Alprazolam XR: Package Insert and Label Information

ALPRAZOLAM XR- alprazolam tablet, extended release
Greenstone LLC

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, Drug Interactions].

  • 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.

DESCRIPTION

Alprazolam XR tablets contain alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds.

The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H -s -triazolo [4,3-α] [1,4] benzodiazepine. The molecular formula is C17 H13 ClN4 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 Alprazolam 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.

CLINICAL PHARMACOLOGY

Pharmacodynamics

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereospecific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.

Pharmacokinetics

Absorption

Following oral administration of Alprazolam (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 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: 6.3–26.9 hours) in healthy adults.

The mean absolute bioavailability of alprazolam from Alprazolam XR tablets is approximately 90%, and the relative bioavailability compared to Alprazolam tablets is 100%. The bioavailability and pharmacokinetics of alprazolam following administration of Alprazolam XR tablets are similar to that for Alprazolam 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 two 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 Alprazolam XR tablets. A high-fat meal given up to 2 hours before dosing with Alprazolam 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 (t1/2 ) were not affected by eating.

There were significant differences in absorption rate for the Alprazolam 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 Alprazolam XR and Alprazolam tablets. In vitro, alprazolam is bound (80%) to human serum protein. Serum albumin accounts for the majority of the binding.

Metabolism

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two 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 Alprazolam and Alprazolam 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 Alprazolam XR and Alprazolam 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.

Elimination

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

Special Populations

While pharmacokinetic studies have not been performed in special populations with Alprazolam XR tablets, the factors (such as age, gender, hepatic or renal impairment) that would affect the pharmacokinetics of alprazolam after the administration of Alprazolam tablets would not be expected to be different with the administration of Alprazolam 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. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0–26.9 hours, n=16) compared to 11.0 hours (range: 6.3–15.8 hours, n=16) in healthy adult subjects. 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. 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.

Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.

Race

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

Pediatrics

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

Gender

Gender has no effect on the pharmacokinetics of alprazolam.

Cigarette Smoking

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

Drug-Drug Interactions

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, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold (see CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS–Drug Interactions).

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 t1/2 was shortened (from 17.1±4.9 to 7.7±1.7 h) following administration of 300 mg/day carbamazepine for 10 days (see PRECAUTIONS–Drug Interactions). However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000–1200 mg/day); the effect at usual carbamazepine doses is unknown.

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 versus 13 h) 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).

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.

CLINICAL EFFICACY TRIALS

The efficacy of Alprazolam XR tablets in the treatment of panic disorder was established in two 6-week, placebo-controlled studies of Alprazolam 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 Alprazolam XR in a dose range of 1 to 10 mg/day, on a once-a-day basis. The effectiveness of Alprazolam 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 seven primary efficacy measures in these studies, and Alprazolam XR was superior to placebo on all seven outcomes in both studies. The mean dose of Alprazolam XR at the last treatment visit was 4.2 mg/day in the first study and 4.6 mg/day in the second.

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

The longer-term efficacy of Alprazolam 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.

Alprazolam XR Indications and Usage

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

This claim is supported on the basis of two positive studies with Alprazolam XR conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder (see CLINICAL EFFICACY TRIALS).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, ie, a discrete period of intense fear or discomfort in which four (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 Alprazolam 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.

CONTRAINDICATIONS

Alprazolam XR tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines.

Alprazolam XR is contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) (see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS–Drug Interactions).

WARNINGS

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including Alprazolam 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 Alprazolam 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 Alprazolam 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 Alprazolam 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 Alprazolam 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).

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 XR 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%–93% of patients treated with Alprazolam tablets tapered completely off therapy compared to 89%–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 XR. In two cases, the patients had completed 6 weeks of treatment with Alprazolam XR6 mg/day before experiencing a single seizure. In one case, the patient abruptly discontinued Alprazolam XR, and in both cases, alcohol intake was implicated. The third case involved multiple seizures after the patient completed treatment with Alprazolam XR 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 Alprazolam greater than 4 mg/day for over 3 months were permitted. Five of these cases clearly occurred during abrupt dose reduction, or discontinuation from daily doses of 2 to 10 mg. Three cases occurred in situations where there was not a clear relationship to abrupt dose reduction or discontinuation. In one instance, seizure occurred after discontinuation from a single dose of 1 mg after tapering at a rate of 1 mg every three days from 6 mg daily. In two 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 Alprazolam. The risk of seizure seems to be greatest 24–72 hours after discontinuation (see DOSAGE AND ADMINISTRATION for recommended tapering and discontinuation schedule).

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