ALPRAZOLAM- alprazolam tablet, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
ALPRAZOLAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY)
Available from:
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Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Alprazolam extended-release tablets are indicated for the treatment of panic disorder, with or without agoraphobia. This claim is supported on the basis of two positive studies with alprazolam extended-release conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic disorder (see CLINICAL EFFICACY TRIALS). Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear
Product summary:
Alprazolam Extended-Release Tablets USP, 0.5 mg are white to off-white, round, biconvex tablets with beveled edge debossed with ‘X’ on one side and ‘70’ on the other side. Bottles of 60 Bottles of 1,000 Bottles of 7,000 Alprazolam Extended-Release Tablets USP, 1 mg are yellow colored, round, biconvex tablets with beveled edge debossed with ‘X’ on one side and ‘73’ on the other side. The tablets may be mottled. Bottles of 60 Bottles of 1,000 Bottles of 7,000 Alprazolam Extended-Release Tablets USP, 2 mg are blue colored, round, biconvex tablets with beveled edge debossed with ‘X’ on one side and ‘74’ on the other side. The tablets may be mottled. Bottles of 60 Bottles of 1,000 Bottles of 7,000 Alprazolam Extended-Release Tablets USP, 3 mg are green colored, round, biconvex tablets with beveled edge debossed with ‘X’ on one side and ‘75’ on the other side. The tablets may be mottled. Bottles of 60 Bottles of 1,000 Bottles of 7,000 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
72189-029-90

ALPRAZOLAM- alprazolam tablet, extended release

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Alprazolam Extended-Release Tablets, USP

(al pra' zoe lam) CIV

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

Alprazolam extended-release tablets are 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 extended-release 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

extended-release tablets affects you.

Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam

extended-release tablets without first talking to your healthcare provider. When taken with alcohol or drugs

that cause sleepiness or dizziness, alprazolam extended-release tablets may make your sleepiness or dizziness

much worse.

Do not take more alprazolam extended-release tablets than prescribed.

What are alprazolam extended-release tablets?

Alprazolam extended-release tablets are a prescription medicine used to treat panic disorder, with or without

a fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)

Alprazolam extended-release tablets are a federal controlled substance (C-IV) because it can be abused or

lead to dependence. Keep alprazolam extended-release tablets in a safe place to prevent misuse and abuse.

Selling or giving away alprazolam extended-release 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 extended-release tablets are safe and effective in children.

Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam extended-

release tablets.

It is not known if alprazolam extended-release tablets are safe and effective for use longer than 8 weeks.

Do not take alprazolam extended-release tablets if:

you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam extended-

release tablets. See the end of this Medication Guide for a complete list of ingredients in alprazolam

extended-release tablets.

you are taking antifungal medicines including ketoconazole and itraconazole

Before you take alprazolam extended-release 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 extended-release tablets may harm your unborn baby.

You and your healthcare provider should decide if you should take alprazolam extended-release 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 extended-

release tablets. You should not breastfeed while taking alprazolam extended-release tablets.

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

medicines, vitamins, and herbal supplements.

Taking alprazolam extended-release tablets with certain other medicines can cause side effects or affect how

well alprazolam extended-release tablets or the other medicines work. Do not start or stop other medicines

without talking to your healthcare provider.

How should I take alprazolam extended-release tablets?

See “What is the most important information I should know about alprazolam extended-release tablets?”

Take alprazolam extended-release tablets exactly as your healthcare provider tells you to take it. Your

healthcare provider will tell you how much alprazolam extended-release tablets to take and when to take it.

Swallow alprazolam extended-release tablets whole. Do not crush, chew or break alprazolam extended-

release tablets.

If you take too much alprazolam, call your healthcare provider or go to the nearest hospital emergency room

right away.

What should I avoid while taking alprazolam extended-release tablets?

Alprazolam extended-release tablets can cause you to be drowsy. Do not drive a car or operate heavy

machinery until you know how alprazolam extended-release tablets affect you.

You should not drink alcohol while taking alprazolam extended-release tablets. Drinking alcohol can

increase your chances of having serious side effects.

What are the possible side effects of alprazolam extended-release tablets?

Alprazolam extended-release tablets may cause serious side effects, including:

See “What is the most important information I should know about alprazolam extended-release tablets?”

