Alprazolam: Package Insert and Label Information (Page 4 of 5)

DRUG ABUSE AND DEPENDENCE

Physical and Psychological Dependence

Withdrawal symptoms similar in character to those noted with sedative/hypnotics and alcohol have occurred following discontinuance of benzodiazepines, including alprazolam. The symptoms can range from mild dysphoria and insomnia to a major syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors and convulsions. Distinguishing between withdrawal emergent signs and symptoms and the recurrence of illness is often difficult in patients undergoing dose reduction. The long term strategy for treatment of these phenomena will vary with their cause and the therapeutic goal. When necessary, immediate management of withdrawal symptoms requires re-institution of treatment at doses of alprazolam sufficient to suppress symptoms. There have been reports of failure of other benzodiazepines to fully suppress these withdrawal symptoms. These failures have been attributed to incomplete cross-tolerance but may also reflect the use of an inadequate dosing regimen of the substituted benzodiazepine or the effects of concomitant medications.

While it is difficult to distinguish withdrawal and recurrence for certain patients, the time course and the nature of the symptoms may be helpful. A withdrawal syndrome typically includes the occurrence of new symptoms, tends to appear toward the end of taper or shortly after discontinuation, and will decrease with time. In recurring panic disorder, symptoms similar to those observed before treatment may recur either early or late, and they will persist.

While the severity and incidence of withdrawal phenomena appear to be related to dose and duration of treatment, withdrawal symptoms, including seizures, have been reported after only brief therapy with alprazolam at doses within the recommended range for the treatment of anxiety (eg, 0.75 to 4 mg/day). Signs and symptoms of withdrawal are often more prominent after rapid decrease of dosage or abrupt discontinuance. The risk of withdrawal seizures may be increased at doses above 4 mg/day (see WARNINGS).

Patients, especially individuals with a history of seizures or epilepsy, should not be abruptly discontinued from any CNS depressant agent, including alprazolam. It is recommended that all patients on alprazolam who require a dosage reduction be gradually tapered under close supervision (see WARNINGS and DOSAGE AND ADMINISTRATION).

Psychological dependence is a risk with all benzodiazepines, including alprazolam. The risk of psychological dependence may also be increased at doses greater than 4 mg/day and with longer term use, and this risk is further increased in patients with a history of alcohol or drug abuse. Some patients have experienced considerable difficulty in tapering and discontinuing from alprazolam, especially those receiving higher doses for extended periods. Addiction-prone individuals should be under careful surveillance when receiving alprazolam. As with all anxiolytics, repeat prescriptions should be limited to those who are under medical supervision.

Controlled Substance Class

Alprazolam is a controlled substance under the Controlled Substance Act by the Drug Enforcement Administration and Alprazolam Tablets have been assigned to Schedule IV.

OVERDOSAGE

Clinical Experience

Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with a combination of a single benzodiazepine, including alprazolam, and alcohol; alcohol levels seen in some of these patients have been lower than those usually associated with alcohol-induced fatality.

The acute oral LD 50 in rats is 331-2171 mg/kg. Other experiments in animals have indicated that cardiopulmonary collapse can occur following massive intravenous doses of alprazolam (over 195 mg/kg; 975 times the maximum recommended daily human dose of 10 mg/day). Animals could be resuscitated with positive mechanical ventilation and the intravenous infusion of norepinephrine bitartrate.

Animal experiments have suggested that forced diuresis or hemodialysis are probably of little value in treating overdosage.

General Treatment of Overdose

Overdosage reports with Alprazolam Tablets are limited. As in all cases of drug overdosage, respiration, pulse rate, and blood pressure should be monitored. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. If hypotension occurs, it may be combated by the use of vasopressors. Dialysis is of limited value. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested.

Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS and PRECAUTIONS should be consulted prior to use.

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/day. In such cases, dosage should be increased cautiously to avoid adverse effects.

Anxiety Disorders and Transient Symptoms of Anxiety

Treatment for patients with anxiety should be initiated with a dose of 0.25 to 0.5 mg given 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. The lowest possible effective dose should be employed and the need for continued treatment reassessed frequently. The risk of dependence may increase with dose and duration of treatment.

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 3 days. Some patients may require an even slower dosage reduction.

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 to 10 mg daily were used. The mean dosage employed was approximately 5 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/day, including approximately 100 patients who received maximum dosages of greater than 9 mg/day. Occasional patients required as much as 10 mg a day to achieve a successful response.

Dose Titration
Treatment may be initiated 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/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, that is, on a three or four times per day schedule.

Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. Dose should be advanced until an acceptable therapeutic response (ie, 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/day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than 4 mg/day for 3 months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. Because of the danger of withdrawal, abrupt discontinuation of treatment should be avoided. (See WARNINGS, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE.)

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, PRECAUTIONS, DRUG ABUSE AND DEPENDENCE).

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, the previous dosing schedule should be reinstituted and, only after stabilization, should a less rapid schedule of discontinuation be attempted. 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. It is suggested that the dose be reduced by no more than 0.5 mg every 3 days, with the understanding that some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

Dosing in Special Populations
In elderly patients, in patients with advanced liver disease or in patients with debilitating 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 side effects occur at the recommended starting dose, the dose may be lowered.

