Alprazolam

RECENT MAJOR CHANGES Warnings and Precautions ( 5.8 ) 08/2022

1 INDICATIONS AND USAGE Alprazolam orally disintegrating tablets are a benzodiazepine indicated for: The treatment of generalized anxiety disorder ( 1.1 ). The efficacy of alprazolam was demonstrated in 5 short-term, placebo-controlled trials. ( 14 ). The treatment of panic disorder, with or without agoraphobia ( 1.2 ). The efficacy of alprazolam in the treatment of panic disorder was established in 2 short-term, placebo-controlled trials ( 14 ). 1.1 Generalized Anxiety Disorder Alprazolam orally disintegrating tablets, USP are indicated for the treatment of generalized anxiety disorder. The efficacy of alprazolam in the treatment of generalized anxiety disorder was demonstrated in 5 short-term, placebo-controlled trials [see Clinical Studies ( 14.1 )] . 1.2 Panic Disorder Alprazolam orally disintegrating tablets, USP are also indicated for the treatment of panic disorder, with or without agoraphobia. The efficacy of alprazolam in the treatment of panic disorder was established in 2 short-term, placebo-controlled trials [see Clinical Studies ( 14.2 )] . Demonstrations of the effectiveness of alprazolam by systematic clinical study are limited to 4 months in duration for generalized anxiety disorder and 4 to 10 weeks duration for panic disorder; however, patients with panic disorder have been treated on an open basis for up to 8 months without apparent loss of benefit. The physician should periodically reassess the usefulness of the drug for the individual patient.

2 DOSAGE AND ADMINISTRATION Dosage should be individualized for maximum beneficial effect. While the usual daily dosages given below will meet the needs of most patients, there will be some who require doses greater than 4 mg per day. In such cases, the dosage should be increased cautiously to avoid adverse reactions. In general, benzodiazepines should be prescribed for short periods. Reevaluate the need for continued therapy before extending the treatment period. Indication Recommended Dose Anxiety Disorder ( 2.1 ) Initial: 0.25 mg to 0.5 mg given three times daily. Maximum: 4 mg per day given in divided doses. Panic Disorder ( 2.2 ) Initial: 0.5 mg given three times daily. Maximum: Doses up to 10 mg per day may be required to achieve a successful response. With dry hands, place the tablet on top of the tongue where it will disintegrate and be swallowed with saliva ( 2.5 ). Depending on response, the dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days ( 2.1 , 2.2 ). Use the lowest possible effective dose. Periodically reassess the need for continued treatment ( 2.1 ). In general, benzodiazepines should be prescribed for short periods ( 2 ). Discontinuation of treatment or dose reduction should be gradual and under close physician supervision. Decrease the dosage by no more than 0.5 mg per day every 3 days. Some patients may require an even slower dosage reduction ( 2.1 , 2.2 ). Dosing in elderly: the starting dose is 0.25 mg, given two or three times daily ( 2.4 ). Severe hepatic impairment: the starting dose is 0.25 mg, given two or three times daily ( 2.4 ). 2.1 Generalized Anxiety Disorder Initiate treatment with a dose of 0.25 mg to 0.5 mg three times daily. The dose may be increased to achieve a maximum therapeutic effect, at intervals of 3 to 4 days, to a maximum daily dose of 4 mg, given in divided doses. Use the lowest possible effective dose, and periodically reassess the need for continued treatment. The risk of dependence can increase with dose and duration of treatment. 2.2 Panic Disorder The successful treatment of many panic disorder patients has required the use of alprazolam at doses greater than 4 mg daily. In controlled trials conducted to establish the efficacy of alprazolam in panic disorder, doses in the range of 1 mg to 10 mg daily were used. The mean dosage employed was approximately 5 mg to 6 mg daily. Among the approximately 1700 patients participating in the panic disorder development program, about 300 received alprazolam in dosages of greater than 7 mg per day, including approximately 100 patients who received maximum dosages of greater than 9 mg per day. Occasional patients required as much as 10 mg a day to achieve a successful response. Dose Titration Initiate treatment with a dose of 0.5 mg three times daily. Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg per day. Slower titration to the dose levels greater than 4 mg per day may be advisable to allow full expression of the pharmacodynamic effect of alprazolam. To lessen the possibility of interdose symptoms, the times of administration should be distributed as evenly as possible throughout the waking hours, (i.e., administered three or four times daily). Generally, therapy should be initiated at a low dose to minimize the risk of adverse responses in patients especially sensitive to the drug. The dose should be advanced until an acceptable therapeutic response (i.e., a substantial reduction in or total elimination of panic attacks) is achieved, intolerance occurs, or the maximum recommended dose is attained. Dose Maintenance For patients receiving doses greater than 4 mg per day, periodically reassess treatment and consider a reduction of dosage. In a controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than 4 mg per day for 3 months were able to taper to 50% of their total daily maintenance dose …

3 DOSAGE FORMS AND STRENGTHS 0.25 mg, 0.5 mg, 1.0 mg, and 2.0 mg scored orally disintegrating tablets, USP. 0.25 mg, 0.5 mg, 1 mg, or 2 mg scored orally disintegrating tablets USP ( 3 )