Abuse and dependence. Taking alprazolam extended-release 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 extended-release

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 extended-release tablets to avoid withdrawal symptoms.

Seizures. Stopping alprazolam extended-release tablets can cause seizures and seizures that will not stop

(status epilepticus).

Mania. Alprazolam extended-release tablets may cause an increase in activity and talking (hypomania and

mania) in people who have depression.

The most common side effects of alprazolam extended-release tablets include:

sedation

difficult or unclear ability to talk

problems with coordination

tiredness

drowsiness

depression

memory problems

These are not all the possible side effects of alprazolam extended-release 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 extended-release tablets?

Store alprazolam extended-release tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C

(59° to 86°F). Keep alprazolam tablets and all medicines out of the reach of children.

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

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

Do not use alprazolam extended-release tablets for a condition for which it was not prescribed.

Do not give alprazolam extended-release 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 extended-release

tablets that is written for health professionals.

What are the ingredients in alprazolam extended-release tablets?

Active ingredient: alprazolam

Inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, and magnesium stearate.

In addition, the 1 mg and 3 mg tablet contains D&C Yellow No. 10 aluminum lake and the 2 mg and 3 mg

tablets contain FD&C Blue No. 2 lake.

For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 038, India

Revised: 07/2018

Revised: 9/2019

Document Id: 91d4bc67-31a8-bd2e-e053-2a95a90a8632

34391-3

Set id: 91d4bc67-31a7-bd2e-e053-2a95a90a8632

Version: 1

Effective Time: 20190905

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ALPRAZOLAM- alprazolam tablet, extended release

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ALPRAZOLAM

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, Drug Interactions).

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.

Alprazolam extended-release tablets USP contain alprazolam which is a triazolo analog of the 1,4

benzodiazepine class of central nervous system-active compounds.

The chemical name of alprazolam is 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4]

benzodiazepine. The molecular formula is C17H13ClN4 which corresponds to a molecular weight of

308.76.

The structural formula is represented below:

[Chemical Structure]

Alprazolam USP is a white to off-white, crystalline powder, which is soluble in methanol or ethanol but

which has no appreciable solubility in water at physiological pH.

Each alprazolam extended-release tablet USP, for oral administration, contains 0.5 mg, 1 mg, 2 mg, or 3

mg of alprazolam. The inactive ingredients are colloidal silicon dioxide, hypromellose, lactose

monohydrate, and magnesium stearate. In addition, the 1 mg and 3 mg tablets contain D&C Yellow No.

10 aluminum lake and the 2 mg and 3 mg tablets contain FD&C Blue No. 2 lake.

Meets USP Dissolution Test 4.

Pharmacodynamics

CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereospecific

receptors at several sites within the central nervous system. Their exact mechanism of action is

unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant

activity varying from mild impairment of task performance to hypnosis.

Pharmacokinetics

Absorption

Following oral administration of alprazolam (immediate-release) tablets, alprazolam is readily absorbed.

Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are

proportional to the dose given; over the dose range of 0.5 to 3 mg, peak levels of 8 to 37 ng/mL were

observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has

been found to be about 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.

The mean absolute bioavailability of alprazolam from alprazolam extended-release tablets is

approximately 90%, and the relative bioavailability compared to alprazolam tablets is 100%. The

bioavailability and pharmacokinetics of alprazolam following administration of alprazolam extended-

release tablets are similar to that for alprazolam tablets, with the exception of a slower rate of

absorption. The slower absorption rate results in a relatively constant concentration that is maintained

between 5 and 11 hours after the dosing. The pharmacokinetics of alprazolam and two of its major active

metabolites (4-hydroxyalprazolam and α-hydroxyalprazolam) are linear, and concentrations are

proportional up to the recommended maximum daily dose of 10 mg given once daily. Multiple dose

studies indicate that the metabolism and elimination of alprazolam are similar for the immediate-release

and the extended-release products.

Food has a significant influence on the bioavailability of alprazolam extended-release tablets. A high-

fat meal given up to 2 hours before dosing with alprazolam extended-release tablets increased the mean

Cmax by about 25%. The effect of this meal on Tmax depended on the timing of the meal, with a

reduction in Tmax by about 1/3 for subjects eating immediately before dosing and an increase in Tmax

by about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure (AUC) and

elimination half-life (t1/2) were not affected by eating.

