Alprazolam Tablets, USP 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 structural formula is:
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 tablet, for oral administration, contains 0.25, 0.5, 1 or 2 mg of Alprazolam.
Alprazolam tablets, 2 mg, are multi-scored and may be divided as shown below:
Inactive ingredients: Colloidal silicon dioxide, docusate sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium benzoate and sodium starch glycolate. In addition, the 0.5 mg tablet contains FD&C Yellow No. 6 Aluminum Lake and the 1 mg tablet contains FD&C Blue No. 1 Aluminum Lake.
Alprazolam - Clinical Pharmacology
Pharmacodynamics
CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific 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, Alprazolam is readily absorbed. Peak concentrations in the plasma occur in 1 to 2 hours following administration. Plasma levels are proportionate 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.
Distribution
In vitro, Alprazolam is bound (80 percent) to human serum protein. Serum albumin accounts for the majority of the binding.
Metabolism/Elimination
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 plasma concentrations of 4-hydroxyAlprazolam and α-hydroxyAlprazolam relative to unchanged Alprazolam concentration were always less than 4%. 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.
Alprazolam and its metabolites are excreted primarily in the urine.
Special Populations
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 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.
The ability of Alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.
Clinical Studies
Anxiety Disorders
Alprazolam tablets were compared to placebo in double blind clinical studies (doses up to 4 mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam tablets were significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physician’s Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient’s Global Impressions and Self-Rating Symptom Scale.
Panic Disorder
Support for the effectiveness of Alprazolam tablets in the treatment of panic disorder came from three short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder.
The average dose of Alprazolam tablets was 5-6 mg/day in two of the studies, and the doses of Alprazolam tablets were fixed at 2 and 6 mg/day in the third study. In all three studies, Alprazolam tablets were superior to placebo on a variable defined as "the number of patients with zero panic attacks" (range, 37-83% met this criterion), as well as on a global improvement score. In two of the three studies, Alprazolam tablets were superior to placebo on a variable defined as "change from baseline on the number of panic attacks per week" (range, 3.3-5.2), and also on a phobia rating scale. A subgroup of patients who were improved on Alprazolam tablets during short-term treatment in one of these trials was continued on an open basis up to 8 months, without apparent loss of benefit.
Indications and Usage for Alprazolam
Anxiety Disorders
Alprazolam tablets are indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSM-III-R] diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.
Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, for a period of 6 months or longer, during which the person has been bothered more days than not by these concerns. At least 6 of the following 18 symptoms are often present in these patients: Motor Tension (trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent urination; trouble swallowing or 'lump in throat'); Vigilance and Scanning (feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or 'mind going blank' because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor.
Anxiety associated with depression is responsive to Alprazolam tablets.
Panic Disorder
Alprazolam tablets are also indicated for the treatment of panic disorder, with or without agoraphobia.
Studies supporting this claim were conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder (see CLINICAL STUDIES).
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.
Demonstrations of the effectiveness of Alprazolam tablets by systematic clinical study are limited to 4 months duration for anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient.
Contraindications
Alprazolam tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines. Alprazolam 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 tablets are contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) (see WARNINGS and PRECAUTIONS-Drug Interactions).
Warnings
Dependence and Withdrawal Reactions, Including Seizures
Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to Alprazolam tablets. These include a spectrum of withdrawal symptoms; the most important is seizure (see DRUG ABUSE AND DEPENDENCE). Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (i.e., 0.75 to 4.0 mg per day), there is some risk of dependence. Spontaneous reporting system data suggest that the risk of dependence and its severity appear to be greater in patients treated with doses greater than 4 mg/day and for long periods (more than 12 weeks). However, in a controlled postmarketing discontinuation study of panic disorder patients, 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.
The importance of dose and the risks of Alprazolam tablets as a treatment for panic disorder: Because the management of panic disorder often requires the use of average daily doses of Alprazolam tablets above 4 mg, the risk of dependence among panic disorder patients may be higher than that among those treated for less severe anxiety. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder showed a high rate of rebound and withdrawal symptoms in patients treated with Alprazolam tablets compared to placebo-treated patients.
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.
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, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose.
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 3 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 ADMINISTRATION for recommended tapering and discontinuation schedule).
