Alprazolam (Page 3 of 7)

5.5 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.

5.6 CNS Depression and Impaired Performance

Because alprazolam 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 alprazolam treatment does not affect them adversely. Caution patients about the simultaneous ingestion of alcohol and other CNS depressant drugs during treatment with alprazolam.

5.7 Mania

Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression.

5.8 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 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 ( 4)].

Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam

Consider dose reduction of alprazolam 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)].

5.9 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)].

5.10 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 ( 2)].

5.11 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.

5.12 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)].


6.1 Clinical Trial Experience

The most commonly reported (greater than or equal to 5% and ~ twice the rate of placebo) adverse reactions with alprazolam treatment are: sedation, impaired coordination, dysarthria, and increased libido.

The data cited in the two tables below are estimates of adverse reactions occurring in patients who participated in clinical trials under the following conditions: relatively short duration (four weeks) placebo-controlled clinical studies with dosages up to 4 mg per 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 per day of alprazolam in patients with panic disorder, with or without agoraphobia.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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 adverse reaction 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 dry mouth in others.)

Table 1: Adverse Reactions Reported in Placebo-Controlled Trials of Alprazolam in Generalized Anxiety Disorder (>2% and at a rate greater than placebo)
Body System/Adverse Reaction Treatment-Emergent Symptom Incidence a
ALPRAZOLAM (%) N = 565 PLACEBO (%) N = 505
Central Nervous System
Sedation 41 22
Lightheadedness 21 19
Dizziness 2 1
Akathisia 2 1
Dry Mouth 15 13
Increased Salivation 4 2
Hypotension 5 2
Dermatitis/Allergy 4 3
a Events reported by 1% or more of alprazolam patients are included.

In addition to the relatively common (i.e., greater than 1%) adverse reactions described in the table above, the following adverse reactions 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.

Table 2: Adverse Reactions Reported in Placebo-Controlled Trials of Alprazolam in Panic Disorder (>2% and greater than placebo)
Body System/Adverse Reaction Treatment-Emergent Symptom Incidence a
ALPRAZOLAM (%) N = 1388 PLACEBO (%) N = 1231
Central Nervous System
Sedation 77 43
Fatigue and Tiredness 49 42
Impaired Coordination 40 18
Irritability 33 30
Memory Impairment 33 22
Cognitive Disorder 29 21
Dysarthria 23 6
Decreased Libido 14 8
Confusional State 10 8
Increased Libido 8 4
Change in Libido (Not Specified) 7 6
Disinhibition 3 2
Talkativeness 2 1
Derealization 2 1
Constipation 26 15
Increased Salivation 6 4
Rash 11 8
Increased Appetite 33 23
Decreased Appetite 28 24
Weight Gain 27 18
Weight Loss 23 17
Micturition Difficulties 12 9
Menstrual Disorders 10 9
Sexual Dysfunction 7 4
Incontinence 2 1
a Events reported by 1% or more of alprazolam patients are included.

In addition to the relatively common (i.e., greater than 1%) adverse reactions described in the table above, the following adverse reactions 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 Warnings and Precautions, ( 5.2)].

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