There were significant differences in absorption rate for the alprazolam extended-release tablet,

depending on the time of day administered, with the Cmax increased by 30% and the Tmax decreased by

an hour following dosing at night, compared to morning dosing.

Distribution

The apparent volume of distribution of alprazolam is similar for alprazolam extended-release and

alprazolam tablets. In vitro, alprazolam is bound (80%) to human serum protein. Serum albumin accounts

for the majority of the binding.

Metabolism

Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to

two major metabolites in the plasma: 4-hydroxyalprazolam and α-hydroxyalprazolam. A benzophenone

derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of

alprazolam. The pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of

alprazolam (4-hydroxyalprazolam and α-hydroxyalprazolam) were similar for alprazolam and alprazolam

extended-release tablets, indicating that the metabolism of alprazolam is not affected by absorption rate.

The plasma concentrations of 4-hydroxyalprazolam and α-hydroxyalprazolam relative to unchanged

alprazolam concentration after both alprazolam extended-release and alprazolam tablets were always

less than 10% and 4%, respectively. The reported relative potencies in benzodiazepine receptor binding

experiments and in animal models of induced seizure inhibition are 0.2 and 0.66, respectively, for 4-

hydroxyalprazolam and α-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-

hydroxyalprazolam and α-hydroxyalprazolam suggest that they are unlikely to contribute much to the

pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.

Elimination

Alprazolam and its metabolites are excreted primarily in the urine. The mean plasma elimination half-life

of alprazolam following administration of alprazolam extended-release tablet ranges from 10.7 to 15.8

hours in healthy adults.

Special Populations

While pharmacokinetic studies have not been performed in special populations with alprazolam

extended-release tablets, the factors (such as age, gender, hepatic or renal impairment) that would affect

the pharmacokinetics of alprazolam after the administration of alprazolam tablets would not be expected

to be different with the administration of alprazolam extended-release tablets.

Changes in the absorption, distribution, metabolism, and excretion of benzodiazepines have been

reported in a variety of disease states including alcoholism, impaired hepatic function, and impaired

renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of

alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9 to 26.9 hours, n=16)

compared to 11 hours (range: 6.3 to 15.8 hours, n=16) in healthy adult subjects. In patients with

alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7

hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In

an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8

hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects.

Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes

transplacental passage and that it is excreted in human milk.

Race — Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in

Asians compared to Caucasians.

Pediatrics — The pharmacokinetics of alprazolam after administration of the alprazolam extended-

release tablet in pediatric patients have not been studied.

Gender — Gender has no effect on the pharmacokinetics of alprazolam.

Cigarette Smoking — Alprazolam concentrations may be reduced by up to 50% in smokers compared to

non-smokers.

Drug-Drug Interactions

Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the

interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4.

Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam

concentrations. Drug products that have been studied in vivo, along with their effect on increasing

alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.7 fold; nefazodone, 1.98 fold;

fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold (see CONTRAINDICATIONS, WARNINGS, and

PRECAUTIONS–Drug Interactions).

CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed

in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.9±0.21

mL/min/kg to 2.13±0.54 mL/min/kg and the elimination t1/2 was shortened (from 17.1±4.9 to 7.7±1.7 h)

following administration of 300 mg/day carbamazepine for 10 days (see PRECAUTIONS–Drug

Interactions). However, the carbamazepine dose used in this study was fairly low compared to the

recommended doses (1000 to 1200 mg/day); the effect at usual carbamazepine doses is unknown.

The ability of alprazolam to induce or inhibit human hepatic enzyme systems has not been determined.

However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the

prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.

CLINICAL EFFICACY TRIALS

The efficacy of alprazolam extended-release tablets in the treatment of panic disorder was established

in two 6-week, placebo-controlled studies of alprazolam extended-release in patients with panic

disorder.

In two 6-week, flexible-dose, placebo-controlled studies in patients meeting DSM-III criteria for panic

disorder, patients were treated with alprazolam extended-release in a dose range of 1 to 10 mg/day, on a

once-a-day basis. The effectiveness of alprazolam extended-release was assessed on the basis of

changes in various measures of panic attack frequency, on various measures of the Clinical Global

Impression, and on the Overall Phobia Scale. In all, there were seven primary efficacy measures in

these studies, and alprazolam extended-release was superior to placebo on all seven outcomes in both

studies. The mean dose of alprazolam extended-release at the last treatment visit was 4.2 mg/day in the

first study and 4.6 mg/day in the second.

