ABUSE SECTION.

9.2 Abuse Alprazolam is benzodiazepine and CNS depressant with potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)]. The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: oRisks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)] oAbuse, Misuse, and Addiction [see Warnings and Precautions (5.2)] oDependence and Withdrawal Reactions [see Warnings and Precautions (5.3)] oEffects on Driving and Operating Machinery [see Warnings and Precautions (5.4)] oNeonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.5)] oPatients with Depression [see Warnings and Precautions (5.7)] oRisks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)]. oRisks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)] oAbuse, Misuse, and Addiction [see Warnings and Precautions (5.2)] oDependence and Withdrawal Reactions [see Warnings and Precautions (5.3)] oEffects on Driving and Operating Machinery [see Warnings and Precautions (5.4)] oNeonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.5)] oPatients with Depression [see Warnings and Precautions (5.7)] oRisks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9)]. The most common adverse reactions reported in clinical trials for generalized anxiety disorder and panic disorder (incidence >5% and at least twice that of placebo) include: impaired coordination, hypotension, dysarthria, and increased libido. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in: o4-week placebo-controlled clinical studies with alprazolam dosages up to mg per day for the acute treatment of generalized anxiety disorder (Table 1) oShort-term (up to 10 weeks) placebo-controlled clinical studies with alprazolam dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).Table 1: Adverse Reactions Occurring in >=1% in Alprazolam-Treated Patients and Greater Than Placebo-Treated Patients in Placebo-Controlled Trials for Generalized AnxietyAlprazolamn=565Placebon=505Nervous system disorders Drowsiness Light-headedness Dizziness AkathisiaGastrointestinal disorders Dry mouth Increased salivation41%21%2%2%15%4%22%19%1%1%13%2%Cardiovascular disordersHypotensionSkin and subcutaneous tissue disorders Dermatitis/allergy5%4%2%3%In addition to the adverse reactions (i.e., greater than 1%) enumerated in the table above for patients with generalized anxiety disorder, 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 Occuring in >=1% in Alprazolam-Treated Patients and Greater Than Placebo-Treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic DisorderAlprazolamn=1388 Placebo n=1231 Drowsiness Fatique and Tiredness Impaired Coordination Irritability Memory Impairment Cognitive Disorder Decreased Libido Dysartharia Confusional state Increased libido Change in libido (not specified) Disinhibition Talkativeness Derealization 77% 49% 40% 33% 33% 29% 14% 23% 10% 8% 7% 3% 2% 2% 43% 42% 18% 30% 22% 21% 8% 6% 8% 4% 6% 2% 1% 1% Gastrointestinal disorders Constipation Increased salivation Skin and subcutaneous tissue disorders Rash26% 6% 11%15% 4% 8%Other Increased appetite Decreased appetite Weight gain Weight loss Micturition difficulties Menstrual disorders Sexual dysfunction Incontinence 33%28%27%23%12%11%7%2%23% 24% 18% 17% 9% 9% 4% 1% In addition to the reactions (i.e., greater than 1%) enumerated in the table above for patients with panic disorder, the following adverse reactions have been reported in association with the use of alprazolam: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepatic enzymes, and jaundice.Adverse Reactions Reported as Reasons for Discontinuation in Treatment of Panic Disorder in Placebo-Controlled TrialsIn larger database comprised of both controlled and uncontrolled studies in which 641 patients received alprazolam, discontinuation-emergent symptoms which occurred at rate of over 5% in patients treated with alprazolam and at greater rate than the placebo-treated group are shown in Table 3.Table 3: Discontinuation-Emergent Symptom Incidence Reported in >=5% of Alprazolam-Treated Patients and Placebo-Treated PatientsAlprazolam-Treated Patientsn=641Nervous system disordersInsomnia Light-headedness Abnormal involuntary movement Headache Muscular twitching Impaired coordination Muscle tone disorders Weakness 29.5%19.3%17.3%17.0%6.9%6.6%5.9%5.8%Psychiatric disordersAnxiety Fatigue and Tiredness Irritability Cognitive disorder Memory impairment Depression Confusional state 19.2%18.4%10.5%10.3%5.5%5.1%5.0%Gastrointestinal disordersNausea/Vomiting Diarrhea Decreased salivation 16.5%13.6%10.6%Metabolism and nutrition disordersWeight loss Decreased appetite 13.3%12.8%Dermatological disordersSweating14.4%Cardiovascular disorders Tachycardia 12.2%Special Senses Blurred vision10.0%n number of patientsThere have also been reports of withdrawal seizures upon rapid decrease or abrupt discontinuation of alprazolam [see Warning and Precautions (5.2) and Drug Abuse and Dependence (9.3)].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, 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.. o4-week placebo-controlled clinical studies with alprazolam dosages up to mg per day for the acute treatment of generalized anxiety disorder (Table 1) oShort-term (up to 10 weeks) placebo-controlled clinical studies with alprazolam dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2).. Drowsiness. Light-headedness. Dizziness. Akathisia. Dry mouth. Increased salivation. Dermatitis/allergy. Drowsiness Fatique and Tiredness Impaired Coordination Irritability Memory Impairment Cognitive Disorder Decreased Libido Dysartharia Confusional state Increased libido Change in libido (not specified) Disinhibition Talkativeness Derealization Gastrointestinal disorders Constipation Increased salivation Rash. Increased appetite Decreased appetite Weight gain Weight loss Micturition difficulties Menstrual disorders Sexual dysfunction Incontinence 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of alprazolam. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Endocrine disordersHyperprolactinemia General disorders and administration site conditions Edema peripheral Hepatobiliary disorders Hepatitis, hepatic failure InvestigationsLiver enzyme elevations Psychiatric disordersHypomania, mania Reproductive system and breast disordersGynecomastia, galactorrhea Skin and subcutaneous tissue disordersPhotosensitivity reaction, angioedema, Stevens-Johnson syndrome.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology When rats were treated with alprazolam at oral doses of mg, 10 mg, and 30 mg/kg day (3 to 29 times the maximum recommended human dose based on mg/m2 body surface area) for years, tendency for dose related increase in the number of cataracts was observed in females and tendency for dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

BOXED WARNING SECTION.

