Alprazolam

1 INDICATIONS AND USAGE Alprazolam extended-release tablets are indicated for the treatment of panic disorder with or without agoraphobia, in adults. Alprazolam extended-release tablets are a benzodiazepine indicated for the treatment of panic disorder with or without agoraphobia, in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended starting oral dosage is 0.5 mg to 1 mg once daily (preferably in the morning). Depending on the response, the dose may be increased at intervals of 3 to 4 days in increments of no more than 1 mg daily. ( 2.1 ) Recommended total daily dosage is 3 mg to 6 mg daily. ( 2.1 ) Swallow tablets whole; do not divide, crush, or chew. ( 2.1 ) When tapering, decrease dosage by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction. ( 2.2 , 5.2 ) See the Full Prescribing Information for the recommended dosage in geriatric patients, patients with hepatic impairment, and with use with ritonavir. ( 2.3 , 2.4 , 2.5 ) 2.1 Recommended Dosage Administer alprazolam extended-release tablets orally once daily, preferably in the morning. Swallow tablets whole; do not divide, crush, or chew. The recommended starting oral dosage for alprazolam extended-release tablets are 0.5 mg to 1 mg once daily. Depending on the response, the dosage may be adjusted at intervals of every 3 to 4 days in increments of no more than 1 mg daily. The recommended dosage range is 3 mg to 6 mg once daily. Controlled trials of alprazolam extended-release tablets for the treatment of panic disorder included dosages in the range of 1 mg to 10 mg per day. Most patients showed a response in the dosage range of 3 mg to 6 mg per day. Occasional patients required as much as 10 mg per day. The longer-term efficacy of alprazolam extended-release tablets has not been systematically evaluated. If alprazolam extended-release tablets are used for periods longer than 8 weeks, the healthcare provider should periodically reassess the usefulness of the drug for the individual patient. After a period of extended freedom from panic attacks, a carefully supervised tapered discontinuation may be attempted, but there is evidence that this may often be difficult to accomplish without recurrence of symptoms and/or the manifestation of withdrawal phenomena [see Dosage and Administration (2.2) , Warnings and Precautions (5.2) ]. 2.2 Discontinuation or Dosage Reduction of Alprazolam Extended-Release Tablets To reduce the risk of withdrawal reactions, use a gradual taper to discontinue alprazolam extended-release tablets or reduce the dosage. If a 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) ]. Reduce the dosage by no more than 0.5 mg every three days. Some patients may benefit from an even more gradual discontinuation. Some patients may prove resistant to all discontinuation regimens. In a controlled postmarketing discontinuation study of panic disorder patients which compared the recommended taper schedule with a slower taper schedule, no difference was observed between the groups in the proportion of patients who tapered to zero dose; however, the slower schedule was associated with a reduction in symptoms associated with a withdrawal syndrome. 2.3 Dosage Recommendations in Geriatric Patients In geriatric patients, the recommended starting dosage of alprazolam extended-release tablets is 0.5 mg once daily. This may be gradually increased if needed and tolerated. Geriatric patients may be sensitive to the effects of benzodiazepines [see Use in Specific Populations (8.5) , Clinical Pharmacology (12.3) ]. 2.4 Dosage Recommendations in Patients with Hepatic Impairment In patients with hepatic impairment, the recommended starting dosage of alprazolam extended-release tablets is 0.5 mg once daily. This may be gradually increased if needed and tolerated [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] . 2.5 Dosage Modifications for Drug Interactions Alprazolam extended-release tablets should be reduced to half of the recommended dosage when a patient is started on ritonavir and alprazolam extended-release tablets t…

5 WARNINGS AND PRECAUTIONS Effects on Driving and Operating Machinery: Patients receiving alprazolam extended-release tablets should be cautioned against operating machinery or driving a motor vehicle, as well as avoiding concomitant use of alcohol and other central nervous system (CNS) depressant drugs. ( 5.4 ) Neonatal Sedation and Withdrawal Syndrome (NOWS): Use of alprazolam extended-release tablets during pregnancy can result in neonatal sedation and neonatal withdrawal syndrome. ( 5.5 , 8.1 ) Patients 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 extended-release tablets, 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 a decision is made to prescribe alprazolam extended-release tablets concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of alprazolam extended-release tablets than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking alprazolam extended-release tablets, prescribe a lower initial dose of the opioid and titrate based upon clinical response. Advise both patients and caregivers about the risks of respiratory depression and sedation when alprazolam extended-release tablets 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 extended-release tablets, 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 extended-release tablets and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of alprazolam extended-release tablets, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of alprazolam extended-release tablets 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 a 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 a gradual taper to discontinue alprazolam extended-release tablets 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…

4 CONTRAINDICATIONS Alprazolam extended-release tablets are contraindicated in patients: with known hypersensitivity to alprazolam or other benzodiazepines. Angioedema has been reported [see Adverse Reactions (6.2) ] . taking strong cytochrome P450 3A (CYP3A) inhibitors (e.g., ketoconazole, itraconazole), except ritonavir [see Dosage and Administration (2.5) , Warnings and Precautions (5.5) , Drug Interactions (7.1) ] . Known hypersensitivity to alprazolam or other benzodiazepines. ( 4 ) Concomitant use with strong cytochrome P450 3A (CYP3A) inhibitors, except ritonavir. ( 4 , 5.5 , 7.1 )