In addition, there were two 8-week, fixed-dose, placebo-controlled studies of alprazolam extended-

release in patients with panic disorder, involving fixed alprazolam extended-release doses of 4 and 6

mg/day, on a once-a-day basis, that did not show a benefit for either dose of alprazolam extended-

release.

The longer-term efficacy of alprazolam extended-release in panic disorder has not been systematically

evaluated.

Analyses of the relationship between treatment outcome and gender did not suggest any differential

responsiveness on the basis of gender.

Alprazolam extended-release tablets are indicated for the treatment of panic disorder, with or without

agoraphobia.

This claim is supported on the basis of two positive studies with alprazolam extended-release

conducted in patients whose diagnoses corresponded closely to the DSM-III-R/IV criteria for panic

disorder (see CLINICAL EFFICACY TRIALS).

Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period

of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and

reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating;

(3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6)

chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or

faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10)

fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills

or hot flushes.

The longer-term efficacy of alprazolam extended-release has not been systematically evaluated. Thus,

the physician who elects to use this drug for periods longer than 8 weeks should periodically reassess

the usefulness of the drug for the individual patient.

Alprazolam extended-release tablets are contraindicated in patients with known sensitivity to this drug

or other benzodiazepines.

Alprazolam extended-release are contraindicated with ketoconazole and itraconazole, since these

medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A)

(see CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS–Drug Interactions).

Risks from Concomitant Use with Opioids

Concomitant use of benzodiazepines, including alprazolam extended-release, 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 extended-release 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 extended-release 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 extended-

release, 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 extended-release are 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 alprazolam 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 alprazolam 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 alprazolam

extended-release tablets has not been systematically studied. Experience in randomized placebo-

controlled discontinuation studies of patients with panic disorder who received alprazolam 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 alprazolam 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% to 93% of patients treated with alprazolam tablets tapered completely off therapy

compared to 89% to 96% of placebo treated patients. In a controlled postmarketing discontinuation

study of panic disorder patients treated with alprazolam 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 alprazolam extended-

release. In two cases, the patients had completed 6 weeks of treatment with alprazolam extended-release

6 mg/day before experiencing a single seizure. In one case, the patient abruptly discontinued alprazolam

extended-release, and in both cases, alcohol intake was implicated. The third case involved multiple

seizures after the patient completed treatment with alprazolam extended-release 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 alprazolam

tablets, the immediate release form of alprazolam. 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 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 alprazolam. The risk of seizure seems to be greatest 24 to 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 alprazolam 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 alprazolam 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 (e.g., the patient forgets, the patient is

admitted to a hospital). Therefore, the dosage of alprazolam extended-release should be reduced or

discontinued gradually (see DOSAGE AND ADMINISTRATION).

CNS Depression and Impaired Performance

Because of its CNS depressant effects, patients receiving alprazolam extended-release 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 alprazolam extended-release.

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 2.7 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%.

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).

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 alprazolam 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 alprazolam tablets. A

decreased systemic alprazolam elimination rate (e.g., increased plasma half-life) has been observed in

both alcoholic liver disease patients and obese patients receiving alprazolam tablets (see CLINICAL

PHARMACOLOGY).

Information for Patients

To assure safe and effective use of alprazolam extended-release, the physician should provide the

patient with the following guidance.

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and

sedation when alprazolam extended-release is used with opioids and not to use such drugs

concomitantly unless supervised by a health care provider.

Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the

opioid have been determined (see Drug Interactions).

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.

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.

Inform your physician if you are nursing.

Until you experience how this medication affects you, do not drive a car or operate potentially

dangerous machinery, etc.

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.

Do not stop taking this medication abruptly or decrease the dose without consulting your physician,

since withdrawal symptoms can occur.

Some patients may find it very difficult to discontinue treatment with alprazolam extended-release 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 alprazolam extended-release 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 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 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).

