24 Hr Alprazolam 0.5 Mg Extended Release Oral Tablet

The mean absolute bioavailability of alprazolam from alprazolam extended-release tablets is approximately 90%, and the relative bioavailability compared to alprazolam tablets is 100%. The bioavailability and pharmacokinetics of alprazolam following administration of alprazolam extended-release 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 extended-release tablets. A high-fat meal given up to 2 hours before dosing with alprazolam extended-release tablets increased the mean C_max by about 25%. The effect of this meal on T_max depended on the timing of the meal, with a reduction in T_max by about 1/3 for subjects eating immediately before dosing and an increase in T_max by about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure (AUC) and elimination half-life (t _½) were not affected by eating.

There were significant differences in absorption rate for the alprazolam extended-release tablet, depending on the time of day administered, with the C_max increased by 30% and the T_max decreased by an hour following dosing at night, compared to morning dosing.

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 extended-release 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.

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 t_½ 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.

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.

In two 6-week, flexible-dose, placebo-controlled studies in patients meeting DSM-III criteria for panic disorder, patients were treated with alprazolam extended-release tablets in a dose range of 1 to 10 mg/day, on a once-a-day basis. The effectiveness of alprazolam extended-release tablets 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 extended-release tablets were superior to placebo on all seven outcomes in both studies. The mean dose of alprazolam extended-release tablet 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 extended-release tablets in patients with panic disorder, involving fixed alprazolam extended-release tablets doses of 4 and 6 mg/day, on a once-a-day basis, that did not show a benefit for either dose of alprazolam extended-release tablets.

The longer-term efficacy of alprazolam extended-release tablets 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.

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%-93% of patients treated with alprazolam tablets tapered completely off therapy compared to 89%-96% of placebo treated patients. In a controlled post-marketing 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 tablets. In two cases, the patients had completed 6 weeks of treatment with alprazolam extended-release tablets 6 mg/day before experiencing a single seizure. In one case, the patient abruptly discontinued alprazolam extended-release tablets, and in both cases, alcohol intake was implicated. The third case involved multiple seizures after the patient completed treatment with alprazolam extended-release tablets 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 tablets 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 tablets 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 tablets. The risk of seizure seems to be greatest 24-72 hours after discontinuation (see DOSAGE AND ADMINISTRATIONfor recommended tapering and discontinuation schedule).

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

Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam (caution and consideration of appropriate alprazolam dose reduction are recommended during co-administration with the following drugs):

Nefazodone:

Co-administration of nefazodone increased alprazolam concentration two-fold.

Fluvoxamine:

Co-administration 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:

Co-administration of cimetidine increased the maximum plasma concentration of alprazolam by 86%, decreased clearance by 42%, and increased half-life by 16%.

Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during co-administration with alprazolam)

Fluoxetine:

Co-administration 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:

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

Oral Contraceptives:

Co-administration 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 co-administration 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 co-administration of any of these with alprazolam (see WARNINGS).

Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.

Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.

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 (e.g., 0.75 to 4 mg/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/day (see WARNINGS).

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 DOSAGE AND ADMINISTRATION).

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/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.

Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.

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.