Xanax XR (Page 4 of 7)

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 doses 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 CYP3A

Carbamazepine 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 to Xanax XR

The information included in the subsection on Adverse Events Observed in Short-Term, Placebo-Controlled Trials with XANAX XR Tablets is based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder.

Adverse event reports were elicited either by general inquiry or by checklist, and were recorded by clinical investigators using terminology of their own choosing. The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment emergent if it occurred for the first time or worsened during therapy following baseline evaluation. In the tables and tabulations that follow, standard MedDRA terminology (version 4.0) was used to classify reported adverse events.

Adverse Events Observed in Short-Term, Placebo-Controlled Trials of XANAX XR

Adverse Events Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials

Approximately 17% of the 531 patients who received XANAX XR in placebo-controlled clinical trials for panic disorder had at least one adverse event that led to discontinuation compared to 8% of 349 placebo-treated patients. The most common events leading to discontinuation and considered to be drug-related (ie, leading to discontinuation in at least 1% of the patients treated with XANAX XR at a rate at least twice that of placebo) are shown in the following table.

Common Adverse Events Leading to Discontinuation of Treatment in Placebo-Controlled Trials
System Organ Class/Adverse Event Percentage of Patients Discontinuing Due to Adverse Events
XANAX XR(n=531) Placebo(n=349)
Nervous system disorders
Sedation 7.5 0.6
Somnolence 3.2 0.3
Dysarthria 2.1 0
Coordination abnormal 1.9 0.3
Memory impairment 1.5 0.3
General disorders/administration site conditions
Fatigue 1.7 0.6
Psychiatric disorders
Depression 2.5 1.2

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated with XANAX XR

The prescriber should be aware that adverse event incidence cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with event incidence obtained from other clinical investigations involving different treatments, uses, and investigators. The cited values, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

The following table shows the incidence of treatment-emergent adverse events that occurred during 6- to 8-week placebo-controlled trials in 1% or more of patients treated with XANAX XR where the incidence in patients treated with XANAX XR was greater than the incidence in placebo-treated patients. The most commonly observed adverse events in panic disorder patients treated with XANAX XR (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased (see table).

Treatment-Emergent Adverse Events: Incidence in Short-Term, Placebo-Controlled Clinical Trials with XANAX XR
System Organ Class/Adverse Event Percentage of Patients Reporting Adverse Event
XANAX XR(n=531) Placebo(n=349)
Nervous system disorders
Sedation 45.2 22.6
Somnolence 23.0 6.0
Memory impairment 15.4 6.9
Dysarthria 10.9 2.6
Coordination abnormal 9.4 0.9
Mental impairment 7.2 5.7
Ataxia 7.2 3.2
Disturbance in attention 3.2 0.6
Balance impaired 3.2 0.6
Paresthesia 2.4 1.7
Dyskinesia 1.7 1.4
Hypoesthesia 1.3 0.3
Hypersomnia 1.3 0
General disorders/administration site conditions
Fatigue 13.9 9.2
Lethargy 1.7 0.6
Infections and infestations
Influenza 2.4 2.3
Upper respiratory tract infections 1.9 1.7
Psychiatric disorders
Depression 12.1 9.2
Libido decreased 6.0 2.3
Disorientation 1.5 0
Confusion 1.5 0.9
Depressed mood 1.3 0.3
Anxiety 1.1 0.6
Metabolism and nutrition disorders
Appetite decreased 7.3 7.2
Appetite increased 7.0 6.0
Anorexia 1.5 0
Gastrointestinal disorders
Dry mouth 10.2 9.7
Constipation 8.1 4.3
Nausea 6.0 3.2
Pharyngolaryngeal pain 3.2 2.6
Investigations
Weight increased 5.1 4.3
Weight decreased 4.3 3.7
Injury, poisoning, and procedural complications
Road traffic accident 1.5 0
Reproductive system and breast disorders
Dysmenorrhea 3.6 2.9
Sexual dysfunction 2.4 1.1
Premenstrual syndrome 1.7 0.6
Musculoskeletal and connective tissue disorders
Arthralgia 2.4 0.6
Myalgia 1.5 1.1
Pain in limb 1.1 0.3
Vascular disorders
Hot flushes 1.5 1.4
Respiratory, thoracic, and mediastinal disorders
Dyspnea 1.5 0.3
Rhinitis allergic 1.1 0.6
Skin and subcutaneous tissue disorders
Pruritis 1.1 0.9

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