×
Overview
What is Alprazolam?
Alprazolam extended-release tablets contain alprazolam which is a tri-azolo 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-a] [1,4] benzodiazepine.
The molecular formula is CHCIN which corresponds to a molecular weight of 308.76.
The structural formula is represented below:
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 extended-release tablet for oral administration contains 0.5 mg, 1 mg, 2 mg, or 3 mg of alprazolam. The inactive ingredients are lactose monohydrate, hypromellose, calcium silicate and magnesium stearate. In addition, the 0.5 mg tablet contains FD&C Blue #2 and D&C Yellow #10. The 1 mg tablet contains D&C Yellow #10. The 2 mg tablet contains FD&C Blue #2.
What does Alprazolam look like?
What are the available doses of Alprazolam?
Sorry No records found.
What should I talk to my health care provider before I take Alprazolam?
Sorry No records found
How should I use Alprazolam?
Alprazolam extended-release 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 extended-release tablets conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder (see ).
Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., 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 extended-release tablets 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.
Alprazolam extended-release tablets may be administered once daily, preferably in the morning. The tablets should be taken intact; they should not be chewed, crushed, or broken.
The suggested total daily dose ranges between 3 to 6 mg/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/day. In such cases, dosage should be increased cautiously to avoid adverse effects.
Dosing in Special Populations
In elderly patients, in patients with advanced liver disease, or in patients with debilitating disease, the usual starting dose of alprazolam extended-release tablets is 0.5 mg once daily. This may be gradually increased if needed and tolerated (see Dose Titration).The elderly may be especially sensitive to the effects of benzodiazepines.
Dose Titration
Treatment with alprazolam extended-release tablets 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/day. Slower titration to the dose levels may be advisable to allow full expression of the pharmacodynamic effect of alprazolam extended-release tablets.
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 (i.e., a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.
Dose Maintenance
In controlled trials conducted to establish the efficacy of alprazolam extended-release tablets in panic disorder, doses in the range of 1 to 10 mg/day were used. Most patients showed efficacy in the dose range of 3 to 6 mg/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 alprazolam extended-release tablets 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.
Dose Reduction
Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided (see , , ).
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 three 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 three days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.
Switch from alprazolam (immediate-release) tablets to alprazolam extended-release tablets
Patients who are currently being treated with divided doses of alprazolam (immediate-release) tablets, for example 3 to 4 times a day, may be switched to alprazolam extended-release 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.
What interacts with Alprazolam?
Sorry No Records found
What are the warnings of Alprazolam?
Sorry No Records found
What are the precautions of Alprazolam?
Sorry No Records found
What are the side effects of Alprazolam?
Sorry No records found
What should I look out for while using Alprazolam?
Alprazolam extended-release tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines.
Alprazolam extended-release tablets may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle glaucoma.
Alprazolam extended-release tablets is contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) (see , and ).
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 ). 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%-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 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 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 for recommended tapering and discontinuation schedule).
Status Epilepticus
The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam 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 alprazolam 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.
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 (e.g., the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of alprazolam extended-release tablets should be reduced or discontinued gradually (see ).
CNS Depression and Impaired Performance
Because of its CNS depressant effects, patients receiving alprazolam extended-release tablets 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 alprazolam extended-release tablets.
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.
Alprazolam Interaction With Drugs That Inhibit Metabolism Via Cytochrome P450 3A
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. 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 2.70 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 ).
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 coadministration with the following drugs)
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 86%, decreased clearance by 42%, and increased half-life by 16%.
Other Drugs Possibly Affecting Alprazolam Metabolism
Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed in the PRECAUTIONS section (see ).
What might happen if I take too much Alprazolam?
Clinical Experience
Overdosage reports with alprazolam 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.
Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.
General Treatment 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. 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.
How should I store and handle Alprazolam?
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Alprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx OnlyAlprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx OnlyAlprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx OnlyAlprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx OnlyAlprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx OnlyAlprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx OnlyAlprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx OnlyAlprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx OnlyAlprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx OnlyAlprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx OnlyAlprazolam Extended-Release Tablets are available as follows:0.5 mg (green, round, biconvex tablets, debossed "IP 9" on one side)Bottles of 30: NDC 21695-602-601 mg (yellow, round, biconvex tablets, debossed "IP 10" on one side)Bottles of 30: NDC 21695-603-602 mg (blue, round, biconvex tablets, debossed "IP 12" on one side)Bottles of 30: NDC 21695-604-603 mg (white, round, biconvex tablets, debossed "IP 13" on one side)Bottles of 30: NDC 21695-605-60Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].Rx Only
×
Clinical Information
Chemical Structure
No Image found
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 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 a-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 by about 25%.The effect of this meal on T depended on the timing of the meal, with a reduction in Tby about 1/3 for subjects eating immediately before dosing and an increase in T by about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure (AUC) and elimination half-life (t) were not affected by eating. There were significant differences in absorption rate for the alprazolam extended-release tablets, depending on the time of day administered, with the C increased by 30% and the T decreased by an hour following dosing at night, compared to morning dosing.