The information included in the subsection on Adverse Events Observed in Short-Term, Placebo-

Controlled Trials with alprazolam extended-release 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 Alprazolam Extended-Release

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

Approximately 17% of the 531 patients who received alprazolam extended-release 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 (i.e., leading to discontinuation in at least 1% of the patients treated

with alprazolam extended-release 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

Alprazolam

Extended-Release

(n=531) Placebo

(n=349)

Nervous system disorders

Sedation

Somnolence

Dysarthria

Coordination abnormal

Memory impairment

General disorders/administration site conditions

Fatigue

Psychiatric disorders

Depression

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

Extended-Release

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 alprazolam extended-release

where the incidence in patients treated with alprazolam extended-release was greater than the incidence

in placebo-treated patients. The most commonly observed adverse events in panic disorder patients

treated with alprazolam extended-release (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

Alprazolam Extended-Release

System Organ Class/Adverse Event Percentage of Patients Reporting Adverse Event

Alprazolam Extended-

Release

(n=531) Placebo

(n=349)

Nervous system disorders

Sedation

Somnolence

Memory impairment

Dysarthria

Coordination abnormal

Mental impairment

Ataxia

Disturbance in attention

Balance impaired

Paresthesia

Dyskinesia

Hypoesthesia

Hypersomnia

45.2

15.4

10.9

22.6

General disorders/administration site conditions

Fatigue

Lethargy

13.9

Infections and infestations

Influenza

Upper respiratory tract infections

Psychiatric disorders

Depression

Libido decreased

Disorientation

Confusion

Depressed mood

Anxiety

12.1

Metabolism and nutrition disorders

Appetite decreased

Appetite increased

Anorexia

Gastrointestinal disorders

Dry mouth

Constipation

Nausea

Pharyngolaryngeal pain

10.2

Investigations

Weight increased

Weight decreased

Injury, poisoning, and procedural complications

Road traffic accident

Reproductive system and breast disorders

Dysmenorrhea

Sexual dysfunction

Premenstrual syndrome

Musculoskeletal and connective tissue disorders

Arthralgia

Myalgia

Pain in limb

Vascular disorders

Hot flushes

Respiratory, thoracic, and mediastinal disorders

Dyspnea

Rhinitis allergic

Skin and subcutaneous tissue disorders

Pruritus

Other Adverse Events Observed During the Premarketing Evaluation of Alprazolam Extended-Release

Tablets

Following is a list of MedDRA terms that reflect treatment-emergent adverse events reported by 531

patients with panic disorder treated with alprazolam extended-release. All potentially important reported

events are included except those already listed in the above table or elsewhere in labeling, those events

for which a drug cause was remote, those event terms that were so general as to be uninformative, and

those events that occurred at rates similar to background rates in the general population. It is important

to emphasize that, although the events reported occurred during treatment with alprazolam extended-

release, they were not necessarily caused by the drug. Events are further categorized by body system

and listed in order of decreasing frequency according to the following definitions: frequent adverse

events are those occurring on 1 or more occasions in at least l/l00 patients; infrequent adverse events

are those occurring in less than l/100 patients but at least l/1000 patients; rare events are those

occurring in fewer than l/1000 patients.

Cardiac disorders: Frequent: palpitation; Infrequent: sinus tachycardia

Ear and Labyrinth disorders: Frequent: Vertigo; Infrequent: tinnitus, ear pain

Eye disorders: Frequent: blurred vision; Infrequent: mydriasis, photophobia

Gastrointestinal disorders: Frequent: diarrhea, vomiting, dyspepsia, abdominal pain; Infrequent:

dysphagia, salivary hypersecretion

General disorders and administration site conditions: Frequent: malaise, weakness, chest pains;

Infrequent: fall, pyrexia, thirst, feeling hot and cold, edema, feeling jittery, sluggishness, asthenia,

feeling drunk, chest tightness, increased energy, feeling of relaxation, hangover, loss of control of

legs, rigors

Musculoskeletal and connective tissue disorders: Frequent: back pain, muscle cramps, muscle twitching

Nervous system disorders: Frequent: headache, dizziness, tremor; Infrequent: amnesia, clumsiness,

syncope, hypotonia, seizures, depressed level of consciousness, sleep apnea syndrome, sleep talking,

stupor

Psychiatric system disorders: Frequent: irritability, insomnia, nervousness, derealization, libido

increased, restlessness, agitation, depersonalization, nightmare; Infrequent: abnormal dreams, apathy,

aggression, anger, bradyphrenia, euphoric mood, logorrhea, mood swings, dysphonia, hallucination,

homicidal ideation, mania, hypomania, impulse control, psychomotor retardation, suicidal ideation