4 CONTRAINDICATIONS Alprazolam orally disintegrating tablets are contraindicated in patients with acute narrow angle glaucoma. Alprazolam orally disintegrating tablets can exacerbate narrow angle closure. Alprazolam orally disintegrating tablets may be used in patients with open angle glaucoma who are receiving appropriate therapy. Alprazolam orally disintegrating tablets are contraindicated in patients treated with potent CYP3A4 inhibitors (e.g., ketoconazole and itraconazole), because these medications significantly impair the oxidative metabolism mediated by cytochrome P450 3A (CYP3A) and can increase alprazolam exposures [see Clinical Pharmacology ( 12.3 ), Warnings and Precautions ( 5.8 ), and Drug Interactions ( 7.4 )] . Acute narrow angle glaucoma. Alprazolam can exacerbate narrow angle closure ( 4 ). Concomitant Use with potent CYP3A inhibitors (e.g., ketoconazole and itraconazole). Can increase the serum concentration of alprazolam ( 4 ).

6 ADVERSE REACTIONS Anxiety Disorder : The most common adverse reactions (greater than or equal to 5% and ~twice the rate of placebo) were sedation, and hypotension. Panic Disorder : The most common adverse reactions included sedation, impaired coordination, dysarthria, and increased libido ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Teva at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience The most commonly reported (greater than or equal to 5% and ~ twice the rate of placebo) adverse reactions with alprazolam treatment are: sedation, impaired coordination, dysarthria, and increased libido. The data cited in the two tables below are estimates of adverse reactions occurring in patients who participated in clinical trials under the following conditions: relatively short duration (four weeks) placebo-controlled clinical studies with dosages up to 4 mg per day of alprazolam (for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety) and short-term (up to ten weeks) placebo-controlled clinical studies with dosages up to 10 mg per day of alprazolam in patients with panic disorder, with or without agoraphobia. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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 adverse reaction 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 dry mouth in others.) Table 1: Adverse Reactions Reported in Placebo-Controlled Trials of Alprazolam in Generalized Anxiety Disorder (>2% and at a rate greater than placebo) GENERALIZED ANXIETY DISORDER Body System/Adverse Reaction Treatment-Emergent Symptom Incidence a ALPRAZOLAM (%) N = 565 PLACEBO (%) N = 505 Central Nervous System Sedation 41 22 Lightheadedness 21 19 Dizziness 2 1 Akathisia 2 1 Gastrointestinal Dry Mouth 15 13 Increased Salivation 4 2 Cardiovascular Hypotension 5 2 Cutaneous Dermatitis/Allergy 4 3 a Events reported by 1% or more of alprazolam patients are included. In addition to the relatively common (i.e., greater than 1%) adverse reactions described in the table above, the following adverse reactions 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. Table 2: Adverse Reactions Reported in Placebo-Controlled Trials of Alprazolam in Panic Disorder (>2% and greater than placebo) PANIC DISORDER Body System/Adverse Reaction Treatment-Emergent Symptom Incidence a ALPRAZOLAM (%) N = 1388 PLACEBO (%) N = 1231 Central Nervous System Sedation 77 43 Fatigue and Tiredness 49 42 Impaired Coordination 40 18 Irritability 33 30 Memory Impairment 33 22 Cognitive Disorder 29 21 Dysarthria 23 6 Decreased Libido 14 8 Confusional State 10 8 Increased Libido 8 4 Change in Libido (Not Specified) 7 6 Disinhibition 3 2 Talkativeness 2 1 Derealization 2 1 Gastrointestinal Constipation 26 15 Increased Salivation 6 4 Cutaneous Rash 11 8 Other Increased Appetite 33 23 Decreased Appetite 28 24 Weight Gain 27 18 Weight Loss 23 17 Micturition Difficulties 12 9 Menstrual Disorders 10 9 Sexual Dysfunction 7 4 Incontinence 2 1 a Events reported by 1% or more of alprazolam patients are included. In addition to the relatively co …

7 DRUG INTERACTIONS Alprazolam produces additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, alcohol and other drugs that produce CNS depression ( 7.1 ). The formulation requires an acidic environment to dissolve; therefore, drugs or diseases that cause dry mouth or raise stomach pH may slow disintegration or dissolution, resulting in decreased absorption ( 7.2 ). Drugs which inhibit the hydroxylation catalyzed by cytochrome P450 3A (CYP3A) metabolic pathway can decrease the clearance of alprazolam and increase the serum concentration ( 7.4 ). 7.1 Use with Other CNS Depressants 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. If alprazolam orally disintegrating tablets are coadministered with other psychotropic agents or anticonvulsant drugs, carefully consider 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, alcohol and other drugs which themselves produce CNS depression. 7.2 Drugs Effecting Salivary Flow and Stomach pH Because alprazolam orally disintegrating tablets disintegrate in the presence of saliva, and the formulation requires an acidic environment to dissolve, concomitant drugs or diseases that cause dry mouth or raise stomach pH might slow disintegration or dissolution, resulting in slowed or decreased absorption. 7.3 Use with Imipramine and Desipramine The steady state plasma concentrations of imipramine and desipramine can increase by approximately 30% and 20%, respectively, when administered concomitantly with alprazolam in doses up to 4 mg per day. The clinical significance of these changes is unknown. 7.4 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 can have a profound effect on the clearance of alprazolam [see Contraindications ( 4 ) and Warnings and Precautions ( 5.8 )] . 7.5 Drugs Demonstrated to be CYP3A Inhibitors of Possible Clinical Significance on the Basis of Clinical Studies Involving Alprazolam Use caution during coadministration of Alprazolam and the following drugs: 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%. 7.6 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 Use caution during the coadministration of Alprazolam and the following : Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction between alprazolam and the following: diltiazem, ison …

