FDA label d6842b45-3bf6-4e95-e053-2a95a90adabc

BOXED WARNING WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death (see WARNINGS, DRUG INTERACTIONS). Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.

WARNINGS Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including alprazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe alprazolam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of alprazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see DRUG INTERACTIONS). 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 DRUG ABUSE AND DEPENDENCE). Even after relatively short-term use at the doses recommended for the treatment of transient anxiety and anxiety disorder (ie, 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 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 as a treatment for panic disorder: Because the management of panic disorder often requires the use of average daily doses of alprazolam 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 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 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. 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 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). 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 (eg, the patient forgets, the patient is admitted to a hospital). Therefore, the dosage of alprazolam should be reduced or discontinued gradually (see DOSAGE AND ADMINISTRATION). CNS Depression and Impaired Performance 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. 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 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).

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, eg, 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 (ie, 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) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg/day of alprazolam 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 (eg, increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event. Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Anxiety Disorders ANXIETY DISORDERS Treatment-Emergent Symptom Incidence* Incidence of Intervention Because of Symptom ALPRAZOLAM PLACEBO ALPRAZOLAM Number of Patients % of Patients Reporting: 565 505 565 Central Nervous System Drowsiness Light-headedness Depression Headache Confusion Insomnia Nervousness Syncope Dizziness Akathisia Tiredness/Sleepiness 41.0 20.8 13.9 12.9 9.9 8.9 4.1 3.1 1.8 1.6 † 21.6 19.3 18.1 19.6 10.0 18.4 10.3 4.0 0.8 1.2 † 15.1 1.2 2.4 1.1 0.9 1.3 1.1 † 2.5 † 1.8 Gastrointestinal Dry Mouth Constipation Diarrhea Nausea/Vomiting Increased Salivation 14.7 10.4 10.1 9.6 4.2 13.3 11.4 10.3 12.8 2.4 0.7 0.9 1.2 1.7 † Cardiovascular Tachycardia/Palpitations Hypotension 7.7 4.7 15.6 2.2 0.4 † Sensory Blurred Vision 6.2 6.2 0.4 Musculoskeletal Rigidity Tremor 4.2 4.0 5.3 8.8 † 0.4 Cutaneous Dermatitis/Allergy 3.8 3.1 0.6 Other Nasal Congestion Weight Gain Weight Loss 7.3 2.7 2.3 9.3 2.7 3.0 † † † *Events reported by 1% or more of alprazolam patients are included. † None reported In addition to the relatively common (ie, 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. Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Panic Disorder PANIC DISORDER Treatment-Emergent Symptom Incidence* ALPRAZOLAM PLACEBO Number of Patients % of Patients Reporting: 1388 1231 Central Nervous System Drowsiness Fatigue and Tiredness Impaired Coordination Irritability Memory Impairment Light-headedness/Dizziness Insomnia Headache Cognitive Disorder Dysarthria Anxiety Abnormal Involuntary Movement Decreased Libido Depression Confusional State Muscular Twitching Increased Libido Change in Libido (Not Specified) Weakness Muscle Tone Disorders Syncope Akathisia Agitation Disinhibition Paresthesia Talkativeness Vasomotor Disturbances Derealization Dream Abnormalities Fear Feeling Warm 76.8 48.6 40.1 33.1 33.1 29.8 29.4 29.2 28.8 23.3 16.6 14.8 14.4 13.8 10.4 7.9 7.7 7.1 7.1 6.3 3.8 3.0 2.9 2.7 2.4 2.2 2.0 1.9 1.8 1.4 1.3 42.7 42.3 17.9 30.1 22.1 36.9 41.8 35.6 20.5 6.3 24.9 21.0 8.0 14.0 8.2 11.8 4.1 5.6 8.4 7.5 4.8 4.3 2.6 1.5 3.2 1.0 2.6 1.2 1.5 1.0 0.5 Gastrointestinal Decreased Salivation Constipation Nausea/Vomiting Diarrhea Abdominal Distress Increased Salivation 32.8 26.2 22.0 20.6 18.3 5.6 34.2 15.4 31.8 22.8 21.5 4.4 Cardio-Respiratory Nasal Congestion Tachycardia Chest Pain Hyperventilation Upper Respiratory Infection 17.4 15.4 10.6 9.7 4.3 16.5 26.8 18.1 14.5 3.7 Sensory Blurred Vision Tinnitus 21.0 6.6 21.4 10.4 Musculoskeletal Muscular Cramps Muscle Stiffness 2.4 2.2 2.4 3.3 Cutaneous Sweating Rash 15.1 10.8 23.5 8.1 Other Increased Appetite Decreased Appetite Weight Gain Weight Loss Micturition Difficulties Menstrual Disorders Sexual Dysfunction Edema Incontinence Infection 32.7 27.8 27.2 22.6 12.2 10.4 7.4 4.9 1.5 1.3 22.8 24.1 17.9 16.5 8.6 8.7 3.7 5.6 0.6 1.7 * Events reported by 1% or more of alprazolam patients are included. In addition to the relatively common (ie, greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients (see PRECAUTIONS, GENERAL). Adverse Events Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled Trials In a larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam, discontinuation-emergent symptoms which occurred at a rate of over 5% in patients treated with alprazolam and at a greater rate than the placebo treated group were as follows: DISCONTINUATION-EMERGENT SYMPTOM INCIDENCE Percentage of 641 Alprazolam-Treated Panic Disorder Patients Reporting Events Body System/Event Neurologic Insomnia Light-headedness Abnormal involuntary movement Headache Muscular twitching Impaired coordination Muscle tone disorders Weakness Psychiatric Anxiety Fatigue and Tiredness Irritability Cognitive Disorder Memory impairment Depression Confusional state 29.5 19.3 17.3 17.0 6.9 6.6 5.9 5.8 19.2 18.4 10.5 10.3 5.5 5.1 5.0 Gastrointestinal Nausea/Vomiting Diarrhea Decreased salivation Metabolic-Nutritional Weight loss Decreased appetite Dermatological Sweating Cardiovascular Tachycardia Special Senses Blurred vision 16.5 13.6 10.6 13.3 12.8 14.4 12.2 10.0 From the studies cited, it has not been determined whether these symptoms are clearly related to the dose and duration of therapy with alprazolam in patients with panic disorder. There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of Alprazolam Tablets (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 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 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: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson syndrome, angioedema, peripheral edema, hyperprolactinemia, gynecomastia, and galactorrhea (see PRECAUTIONS).