HOW SUPPLIED

Alprazolam Tablets, USP are available as follows:

0.25 mg (white, oval, scored on one side: S left of bisect 900 to right)
Bottles of 90 NDC 67253-900-09
Bottles of 100 NDC 67253-900-10
Bottles of 500 NDC 67253-900-50
Bottles of 1000 NDC 67253-900-11

0.5 mg (yellow, oval, scored on one side; S left of bisect 901 to right)
Bottles of 100 NDC 67253-901-10
Bottles of 500 NDC 67253-901-50
Bottles of 1000 NDC 67253-901-11

1 mg (green, oval, scored on one side; S left of bisect 902 to right)
Bottles of 100 NDC 67253-902-10
Bottles of 500 NDC 67253-902-50
Bottles of 1000 NDC 67253-902-11

2 mg (green, elongated, rectangular-shaped, multi-scored; S left of bisect, 90 center and 3 to right)
Bottles of 100 NDC 67253-903-10
Bottles of 500 NDC 67253-903-50

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Rx only

ANIMAL STUDIES

When rats were treated with alprazolam at 3, 10, and 30 mg/kg/day (15 to 150 times the maximum recommended human dose) orally for 2 years, a tendency for a dose related increase in the number of cataracts was observed in females and a tendency for a dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

Distributed by:
Par Pharmaceutical
Chestnut Ridge, NY 10977

300 172 990 138 Revised: 01/17

MEDICATION GUIDE Alprazolam Tablets (al pra’ zoe lam), C-IV

What is the most important information I should know about alprazolam tablets?

  • Alprazolam tablets is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.
  • Alprazolam tablets can make you sleepy or dizzy, and can slow your thinking and motor skills.
    • Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affects you.
    • Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse.
  • Do not take more alprazolam tablets than prescribed.

What is alprazolam tablets?

  • Alprazolam tablets is a prescription medicine used:
    • to treat anxiety disorders
    • for the short-term relief of the symptoms of anxiety
    • to treat panic disorder with or without a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)
  • Alprazolam tablets is a federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep alprazolam tablets in a safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.
  • It is not known if alprazolam tablets is safe and effective in children.
  • Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets.
  • It is not known if alprazolam tablets is safe and effective when used to treat anxiety disorder for longer than 4 months.
  • It is not known if alprazolam tablets is safe and effective when used to treat panic disorder for longer than 10 weeks.

Do not take alprazolam tablets if:

  • you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam tablets. See the end of this Medication Guide for a complete list of ingredients in alprazolam tablets.
  • you are taking antifungal medicines including ketoconazole and itraconazole

Before you take alprazolam tablets, tell your healthcare provider about all of your medical conditions, including if you:

  • have or have had depression, mood problems, or suicidal thoughts or behavior
  • have liver or kidney problems
  • have lung disease or breathing problems
  • are pregnant or plan to become pregnant. Alprazolam tablets may harm your unborn baby. You and your healthcare provider should decide if you should take alprazolam tablets while you are pregnant.
  • are breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take alprazolam tablets. You should not breastfeed while taking alprazolam tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I take alprazolam tablets?

  • See “What is the most important information I should know about alprazolam tablets?”
  • Take alprazolam tablets exactly as your healthcare provider tells you to take it. Your healthcare provider will tell you how much alprazolam tablets to take and when to take it.
  • If you take too much alprazolam tablets, call your healthcare provider or go to the nearest hospital emergency room right away.

What should I avoid while taking alprazolam tablets?

  • Alprazolam tablets can cause you to be drowsy. Do not drive a car or operate heavy machinery until you know how alprazolam tablets affects you.
  • You should not drink alcohol while taking alprazolam tablets. Drinking alcohol can increase your chances of having serious side effects.

What are the possible side effects of alprazolam tablets?

Alprazolam tablets may cause serious side effects, including:

  • See “What is the most important information I should know about alprazolam tablets?”
  • Abuse and dependence. Taking alprazolam tablets can cause physical and psychological dependence. Physical and psychological dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction.
  • Withdrawal symptoms. You may have withdrawal symptoms if you stop taking alprazolam tablets suddenly. Withdrawal symptoms can be serious and include seizures. Mild withdrawal symptoms include a depressed mood and trouble sleeping. Talk to your healthcare provider about slowly stopping alprazolam tablets to avoid withdrawal symptoms.
  • Seizures. Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus).
  • Mania. Alprazolam tablets may cause an increase in activity and talking (hypomania and mania) in people who have depression.
The most common side effects of alprazolam tablets include drowsiness and lightheadedness. These are not all the possible side effects of alprazolam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store alprazolam tablets?

  • Store alprazolam tablets between 68°F to 77°F 20°C to 25°C
  • Keep alprazolam tablets and all medicines out of the reach of children.

General information about the safe and effective use of alprazolam tablets.

  • Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
  • Do not use alprazolam tablets for a condition for which it was not prescribed.
  • Do not give alprazolam tablets to other people, even if they have the same symptoms that you have. It may harm them.
  • You can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals.

What are the ingredients in alprazolam tablets?

Active ingredient: alprazolam

Inactive ingredients: crospovidone, docusate sodium, lactose, magnesium stearate, microcrystalline cellulose, silicon dioxide, sodium benzoate and starch 1500. In addition, the 0.5 mg tablet contains D&C Yellow No. 10 and the 1 mg and 2 mg tablet contains Green Lake Blend.

Distributed by: Par Pharmaceutical, Chestnut Ridge, NY 10977 1-800-828-9393
This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 01/2017

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