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for 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 [see Warnings and Precautions (5.1), Drug Interactions (7.1)]. oThe use of benzodiazepines, including alprazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing alprazolam and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)]. oThe continued use of benzodiazepines, including alprazolam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].. oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for 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 [see Warnings and Precautions (5.1), Drug Interactions (7.1)]. oThe use of benzodiazepines, including alprazolam, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing alprazolam and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)]. oThe continued use of benzodiazepines, including alprazolam, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.2), Warnings and Precautions (5.3)].. WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS See full prescribing information for complete boxed warning.oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing 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. (5.1, 7.1) oThe use of benzodiazepines, including alprazolam tablets, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing alprazolam tablets and throughout treatment, assess each patients risk for abuse, misuse, and addiction. (5.2) oAbrupt discontinuation or rapid dosage reduction of alprazolam tablets after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam tablets or reduce the dosage. (2.2, 5.3). oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing 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. (5.1, 7.1) oThe use of benzodiazepines, including alprazolam tablets, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Before prescribing alprazolam tablets and throughout treatment, assess each patients risk for abuse, misuse, and addiction. (5.2) oAbrupt discontinuation or rapid dosage reduction of alprazolam tablets after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam tablets or reduce the dosage. (2.2, 5.3).

GERIATRIC USE SECTION.

8.5 Geriatric Use Alprazolam-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. Therefore, dosage reduction of alprazolam is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisNo evidence of carcinogenic potential was observed in rats or mice administered alprazolam for 2-years at doses up to 30 and 10 mg/kg day respectively. These doses are 29 times and 4.8 times the maximum recommended human dose of 10 mg/day based on mg/m2 body surface area, respectively. Mutagenesis Alprazolam was negative in the in vitro Ames bacterial reverse mutation assay and DNA Damage/Alkaline Elution Assay and in vivo rat micronucleus genetic toxicology assays. Impairment of FertilityAlprazolam produced no impairment of fertility in rats at doses up to mg/kg per day, which is approximately times the maximum recommended human dose of 10 mg per day based on mg/m2 body surface area.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Alprazolam is 1,4 benzodiazepine. Alprazolam exerts its effect for the acute treatment of generalized anxiety disorder and panic disorder through binding to the benzodiazepine site of gamma-aminobutyric acid-A (GABAA) receptors in the brain and enhances GABA-mediated synaptic inhibition.. 12.3 Pharmacokinetics Plasma levels of alprazolam increase proportionally to the dose over the range of 0.5 to 3.0 mg.. Absorption. Following oral administration, peak plasma concentration of alprazolam (Cmax) occurs in to hours post dose.. Distribution. Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding.. Elimination. The mean plasma elimination half-life (T1/2) of alprazolam is approximately 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.. Metabolism. Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to major active metabolites in the plasma: 4-hydroxyalprazolam and -hydroxyalprazolam. The plasma circulation levels of the two active metabolites are less than 4% of the parent. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and -hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and -hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam.. Excretion. Alprazolam and its metabolites are excreted primarily in the urine.. Specific Populations. Geriatric Patients The mean T1/2 of alprazolam was 16.3 hours (range: 9.0 to 26.9 hours) in healthy elderly subjects compared to 11.0 hours (range: 6.3 to -15.8 hours, n=16) in healthy younger adult subjects. Obese Patients The mean T1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in group of obese subjects. Patients with Hepatic Impairment The mean T1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease. Racial or Ethnic Groups Maximal concentrations and T1/2 of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians. Smoking Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers. Drug Interaction Studies In Vivo Studies Most of the interactions that have been documented with alprazolam are with drugs that modulate CYP3A4 activity. Compounds that are inhibitors or inducers of CYP3A would be expected to increase or decrease plasma alprazolam concentrations, respectively. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.66 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4), Warnings and Precautions (5.5), Drug Interactions (7.2)]. Other studied drugs include: Cimetidine Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T1/2 by 16%. Fluoxetine Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T1/2 by 17%, and decreased measured psychomotor performance. Oral Contraceptives Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T1/2 by 29%. Carbamazepine The oral clearance of alprazolam (given in 0.8 mg single dose) was increased from 0.90+-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 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2)]. However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 to 1200 mg per day); the effect at usual carbamazepine doses is unknown. Ritonavir Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect Cmax of alprazolam. The elimination T1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5)]. Sertraline single dose of alprazolam mg and steady state dose of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. 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 in doses up to mg per day. Warfarin Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. In Vitro Studies Data from in vitro studies of alprazolam suggest possible drug interaction of alprazolam with paroxetine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined.. Cimetidine. Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T1/2 by 16%. Fluoxetine. Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T1/2 by 17%, and decreased measured psychomotor performance. Oral Contraceptives. Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T1/2 by 29%. Carbamazepine. The oral clearance of alprazolam (given in 0.8 mg single dose) was increased from 0.90+-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 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2)]. However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 to 1200 mg per day); the effect at usual carbamazepine doses is unknown. Ritonavir. Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect Cmax of alprazolam. The elimination T1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5)]. Sertraline. single dose of alprazolam mg and steady state dose of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. 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 in doses up to mg per day. Warfarin. Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Generalized Anxiety Disorder Alprazolam was compared to placebo in double-blind clinical studies (doses up to mg per day) in patients with diagnosis of anxiety or anxiety with associated depressive symptomatology. Alprazolam was significantly better than placebo at each of the evaluation periods of these 4-week studies as judged by the following psychometric instruments: Physicians Global Impressions, Hamilton Anxiety Rating Scale, Target Symptoms, Patients Global Impressions, and Self-Rating Symptom Scale.. 14.2 Panic Disorder The effectiveness of alprazolam in the treatment of panic disorder was studied in short-term, placebo-controlled studies (up to 10 weeks) in patients with diagnoses closely corresponding to DSM-III-R criteria for panic disorder. The average dose of alprazolam was mg to mg per day in of the studies, and the doses of alprazolam were fixed at mg and mg per day in the third study. In all studies, alprazolam was superior to placebo on variable defined as the number of patients with zero panic attacks (range, 37% to 83% met this criterion), as well as on global improvement score. In of the studies, alprazolam was superior to placebo on variable defined as change from baseline on the number of panic attacks per week (range, 3.3 to 5.2), and also on phobia rating scale. subgroup of patients who improved on alprazolam during short-term treatment in of these trials was continued on an open basis up to months, without apparent loss of benefit.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Alprazolam is contraindicated in patients:owith known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2)]. otaking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2.6), Warnings and Precautions (5.5), Drug Interactions (7.1)]. owith known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2)]. otaking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2.6), Warnings and Precautions (5.5), Drug Interactions (7.1)]. oKnown hypersensitivity to alprazolam or other benzodiazepines. (4) oConcomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. (4, 5.5, 7.1). oKnown hypersensitivity to alprazolam or other benzodiazepines. (4) oConcomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. (4, 5.5, 7.1).