7 DRUG INTERACTIONS Use with Opioids: Increase the risk of respiratory depression. ( 7.1 ) Use with Other CNS Depressants: Produces additive CNS depressant effects. ( 7.1 ) Use with Digoxin: Increase the risk of digoxin toxicity. ( 7.1 ) Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. ( 4 , 5.5 , 7.1 ) Use with CYP3A Inducers: Increase the risk of reduced efficacy of alprazolam. ( 7.1 ) 7.1 Drugs Having Clinically Important Interactions with Alprazolam Extended-Release Tablets Table 4 includes clinically significant drug interactions with alprazolam extended-release tablets [see Clinical Pharmacology (12.3) ] . Table 4: Clinically Significant Drug Interactions with Alprazolam Extended-Release Tablets Opioids Clinical 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 gamma-aminobutyric acid (GABA A ) 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 extended-release tablets 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 Depressants Clinical 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 extended-release tablets 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 extended-release tablets with strong CYP3A inhibitors has a 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 extended-release tablets with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4) , Warnings and Precautions (5.5) ]. Examples Ketoconazole, itraconazole, clarithromycin Moderate or Weak Inhibitors of CYP3A Clinical implication Concomitant use of alprazolam extended-release tablets with CYP3A inhibitors may increase the concentrations of alprazolam extended-release tablets, resulting in increased risk of adverse reactions [see Clinical Pharmacology (12.3) ]. Prevention or management Avoid use and consider appropriate dose reduction when alprazolam extended-release tablets are coadministered with a moderate or weak CYP3A inhibitor [see Warnings and Precautions (5.5) ]. Examples Nefazodone, fluvoxamine, cimetidine, erythromycin CYP3A Inducers Clinical 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 Ritonavir Clinical 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 affe…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to alprazolam extended-release tablets 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 Summary Neonates 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 a 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 a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Benzodiazepines cross the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to 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 a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1) ] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2) ] Dependence and Withdrawal Reactions [see Warnings and Precautions (5.3) ] Effects on Driving and Operating Machinery [see Warnings and Precautions (5.4) ] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.5) ] Patients with Depression [see Warnings and Precautions (5.7) ] Risks in Patients with Impaired Respiratory Function [see Warnings and Precautions (5.9) ] The most common adverse reactions in panic disorder patients treated with alprazolam extended-release tablets (incidence of > 5% and at least twice that of placebo) include: somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased, constipation, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The information included in the section on Adverse Reactions Observed in Short-Term, Placebo-Controlled Trials with alprazolam extended-release tablets are based on pooled data of five 6- and 8-week placebo-controlled clinical studies in panic disorder. Adverse Reactions Observed in Short-Term, Placebo-Controlled Trials of Alprazolam Extended-Release Tablets Adverse Reactions Reported as Reasons for Discontinuation of Treatment in Placebo-Controlled Trials Approximately 17% of the 531 patients who received alprazolam extended-release tablets in placebo-controlled clinical trials for panic disorder had at least 1 adverse event that led to discontinuation compared to 8% of 349 placebo-treated patients. The most common events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of the patients treated with alprazolam extended-release tablets at a rate at least twice that of placebo) are shown in Table 1. Table 1: Adverse Reactions Leading to Discontinuation in ≥1% of alprazolam extended-release tablets-treated Patients and at least twice the Rate of Placebo-treated Patients in Placebo-Controlled Trials n=number of patients Percentage of Patients Discontinuing Due to Adverse Reactions Alprazolam extended-release tablets (n=531) Placebo (n=349) Nervous system disorders Sedation Somnolence Dysarthria Coordination abnormal Memory impairment 7.5 3.2 2.1 1.9 1.5 0.6 0.3 0 0.3 0.3 General disorders/administration site conditions Fatigue 1.7 0.6 Psychiatric disorders Depression 2.5 1.2 Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated with Alprazolam Extended-Release Tablets Table 2 shows the incidence of adverse reactions that occurred during 6- and 8-week placebo-controlled trials in 1% or more of patients treated with alprazolam extended-release tablets where the incidence in patients treated with alprazolam extended-release tablets was greater than the incidence in placebo-treated patients. The most commonly observed adverse reactions in panic disorder patients treated with alprazolam extended-release tablets (incidence of 5% or greater and at least twice the incidence in placebo patients) were: sedation, somnolence, memory impairment, dysarthria, coordination abnormal, ataxia, libido decreased. Table 2: Adverse Reactions Occuring in ≥1% in alprazolam-treated Patients and Greater than Placebo-treated Patients in 6 and 8 week Placebo-Controlled Trials Panic Disorder Alprazolam extended-release tablets (n=531) Placebo (n=349) Nervous system disorders Sedation Somnolence Memory Impairment …