warnings and cautions
5 WARNINGS AND PRECAUTIONS • Suicide: As with other psychotropic medications, use precautions with respect to administration of the drug and size of the prescription, especially in patients who are severely depressed or in patients where there is reason to expect concealed suicidal ideation or plans ( 5.1 ). • Status Epilepticus and Seizure: can occur during discontinuation of NIRAVAM ( 5.2 ). • Physical dependence to NIRAVAM can occur, even after relatively short-term use at the recommended doses ( 5.3 ). • Withdrawal reactions , such as seizures, can occur during dosage reduction. Avoid abrupt discontinuation. Reduce or discontinue the dose gradually ( 5.3 ). • Fetal Harm: Benzodiazepines can cause fetal harm when administered to pregnant women ( 5.4 ). • CNS Depression and Impaired Cognitive and Motor Performance: caution patients against engaging in hazardous occupations or activities requiring complete mental alertness, until they are reasonably certain that NIRAVAM treatment does not affect them adversely. Caution patients about the use of alcohol and other CNS depressant drugs during treatment with NIRAVAM ( 5.5 ). • Interdose anxiety symptoms: can occur at prescribed maintenance doses. Consider dividing the daily dose into more frequent administrations ( 5.8 ). • Patients with Concomitant Illnes : In the elderly or debilitated patients, the smallest effective dose is recommended to preclude the development of ataxia or oversedation. There have been rare reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam ( 5.11 ). 5.1 Suicide and Overdose 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. 5.2 Status Epilepticus 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. 5.3 Dependence and Withdrawal Reactions, Including Seizures NIRAVAM is a Schedule IV controlled substance. The use of benzodiazepines, including NIRAVAM, may lead to physical and psychological dependence. In general, benzodiazepines should be prescribed for short periods. Even after relatively short-term use at the recommended doses, there is some risk of dependence and withdrawal symptoms [ see Dependence ( 9.3 ) ]. Certain adverse clinical events, some life-threatening, are a direct consequence of physical dependence to NIRAVAM. These include a spectrum of withdrawal symptoms; the most important is seizure [ see Drug Abuse and Dependence ( 9.3 ) ]. 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 per 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 greater than 4 mg per day had more difficulty tapering to zero dose than those treated with less than 4 mg per day. The importance of dose and the risks of NIRAVAM as a treatment for panic disorder Because the management of panic disorder often requires the use of average daily doses of NIRAVAM 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 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 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 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 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 mg 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. The risk of seizure seems to be greatest 24 - 72 hours after discontinuation [ see Dosage and Administration ( 2 ) ]. To discontinue treatment in patients taking NIRAVAM, the dosage should be reduced gradually. Decrease the daily dosage of NIRAVAM by no more than 0.5 mg every three days [ see Dosage and Administration ( 2 ) ]. 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. 5.4 Risk of Fetal Harm Benzodiazepines can potentially cause fetal harm when administered to pregnant women. If NIRAVAM 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, NIRAVAM 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. 5.5 CNS Depression and Impaired Performance Because NIRAVAM has CNS depressant effects and has the potential to impair judgment, cognition, and motor performance, caution patients against engaging in hazardous occupations or activities requiring complete mental alertness such as operating machinery or driving a motor vehicle, until they are reasonably certain that NIRAVAM treatment does not affect them adversely. Caution patients about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with NIRAVAM. 5.6 Mania Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression. 5.7 NIRAVAM Interaction with Drugs that Inhibit Metabolism via Cytochrome P450 3A The initial step in NIRAVAM metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs that inhibit this metabolic pathway may have a profound effect on the clearance of NIRAVAM. Consequently, NIRAVAM should be avoided in patients receiving potent inhibitors of CYP3A. With drugs inhibiting CYP3A to a lesser but still significant degree, NIRAVAM should be used only with caution and consideration of appropriate dosage reduction. For some drugs, an interaction with NIRAVAM 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 NIRAVAM 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 ( 4 ) ]. Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam Consider dose reduction of NIRAVAM 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 affect alprazolam metabolism by inhibition of CYP3A [ see Drug Interactions ( 7.6 ) ]. 5.8 Interdose Symptoms Early morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses of alprazolam. 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 ( 2 ) ]. 5.9 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 NIRAVAM should be reduced or discontinued gradually [ see Dosage and Administration ( 2 ) ]. 5.10 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. 5.11 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 ( 2 ) ]. 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. 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 [ see Clinical Pharmacology ( 12 ) ].