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XANAX® XR, CIV (alprazolam) Warnings and Precautions

WARNINGS

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including XANAX XR, 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 XANAX XR 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 XANAX XR than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking XANAX XR, 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 XANAX XR 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 doses of ≤ 4 mg/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 who received XANAX Tablets, 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 XANAX Tablets greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.

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.

The rate of relapse, rebound, and withdrawal in patients with panic disorder who received XANAX XR Tablets has not been systematically studied. Experience in randomized placebo-controlled discontinuation studies of patients with panic disorder who received XANAX Tablets showed a high rate of rebound and withdrawal symptoms compared to placebo treated patients.

In a controlled clinical trial in which 63 patients were randomized to XANAX Tablets 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 XANAX Tablets tapered completely off therapy compared to 89%–96% of placebo treated patients. In a controlled postmarketing discontinuation study of panic disorder patients treated with XANAX Tablets, the duration of treatment (3 months compared to 6 months) had no effect on the ability of patients to taper to zero dose.

Seizures were reported for three patients in panic disorder clinical trials with XANAX XR. In two cases, the patients had completed 6 weeks of treatment with XANAX XR 6 mg/day before experiencing a single seizure. In one case, the patient abruptly discontinued XANAX XR, and in both cases, alcohol intake was implicated.The third case involved multiple seizures after the patient completed treatment with XANAX XR 4 mg/day and missed taking the medication on the first day of taper. All three patients recovered without sequelae.

Seizures have also been observed in association with dose reduction or discontinuation of XANAX Tablets, the immediate release form of alprazolam. Seizures attributable to XANAX 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 XANAX 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 three 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 XANAX. 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

The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of XANAX Tablets. 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 XANAX Tablets have been reported in patients with panic disorder taking prescribed maintenance doses. 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.

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 XANAX XR should be reduced or discontinued gradually (see DOSAGE AND ADMINISTRATION).

CNS Depression and Impaired Performance

Because of its CNS depressant effects, patients receiving XANAX XR 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 XANAX XR.

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%.

HIV protease inhibitors

Interactions involving HIV protease inhibitors (eg, ritonavir) and alprazolam are complex and time dependent. Low doses of ritonavir resulted in a large impairment of alprazolam clearance, prolonged its elimination half-life and enhanced clinical effects. However, upon extended exposure to ritonavir, CYP3A induction offset this inhibition. This interaction will require a dose-adjustment or discontinuation of alprazolam.

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).


PRECAUTIONS

General

Suicide

As with other psychotropic medications, the usual precautions with respect to administration of the drug and size of the prescription are indicated for severely depressed patients or those in whom there is reason to expect concealed suicidal ideation or plans. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients.

Mania

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

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.

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). 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 XANAX Tablets. A decreased systemic alprazolam elimination rate (eg, increased plasma half-life) has been observed in both alcoholic liver disease patients and obese patients receiving XANAX Tablets (see CLINICAL PHARMACOLOGY).

Information for Patients

To assure safe and effective use of XANAX XR, the physician should provide the patient with the following guidance.

  1. Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when XANAX XR is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider.
  2. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see Drug Interactions).
  3. Inform your physician about any alcohol consumption and medicine you are taking now, including medication you may buy without a prescription. Alcohol should generally not be used during treatment with benzodiazepines.
  4. Not recommended for use in pregnancy. Therefore, inform your physician if you are pregnant, if you are planning to have a child, or if you become pregnant while you are taking this medication.
  5. Inform your physician if you are nursing.
  6. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
  7. Do not increase the dose even if you think the medication "does not work anymore" without consulting your physician. Benzodiazepines, even when used as recommended, may produce emotional and/or physical dependence.
  8. Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.
  9. Some patients may find it very difficult to discontinue treatment with XANAX XR due to severe emotional and physical dependence. Discontinuation symptoms, including possible seizures, may occur following discontinuation from any dose, but the risk may be increased with extended use at doses greater than 4 mg/day, especially if discontinuation is too abrupt. It is important that you seek advice from your physician to discontinue treatment in a careful and safe manner. Proper discontinuation will help to decrease the possibility of withdrawal reactions that can range from mild reactions to severe reactions such as seizure.

Laboratory Tests

Laboratory tests are not ordinarily required in otherwise healthy patients. However, when treatment is protracted, periodic blood counts, urinalysis, and blood chemistry analyses are advisable in keeping with good medical practice.

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 XANAX XR 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 coadministered with other psychotropic medications, anticonvulsants, antihistaminics, ethanol and other drugs which themselves produce CNS depression.

Use with Digoxin

Increased digoxin concentrations have been reported when alprazolam was given, especially in elderly (>65 years of age). Patients who receive alprazolam and digoxin should therefore be monitored for signs and symptoms related to digoxin toxicity.

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 XANAX 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 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).

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