ALPRAZOLAM - alprazolam tablet 
Mylan Pharmaceuticals Inc.

----------

ALPRAZOLAM TABLETS, USP
0.25 mg, 0.5 mg, 1 mg and 2 mg

CIV

Rx only

DESCRIPTION

Alprazolam 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 structural formula is represented below.

Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH.

Each tablet, for oral administration, contains 0.25, 0.5, 1 or 2 mg of alprazolam.

Inactive ingredients are: colloidal silicon dioxide, croscarmellose sodium, docusate sodium, lactose (hydrous), magnesium stearate, microcrystalline cellulose, sodium benzoate and sodium lauryl sulfate. In addition, the 0.5 mg tablet contains FD&C Yellow #6 Lake and the 1 mg tablet contains FD&C Blue #2.

CLINICAL PHARMACOLOGY

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

Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportionate 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 predominant metabolites are α-hydroxy-alprazolam and a benzophenone derived from alprazolam. The biological activity of α-hydroxy-alprazolam is approximately one-half that of alprazolam. The benzophenone metabolite is essentially inactive. Plasma levels of these metabolites are extremely low, thus precluding precise pharmacokinetic description. However, their half-lives appear to be of the same order of magnitude as that of alprazolam. Alprazolam and its metabolites are excreted primarily in the urine.

The ability of alprazolam to induce human hepatic enzyme systems has not yet 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.

In vitro, alprazolam is bound (80 percent) to human serum protein.

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 secreted in human milk.

INDICATIONS AND USAGE

Alprazolam tablets are indicated for the management of anxiety disorder (a condition corresponding most closely to the APA Diagnostic and Statistical Manual [DSM-III-R] diagnosis of generalized anxiety disorder) or the short-term relief of symptoms of anxiety. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

Generalized anxiety disorder is characterized by unrealistic or excessive anxiety and worry (apprehensive expectation) about two or more life circumstances, for a period of six months or longer, during which the person has been bothered more days than not by these concerns. At least 6 of the following 18 symptoms are often present in these patients: Motor Tension (trembling, twitching, or feeling shaky; muscle tension, aches, or soreness; restlessness; easy fatigability); Autonomic Hyperactivity (shortness of breath or smothering sensations; palpitations or accelerated heart rate; sweating, or cold clammy hands; dry mouth; dizziness or light-headedness; nausea, diarrhea, or other abdominal distress; flushes or chills; frequent urination; trouble swallowing or ‘lump in throat’); Vigilance and Scanning (feeling keyed up or on edge; exaggerated startle response; difficulty concentrating or ‘mind going blank’ because of anxiety; trouble falling or staying asleep; irritability). These symptoms must not be secondary to another psychiatric disorder or caused by some organic factor.

Anxiety associated with depression is responsive to alprazolam.

Demonstrations of the effectiveness of alprazolam by systematic clinical study are limited to four months duration for anxiety disorder. The physician should periodically reassess the usefulness of the drug for the individual patient.

CONTRAINDICATIONS

Alprazolam tablets are contraindicated in patients with known sensitivity to this drug or other benzodiazepines. Alprazolam may be used in patients with open angle glaucoma who are receiving appropriate therapy, but is contraindicated in patients with acute narrow angle glaucoma.

Alprazolam is contraindicated with ketoconazole and itraconazole, since these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP 3A) (see WARNINGS and PRECAUTIONS-Drug Interactions).

WARNINGS

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 the doses recommended for the treatment of transient anxiety and anxiety disorder (i.e., 0.75 to 4 mg per 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 then 4 mg/day and for long periods (more than 12 weeks). Patients treated with doses of alprazolam greater than 4 mg/day had more difficulty tapering to zero dose than those treated with less than 4 mg/day.

Status epilepticus and its treatment

The medical event voluntary reporting system shows that withdrawal seizures have been reported in association with the discontinuation of alprazolam. In most cases, only a single seizure was reported; however, multiple seizures and status epilepticus were reported as well. Ordinarily, the treatment of status epilepticus of any etiology involves use of intravenous benzodiazepines plus phenytoin or barbiturates, maintenance of a patent airway and adequate hydration. For additional details regarding therapy, consultation with an appropriate specialist may be considered.

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, etc.). Therefore, the dosage of alprazolam should be reduced or discontinued gradually (see DOSAGE AND ADMINISTRATION).

Alprazolam tablets are not of value in the treatment of psychotic patients and should not be employed in lieu of appropriate treatment for psychosis. Because of its CNS depressant effects, patients receiving alprazolam 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.

