Xanax

Warnings and Precautions ( 5.8 ) 1/2023

1 INDICATIONS AND USAGE XANAX is indicated for the: • acute treatment of generalized anxiety disorder (GAD) in adults. • treatment of panic disorder (PD), with or without agoraphobia in adults. XANAX is a benzodiazepine indicated for the: • Acute treatment of generalized anxiety disorder in adults. ( 1 ) • Treatment of panic disorder with or without agoraphobia in adults. ( 1 )

2 DOSAGE AND ADMINISTRATION • Generalized Anxiety Disorder : ( 2.1 ) o Recommended starting oral dosage is 0.25 mg to 0.5 mg three times daily. o Dosage may be increased, at intervals of every 3 to 4 days, to a maximum recommended daily dose of 4 mg, given in divided doses. o Use the lowest possible effective dose and frequently assess the need for continued treatment. • Panic Disorder : Recommended starting oral dosage is 0.5 mg three times daily. The dosage may be increased at intervals of every 3 to 4 days in increments of no more than 1 mg per day. ( 2.2 ) • When tapering, decrease dosage by no more than 0.5 mg every 3 days. Some patients may require an even slower dosage reduction. ( 2.3 , 5.2 ) • See 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 XANAX 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 3 to 4 days. The maximum recommended dosage is 4 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 XANAX 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 3 to 4 days in increments of no more than 1 mg per day. Controlled trials of XANAX in the treatment of panic disorder included dosages in the range of 1 mg to 10 mg daily. The mean dosage was approximately 5 mg to 6 mg daily. Occasional patients required as much as 10 mg per day. For patients receiving doses greater than 4 mg per day, periodic reassessment and consideration of dosage reduction is advised. In a controlled postmarketing dose-response study, patients treated with doses of XANAX greater than 4 mg per day for 3 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 XANAX is unknown. 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 (2.3) ] . 2.3 Discontinuation or Dosage Reduction of XANAX To reduce the risk of withdrawal reactions, use a gradual taper to discontinue XANAX 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) ] . Reduced the dosage by no more than 0.5 mg every 3 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. 2.4 Dosage Recommendations in Geriatric Patients In geriatric patients, the recommended starting oral dosage of XANAX is 0.25 mg, given 2 or 3 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) , Clinica …

3 DOSAGE FORMS AND STRENGTHS XANAX tablets are available as: • 0.25 mg: white, oval, scored, imprinted “XANAX 0.25” • 0.5 mg: peach, oval, scored, imprinted “XANAX 0.5” • 1 mg: blue, oval, scored, imprinted “XANAX 1.0” • 2 mg: white, oblong, multi-scored, imprinted “XANAX ” on one side and “2” on the reverse side Tablets: 0.25 mg, 0.5 mg, 1 mg, and 2 mg ( 3 )

4 CONTRAINDICATIONS XANAX is 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 (2.6) , 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 )

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) ] • Patients with Depression [see Warnings and Precautions (5.6) ] • Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.8) ] • Risks 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 Viatris at 1-877-446-3679 (1-877-4-INFO-RX) 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 data in the two tables below are estimates of adverse reaction incidence among adult patients who participated in: • 4-week placebo-controlled clinical studies with XANAX dosages up to 4 mg per day for the acute treatment of generalized anxiety disorder (Table 1) • Short-term (up to 10 weeks) placebo-controlled clinical studies with XANAX dosages up to 10 mg per day for panic disorder, with or without agoraphobia (Table 2). Table 1: Adverse Reactions Occurring in ≥1% in XANAX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials for Generalized Anxiety XANAX n=565 Placebo n=505 Nervous system disorders Drowsiness 41% 22% Light-headedness 21% 19% Dizziness 2% 1% Akathisia 2% 1% Gastrointestinal disorders Dry mouth 15% 13% Increased salivation 4% 2% Cardiovascular disorders Hypotension 5% 2% Skin and subcutaneous tissue disorders Dermatitis/allergy 4% 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 Occurring in ≥1% in XANAX-treated Patients and Greater than Placebo-treated Patients in Placebo-Controlled Trials (Up to 10 Weeks) for Panic Disorder XANAX n=1388 Placebo n=1231 Drowsiness Fatigue and Tiredness Impaired Coordination Irritability Memory Impairment Cognitive Disorder Decreased Libido Dysarthria Confusional state 77% 49% 40% 33% 33% 29% 14% 23% 10% 43% 42% 18% 30% 22% 21% 8% 6% 8% Increased libido 8% 4% Change in libido (not specified) 7% 6% Disinhibition 3% 2% Talkativeness 2% 1% Derealization 2% 1% Gastrointestinal disorders Constipation 26% 15% Increased salivation 6% 4% Skin and subcutaneous tissue disorders Rash 11% 8% Other Increased appetite 33% 23% Decreased appetite 28% 24% Weight gain 27% 18% Weight loss 23% 17% Micturition difficulties 12% 9% Menstrual disorders 11% 9% Sexual dysfunction 7% 4% Incontinence 2% 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 XANAX: seizures, hallucinations, depersonalization, taste alterations, diplopia, elevated bilirubin, elevated hepa …