Distribution
The apparent volume of distribution of alprazolam is similar for alprazolam extended-release tablets 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 a-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their halflives appear to be similar to that of alprazolam. The pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and a-hydroxyalprazolam) were similar for alprazolam and alprazolam extended-release tablets, indicating that the metabolism of alprazolam is not affected by absorption rate. The plasma concentrations of 4-hydroxyalprazolam and a-hydroxyalprazolam relative to unchanged alprazolam concentration after both alprazolam extended-release tablets 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 a-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 extended-release tablets ranges from 10.7-15.8 hours in healthy adults.
Special Populations
While pharmacokinetic studies have not been performed in special populations with alprazolam extended-release 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 extended-release 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 extended-release tablets 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 , , and ).
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 was shortened (from 17.1 ± 4.9 to 7.7 ± 1.7 h) following administration of 300 mg/day carbamazepine for 10 days (see ). 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.
Non-Clinical Toxicology
Alprazolam extended-release tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines.
Alprazolam extended-release tablets may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle glaucoma.
Alprazolam extended-release tablets is contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) (see , and ).
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 ). 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%-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 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 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 for recommended tapering and discontinuation schedule).
Status Epilepticus
The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam 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 alprazolam 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.
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 (e.g., the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of alprazolam extended-release tablets should be reduced or discontinued gradually (see ).
CNS Depression and Impaired Performance
Because of its CNS depressant effects, patients receiving alprazolam extended-release tablets 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 alprazolam extended-release tablets.
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.
Alprazolam Interaction With Drugs That Inhibit Metabolism Via Cytochrome P450 3A
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam. 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 2.70 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 ).
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 coadministration with the following drugs)
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 86%, decreased clearance by 42%, and increased half-life by 16%.
Other Drugs Possibly Affecting Alprazolam Metabolism
Other drugs possibly affecting alprazolam metabolism by inhibition of CYP3A are discussed in the PRECAUTIONS section (see ).
CNS Active Drugs
Methylphenidate
In a single-dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with methylphenidate (40 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of PROVIGIL may be delayed by approximately one hour when coadministered with methylphenidate.
In a multiple-dose, steady-state study in healthy volunteers, modafinil was administered once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days. Administration of methylphenidate (20 mg/day) during days 22-28 of modafinil treatment 8 hours after the daily dose of modafinil did not cause any significant alterations in the pharmacokinetics of modafinil.
Dextroamphetamine
In a single dose study in healthy volunteers, simultaneous administration of modafinil (200 mg) with dextroamphetamine (10 mg) did not cause any significant alterations in the pharmacokinetics of either drug. However, the absorption of PROVIGIL may be delayed by approximately one hour when coadministered with dextroamphetamine.
In a multiple-dose, steady-state study in healthy volunteers, modafinil was administered once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days. Administration of dextroamphetamine (20 mg/day) during days 22-28 of modafinil treatment 7 hours after the daily dose of modafinil did not cause any significant alterations in the pharmacokinetics of modafinil.
Clomipramine
The coadministration of a single dose of clomipramine (50 mg) on the first of three days of treatment with modafinil (200 mg/day) in healthy volunteers did not show an effect on the pharmacokinetics of either drug. However, one incident of increased levels of clomipramine and its active metabolite desmethylclomipramine has been reported in a patient with narcolepsy during treatment with modafinil.
Triazolam
In the drug interaction study between PROVIGIL and ethinyl estradiol (EE), on the same days as those for the plasma sampling for EE pharmacokinetics, a single dose of triazolam (0.125 mg) was also administered. Mean C and AUC of triazolam were decreased by 42% and 59%, respectively, and its elimination half-life was decreased by approximately an hour after the modafinil treatment.
Monoamine Oxidase (MAO) Inhibitors
Interaction studies with monoamine oxidase inhibitors have not been performed. Therefore, caution should be used when concomitantly administering MAO inhibitors and modafinil.
Other Drugs
Warfarin
There were no significant changes in the pharmacokinetic profiles of R- and S-warfarin in healthy subjects given a single dose of racemic warfarin (5 mg) following chronic administration of modafinil (200 mg/day for 7 days followed by 400 mg/day for 27 days) relative to the profiles in subjects given placebo. However, more frequent monitoring of prothrombin times/INR is advisable whenever PROVIGIL is coadministered with warfarin (See
)
Ethinyl Estradiol
Administration of modafinil to female volunteers once daily at 200 mg/day for 7 days followed by 400 mg/day for 21 days resulted in a mean 11% decrease in C and 18% decrease in AUC of ethinyl estradiol (EE; 0.035 mg; administered orally with norgestimate). There was no apparent change in the elimination rate of ethinyl estradiol.
Cyclosporine
One case of an interaction between modafinil and cyclosporine, a substrate of CYP3A4, has been reported in a 41 year old woman who had undergone an organ transplant. After one month of administration of 200 mg/day of modafinil, cyclosporine blood levels were decreased by 50%. The interaction was postulated to be due to the increased metabolism of cyclosporine, since no other factor expected to affect the disposition of the drug had changed. Dosage adjustment for cyclosporine may be needed.
