INDICATIONS AND USAGE 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 six 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.

Panic Disorder Alprazolam is 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, ie, 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 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.

WARNINGS 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 (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).

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% to 93% of patients treated with alprazolam tapered completely off therapy compared to 89% to 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 to 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 (e.g., 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 2.7 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 Events reported by 1% or more of alprazolam patients are included.

Incidence of Intervention Because of Symptom Alprazolam Placebo Alprazolam Number of Patients 565 505 565 % of Patients Reporting: 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 None reported 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.

Treatment-Emergent Adverse Events Reported in Placebo-Controlled Trials of Panic Disorder PANIC DISORDER Treatment-Emergent Symptom Incidence Events reported by 1% or more of alprazolam patients are included.

Alprazolam Placebo Number of Patients 1388 1231 % of Patients Reporting: 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 1.9 1.2 Dream Abnormalities 1.8 1.5 Fear 1.4 1.0 Feeling Warm 1.3 0.5 Gastrointestinal Decreased Salivation 32.8 34.2 Constipation 26.2 15.4 Nausea/Vomiting 22.0 31.8 Diarrhea 20.6 22.8 Abdominal Distress 18.3 21.5 Increased Salivation 5.6 4.4 Cardio-Respiratory Nasal Congestion 17.4 16.5 Tachycardia 15.4 26.8 Chest Pain 10.6 18.1 Hyperventilation 9.7 14.5 Upper Respiratory Infection 4.3 3.7 Sensory Blurred Vision 21.0 21.4 Tinnitus 6.6 10.4 Musculoskeletal Muscular Cramps 2.4 2.4 Muscle Stiffness 2.2 3.3 Cutaneous Sweating 15.1 23.5 Rash 10.8 8.1 Other Increased Appetite 32.7 22.8 Decreased Appetite 27.8 24.1 Weight Gain 27.2 17.9 Weight Loss 22.6 16.5 Micturition Difficulties 12.2 8.6 Menstrual Disorders 10.4 8.7 Sexual Dysfunction 7.4 3.7 Edema 4.9 5.6 Incontinence 1.5 0.6 Infection 1.3 1.7 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 Gastrointestinal Insomnia 29.5 Nausea/Vomiting 16.5 Light-headedness 19.3 Diarrhea 13.6 Abnormal involuntary movement 17.3 Decreased salivation 10.6 Headache 17.0 Metabolic-Nutritional Muscular twitching 6.9 Weight loss 13.3 Impaired coordination 6.6 Decreased appetite 12.8 Muscle tone disorders 5.9 Weakness 5.8 Dermatological Psychiatric Sweating 14.4 Anxiety 19.2 Fatigue and Tiredness 18.4 Cardiovascular Irritability 10.5 Tachycardia 12.2 Cognitive disorder 10.3 Memory impairment 5.5 Special Senses Depression 5.1 Blurred vision 10.0 Confusional state 5.0 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 ).