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance Alprazolam is Schedule IV controlled substance.

DEPENDENCE SECTION.

9.3 Dependence Alprazolam may produce physical dependence from continued therapy. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)]. To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)]. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal SyndromeProtracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond to weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to alprazolam may develop from continued therapy. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose). Tolerance to the therapeutic effect of alprazolam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DESCRIPTION SECTION.

11 DESCRIPTION Alprazolam, USP is 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-] [1,4] benzodiazepine. The structural formula is:Alprazolam, USP is white to off-white crystalline powder, which is soluble in alcohol but which has no appreciable solubility in water at physiological pH.Each alprazolam tablet, USP, for oral administration, contains 0.25, 0.5, or mg of alprazolam, USP.Inactive ingredients: docusate sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium benzoate. Additionally, the 0.5 mg also contains FD&C Yellow Aluminum Lake, and the mg also contains FD&C Blue Aluminum Lake.. Alprazolam Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oGeneralized Anxiety Disorder:(2.1)Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily. Dosage may be increased, at intervals of every to days, to maximum recommended daily dose of mg, given in divided doses. Use the lowest possible effective dose and frequently assess the need for continued treatment. oPanic Disorder: Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every to days in increments of no more than mg per day. (2.2)oWhen tapering, decrease dosage by no more than 0.5 mg every days. Some patients may require an even slower dosage reduction. (2.3, 5.2) oSee the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. (2.4, 2.5, 2.6). oGeneralized Anxiety Disorder:(2.1). Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily. Dosage may be increased, at intervals of every to days, to maximum recommended daily dose of mg, given in divided doses. Use the lowest possible effective dose and frequently assess the need for continued treatment. oPanic Disorder: Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every to days in increments of no more than mg per day. (2.2). oWhen tapering, decrease dosage by no more than 0.5 mg every days. Some patients may require an even slower dosage reduction. (2.3, 5.2) oSee the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. (2.4, 2.5, 2.6). 2.1 Dosage in Generalized Anxiety Disorder The recommended starting oral dosage of alprazolam for the acute treatment of patients with GAD is 0.25 mg to 0.5 mg administered three times daily. Depending upon the response, the dosage may be adjusted at intervals of every to days. The maximum recommended dosage is mg daily (in divided doses). Use the lowest possible effective dose and frequently assess the need for continued treatment [see Warnings and Precautions (5.2)].. 2.2 Dosage in Panic Disorder The recommended starting oral dosage of alprazolam for the treatment of PD is 0.5 mg three times daily. Depending on the response, the dosage may be increased at intervals of every to days in increments of no more than mg per day. Controlled trials of alprazolam in the treatment of panic disorder included dosages in the range of mg to 10 mg daily. The mean dosage was approximately mg to mg daily. Occasional patients required as much as 10 mg per day. For patients receiving doses greater than mg per day, periodic reassessment and consideration of dosage reduction is advised. In controlled postmarketing dose-response study, patients treated with doses of alprazolam greater than mg per day for months were able to taper to 50% of their total maintenance dose without apparent loss of clinical benefit. The necessary duration of treatment for PD in patients responding to alprazolam is unknown. After period of extended freedom from panic attacks, 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 [see Dosage and Administration (2.3)]. 2.3 Discontinuation or Dosage Reduction of Alprazolam To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage. If patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions 5.3), Drug Abuse and Dependence (9.3)]. Reduced the dosage by no more than 0.5 mg every days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens. In controlled postmarketing discontinuation study of panic disorder patients which compared the recommended taper schedule with 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 reduction in symptoms associated with withdrawal syndrome.. 2.4 Dosage Recommendations in Geriatric Patients In geriatric patients, the recommended starting oral dosage of alprazolam is 0.25 mg, given or times daily. This may be gradually increased if needed and tolerated. Geriatric patients may be especially sensitive to the effects of benzodiazepines. If adverse reactions occur at the recommended starting dosage, the dosage may be reduced [see Use in Specific Populations (8.5), Clinical Pharmacology (12.3)].. 2.5 Dosage Recommendations in Patients With Hepatic Impairment In patients with hepatic impairment, the recommended starting oral dosage of alprazolam is 0.25 mg, given or times daily. This may be gradually increased if needed and tolerated. If adverse reactions occur at the recommended starting dose, the dosage may be reduced [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].. 2.6 Dosage Modifications for Drug Interactions Alprazolam should be reduced to half of the recommended dosage when patient is started on ritonavir and alprazolam together, or when ritonavir administered to patient treated with alprazolam. Increase the alprazolam dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam together. It is not necessary to reduce alprazolam dose in patients who have been taking ritonavir for more than 10 to 14 days. Alprazolam is contraindicated with concomitant use of all strong CYP3A inhibitors, except ritonavir [see Contraindications (4), Warnings and Precautions (5.5)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Alprazolam tablets are available as: o0.25 mg: white, oval, debossed GG 256 on one side and scored on the reverse side o0.5 mg: peach, oval, debossed GG 257 on one side and scored on the reverse sideo1 mg: blue, oval, debossed GG 258 on one side and scored on the reverse sideo2 mg: white, rectangular, multi-scored, debossed GG 249 on one side and plain on the reverse side. o0.25 mg: white, oval, debossed GG 256 on one side and scored on the reverse side o0.5 mg: peach, oval, debossed GG 257 on one side and scored on the reverse side. o1 mg: blue, oval, debossed GG 258 on one side and scored on the reverse side. o2 mg: white, rectangular, multi-scored, debossed GG 249 on one side and plain on the reverse side. Tablets: 0.25 mg, 0.5 mg, mg, and mg (3).

