Alprazolam (Page 4 of 8)

Drug Interactions

Use with Opioids
The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.

Use with Other CNS Depressants
If Alprazolam Tablets are to be combined with other psychotropic agents or anticonvulsant drugs, careful consideration should be given to the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when co-administered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.

Use with Imipramine and Desipramine
The steady state plasma concentrations of imipramine and desipramine have been reported to be increased an average of 31% and 20%, respectively, by the concomitant administration of Alprazolam Tablets in doses up to 4 mg/day. The clinical significance of these changes is unknown.

Drugs that inhibit alprazolam metabolism via cytochrome P450 3A
The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome P450 3A (CYP3A). Drugs which inhibit this metabolic pathway may have a profound effect on the clearance of alprazolam (see CONTRAINDICATIONS and WARNINGS for additional drugs of this type).

Drugs demonstrated to be CYP3A inhibitors of possible clinical significance on the basis of clinical studies involving alprazolam (caution is recommended during coadministration with alprazolam)

Fluoxetine—Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased half-life by 17%, and decreased measured psychomotor performance.

Propoxyphene—Coadministration of propoxyphene decreased the maximum plasma concentration of alprazolam by 6%, decreased clearance by 38%, and increased half-life by 58%.

Oral Contraceptives—Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased half-life by 29%.

Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during coadministration with alprazolam)

Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction with alprazolam for the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice. Data from in vitro studies of alprazolam suggest a possible drug interaction with alprazolam for the following: sertraline and paroxetine. However, data from an in vivo drug interaction study involving a single dose of alprazolam 1 mg and steady state dose of sertraline (50 to 150 mg/day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine. Caution is recommended during the coadministration of any of these with alprazolam (see WARNINGS).

Drugs demonstrated to be inducers of CYP3ACarbamazepine can increase alprazolam metabolism and therefore can decrease plasma levels of alprazolam.

Drug/Laboratory Test Interactions

Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for a specific drug or specific test.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenic potential was observed during 2-year bioassay studies of alprazolam in rats at doses up to 30 mg/kg/day (150 times the maximum recommended daily human dose of 10 mg/day) and in mice at doses up to 10 mg/kg/day (50 times the maximum recommended daily human dose).

Alprazolam was not mutagenic in the rat micronucleus test at doses up to 100 mg/kg, which is 500 times the maximum recommended daily human dose of 10 mg/day. Alprazolam also was not mutagenic in vitro in the DNA Damage/Alkaline Elution Assay or the Ames Assay.

Alprazolam produced no impairment of fertility in rats at doses up to 5 mg/kg/day, which is 25 times the maximum recommended daily human dose of 10 mg/day.

Pregnancy

Teratogenic Effects: Pregnancy Category D: (See WARNINGS section). Nonteratogenic Effects: It should be considered that the child born of a mother who is receiving benzodiazepines may be at some risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity and respiratory problems have been reported in children born of mothers who have been receiving benzodiazepines.

Labor and Delivery

Alprazolam has no established use in labor or delivery.

Nursing Mothers

Benzodiazepines are known to be excreted in human milk. It should be assumed that alprazolam is as well. Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight. As a general rule, nursing should not be undertaken by mothers who must use alprazolam.

Pediatric Use

Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established.

Geriatric Use

The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

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 SystemDrowsinessLight-headednessDepressionHeadacheConfusionInsomniaNervousnessSyncopeDizzinessAkathisiaTiredness/Sleepiness

41.020.813.912.99.98.94.13.11.81.6†

21.619.318.119.610.018.410.34.00.81.2† 15.11.22.41.10.91.31.1†2.5†1.8
GastrointestinalDry MouthConstipationDiarrheaNausea/VomitingIncreased Salivation 14.710.410.19.64.2 13.311.410.312.82.4 0.70.91.21.7†
CardiovascularTachycardia/PalpitationsHypotension 7.74.7 15.62.2 0.4†

SensoryBlurred Vision

6.2 6.2 0.4
MusculoskeletalRigidityTremor 4.24.0 5.38.8 †0.4

CutaneousDermatitis/Allergy

3.8 3.1 0.6
OtherNasal CongestionWeight GainWeight Loss

7.32.72.3

9.32.73.0 †††

*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 SystemDrowsinessFatigue and TirednessImpaired CoordinationIrritabilityMemory ImpairmentLight-headedness/DizzinessInsomniaHeadacheCognitive DisorderDysarthriaAnxietyAbnormal Involuntary MovementDecreased LibidoDepressionConfusional StateMuscular TwitchingIncreased LibidoChange in Libido (Not Specified)WeaknessMuscle Tone DisordersSyncopeAkathisiaAgitationDisinhibitionParesthesiaTalkativenessVasomotor DisturbancesDerealizationDream AbnormalitiesFearFeeling Warm 76.848.640.133.133.129.829.429.228.823.316.614.814.413.810.47.97.77.17.16.33.83.02.92.72.42.22.01.91.81.41.3 42.742.317.930.122.136.941.835.620.56.324.921.08.014.08.211.84.15.68.47.54.84.32.61.53.21.02.61.21.51.00.5
GastrointestinalDecreased SalivationConstipationNausea/VomitingDiarrheaAbdominal DistressIncreased Salivation 32.826.222.020.618.35.6 34.215.431.822.821.54.4
Cardio-RespiratoryNasal CongestionTachycardiaChest PainHyperventilationUpper Respiratory Infection 17.415.410.69.74.3 16.526.818.114.53.7
SensoryBlurred VisionTinnitus 21.06.6 21.410.4
MusculoskeletalMuscular CrampsMuscle Stiffness 2.42.2 2.43.3
CutaneousSweatingRash 15.110.8 23.58.1
OtherIncreased AppetiteDecreased AppetiteWeight GainWeight LossMicturition DifficultiesMenstrual DisordersSexual DysfunctionEdemaIncontinenceInfection 32.727.827.222.612.210.47.44.91.51.3 22.824.117.916.58.68.73.75.60.61.7
* 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).

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