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 (CYP 3A). 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 CYP 3A. With drugs inhibiting CYP 3A 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 CYP 3A.

Potent CYP 3A inhibitors

Azole antifungal agents—Although in vivo interaction data with alprazolam are not available, ketoconazole and itraconazole are potent CYP 3A inhibitors and the coadministration of alprazolam with them is not recommended. Other azole-type antifungal agents should also be considered potent CYP 3A inhibitors and the coadministration of alprazolam with them is not recommended (see CONTRAINDICATIONS).

Drugs demonstrated to be CYP 3A 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 CYP 3A are discussed in the PRECAUTIONS section (see PRECAUTIONS-Drug Interactions).

PRECAUTIONS

General

If alprazolam 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 (see Drug Interactions).

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.

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. 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 (see CLINICAL PHARMACOLOGY).

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

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.

Information for Patients

For all users of alprazolam

To assure safe and effective use of benzodiazepines, all patients prescribed alprazolam should be provided with the following guidance.

1. 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.
2. 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.
3. Inform your physician if you are nursing.
4. Until you experience how this medication affects you, do not drive a car or operate potentially dangerous machinery, etc.
5. 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.
6. Do not stop taking this medication abruptly or decrease the dose without consulting your physician, since withdrawal symptoms can occur.

Laboratory Tests

Laboratory tests are not ordinarily required in otherwise healthy patients.

Drug Interactions

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.

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 (CYP 3A). 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 CYP 3A 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 CYP 3A 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. 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).

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 the age of 18 years have not been established.

Geriatric Use

The elderly may be more sensitive to the effects of benzodiazepines. They exhibit higher plasma alprazolam concentrations due to reduced clearance of the drug as compared with a younger population receiving the same doses. The smallest effective dose of alprazolam should be used in the elderly to preclude the development of ataxia and oversedation (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

ADVERSE REACTIONS

Side effects to alprazolam tablets, if they occur, are generally observed at the beginning of therapy and usually disappear upon continued medication. In the usual patient, the most frequent side effects are likely to be an extension of the pharmacological activity of alprazolam, e.g., drowsiness or light-headedness.

The data cited in the table below are estimates of untoward clinical event incidence among patients who participated under the following clinical conditions: relatively short duration (i.e.,four weeks) placebo-controlled clinical studies with dosages up to 4 mg/day of alprazolam (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety).

These data cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics, and other factors often differ from those in clinical trials. These figures cannot be compared with those obtained from other clinical studies involving related drug products and placebo as each group of drug trials are conducted under a different set of conditions.

Comparison of the cited figures, however, can provide the prescriber with some basis for estimating the relative contributions of drug and non-drug factors to the untoward event incidence in the population studied. Even this use must be approached cautiously, as a drug may relieve a symptom in one patient but induce it in others. (For example, an anxiolytic drug may relieve dry mouth [a symptom of anxiety] in some subjects but induce it [an untoward event] in others.)

Additionally, for anxiety disorders the cited figures can provide the prescriber with an indication as to the frequency with which physician intervention (e.g., increased surveillance, decreased dosage or discontinuation of drug therapy) may be necessary because of the untoward clinical event.

ANXIETY DISORDERS

* Events reported by 1% or more of alprazolam patients are included. † None reported;
	Treatment-Emergent Symptom Incidence* Alprazolam	Placebo
Number of Patients	565	505
% of Patients Reporting:
Central Nervous System
Drowsiness	41.0	21.6
Light-headedness	20.8	19.3
Depression	13.9	18.1
Headache	12.9	19.6
Confusion	9.9	10.9
Insomnia	8.9	18.4
Nervousness	4.1	10.3
Syncope	3.1	4.0
Dizziness	1.8	0.8
Akathisia	1.6	1.2
Tiredness/Sleepiness	†	†
Gastrointestinal
Dry Mouth	14.7	13.3
Constipation	10.4	11.4
Diarrhea	10.1	10.3
Nausea/Vomiting	9.6	12.8
Increased Salivation	4.2	2.4
Cardiovascular
Tachycardia/
Palpitations	7.7	15.6
Hypotension	4.7	2.2
Sensory
Blurred Vision	6.2	6.2
Musculoskeletal
Rigidity	4.2	5.3
Tremor	4.0	8.8
Cutaneous
Dermatitis/Allergy	3.8	3.1
Other
Nasal Congestion	7.3	9.3
Weight Gain	2.7	2.7
Weight Loss	2.3	3.0
	Incidence of Intervention Because of Symptom Alprazolam
Number of Patients	565
% of Patients Reporting:
Central Nervous System
Drowsiness	15.1
Light-headedness	1.2
Depression	2.4
Headache	1.1
Confusion	0.9
Insomnia	1.3
Nervousness	1.1
Syncope	†
Dizziness	2.5
Akathisia	†
Tiredness/Sleepiness	1.8
Gastrointestinal
Dry Mouth	0.7
Constipation	0.9
Diarrhea	1.2
Nausea/Vomiting	1.7
Increased Salivation	†
Cardiovascular
Tachycardia/Palpitations	0.4
Hypotension	†
Sensory
Blurred Vision	0.4
Musculoskeletal
Rigidity	†
Tremor	0.4
Cutaneous
Dermatitis/Allergy	0.6
Other
Nasal Congestion	†
Weight Gain	†
Weight Loss	†