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Alprazolam is Schedule IV controlled substance.. 9.2 Abuse Alprazolam is benzodiazepine and CNS depressant with potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)]. The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).. 9.3 Dependence Alprazolam may produce physical dependence from continued therapy. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)]. To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage [see Dosage and Administration (2.3), Warnings and Precautions (5.3)]. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal SyndromeProtracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond to weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance Tolerance to alprazolam may develop from continued therapy. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose). Tolerance to the therapeutic effect of alprazolam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oUse with Opioids: Increase the risk of respiratory depression. (7.1) oUse with Other CNS Depressants: Produces additive CNS depressant effects. (7.1) oUse with Digoxin: Increase the risk of digoxin toxicity. (7.1) oUse with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. (4, 5.6, 7.1)oUse with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. (7.1). oUse with Opioids: Increase the risk of respiratory depression. (7.1) oUse with Other CNS Depressants: Produces additive CNS depressant effects. (7.1) oUse with Digoxin: Increase the risk of digoxin toxicity. (7.1) oUse with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. (4, 5.6, 7.1). oUse with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. (7.1). 7.1 Drugs Having Clinically Important Interactions With Alprazolam Table includes clinically significant drug interactions with alprazolam [see Clinical Pharmacology (12.3)].Table 4: Clinically Significant Drug Interactions With AlprazolamOpioidsClinical implication 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 gammaaminobutyric acid(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. Prevention or management Limit dosage and duration of concomitant use of alprazolam and opioids, and monitor patients closely for respiratory depression and sedation [see Warnings and Precautions 5.1)]. Examples Morphine, buprenorphine, hydromorphone, oxymorphone, oxycodone, fentanyl, methadone, alfentanil, butorpenol, codeine, dihydrocodeine, meperidine, pentazocine, remifentanil, sufentanil, tapentadol, tramadol. CNS DepressantsClinical implication The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other CNS depressants. Prevention or management Limit dosage and duration of alprazolam during concomitant use with CNS depressants [see Warnings and Precautions (5.3)]. Examples Psychotropic medications, anticonvulsants, antihistaminics, ethanol, and other drugs which themselves produce CNS depression. Strong Inhibitors of CYP3A (except ritonavir)Clinical implication Concomitant use of alprazolam with strong CYP3A inhibitors has profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see Clinical Pharmacology (12.3)]. Prevention or management Concomitant use of alprazolam with strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)]. Examples Ketoconazole, itraconazole, clarithromycin Moderate or Weak Inhibitors of CYP3AClinical implication Concomitant use of alprazolam with CYP3A inhibitors may increase the concentrations of alprazolam, resulting in increased risk of adverse reactions of alprazolam [see Clinical Pharmacology (12.3)]. Prevention or management Avoid use and consider appropriate dose reduction when alprazolam is coadministered with moderate or weak CYP3A inhibitor [see Warnings and Precautions (5.5)]. Examples Nefazodone, fluvoxamine, cimetidine, erythromycin CYP3A InducersClinical implication Concomitant use of CYP3A inducers can increase alprazolam metabolism and therefore can decease plasma levels of alprazolam [see Clinical Pharmacology (12.3)]. Prevention or management Caution is recommended during coadministration with alprazolam. Examples Carbamazepine, phenytoin RitonavirClinical implication Interactions involving ritonavir and alprazolam are complex and time dependent. Short term administration of ritonavir increased alprazolam exposure due to CYP3A4 inhibition. Following long term treatment of ritonavir (>10 to 14 days), CYP3A4 induction offsets this inhibition. Alprazolam exposure was not meaningfully affected in the presence of ritonavir. Prevention or management Reduce alprazolam dosage when ritonavir and alprazolam are initiated concomitantly, or when ritonavir is added to regimen where alprazolam is stabilized. Increase alprazolam dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam concomitantly. No dosage adjustment of alprazolam is necessary in patients receiving ritonavir for more than 10 to14 days [see Dosage and Administration (2.6)]. Concomitant use of alprazolam with strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications (4), Warnings and Precautions (5.5)]. DigoxinClinical implication Increased digoxin concentrations have been reported when alprazolam was given, especially in geriatric patients( >65 years of age). Prevention or management In patients on digoxin therapy, measure serum digoxin concentrations before initiating alprazolam. Continue monitoring digoxin serum concentration and toxicity frequently. Reduce the digoxin dose if necessary. 7.2 Drug/Laboratory Test Interactions Although interactions between benzodiazepines and commonly employed clinical laboratory tests have occasionally been reported, there is no consistent pattern for specific drug or specific test.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Alprazolam tablets, USP for oral administration are in the following strengths and package configurations:Alprazolam TabletsPackage ConfigurationTablet Strength (mg)NDCPrintBottles of 100 Bottles of 500 Bottles of 10000.25 mgNDC 0781-1061-01NDC 0781-1061-05 NDC 0781-1061-10 Oval, white tablets debossed GG 256 on one side and scored on the reverse sideBottles of 100 Bottles of 500 Bottles of 10000.5 mgNDC 0781-1077-01 NDC 0781-1077-05 NDC 0781-1077-10 Oval, peach tablets debossed GG 257 on one side and scored on the reverse sideBottles of 100 Bottles of 500 Bottles of 10001 mgNDC 0781-1079-01 NDC 0781-1079-05 NDC 0781-1079-10Oval, blue tablets debossed GG 258 on one side and scored on the reverse sideBottles of 100 Bottles of 500 mgNDC 0781-1089-01 NDC 0781-1089-05Rectangular white multi-scored tablets debossed GG 249 on one side and plain on the reverse side. Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense contents in tight, light-resistant container as defined in the USP with child-resistant closure.KEEP OUT OF THE REACH OF CHILDREN.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Alprazolam tablets are indicated for the: oacute treatment of generalized anxiety disorder (GAD) in adults. otreatment of panic disorder (PD), with or without agoraphobia in adults.. oacute treatment of generalized anxiety disorder (GAD) in adults. otreatment of panic disorder (PD), with or without agoraphobia in adults.. Alprazolam tablets are benzodiazepine indicated for the: oAcute treatment of generalized anxiety disorder in adults. (1) oTreatment of panic disorder with or without agoraphobia in adults. (1). oAcute treatment of generalized anxiety disorder in adults. (1) oTreatment of panic disorder with or without agoraphobia in adults. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks From Concomitant Use With Opioids Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when alprazolam is used with opioids and not to use such drugs concomitantly unless supervised by healthcare provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Warnings and Precautions (5.1), Drug Interactions (7.1)]. Abuse, Misuse, and Addiction Inform patients that the use of alprazolam, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2), Drug Abuse and Dependence (9.2)]. Withdrawal ReactionsInform patients that the continued use of alprazolam may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of alprazolam may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of alprazolam may require slow taper [see Warnings and Precautions (5.3), Drug Abuse and Dependence (9.3)]. Effects on Driving and Operating MachineryAdvise patients not to drive motor vehicle or operate heavy machinery while taking alprazolam due to its CNS depressant effects. Also advise patients to avoid use of alcohol or other CNS depressants while taking alprazolam [see Warnings and Precautions (5.3)]. Patients with DepressionAdvise patients, their families, and caregivers to look for signs of suicidality or worsening depression, and to inform the patients healthcare provider immediately [see Warnings and Precautions (5.6)]. Concomitant MedicationsAdvise patients to inform their healthcare provider of all medicines they take, including prescription and nonprescription medications, vitamins and herbal supplements [see Drug Interactions (7)]. Pregnancy Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Advise mothers using alprazolam to monitor neonates for signs of sedation, respiratory depression, withdrawal symptoms, and feeding problems. Instruct patients to inform their healthcare provider if they are pregnant or intend to become pregnant during treatment with alprazolam [see Warnings and Precautions (5.4)]. Advise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam during pregnancy [see Use in Specific Populations (8.1)]. Lactation Advise women not to breastfeed during treatment with alprazolam [see Use in Specific Populations (8.2)].This products labeling may have been updated. For the most recent prescribing information, please visit www.sandoz.com.

