Suvorexant

7 DRUG INTERACTIONS CYP3A inhibitors: Recommended dose is 5 mg when used with moderate CYP3A inhibitors. Dose can be increased to 10 mg once per night if the 5 mg dose is not effective. Not recommended for use in patients taking strong CYP3A inhibitors ( 2.4 , 7.2 ). Strong CYP3A inducers: Efficacy may be reduced ( 7.2 ). Digoxin: Monitor digoxin concentrations ( 7.3 ).

7.1 CNS-Active Agents When BELSOMRA was co-administered with alcohol, additive psychomotor impairment was demonstrated. There was no alteration in the pharmacokinetics of BELSOMRA [see Warnings and Precautions (5.1 , 5.3) and Clinical Pharmacology (12.3) ].

7.2 Effects of Other Drugs on BELSOMRA Metabolism by CYP3A is the major elimination pathway for suvorexant. CYP3A Inhibitors Concomitant use of BELSOMRA with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan) is not recommended [see Clinical Pharmacology (12.3) ]. The recommended dose of BELSOMRA is 5 mg in subjects receiving moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil).

The dose generally should not exceed 10 mg in patients receiving moderate CYP3A inhibitors [see Clinical Pharmacology (12.3) ]. CYP3A Inducers Suvorexant exposure can be substantially decreased when co-administered with strong CYP3A inducers (e.g., rifampin, carbamazepine and phenytoin). The efficacy of BELSOMRA may be reduced [see Clinical Pharmacology (12.3) ].

7.3 Effects of BELSOMRA on Other Drugs Digoxin Concomitant administration of BELSOMRA with digoxin slightly increased digoxin levels due to inhibition of intestinal P-gp. Digoxin concentrations should be monitored when co-administering BELSOMRA with digoxin [see Clinical Pharmacology (12.3) ].

8.1 Pregnancy Risk Summary Available data from postmarketing reports with BELSOMRA use in pregnant women are insufficient to establish a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of suvorexant to pregnant rats and rabbits during the period of organogenesis decreased maternal body weight and/or weight gain at doses ≥ 30 and 28 times the maximum recommended human dose (MRHD) of 20 mg based on AUC in the rat and rabbit, respectively.

Suvorexant caused decreased fetal weight at doses ≥ 86 times the MRHD based on AUC in the rat and did not cause significant fetal toxicity at doses up to 28 times the MRHD based on AUC in the rabbit. The no observed adverse effect levels (NOAELs) for fetal toxicity are 25 and 28 times the MRHD based on AUC in the rat and rabbit, respectively. Oral administration of suvorexant to pregnant rats during pregnancy and lactation caused decreased maternal and pup body weight or weight gain at approximately 48 times the MRHD based on AUC. The NOAEL for development toxicity in the rat is 25 times the MRHD based on AUC (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 US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Suvorexant was administered orally to pregnant rats during the period of organogenesis in two separate studies at doses of 30, 150, and 1000 mg/kg/day or 30, 80, and 325 mg/kg/day, which are approximately 3 to 93 times the MRHD based on AUC.

Suvorexant decreased maternal weights at doses ≥ 150 mg/kg/day and fetal weights at doses ≥ 325 mg/kg/day. The NOAEL for both maternal and fetal toxicity is 80 mg/kg/day, which is approximately 25 times the MRHD based on AUC. Suvorexant was administered orally to pregnant rabbits during the period of organogenesis in two separate studies at doses of 40, 100, and 300 mg/kg/day or 50, 150, and 325 mg/kg/day, which are approximately 3 to 70 times the MRHD based on AUC. Suvorexant decreased maternal body weight or weight gain at doses ≥ 150 mg/kg/day. Suvorexant caused excessive maternal toxicity that led to premature deaths at 325 mg/kg/day, which precluded fetal evaluation.

Suvorexant did not cause significant fetal toxicity at doses up to 300 mg/kg/day. The NOAELs for maternal and…