Renal and urinary disorders: Frequent: difficulty in micturition; Infrequent: urinary frequency, urinary

incontinence

Respiratory, thoracic, and mediastinal disorders: Frequent: nasal congestion, hyperventilation;

Infrequent: choking sensation, epistaxis, rhinorrhea

Skin and subcutaneous tissue disorders: Frequent: sweating increased; Infrequent: clamminess, rash,

urticaria

Vascular disorders: Infrequent: hypotension

The categories of adverse events reported in the clinical development program for alprazolam tablets in

the treatment of panic disorder differ somewhat from those reported for alprazolam extended-release

tablets because the clinical trials with alprazolam tablets and alprazolam extended-release tablets used

different standard medical nomenclature for reporting the adverse events. Nevertheless, the types of

adverse events reported in the clinical trials with alprazolam tablets were generally the same as those

reported in the clinical trials with alprazolam extended-release tablets.

Discontinuation-Emergent Adverse Events Occurring at an Incidence of 5% or More Among Patients

Treated with Alprazolam Extended-Release

The following table shows the incidence of discontinuation-emergent adverse events that occurred

during short-term, placebo-controlled trials in 5% or more of patients treated with alprazolam extended-

release where the incidence in patients treated with alprazolam extended-release was two times greater

than the incidence in placebo-treated patients.

Discontinuation-Emergent Symptoms: Incidence in Short-Term, Placebo-Controlled Trials with

Alprazolam Extended-Release

System Organ Class/

Adverse Event Percentage of Patients Reporting

Adverse Event

Alprazolam Extended-

Release

(n=422) Placebo

(n=261)

Nervous system disorders

Tremor

Headache

Hypoesthesia

Paraesthesia

28.2

26.5

10.7

12.6

Psychiatric disorders

Insomnia

Nervousness

Depression

Derealization

Anxiety

Depersonalization

24.2

21.8

10.9

Gastrointestinal disorders

Diarrhea

12.1

Respiratory, thoracic and mediastinal disorders

Hyperventilation

Metabolism and nutrition disorders

Appetite decreased

Musculoskeletal and connective tissue disorders

Muscle twitching

Vascular disorders

Hot flushes

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of

alprazolam (see WARNINGS).

To discontinue treatment in patients taking alprazolam extended-release tablets, the dosage should be

reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of

alprazolam extended-release tablets be decreased by no more than 0.5 mg every three days (see

DOSAGE AND ADMINISTRATION). 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.

As with all benzodiazepines, paradoxical reactions such as stimulation, increased muscle spasticity,

sleep disturbances, hallucinations, and other adverse behavioral effects such as agitation, rage,

irritability, and aggressive or hostile behavior have been reported rarely. In many of the spontaneous

case reports of adverse behavioral effects, patients were receiving other CNS drugs concomitantly

and/or were described as having underlying psychiatric conditions. Should any of the above events

occur, alprazolam should be discontinued. Isolated published reports involving small numbers of

patients have suggested that patients who have borderline personality disorder, a prior history of

violent or aggressive behavior, or alcohol or substance abuse may be at risk for such events. Instances

of irritability, hostility, and intrusive thoughts have been reported during discontinuation of alprazolam

in patients with posttraumatic stress disorder.

Post Introduction Reports

Various adverse drug reactions have been reported in association with the use of alprazolam tablets

since market introduction. The majority of these reactions were reported through the medical event

voluntary reporting system. Because of the spontaneous nature of the reporting of medical events and

the lack of controls, a causal relationship to the use of alprazolam tablets cannot be readily determined.

Reported events include: gastrointestinal disorder, hypomania, mania, liver enzyme elevations, hepatitis,

hepatic failure, Stevens-Johnson syndrome, angioedema, peripheral edema, hyperprolactinemia,

gynecomastia, and galactorrhea (see PRECAUTIONS).

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 (e.g., 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 extended-release tablets have been assigned to Schedule IV.

Clinical Experience

Overdosage reports with alprazolam tablets are limited. 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.

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

treating overdosage.

General Treatment of Overdose

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.

Alprazolam extended-release tablets may be administered once daily, preferably in the morning. The

tablets should be taken intact; they should not be chewed, crushed, or broken.