8 USE IN SPECIFIC POPULATIONS Teratogenic Effects : Pregnancy Category D. Alprazolam can cause fetal harm ( 8.1 ). Nonteratogenic Effects : A neonate born to a mother who is treated with alprazolam may be at risk for withdrawal, flaccidity, and respiratory problems ( 8.1 ). Nursing Mothers : Chronic administration of diazepam to nursing mothers has been reported to cause their infants to become lethargic and to lose weight ( 8.3 ). Geriatric Use : The elderly exhibit higher plasma concentrations due to reduced clearance, compared with a younger population receiving the same doses ( 8.5 ). Pediatric Use : Safety and effectiveness of alprazolam in individuals below 18 years of age have not been established ( 8.4 ). 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medication, including Alprazolam orally disintegrating tablets, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/ . Risk Summary Neonates born to mothers using benzodiazepines late stages in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions ( 5.8 ) and Clinical Considerations] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear drug association with benzodiazepines and major birth defects (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Benzodiazepines cross the placenta and may produce respiratory depression, and sedation in neonates. Monitor neonates exposed to alprazolam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to alprazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions ( 5.8 )] . Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with Alprazolam orally disintegrating tablets. 8.4 Pediatric Use Safety and effectiveness of alprazolam in individuals below 18 years of age have not been studied. 8.5 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, 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 o …

12.1 Mechanism of Action The exact mechanism of action of alprazolam is unknown. Benzodiazepines bind to gamma aminobutyric acid (GABA) receptors in the brain and enhance GABA-mediated synaptic inhibition; such actions may be responsible for the efficacy of alprazolam in anxiety disorder and panic disorder.

11 DESCRIPTION Alprazolam orally disintegrating tablets, USP contain alprazolam, USP which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds. Alprazolam orally disintegrating tablets, USP are an orally administered formulation of alprazolam, USP which rapidly disintegrates on the tongue and does not require water to aid dissolution or swallowing. The chemical name of alprazolam, USP is 8-Chloro-1-methyl-6-phenyl-4H- s -triazolo [4,3-α] [1,4] benzodiazepine. The molecular formula is C 17 H 13 CIN 4 and the molecular weight is 308.76. The structural formula is: Alprazolam, USP is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH. The structural formula of is alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine. The molecular formula is C17H13CIN4 and the molecular weight is 308.76. 11.1 Alprazolam Orally Disintegrating Tablets Each orally disintegrating tablet contains either 0.25 mg, 0.5 mg, 1 mg, or 2 mg of alprazolam, USP and the following inactive ingredients: corn starch, crospovidone, magnesium stearate, mannitol, methacrylic acid copolymer (type C), microcrystalline cellulose, natural and artificial orange flavor, polysorbate 80, sodium lauryl sulfate, sucralose. In addition, the 1 mg and 2 mg tablets contain ferric oxide (yellow 10 synthetic yellow iron oxide). Product meets USP Dissolution Test 2. Product meets USP Disintegration Test 2.

10 OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions ( 5.2 )] . Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting a poison center (1-800-222-1222), poisoncontrol.org, or medical toxicologist for additional overdosage management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING Alprazolam orally disintegrating tablets, USP 0.25 mg are white to off-white, round, scored, flat face, beveled edge tablets debossed ‘110’ on the scored side and plain on the other. They are supplied as follows: Blisters of 10 x 10 NDC 49884-110-74 Alprazolam orally disintegrating tablets, USP 0.5 mg are white to off-white, round, scored, flat face, beveled edge tablets debossed ‘111’ on the scored side and plain on the other. They are supplied as follows: Blisters of 10 x 10 NDC 49884-111-74 Alprazolam orally disintegrating tablets, USP 1 mg are white to off-white, round, scored, flat face, beveled edge tablets debossed ‘213’ on the scored side and plain on the other. They are supplied as follows: Blisters of 10 x 10 NDC 49884-213-74 Alprazolam orally disintegrating tablets, USP 2 mg are white to off-white, round, scored, flat face, beveled edge tablets debossed ‘214’ on the scored side and plain on the other. They are supplied as follows: Blisters of 10 x 10 NDC 49884-214-74 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86oF) [See USP Controlled Room Temperature]. Protect from moisture. Dispense in tight, light-resistant containers as defined in the USP. Keep container tightly closed.