministration of any of these with alprazolam (see WARNINGS ). Drugs demonstrated to be inducers of CYP3A Carbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.

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.