In addition to the relatively common (i.e., greater than 1%) untoward events enumerated in the table above, the following adverse events have been reported in association with the use of benzodiazepines: dystonia, irritability, concentration difficulties, anorexia, transient amnesia or memory impairment, loss of coordination, fatigue, seizures, sedation, slurred speech, jaundice, musculoskeletal weakness, pruritus, diplopia, dysarthria, changes in libido, menstrual irregularities, incontinence and urinary retention.

There have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam tablets (see WARNINGS).

To discontinue treatment in patients taking alprazolam, the dosage should be reduced slowly in keeping with good medical practice. It is suggested that the daily dosage of alprazolam 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.

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 post-traumatic stress disorder.

Laboratory analyses were performed on patients participating in the clinical program for alprazolam. The following incidences of abnormalities shown below were observed in patients receiving alprazolam and in patients in the corresponding placebo group. Few of these abnormalities were considered to be of physiological significance.

* Less than 1%
	ALPRAZOLAM
	Low	High
Hematology
Hematocrit	*	*
Hemoglobin	*	*
Total WBC Count	1.4	2.3
Neutrophil Count	2.3	3.0
Lymphocyte Count	5.5	7.4
Monocyte Count	5.3	2.8
Eosinophil Count	3.2	9.5
Basophil Count	*	*
Urinalysis
Albumin	—	*
Sugar	—	*
RBC/HPF	—	3.4
WBC/HPF	—	25.7
Blood Chemistry
Creatinine	2.2	1.9
Bilirubin	*	1.6
SGOT	*	3.2
Alkaline Phosphatase	*	1.7
	PLACEBO
	Low	High
Hematology
Hematocrit	*	*
Hemoglobin	*	*
Total WBC Count	1.0	2.0
Neutrophil Count	4.2	1.7
Lymphocyte Count	5.4	9.5
Monocyte Count	6.4	*
Eosinophil Count	3.3	7.2
Basophil Count	*	*
Urinalysis
Albumin	—	*
Sugar	—	*
RBC/HPF	—	5.0
WBC/HPF	—	25.9
Blood Chemistry
Creatinine	3.5	1.0
Bilirubin	*	*
SGOT	1.0	1.8
Alkaline Phosphatase	*	1.8

When treatment with alprazolam is protracted, periodic blood counts, urinalysis and blood chemistry analyses are advisable.

Minor changes in EEG patterns, usually low-voltage fast activity have been observed in patients during therapy with alprazolam and are of no known significance.

Post Introduction Reports

Various adverse drug reactions have been reported in association with the use of alprazolam 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 cannot be readily determined. Reported events include: liver enzyme elevations, hepatitis, hepatic failure, Stevens-Johnson Syndrome, hyperprolactinemia, gynecomastia and galactorrhea.

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 reinstitution 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 dosage 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 the taper or shortly after discontinuation, and will decrease with time.

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 tablets have been assigned to Schedule IV.

OVERDOSAGE

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 LD50 in rats is 331 to 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 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.

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.

HOW SUPPLIED

Alprazolam tablets are available containing 0.25 mg, 0.5 mg, 1 mg or 2 mg of alprazolam.

The 0.25 mg tablets are white, round, scored tablets debossed with MYLAN over A. They are available as follows:

NDC 0378-4001-01
bottles of 100 tablets

NDC 0378-4001-05
bottles of 500 tablets

The 0.5 mg tablets are peach, round, scored tablets debossed with MYLAN over A3. They are available as follows:

NDC 0378-4003-01
bottles of 100 tablets

NDC 0378-4003-05
bottles of 500 tablets

The 1 mg tablets are blue, round, scored tablets debossed with MYLAN over A1. They are available as follows:

NDC 0378-4005-01
bottles of 100 tablets

NDC 0378-4005-05
bottles of 500 tablets

The 2 mg tablets are white, round quadrisect scored tablets debossed with MYLAN over A4. They are available as follows:

NDC 0378-4007-01
bottles of 100 tablets

STORE AT CONTROLLED ROOM TEMPERATURE 15°–30°C (59°–86°F).