LACTATION SECTION.

8.2 Lactation Risk SummaryLimited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation and withdrawal symptoms in breastfed neonates and infants exposed to alprazolam. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with alprazolam.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Alprazolam is 1,4 benzodiazepine. Alprazolam exerts its effect for the acute treatment of generalized anxiety disorder and panic disorder through binding to the benzodiazepine site of gamma-aminobutyric acid-A (GABAA) receptors in the brain and enhances GABA-mediated synaptic inhibition.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility CarcinogenesisNo evidence of carcinogenic potential was observed in rats or mice administered alprazolam for 2-years at doses up to 30 and 10 mg/kg day respectively. These doses are 29 times and 4.8 times the maximum recommended human dose of 10 mg/day based on mg/m2 body surface area, respectively. Mutagenesis Alprazolam was negative in the in vitro Ames bacterial reverse mutation assay and DNA Damage/Alkaline Elution Assay and in vivo rat micronucleus genetic toxicology assays. Impairment of FertilityAlprazolam produced no impairment of fertility in rats at doses up to mg/kg per day, which is approximately times the maximum recommended human dose of 10 mg per day based on mg/m2 body surface area.. 13.2 Animal Toxicology and/or Pharmacology When rats were treated with alprazolam at oral doses of mg, 10 mg, and 30 mg/kg day (3 to 29 times the maximum recommended human dose based on mg/m2 body surface area) for years, tendency for dose related increase in the number of cataracts was observed in females and tendency for dose related increase in corneal vascularization was observed in males. These lesions did not appear until after 11 months of treatment.

OVERDOSAGE SECTION.

10 OVERDOSAGE 10.1 Clinical Experience Manifestations of alprazolam overdosage include somnolence, confusion, impaired coordination, diminished reflexes, and coma. Death has been reported in association with overdoses of alprazolam by itself, as it has with other benzodiazepines. In addition, fatalities have been reported in patients who have overdosed with combination of 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.. 10.2 Management of Overdose In case of an overdosage, consult Certified Poison Control Center at 1-800-222-1222 for latest recommendations. 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. As with the management of intentional overdosing with any drug, it should be borne in mind that multiple agents may have been ingested. Flumazenil may be useful in situations when an overdose with 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 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 risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert should be consulted prior to use.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 0781-1061-01AlprazolamTablets, USP CIV0.25 mgRx onlyPHARMACIST: Dispense the Medication Guide provided separately to each patient.100 TabletsSANDOZ. 025mg-100Tabs.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Safety and effectiveness of alprazolam have not been established in pediatric patients.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Plasma levels of alprazolam increase proportionally to the dose over the range of 0.5 to 3.0 mg.. Absorption. Following oral administration, peak plasma concentration of alprazolam (Cmax) occurs in to hours post dose.. Distribution. Alprazolam is 80% bound to human serum protein, and albumin accounts for the majority of the binding.. Elimination. The mean plasma elimination half-life (T1/2) of alprazolam is approximately 11.2 hours (range: 6.3 to 26.9 hours) in healthy adults.. Metabolism. Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to major active metabolites in the plasma: 4-hydroxyalprazolam and -hydroxyalprazolam. The plasma circulation levels of the two active metabolites are less than 4% of the parent. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and -hydroxyalprazolam. The low concentrations and low potencies of 4-hydroxyalprazolam and -hydroxyalprazolam indicate that they unlikely contribute much to the effects of alprazolam. benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam.. Excretion. Alprazolam and its metabolites are excreted primarily in the urine.. Specific Populations. Geriatric Patients The mean T1/2 of alprazolam was 16.3 hours (range: 9.0 to 26.9 hours) in healthy elderly subjects compared to 11.0 hours (range: 6.3 to -15.8 hours, n=16) in healthy younger adult subjects. Obese Patients The mean T1/2 of alprazolam was 21.8 hours (range: 9.9 to 40.4 hours) in group of obese subjects. Patients with Hepatic Impairment The mean T1/2 of alprazolam was 19.7 hours (range: 5.8 to 65.3 hours) in patients with alcoholic liver disease. Racial or Ethnic Groups Maximal concentrations and T1/2 of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians. Smoking Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers. Drug Interaction Studies In Vivo Studies Most of the interactions that have been documented with alprazolam are with drugs that modulate CYP3A4 activity. Compounds that are inhibitors or inducers of CYP3A would be expected to increase or decrease plasma alprazolam concentrations, respectively. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.66 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold [see Contraindications (4), Warnings and Precautions (5.5), Drug Interactions (7.2)]. Other studied drugs include: Cimetidine Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T1/2 by 16%. Fluoxetine Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T1/2 by 17%, and decreased measured psychomotor performance. Oral Contraceptives Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T1/2 by 29%. Carbamazepine The oral clearance of alprazolam (given in 0.8 mg single dose) was increased from 0.90+-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 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2)]. However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 to 1200 mg per day); the effect at usual carbamazepine doses is unknown. Ritonavir Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect Cmax of alprazolam. The elimination T1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5)]. Sertraline single dose of alprazolam mg and steady state dose of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. 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 in doses up to mg per day. Warfarin Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. In Vitro Studies Data from in vitro studies of alprazolam suggest possible drug interaction of alprazolam with paroxetine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined.. Cimetidine. Coadministration of cimetidine increased the maximum plasma concentration of alprazolam by 82%, decreased clearance by 42%, and increased T1/2 by 16%. Fluoxetine. Coadministration of fluoxetine with alprazolam increased the maximum plasma concentration of alprazolam by 46%, decreased clearance by 21%, increased T1/2 by 17%, and decreased measured psychomotor performance. Oral Contraceptives. Coadministration of oral contraceptives increased the maximum plasma concentration of alprazolam by 18%, decreased clearance by 22%, and increased T1/2 by 29%. Carbamazepine. The oral clearance of alprazolam (given in 0.8 mg single dose) was increased from 0.90+-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 hour) following administration of 300 mg per day carbamazepine for 10 days [see Drug Interactions (7.2)]. However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000 to 1200 mg per day); the effect at usual carbamazepine doses is unknown. Ritonavir. Interactions involving HIV protease inhibitors (e.g., ritonavir) and alprazolam are complex and time dependent. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect Cmax of alprazolam. The elimination T1/2 was prolonged (30 hours versus 13 hours). However, upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination T1/2 of alprazolam was not significantly changed [see Warnings and Precautions (5.5)]. Sertraline. single dose of alprazolam mg and steady state dose of sertraline (50 mg to 150 mg per day) did not reveal any clinically significant changes in the pharmacokinetics of alprazolam. 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 in doses up to mg per day. Warfarin. Alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.

