Alprazolam extended-release

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 affected in the presence of ritonavir. Prevention or management Reduce alprazolam extended-release tablets dose when a patient is initiated with ritonavir and alprazolam extended-release tablets concomitantly, or when ritonavir is added to a regimen where alprazolam extended-release tablets are stabilized. Increase alprazolam extended-release tablets dosage to the target dosage after 10 to 14 days of dosing ritonavir and alprazolam extended-release tablets concomitantly. No dosage adjustment of alprazolam extended-release tablets is necessary in patients receiving ritonavir for more than 10 to 14 days [see Dosage and Administration (2.5) ] .

Concomitant use of alprazolam extended-release tablets with a strong CYP3A inhibitor, except ritonavir, is contraindicated [see Contraindications (4) , Warnings and Precautions (5.5) ]. Digoxin Clinical 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 extended-release tablets. 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 a specific drug or specific test.

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including alprazolam extended-release tablets during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late 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. 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 alprazolam extended-release tablets during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to alprazolam extended-release tablets 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.