Status Epilepticus and its Treatment
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 of Alprazolam tablets. 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. In these situations, it is recommended that the same total daily dose be given divided as more frequent administrations (see DOSAGE AND ADMINISTRATION).
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 tablets should be reduced or discontinued gradually (see DOSAGE AND ADMINISTRATION).
CNS Depression and Impaired Performance
Because of its CNS depressant effects, patients receiving Alprazolam 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 tablets.
Risk of Fetal Harm
Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If Alprazolam tablets are 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 tablets are 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 CONTRAINDICATIONS).
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 PRECAUTIONS-Drug Interactions).
Precautions
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 tablets.
Use in Patients with Concomitant Illness
It is recommended that the dosage be limited to the smallest effective dose to preclude the development of ataxia or oversedation which may be a particular problem in elderly or debilitated patients (see DOSAGE AND ADMINISTRATION). 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 CLINICAL PHARMACOLOGY).
Information for Patients
For all users of Alprazolam tablets:
To assure safe and effective use of benzodiazepines, all patients prescribed Alprazolam tablets should be provided with the following guidance.
- Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
- Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication.
- Inform your physician if you are nursing.
- Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
- Do not increase the dose even if you think the medication "does not work anymore" without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.
- Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.
The use of Alprazolam tablets at doses greater than 4 mg/day, often necessary to treat panic disorder, is accompanied by risks that you need to carefully consider. When used at doses greater than 4 mg/day, which may or may not be required for your treatment, Alprazolam tablets have the potential to cause severe emotional and physical dependence in some patients and these patients may find it exceedingly difficult to terminate treatment. In two controlled trials of 6 to 8 weeks duration where the ability of patients to discontinue medication was measured, 7 to 29% of patients treated with Alprazolam tablets did not completely taper off therapy. In a controlled postmarketing discontinuation study of panic disorder patients, the patients treated with doses of Alprazolam tablets greater than 4 mg/day had more difficulty tapering to zero dose than patients treated with less than 4 mg/day. In all cases, it is important that your physician help you discontinue this medication in a careful and safe manner to avoid overly extended use of Alprazolam tablets.
In addition, the extended use at doses greater than 4 mg/day appears to increase the incidence and severity of withdrawal reactions when Alprazolam tablets are discontinued. These are generally minor but seizure can occur, especially if you reduce the dose too rapidly or discontinue the medication abruptly. Seizure can be life-threatening.
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 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 co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.
Use with Imipramine and Desipramine
The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of Alprazolam tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.
Drugs that inhibit Alprazolam metabolism via cytochrome P450 3A
The initial step in Alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of Alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type).
Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving Alprazolam (caution is recommended during coadministration with Alprazolam)
Fluoxetine—Coadministration of fluoxetine with Alprazolam increased the maximum plasma concentration of Alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.
Propoxyphene—Coadministration of propoxyphene decreased the maximum plasma concentration of Alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%.
Oral Contraceptives—Coadministration of oral contraceptives increased the maximum plasma concentration of Alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%.
Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to Alprazolam or on the basis of in vitro studies with Alprazolam or other benzodiazepines (caution is recommended during coadministration with Alprazolam)
Available data from clinical studies of benzodiazepines other than Alprazolam suggest a possible drug interaction with Alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of Alprazolam suggest a possible drug interaction with Alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of Alprazolam 1 mg and steady state doses of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of Alprazolam. Data from in vitro studies of benzodiazepines other than Alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with Alprazolam (see WARNINGS).
Drugs demonstrated to be inducers of CYP3A
Carbamazepine can increase Alprazolam metabolism and therefore can decrease plasma levels of Alprazolam.
Drug/Laboratory Test Interactions
Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.
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 WARNINGS 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 tablets have 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 tablets.
Pediatric Use
Safety and effectiveness of Alprazolam tablets 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 tablets should be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Adverse Reactions
Side effects to Alprazolam tablets, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. In the usual patient, the most frequent side effects are likely to be an extension of the pharmacological activity of Alprazolam, e.g., drowsiness or light-headedness.
The data cited in the two tables below are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (i.e., four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of Alprazolam tablets (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg/day of Alprazolam tablets in patients with panic disorder, with or without agoraphobia.
These data cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics, and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials are conducted under a different set of conditions.
Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the untoward event incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth [a symptom of anxiety] in some subjects but induce it [an untoward event] in others.)
Additionally, for anxiety disorders the cited figures can provide the prescriber with an indication as to the frequency with which physician intervention (e.g., increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event.
| ANXIETY DISORDERS | |||
|---|---|---|---|
| Treatment-Emergent Symptom Incidence* | Incidence of Intervention Because of Symptom | ||
| Alprazolam TABLETS | PLACEBO | Alprazolam TABLETS | |
| |||
| Number of Patients % of Patients Reporting: | 565 | 505 | 565 |
| Central Nervous System | |||
| Drowsiness | 41.0 | 21.6 | 15.1 |
| Light-headedness | 20.8 | 19.3 | 1.2 |
| Depression | 13.9 | 18.1 | 2.4 |
| Headache | 12.9 | 19.6 | 1.1 |
| Confusion | 9.9 | 10.0 | 0.9 |
| Insomnia | 8.9 | 18.4 | 1.3 |
| Nervousness | 4.1 | 10.3 | 1.1 |
| Syncope | 3.1 | 4.0 | † |
| Dizziness | 1.8 | 0.8 | 2.5 |
| Akathisia | 1.6 | 1.2 | † |
| Tiredness/Sleepiness | † | † | 1.8 |
| Gastrointestinal | |||
| Dry Mouth | 14.7 | 13.3 | 0.7 |
| Constipation | 10.4 | 11.4 | 0.9 |
| Diarrhea | 10.1 | 10.3 | 1.2 |
| Nausea/Vomiting | 9.6 | 12.8 | 1.7 |
| Increased Salivation | 4.2 | 2.4 | † |
| Cardiovascular | |||
| Tachycardia/Palpitations | 7.7 | 15.6 | 0.4 |
| Hypotension | 4.7 | 2.2 | † |
| Sensory | |||
| Blurred Vision | 6.2 | 6.2 | 0.4 |
| Musculoskeletal | |||
| Rigidity | 4.2 | 5.3 | † |
| Tremor | 4.0 | 8.8 | 0.4 |
| Cutaneous | |||
| Dermatitis/Allergy | 3.8 | 3.1 | 0.6 |
| Other | |||
| Nasal Congestion | 7.3 | 9.3 | † |
| Weight Gain | 2.7 | 2.7 | † |
| Weight Loss | 2.3 | 3.0 | † |
In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.
| PANIC DISORDERS | ||
|---|---|---|
| Treatment-Emergent Symptom Incidence* | ||
| Alprazolam TABLETS | PLACEBO | |
| ||
| Number of Patients % of Patients Reporting: | 1388 | 1231 |
| Central Nervous System | ||
| Drowsiness | 76.8 | 42.7 |
| Fatigue and Tiredness | 48.6 | 42.3 |
| Impaired Coordination | 40.1 | 17.9 |
| Irritability | 33.1 | 30.1 |
| Memory Impairment | 33.1 | 22.1 |
| Light-headedness/Dizziness | 29.8 | 36.9 |
| Insomnia | 29.4 | 41.8 |
| Headache | 29.2 | 35.6 |
| Cognitive Disorder | 28.8 | 20.5 |
| Dysarthria | 23.3 | 6.3 |
| Anxiety | 16.6 | 24.9 |
| Abnormal Involuntary Movement | 14.8 | 21.0 |
| Decreased Libido | 14.4 | 8.0 |
| Depression | 13.8 | 14.0 |
| Confusional State | 10.4 | 8.2 |
| Muscular Twitching | 7.9 | 11.8 |
| Increased Libido | 7.7 | 4.1 |
| Change in Libido (Not Specified) | 7.1 | 5.6 |
| Weakness | 7.1 | 8.4 |
| Muscle Tone Disorders | 6.3 | 7.5 |
| Syncope | 3.8 | 4.8 |
| Akathisia | 3.0 | 4.3 |
| Agitation | 2.9 | 2.6 |
| Disinhibition | 2.7 | 1.5 |
| Paresthesia | 2.4 | 3.2 |
| Talkativeness | 2.2 | 1.0 |
| Vasomotor Disturbances | 2.0 | 2.6 |
| Derealization | ||
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