PREGNANCY SECTION.

8.1 Pregnancy Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Other Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/. Risk SummaryNeonates born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal [see Warnings and Precautions (5.4), Clinical Considerations)]. Overall available data from published observational studies of pregnant women exposed to alprazolam have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 benzodiazepines during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly [see Warnings and Precautions (5.4)]. Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report 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. At this time, there is no clear evidence that alprazolam exposure in early pregnancy can cause major birth defects. Neonates exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation and neonatal withdrawal symptoms.

RECENT MAJOR CHANGES SECTION.

Boxed Warning 2/2021Dosage and Administration (2.3) 2/2021Warnings and Precautions (5.2, 5.3) 2/2021.

SPL MEDGUIDE SECTION.

MEDICATION GUIDEAlprazolam Tablets, USP CIV(al PRAY zoe lam) What is the most important information should know about alprazolam tabletsoAlprazolam tablets are benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens:shallow or slowed breathingbreathing stops (which may lead to the heart stopping)excessive sleepiness (sedation)Do not drive or operate heavy machinery until you know how taking alprazolam tablets with opioids affects you.oRisk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including alprazolam tablets, which can lead to overdose and serious side effects including coma and death.Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including alprazolam tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take alprazolam tablets as prescribed by your healthcare provider.Take alprazolam tablets exactly as your healthcare provider prescribed.Do not share your alprazolam tablets with other people.Keep alprazolam tablets in safe place and away from children.oPhysical dependence and withdrawal reactions. Alprazolam tablets can cause physical dependence and withdrawal reactions.Do not suddenly stop taking alprazolam tablets. Stopping alprazolam tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.oDo not take more alprazolam tablets than prescribed or take alprazolam tablets for longer than prescribed.What are alprazolam tabletsoAlprazolam tablets are prescription medicine used:to treat anxiety disordersfor the short-term relief of the symptoms of anxietyto treat panic disorder with or without fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia)oAlprazolam tablets are federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep alprazolam tablets in safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.oIt is not known if alprazolam tablets are safe and effective in children.oElderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets.oIt is not known if alprazolam tablets are safe and effective when used to treat anxiety disorder for longer than monthsoIt is not known if alprazolam tablets are safe and effective when used to treat panic disorder for longer than 10 weeks.Do not take alprazolam tablets if:oyou are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam tablets. See the end of this Medication Guide for complete list of ingredients in alprazolam tablets.oyou are taking antifungal medicines including ketoconazole and itraconazole.Before you take alprazolam tablets, tell your healthcare provider about all of your medical conditions, including if you:ohave or have had depression, mood problems, or suicidal thoughts or behaviorohave liver or kidney problemsohave lung disease or breathing problemsoare pregnant or plan to become pregnant. Alprazolam tablets may harm your unborn baby. You and your healthcare provider should decide if you should take alprazolam tablets while you are pregnant.oare breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take alprazolam tablets. You should not breastfeed while taking alprazolam tablets.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Taking alprazolam tablets with certain other medicines can cause side effects or affect how well alprazolam tablets or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.How should take alprazolam tabletsoSee What is the most important information should know about alprazolam tabletsoTake alprazolam tablets exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many alprazolam tablets to take and when to take them.oIf you take too many alprazolam tablets, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of alprazolam tabletsAlprazolam tablets may cause serious side effects, including:oSee What is the most important information should know about alprazolam tabletsoSeizures. Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus).oMania. Alprazolam tablets may cause an increase in activity and talking (hypomania and mania) in people who have depression.Alprazolam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affect you.Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse. The most common side effects of alprazolam tablets include:oproblems with coordinationohypotensionotrouble saying words clearly (dysarthria) ochanges in sex drive (libido) These are not all the possible side effects of alprazolam tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store alprazolam tabletsoStore alprazolam tablets between 68 to 77F (20 to 25C)oKEEP OUT OF THE REACH OF CHILDRENGeneral information about the safe and effective use of alprazolam tablets.oMedicines are sometimes prescribed for purposes other than those listed in Medication Guide.oDo not use alprazolam tablets for condition for which they were not prescribed.oDo not give alprazolam tablets to other people, even if they have the same symptoms that you have. They may harm them.oYou can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals.What are the ingredients in alprazolam tabletsActive ingredient: alprazolamInactive ingredients: docusate sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium benzoate. Additionally, the 0.5 mg also contains FD&C Yellow Aluminum Lake, and the mg also contains FD&C Blue Aluminum Lake.This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured bySandoz Inc.Princeton, NJ 0854046299643MF42029400REV11/21. oAlprazolam tablets are benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.. Get emergency help right away if any of the following happens:. shallow or slowed breathing. breathing stops (which may lead to the heart stopping). excessive sleepiness (sedation). oRisk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including alprazolam tablets, which can lead to overdose and serious side effects including coma and death.. Serious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including alprazolam tablets. