Alprazolam: Package Insert and Label Information

ALPRAZOLAM- alprazolam tablet, orally disintegrating
Actavis Pharma, Inc.

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death [ see Warnings and Precautions (5.1), Drug Interactions (7.1)].

  • Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

  • Limit dosages and durations to the minimum required.

  • Follow patients for signs and symptoms of respiratory depression and sedation.

1 INDICATIONS AND USAGE

1.1 Generalized Anxiety Disorder

Alprazolam orally disintegrating tablets, USP are indicated for the treatment of generalized anxiety disorder.

The efficacy of alprazolam in the treatment of generalized anxiety disorder was demonstrated in 5 short-term, placebo-controlled trials [see Clinical Studies ( 14.1)].

1.2 Panic Disorder

Alprazolam orally disintegrating tablets, USP are also indicated for the treatment of panic disorder, with or without agoraphobia.

The efficacy of alprazolam in the treatment of panic disorder was established in 2 short-term, placebo-controlled trials [see Clinical Studies ( 14.2)].

Demonstrations of the effectiveness of alprazolam by systematic clinical study are limited to 4 months in duration for generalized 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.

2 DOSAGE AND ADMINISTRATION

Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who require doses greater than 4 mg per day. In such cases, the dosage should be increased cautiously to avoid adverse reactions. In general, benzodiazepines should be prescribed for short periods. Reevaluate the need for continued therapy before extending the treatment period.

2.1 Generalized Anxiety Disorder

Initiate treatment with a dose of 0.25 mg to 0.5 mg three times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. Use the lowest possible effective dose, and periodically reassess the need for continued treatment. The risk of dependence can increase with dose and duration of treatment.

The dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction.

2.2 Panic Disorder

The successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 mg to 10 mg daily were used. The mean dosage employed was approximately 5 mg to 6 mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received alprazolam in dosages of greater than 7 mg per day, including approximately 100 patients who received maximum dosages of greater than 9 mg per day. Occasional patients required as much as 10 mg a day to achieve a successful response.

Dose Titration

Initiate treatment with a dose of 0.5 mg three times daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg per day may be advisable to allow full expression of the pharmacodynamic effect of alprazolam. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, (i.e., administered three or four times daily).

Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. The dose should be advanced until an acceptable therapeutic response (i.e., a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained.

Dose Maintenance

For patients receiving doses greater than 4 mg per day, periodically reassess treatment and consider a reduction of dosage. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than 4 mg per day for 3 months were able to taper to 50% of their total daily maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, avoid abrupt discontinuation of treatment [see Warnings and Precautions (5.4), Drug Abuse and Dependence ( 9.3)].

The necessary duration of treatment for panic disorder patients responding to alprazolam is unknown. After a period of extended freedom from attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena.

Dose Reduction

Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided [see Warnings and Precautions (5.4), Drug Abuse and Dependence ( 9.3)].

In all patients, dosage should be reduced gradually when discontinuing therapy or when decreasing the daily dosage. Although there are no systematically collected data to support a specific discontinuation schedule, it is suggested that the daily dosage be decreased by no more than 0.5 mg every three days. Some patients may require an even slower dosage reduction.

In any case, reduction of dose must be undertaken under close supervision and must be gradual. If significant withdrawal symptoms develop, reinstitute the previous stable dosing schedule. After stabilization, consider using a less rapid schedule of discontinuation. In a controlled postmarketing discontinuation study of panic disorder patients which compared this recommended taper schedule with a slower taper schedule, there was no difference between the groups in the proportion of patients who tapered and completely discontinued treatment with alprazolam; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. Reduce the dose by no more than 0.5 mg every 3 days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

2.3 Dosing in Special Populations

In elderly patients, in patients with advanced liver disease, or in patients with debilitating disease (e.g., severe pulmonary disease), the usual starting dose is 0.25 mg, given two or three times daily. This may be gradually increased if needed and tolerated. The elderly may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dose, the dose may be lowered.

2.4 Instructions to be Given to Patients for Use/Handling Alprazolam Orally Disintegrating Tablets

Just prior to administration, with dry hands, remove the tablet from the bottle. Immediately place the alprazolam orally disintegrating tablet on top of the tongue where it will disintegrate and be swallowed with saliva. Administration with liquid is not necessary.

Discard any cotton that was included in the bottle and reseal the bottle tightly to prevent introducing moisture that might cause the tablets to disintegrate.

3 DOSAGE FORMS AND STRENGTHS

0.25 mg, 0.5 mg, 1 mg, and 2 mg scored orally disintegrating tablets.

4 CONTRAINDICATIONS

Alprazolam orally disintegrating tablets are contraindicated in patients with acute narrow angle glaucoma. Alprazolam orally disintegrating tablets can exacerbate narrow angle closure. Alprazolam orally disintegrating tablets may be used in patients with open angle glaucoma who are receiving appropriate therapy.

Alprazolam orally disintegrating tablets are contraindicated in patients treated with potent CYP3A4 inhibitors (e.g., ketoconazole and itraconazole), because these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) and can increase alprazolam exposures [see Clinical Pharmacology ( 12.3), Warnings and Precautions (5.8), and Drug Interactions ( 7.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including alprazolam, 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 alprazolam 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 alprazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam, 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 alprazolam 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 (7.1), Patient Counseling (17)].

5.2 Suicide and Overdose

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.

5.3 Status Epilepticus

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.

5.4 Dependence and Withdrawal Reactions, Including Seizures

Alprazolam is a Schedule IV controlled substance. The use of benzodiazepines, including alprazolam, may lead to physical and psychological dependence. In general, benzodiazepines should be prescribed for short periods. Even after relatively short-term use at the recommended doses, there is some risk of dependence and withdrawal symptoms [see Dependence ( 9.3)].

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 ( 9.3)]. 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 per 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 per day had more difficulty tapering to zero dose than those treated with less than 4 mg per 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 mg 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 ( 2)].

To discontinue treatment in patients taking alprazolam, the dosage should be reduced gradually. Decrease the daily dosage of alprazolam by no more than 0.5 mg every three days [see Dosage and Administration ( 2)]. 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.

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