Potential Interactions with Drugs That Inhibit, Induce, or are Metabolized by Cytochrome P-450 Isoenzymes and Other Hepatic Enzymes
In in vitro studies using primary human hepatocyte cultures, modafinil was shown to slightly induce CYP1A2, CYP2B6 and CYP3A4 in a concentration-dependent manner. Although induction results based on in vitro experiments are not necessarily predictive of response in vivo, caution needs to be exercised when PROVIGIL is coadministered with drugs that depend on these three enzymes for their clearance. Specifically, lower blood levels of such drugs could result (See Other Drugs, above).
The exposure of human hepatocytes to modafinil in vitro produced an apparent concentration-related suppression of expression of CYP2C9 activity suggesting that there is a potential for a metabolic interaction between modafinil and the substrates of this enzyme (e.g., S-warfarin and phenytoin). In a subsequent clinical study in healthy volunteers, chronic modafinil treatment did not show a significant effect on the single-dose pharmacokinetics of warfarin when compared to placebo (see
).
In vitro studies using human liver microsomes showed that modafinil reversibly inhibited CYP2C19 at pharmacologically relevant concentrations of modafinil. CYP2C19 is also reversibly inhibited, with similar potency, by a circulating metabolite, modafinil sulfone. Although the maximum plasma concentrations of modafinil sulfone are much lower than those of parent modafinil, the combined effect of both compounds could produce sustained partial inhibition of the enzyme. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, propranolol, phenytoin (also via CYP2C9) or S-mephenytoin may have prolonged elimination upon coadministration with PROVIGIL and may require dosage reduction and monitoring for toxicity.
Tricyclic antidepressants
CYP2C19 also provides an ancillary pathway for the metabolism of certain tricyclic antidepressants (e.g., clomipramine and desipramine) that are primarily metabolized by CYP2D6. In tricyclic-treated patients deficient in CYP2D6 (i.e., those who are poor metabolizers of debrisoquine; 7-10% of the Caucasian population; similar or lower in other populations), the amount of metabolism by CYP2C19 may be substantially increased. PROVIGIL may cause elevation of the levels of the tricyclics in this subset of patients. Physicians should be aware that a reduction in the dose of tricyclic agents might be needed in these patients.
In addition, due to the partial involvement of CYP3A4 in the metabolic elimination of modafinil, coadministration of potent inducers of CYP3A4 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) could alter the plasma levels of modafinil.
General
Suicide
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.
Mania
Episodes of hypomania and mania have been reported in association with the use of alprazolam tablets in patients with depression.
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.
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 ). 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 alprazolam tablets. A decreased systemic alprazolam elimination rate (e.g., increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving alprazolam tablets (see ).
Information for Patients
To assure safe and effective use of alprazolam extended-release tablets, the physician should provide the patient with the following guidance.
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.
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 cyto-chrome P450 3A
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P4503A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam (see and 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 ).
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose).
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.
Pregnancy
Teratogenic Effects: Pregnancy Category D: (see section).
Nonteratogenic Effects: 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 and Delivery
Alprazolam has no established use in labor or delivery.
Nursing Mothers
Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. 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.
Pediatric Use
Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established.
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 (see and ).
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 Tablets
Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials
Approximately 17% of the 531 patients who received alprazolam extended-release tablets 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 tablets at a rate at least twice that of placebo) are shown in the following table.
Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam Extended-Release Tablets
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 tablets where the incidence in patients treated with alprazolam extended-release tablets was greater than the incidence in placebo-treated patients. The most commonly observed adverse events in panic disorder patients treated with alprazolam extended-release tablets (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).
Other Adverse Events Observed During the Premarketing Evaluation of Alprazolam Extended-Release Tablets
Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported by 531 patients with panic disorder treated with alprazolam extended-release tablets. 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 alprazolam extended-release tablets, 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 1/100 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1000 patients; rare events are those occurring in fewer than 1/1000 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 alprazolam tablets in the treatment of panic disorder differ somewhat from those reported for alprazolam extended-release tablets because the clinical trials with alprazolam tablets and alprazolam extended-release tablets used different standard medical nomenclature for reporting the adverse events. Nevertheless, the types of adverse events reported in the clinical trials with alprazolam tablets were generally the same as those reported in the clinical trials with alprazolam extended-release tablets.
Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More Among Patients Treated with Alprazolam Extended-Release Tablets
The following table shows the incidence of discontinuation-emergent adverse events that occurred during short-term, placebo-controlled trials in 5% or more of patients treated with alprazolam extended-release tablets where the incidence in patients treated with alprazolam extended-release tablets was two times greater than the incidence in placebo-treated patients.
There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam (see ).
To discontinue treatment in patients taking alprazolam extended-release tablets, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam extended-release tablets be decreased by no more than 0.5 mg every three days (see ). 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.
Post Introduction Reports
Various adverse drug reactions have been reported in association with the use of alprazolam tablets since market introduction. The majority of these reactions were reported through the medical event voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and the lack of controls, a causal relationship to the use of alprazolam tablets cannot be readily determined. Reported events include: liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, hyperprolactinemia, gynecomastia, and galactorrhea.