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. You can develop an addiction even if you take alprazolam tablets as prescribed by your healthcare provider.. Take alprazolam tablets exactly as your healthcare provider prescribed.. Do not share your alprazolam tablets with other people.. Keep alprazolam tablets in safe place and away from children.. oPhysical dependence and withdrawal reactions. Alprazolam tablets can cause physical dependence and withdrawal reactions.. Do not suddenly stop taking alprazolam tablets. Stopping alprazolam tablets suddenly can cause serious and life-threatening side effects, including, unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. Some people who suddenly stop benzodiazepines, have symptoms that can last for several weeks to more than 12 months, including, anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.. Physical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.. oDo not take more alprazolam tablets than prescribed or take alprazolam tablets for longer than prescribed.. oAlprazolam tablets are prescription medicine used:. to treat anxiety disorders. for the short-term relief of the symptoms of anxiety. to treat panic disorder with or without fear of places and situations that might cause panic, helplessness, or embarrassment (agoraphobia). oAlprazolam tablets are federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep alprazolam tablets in safe place to prevent misuse and abuse. Selling or giving away alprazolam tablets may harm others, and is against the law. Tell your healthcare provider if you have abused or been dependent on alcohol, prescription medicines or street drugs.. oIt is not known if alprazolam tablets are safe and effective in children.. oElderly patients are especially susceptible to dose related adverse effects when taking alprazolam tablets.. oIt is not known if alprazolam tablets are safe and effective when used to treat anxiety disorder for longer than months. oIt is not known if alprazolam tablets are safe and effective when used to treat panic disorder for longer than 10 weeks.. oyou are allergic to alprazolam, other benzodiazepines, or any of the ingredients in alprazolam tablets. See the end of this Medication Guide for complete list of ingredients in alprazolam tablets.. oyou are taking antifungal medicines including ketoconazole and itraconazole.. ohave or have had depression, mood problems, or suicidal thoughts or behavior. ohave liver or kidney problems. ohave lung disease or breathing problems. oare pregnant or plan to become pregnant. Alprazolam tablets may harm your unborn baby. You and your healthcare provider should decide if you should take alprazolam tablets while you are pregnant.. oare breastfeeding or plan to breastfeed. Alprazolam passes into your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take alprazolam tablets. You should not breastfeed while taking alprazolam tablets.. oSee What is the most important information should know about alprazolam tablets. oTake alprazolam tablets exactly as your healthcare provider tells you to take them. Your healthcare provider will tell you how many alprazolam tablets to take and when to take them.. oIf you take too many alprazolam tablets, call your healthcare provider or go to the nearest hospital emergency room right away.. oSee What is the most important information should know about alprazolam tablets. oSeizures. Stopping alprazolam tablets can cause seizures and seizures that will not stop (status epilepticus).. oMania. Alprazolam tablets may cause an increase in activity and talking (hypomania and mania) in people who have depression.Alprazolam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affect you.Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse. Alprazolam tablets can make you sleepy or dizzy and can slow your thinking and motor skills. Do not drive, operate heavy machinery, or do other dangerous activities until you know how alprazolam tablets affect you.. Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking alprazolam tablets without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, alprazolam tablets may make your sleepiness or dizziness much worse.. oproblems with coordination. ohypotension. otrouble saying words clearly (dysarthria) ochanges in sex drive (libido) oStore alprazolam tablets between 68 to 77F (20 to 25C). oKEEP OUT OF THE REACH OF CHILDREN. oMedicines are sometimes prescribed for purposes other than those listed in Medication Guide.. oDo not use alprazolam tablets for condition for which they were not prescribed.. oDo not give alprazolam tablets to other people, even if they have the same symptoms that you have. They may harm them.. oYou can ask your pharmacist or healthcare provider for information about alprazolam tablets that is written for health professionals.

SPL UNCLASSIFIED SECTION.

2.1 Dosage in Generalized Anxiety Disorder The recommended starting oral dosage of alprazolam for the acute treatment of patients with GAD is 0.25 mg to 0.5 mg administered three times daily. Depending upon the response, the dosage may be adjusted at intervals of every to days. The maximum recommended dosage is mg daily (in divided doses). Use the lowest possible effective dose and frequently assess the need for continued treatment [see Warnings and Precautions (5.2)].

STORAGE AND HANDLING SECTION.