PROTECT FROM LIGHT.

Dispense in a tight, light-resistant container using a child-resistant closure. Keep container tightly closed.

ANIMAL PHARMACOLOGY

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.

CLINICAL STUDIES

Alprazolam tablets were compared to placebo in double blind clinical studies (doses up to 4 mg/day) in patients with a diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these four week studies as judged by the following psychometric instruments: Physician's Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patient's Global Impressions and Self-Rating Symptom Scale.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

REV MARCH 2001
ALP:R7

ALPRAZOLAM  alprazolam  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0378-4001 Route of Administration ORAL DEA Schedule CIV

INGREDIENTS Name (Active Moiety) Type Strength Alprazolam (Alprazolam) Active 0.25 MILLIGRAM  In 1 TABLET colloidal silicon dioxide Inactive   croscarmellose sodium Inactive   docusate sodium Inactive   lactose (hydrous) Inactive   magnesium stearate Inactive   microcrystalline cellulose Inactive   sodium benzoate Inactive   sodium lauryl sulfate Inactive

Product Characteristics Color WHITE Score 2 pieces Shape ROUND Size 7mm Flavor Imprint Code MYLAN;A Contains      Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0378-4001-01 100 TABLET In 1 BOTTLE, PLASTIC None 2 0378-4001-05 500 TABLET In 1 BOTTLE, PLASTIC None

ALPRAZOLAM  alprazolam  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0378-4003 Route of Administration ORAL DEA Schedule CIV

INGREDIENTS Name (Active Moiety) Type Strength Alprazolam (Alprazolam) Active 0.5 MILLIGRAM  In 1 TABLET colloidal silicon dioxide Inactive   croscarmellose sodium Inactive   docusate sodium Inactive   lactose (hydrous) Inactive   magnesium stearate Inactive   microcrystalline cellulose Inactive   sodium benzoate Inactive   sodium lauryl sulfate Inactive   FD&C Yellow #6 Lake Inactive

Product Characteristics Color PINK (Peach) Score 2 pieces Shape ROUND Size 7mm Flavor Imprint Code MYLAN;A3 Contains      Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0378-4003-01 100 TABLET In 1 BOTTLE, PLASTIC None 2 0378-4003-05 500 TABLET In 1 BOTTLE, PLASTIC None

ALPRAZOLAM  alprazolam  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0378-4005 Route of Administration ORAL DEA Schedule CIV

INGREDIENTS Name (Active Moiety) Type Strength Alprazolam (Alprazolam) Active 1 MILLIGRAM  In 1 TABLET colloidal silicon dioxide Inactive   croscarmellose sodium Inactive   docusate sodium Inactive   lactose (hydrous) Inactive   magnesium stearate Inactive   microcrystalline cellulose Inactive   sodium benzoate Inactive   sodium lauryl sulfate Inactive   FD&C Blue #2 Inactive

Product Characteristics Color BLUE Score 2 pieces Shape ROUND Size 7mm Flavor Imprint Code MYLAN;A1 Contains      Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0378-4005-01 100 TABLET In 1 BOTTLE, PLASTIC None 2 0378-4005-05 500 TABLET In 1 BOTTLE, PLASTIC None

ALPRAZOLAM  alprazolam  tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 0378-4007 Route of Administration ORAL DEA Schedule CIV

INGREDIENTS Name (Active Moiety) Type Strength Alprazolam (Alprazolam) Active 2 MILLIGRAM  In 1 TABLET colloidal silicon dioxide Inactive   croscarmellose sodium Inactive   docusate sodium Inactive   lactose (hydrous) Inactive   magnesium stearate Inactive   microcrystalline cellulose Inactive   sodium benzoate Inactive   sodium lauryl sulfate Inactive

Product Characteristics Color WHITE Score 4 pieces Shape ROUND Size 7mm Flavor Imprint Code MYLAN;A4 Contains      Coating false Symbol false

Packaging # NDC Package Description Multilevel Packaging 1 0378-4007-01 100 TABLET In 1 BOTTLE, PLASTIC None

Revised: 12/2006Mylan Pharmaceuticals Inc.