FDA label 80b0c6da-e166-48ad-8ab7-1c89f8edabc8

WARNINGSDependence and Withdrawal Reactions, Including Seizures Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to alprazolam. These include a spectrum of withdrawal symptoms; the most important is seizure (See DRUG ABUSE AND DEPENDENCE ). Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (i.e., 0.75 to 4 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). 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. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well. Ordinarily, the treatment of status epilepticus of any etiology involves use of intravenous benzodiazepines plus phenytoin or barbiturates, maintenance of a patent airway and adequate hydration. For additional details regarding therapy, consultation with an appropriate specialist may be considered. 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, etc.). Therefore, the dosage of alprazolam should be reduced or discontinued gradually (See DOSAGE AND ADMINISTRATION ). Alprazolam is not of value in the treatment of psychotic patients and should not be employed in lieu of appropriate treatment for psychosis. Because of its CNS depressant effects, patients receiving alprazolam 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. 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 (CYP 3A). 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 CYP 3A. With drugs inhibiting CYP 3A 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 pharmocologic class. The following are examples of drugs known to inhibit the metabolism of alprazolam and/or related benzodiazepines, presumably through inhibition of CYP 3A. Potent CYP 3A Inhibitors: Azole antifungal agents – Although in vivo interaction data with alprazolam are not available, ketoconazole and itraconazole are potent CYP 3A inhibitors and the coadministration of alprazolam with them is not recommended. Other azole-type antifungal agents should also be considered potent CYP 3A inhibitors and the coadministration of alprazolam with them is not recommended (see CONTRAINDICATIONS ). Drugs Demonstrated to be CYP 3A Inhibitors on the Basis of Clinical Studies Involving Alprazolam (caution and consideration of appropriate alprazolam dose reduction are recomended 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 CYP 3A are discussed in the PRECAUTIONS section (see PRECAUTIONS-Drug Interactions ).

ADVERSE REACTIONS Side effects to alprazolam, 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, eg, drowsiness or lightheadedness. The data cited in the table 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 (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety). 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 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. There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam (See WARNINGS ). To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam be decreased by no more than 0.5 mg every three days (See DOSAGE AND ADMINISTRATION ). Some patients may require an even slower dosage reduction. 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. Laboratory analyses were performed on all patients participating in the clinical program for alprazolam. The following incidences of abnormalities shown below were observed in patients receiving alprazolam and in patients in the corresponding placebo group. Few of these abnormalities were considered to be of physiological significance. When treatment with alprazolam is protracted, periodic blood counts, urinalysis and blood chemistry analyses are advisable. Minor changes in EEG patterns, usually low-voltage fast activity have been observed in patients during therapy with alprazolam and are of no known significance. Post Introduction Reports Various adverse drug reactions have been reported in association with the use of alprazolam 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 cannot be readily determined. Reported events include: liver enzyme elevations, hepatitis, hepatic failure, Stevens Johnson Syndrome, hyperprolactinemia, gynecomastia and galactorrhea