Store at 20 to 25C (68 to 77F) [see USP Controlled Room Temperature].Dispense contents in tight, light-resistant container as defined in the USP with child-resistant closure.KEEP OUT OF THE REACH OF CHILDREN.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS Lactation:Breastfeeding not recommended. (8.2). 8.1 Pregnancy Pregnancy Exposure RegistryThere is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Other Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/othermedications/. Risk SummaryNeonates born to mothers using benzodiazepines during the later stages of pregnancy have been reported to experience symptoms of sedation and neonatal withdrawal [see Warnings and Precautions (5.4), Clinical Considerations)]. Overall available data from published observational studies of pregnant women exposed to alprazolam have not established drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 benzodiazepines during pregnancy and labor for signs of sedation, respiratory depression, withdrawal, and feeding problems and manage accordingly [see Warnings and Precautions (5.4)]. Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report 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. At this time, there is no clear evidence that alprazolam exposure in early pregnancy can cause major birth defects. Neonates exposed to benzodiazepines during the late third trimester of pregnancy or during labor have been reported to exhibit sedation and neonatal withdrawal symptoms.. 8.2 Lactation Risk SummaryLimited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation and withdrawal symptoms in breastfed neonates and infants exposed to alprazolam. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed neonates and infants, advise patients that breastfeeding is not recommended during treatment with alprazolam.. 8.4 Pediatric Use Safety and effectiveness of alprazolam have not been established in pediatric patients.. 8.5 Geriatric Use Alprazolam-treated geriatric patients had higher plasma concentrations of alprazolam (due to reduced clearance) compared to younger adult patients receiving the same doses. Therefore, dosage reduction of alprazolam is recommended in geriatric patients [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].. 8.6 Hepatic Impairment Patients with alcoholic liver disease exhibit longer elimination half-life (19.7 hours), compared to healthy subjects (11.4 hours). This may be caused by decreased clearance of alprazolam in patients with alcoholic liver disease. Dosage reduction of alprazolam is recommended in patients with hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oEffects on Driving and Operating Machinery: Patients receiving alprazolam should be cautioned against operating machinery or driving motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. (5.4) oNeonatal Sedation and Withdrawal Syndrome (NOWS): Use of alprazolam during pregnancy can result in neonatal sedation and neonatal withdrawal syndrome. (5.5, 8.1) oPatients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. (5.7). oEffects on Driving and Operating Machinery: Patients receiving alprazolam should be cautioned against operating machinery or driving motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. (5.4) oNeonatal Sedation and Withdrawal Syndrome (NOWS): Use of alprazolam during pregnancy can result in neonatal sedation and neonatal withdrawal syndrome. (5.5, 8.1) oPatients with Depression: Exercise caution in patients with signs or symptoms of depression. Prescribe the least number of tablets feasible to avoid intentional overdosage. (5.7). 5.1 Risks from Concomitant Use With Opioids Concomitant use of benzodiazepines, including alprazolam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs 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 decision is made to prescribe alprazolam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe lower initial dose of alprazolam than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in patient already taking alprazolam, prescribe lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see Drug Interactions (7.1)].. 5.2 Abuse, Misuse, and Addiction The use of benzodiazepines, including alprazolam, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence 9.2)]. Before prescribing alprazolam and throughout treatment, assess each patients risk for abuse, misuse, and addiction (e.g., using standardized screening tool). Use of alprazolam, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.. 5.3 Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use gradual taper to discontinue alprazolam or reduce the dosage (a patient-specific plan should be used to taper the dose) [see Dosage and Administration 2.3)]. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.Acute Withdrawal Reactions The continued use of benzodiazepines, including alprazolam, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of alprazolam after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence 9.3)]. Protracted Withdrawal SyndromeIn some cases, benzodiazepine users have developed protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence 9.3)]. Certain adverse clinical events, some life-threatening, are direct consequence of physical dependence to alprazolam. These include spectrum of withdrawal symptoms; the most important is seizure [see Drug Abuse and Dependence (9.3)]. 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 mg/day and for long periods (more than 12 weeks). However, in controlled postmarketing discontinuation study of panic disorder patients who received alprazolam, the duration of treatment (3 months compared to months) had no effect on the ability of patients to taper to zero dose. In contrast, patients treated with doses of alprazolam greater than mg/day had more difficulty tapering to zero dose than those treated with less than mg/day. In controlled clinical trial in which 63 patients were randomized to alprazolam and where withdrawal symptoms were specifically sought, the following were identified as symptoms of withdrawal: heightened sensory perception, impaired concentration, dysosmia, clouded sensorium, paresthesias, muscle cramps, muscle twitch, diarrhea, blurred vision, appetite decrease, and weight loss. Other symptoms, such as anxiety and insomnia, were frequently seen during discontinuation, but it could not be determined if they were due to return of illness, rebound, or withdrawal. Interdose SymptomsEarly morning anxiety and emergence of anxiety symptoms between doses of alprazolam have been reported in patients with panic disorder taking prescribed maintenance doses. These symptoms may reflect the development of tolerance or 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.. 5.4 Effects on Driving and Operating Machinery 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 motor vehicle. For the same reason, patients should be cautioned about the concomitant use of alcohol and other CNS depressant drugs during treatment with alprazolam [see Drug Interactions (7.1)].. 5.5 Neonatal Sedation and Withdrawal Syndrome Use of alprazolam during later stages of pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate. Observe newborns for signs of sedation and neonatal withdrawal syndrome and manage accordingly [see Use in Specific Populations (8.1)].. 5.6 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 profound effect on the clearance of alprazolam.Strong CYP3A InhibitorsAlprazolam is contraindicated in patients receiving strong inhibitors of CYP3A (such as azole antifungal agents), except ritonavir [see Contraindications (4)]. Ketoconazole and itraconazole have been shown in vivo to increase plasma alprazolam concentrations 3.98 fold and 2.70 fold, respectively. Dosage adjustment is necessary when alprazolam and ritonavir are initiated concomitantly or when ritonavir is added to stable dosage of alprazolam [see Dosage and Administration (2.6), Drug Interactions (7.1)]. Drugs demonstrated to be CYP3A inhibitors on the basis of clinical studies involving alprazolam: nefazodone, fluvoxamine, and cimetidine [see Drug Interaction (7.1), Clinical Pharmacology (12.3)]. Use caution and consider dose reduction of alprazolam, as appropriate, during co-administration with these drugs.. 5.7 Patients With Depression Benzodiazepines may worsen depression. Panic disorder has been associated with primary and secondary major depressive disorders and increased reports of suicide among untreated patients. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered in patients with depression.. 5.8 Mania Episodes of hypomania and mania have been reported in association with the use of alprazolam in patients with depression [see Adverse Reactions (6.2)].. 5.9 Risk in Patients With Impaired Respiratory Function There have been reports of death in patients with severe pulmonary disease shortly after the initiation of treatment with alprazolam. Closely monitor patients with impaired respiratory function. If signs and symptoms of respiratory depression, hypoventilation, or apnea occur, discontinue alprazolam.