The suggested total daily dose ranges between 3 to 6 mg/day. Dosage should be individualized for

maximum beneficial effect. While the suggested total daily dosages given will meet the needs of most

patients, there will be some patients who require doses greater than 6 mg/day. In such cases, dosage

should be increased cautiously to avoid adverse effects.

Dosing in Special Populations

In elderly patients, in patients with advanced liver disease, or in patients with debilitating disease, the

usual starting dose of alprazolam extended-release tablets is 0.5 mg once daily. This may be gradually

increased if needed and tolerated (see Dose Titration). The elderly may be especially sensitive to the

effects of benzodiazepines.

Dose Titration

Treatment with alprazolam extended-release tablets may be initiated with a dose of 0.5 mg to 1 mg once

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/day. Slower titration to the dose levels may be advisable to allow full expression of

the pharmacodynamic effect of alprazolam extended-release tablets.

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 (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

In controlled trials conducted to establish the efficacy of alprazolam extended-release tablets in panic

disorder, doses in the range of 1 to 10 mg/day were used. Most patients showed efficacy in the dose

range of 3 to 6 mg/day. Occasional patients required as much as 10 mg/day to achieve a successful

response.

The necessary duration of treatment for panic disorder patients responding to alprazolam extended-

release tablets is unknown. However, periodic reassessment is advised. 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 three days, with the understanding that some patients may benefit from an

even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens.

Switch from Alprazolam (Immediate-Release) Tablets to Alprazolam Extended-Release Tablets

Patients who are currently being treated with divided doses of alprazolam (immediate-release) tablets,

for example 3 to 4 times a day, may be switched to alprazolam extended-release tablets at the same total

daily dose taken once daily. If the therapeutic response after switching is inadequate, the dosage may be

titrated as outlined above.

Alprazolam Extended-Release Tablets USP, 0.5 mg are white to off-white, round, biconvex tablets with

beveled edge debossed with ‘X’ on one side and ‘70’ on the other side.

Bottles of 60

Bottles of 1,000

Bottles of 7,000

Alprazolam Extended-Release Tablets USP, 1 mg are yellow colored, round, biconvex tablets with

beveled edge debossed with ‘X’ on one side and ‘73’ on the other side. The tablets may be mottled.

Bottles of 60

Bottles of 1,000

Bottles of 7,000

Alprazolam Extended-Release Tablets USP, 2 mg are blue colored, round, biconvex tablets with

beveled edge debossed with ‘X’ on one side and ‘74’ on the other side. The tablets may be mottled.

Bottles of 60

Bottles of 1,000

Bottles of 7,000

Alprazolam Extended-Release Tablets USP, 3 mg are green colored, round, biconvex tablets with

beveled edge debossed with ‘X’ on one side and ‘75’ on the other side. The tablets may be mottled.

Bottles of 60

Bottles of 1,000

Bottles of 7,000

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP

Controlled Room Temperature].

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.

Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides

Alprazolam Extended-Release Tablets, USP

(al pra' zoe lam) CIV

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

Alprazolam extended-release tablets are 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 extended-release 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

extended-release tablets affects you.

Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam

extended-release tablets without first talking to your healthcare provider. When taken with alcohol or

drugs that cause sleepiness or dizziness, alprazolam extended-release tablets may make your sleepiness

or dizziness much worse.

Do not take more alprazolam extended-release tablets than prescribed.

What are alprazolam extended-release tablets?

Alprazolam extended-release tablets are a prescription medicine used to treat panic disorder, with or

without a fear of places and situations that might cause panic, helplessness, or embarrassment

(agoraphobia)

Alprazolam extended-release tablets are a federal controlled substance (C-IV) because it can be abused

or lead to dependence. Keep alprazolam extended-release tablets in a safe place to prevent misuse and

abuse. Selling or giving away alprazolam extended-release 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 extended-release tablets are safe and effective in children.

Elderly patients are especially susceptible to dose related adverse effects when taking alprazolam

extended-release tablets.

It is not known if alprazolam extended-release tablets are safe and effective for use longer than 8

weeks.

Do not take alprazolam extended-release tablets if:

you are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam extended-

release tablets. See the end of this Medication Guide for a complete list of ingredients in alprazolam

extended-release tablets.

you are taking antifungal medicines including ketoconazole and itraconazole

Before you take alprazolam extended-release 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 extended-release tablets may harm your unborn

baby. You and your healthcare provider should decide if you should take alprazolam extended-release

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

extended-release tablets. You should not breastfeed while taking alprazolam extended-release tablets.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements.