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 XANAX Table 4 includes clinically significant drug interactions with XANAX [see Clinical Pharmacology (12.3) ] . Table 4: Clinically Significant Drug Interactions with XANAX 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 XANAX 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, butorphanol, 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 XANAX 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 XANAX 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 XANAX 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 XANAX with CYP3A inhibitors may increase the concentrations of XANAX, 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 XANAX is 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 XANAX. 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 affected in the presence of ritonavir. Prevention or management Reduce XANAX dosage when ritonavir and XANAX are initiated concomitantly, or when ritonavir is added to a regimen where XANAX is stabilized. Increase XANAX dosage to the target dosage after 10 to 14 days of dosing ritonav …

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including XANAX, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8) and Clinical Considerations) ] . Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to XANAX during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to XANAX during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8) ] . Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco, and other medications, have not confirmed these findings. 8.2 Lactation Risk Summary Limited data from published literature reports the presence of alprazolam in human breast milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of alprazolam on lactation are unknown. Because of the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with XANAX. 8.4 Pediatric Use Safety and effectiveness of XANAX have not been established in pediatric patients. 8.5 Geriatric Use XANAX-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 XANAX 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 a 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 XANAX is recommended in patients with hepatic impairment [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ] .

12.1 Mechanism of Action Alprazolam is a 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 (GABA A ) receptors in the brain and enhances GABA-mediated synaptic inhibition.

11 DESCRIPTION XANAX contains alprazolam which is a triazolo analog of the 1,4 benzodiazepine class of central nervous system-active compounds. The chemical name of alprazolam is 8-Chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-α] [1,4] benzodiazepine. The structural formula is: Alprazolam is a white crystalline powder, which is soluble in methanol or ethanol but which has no appreciable solubility in water at physiological pH. Each XANAX tablet, for oral administration, contains 0.25 mg, 0.5 mg, 1 mg, or 2 mg of alprazolam. Inactive ingredients: cellulose, corn starch, docusate sodium, lactose, magnesium stearate, silicon dioxide and sodium benzoate. In addition, the 0.5 mg tablet contains FD&C Yellow No. 6 and the 1 mg tablet contains FD&C Blue No. 2. alprazolam structural formula

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

16 HOW SUPPLIED/STORAGE AND HANDLING XANAX is supplied in the following strengths and package configurations: XANAX Tablets Package Configuration Tablet Strength (mg) NDC Print Bottles of 100 Reverse Numbered Unit dose (100) Bottles of 500 Bottles of 1000 0.25 mg NDC 0009-0029-01 NDC 0009-0029-46 NDC 0009-0029-02 NDC 0009-0029-14 white, oval, scored, imprinted “XANAX 0.25” Bottles of 100 Reverse Numbered Unit dose (100) Bottles of 500 Bottles of 1000 0.5 mg NDC 0009-0055-01 NDC 0009-0055-46 NDC 0009-0055-03 NDC 0009-0055-15 peach, oval, scored, imprinted “XANAX 0.5” Bottles of 100 Bottles of 500 Bottles of 1000 1 mg NDC 0009-0090-01 NDC 0009-0090-04 NDC 0009-0090-13 blue, oval, scored, imprinted “XANAX 1.0” Bottles of 100 Bottles of 500 2 mg NDC 0009-0094-01 NDC 0009-0094-03 white, oblong, multi-scored, imprinted “XANAX” on one side and “2” on the reverse side Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].