Taking alprazolam extended-release tablets with certain other medicines can cause side effects or

affect how well alprazolam extended-release tablets or the other medicines work. Do not start or stop

other medicines without talking to your healthcare provider.

How should I take alprazolam extended-release tablets?

See “What is the most important information I should know about alprazolam extended-release tablets?”

Take alprazolam extended-release tablets exactly as your healthcare provider tells you to take it. Your

healthcare provider will tell you how much alprazolam extended-release tablets to take and when to take

Swallow alprazolam extended-release tablets whole. Do not crush, chew or break alprazolam extended-

release tablets.

If you take too much alprazolam, call your healthcare provider or go to the nearest hospital emergency

room right away.

What should I avoid while taking alprazolam extended-release tablets?

Alprazolam extended-release tablets can cause you to be drowsy. Do not drive a car or operate heavy

machinery until you know how alprazolam extended-release tablets affect you.

You should not drink alcohol while taking alprazolam extended-release tablets. Drinking alcohol can

increase your chances of having serious side effects.

What are the possible side effects of alprazolam extended-release tablets?

Alprazolam extended-release tablets may cause serious side effects, including:

See “What is the most important information I should know about alprazolam extended-release tablets?”

Abuse and dependence. Taking alprazolam extended-release 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 extended-

release 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 extended-release tablets to avoid withdrawal symptoms.

Seizures. Stopping alprazolam extended-release tablets can cause seizures and seizures that will not

stop (status epilepticus).

Mania. Alprazolam extended-release tablets may cause an increase in activity and talking (hypomania and

mania) in people who have depression.

The most common side effects of alprazolam extended-release tablets include:

sedation

difficult or unclear ability to talk

problems with coordination

tiredness

drowsiness

depression

memory problems

These are not all the possible side effects of alprazolam extended-release 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 extended-release tablets?

Store alprazolam extended-release tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to

30°C (59° to 86°F). Keep alprazolam tablets and all medicines out of the reach of children.

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

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

Do not use alprazolam extended-release tablets for a condition for which it was not prescribed.

Do not give alprazolam extended-release 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 extended-release

tablets that is written for health professionals.

What are the ingredients in alprazolam extended-release tablets?

Active ingredient: alprazolam

Inactive ingredients: colloidal silicon dioxide, hypromellose, lactose monohydrate, and magnesium

stearate. In addition, the 1 mg and 3 mg tablet contains D&C Yellow No. 10 aluminum lake and the 2 mg

and 3 mg tablets contain FD&C Blue No. 2 lake.

For more information, call Aurobindo Pharma USA, Inc. at 1-866-850-2876

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Dispense with Medication Guide available at: www.aurobindousa.com/product-medication-guides

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520

Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 038, India

Revised: 07/2018

ALPRAZOLAM

alprazolam tablet, extended release

Product Information

Product T ype

HUMAN

PRESCRIPTION DRUG

Ite m Code (Source )

NDC:7218 9 -

0 29 (NDC:6 58 6 2-455)

Route of Administration

ORAL

DEA Sche dule

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

ALPRAZO LAM (UNII: YU55MQ3IZY) (ALPRAZOLAM - UNII:YU55MQ3IZY)

ALPRAZOLAM

1 mg

Inactive Ingredients

Ingredient Name

Stre ng th

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SE 2 2 0 8 ( 10 0 MPA.S) (UNII: B1QE5P712K)

D&C YELLO W NO . 10 (UNII: 35SW5USQ3G)

HYPRO MELLO SE 2 2 0 8 ( 4 0 0 0 MPA.S) (UNII: 39 J8 0 LT57T)

Product Characteristics

Color

ye llo w

S core

no sco re

S hap e

ROUND ((Bico nvex))

S iz e

9 mm

Flavor

Imprint Code

X;73

Contains

Packag ing

Dire ct_Rx

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:7218 9 -0 29 -9 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 5/20 19

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 0 8 71

0 9 /0 5/20 19

Labeler -

Direct_Rx (079254320)

Registrant -

Direct_Rx (079254320)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Dire c t_Rx

0 79 254320

re pa c k(7218 9 -0 29 )

Revised: 9/2019

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