b'Dimensions: 7.875 x 10.75reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate theirvariability such that clinically meaningful respiratory effects of BELSOMRA in obstructive sleep apnea cannot be frequency or establish a causal relationship to drug exposure.excluded. BELSOMRA has not been studied in patients with severe obstructive sleep apnea [see Warnings and Cardiac disorders: palpitations, tachycardiaPrecautions].Gastrointestinal disorders: nausea, vomitingChronic Obstructive Pulmonary DiseaseNervous system disorders: psychomotor hyperactivityThe respiratory depressant effect of BELSOMRA was evaluated after one night and after four consecutive nights of Psychiatric disorders: anxiety treatment in a randomized, placebo-controlled, 2-period crossover study in patients (n=25) with mild to moderate Skin and subcutaneous tissue disorders: pruritus chronic obstructive pulmonary disease (COPD). BELSOMRA (40 mg in non-elderly, 30 mg in elderly) had no DRUG INTERACTIONS respiratory depressant effects in patients with mild to moderate COPD, as measured by oxygen saturation. There was CNS-Active Agents wide inter- and intra-individual variability such that clinically meaningful respiratory effects of BELSOMRA in COPD cannot be excluded. BELSOMRA has not been studied in patients with severe COPD [see Warnings and Precautions].When BELSOMRA was co-administered with alcohol, additive psychomotor impairment was demonstrated. There wasPatients with Hepatic Impairmentno alteration in the pharmacokinetics of BELSOMRA [see Warnings and Precautions]. No dose adjustment is required in patients with mild and moderate hepatic impairment. BELSOMRA has not been Effects of Other Drugs on BELSOMRA studied in patients with severe hepatic impairment and is not recommended for these patients.Metabolism by CYP3A is the major elimination pathway for suvorexant. Patients with Renal ImpairmentCYP3A Inhibitors No dose adjustment is required in patients with renal impairment.Concomitant use of BELSOMRA with strong inhibitors of CYP3A (e.g., ketoconazole, itraconazole, posaconazole,DRUG ABUSE AND DEPENDENCEclarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan) is not recommended. Controlled SubstanceThe recommended dose of BELSOMRA is 5 mg in subjects receiving moderate CYP3A inhibitors (e.g., amprenavir,BELSOMRA contains suvorexant, a Schedule IV controlled substance.aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib,Abuseverapamil). The dose generally should not exceed 10 mg in patients receiving moderate CYP3A inhibitors. Abuse of BELSOMRA poses an increased risk of somnolence, daytime sleepiness, impaired reaction time and CYP3A Inducers impaired driving skills [see Warnings and Precautions]. Patients at risk for abuse may include those with prolonged Suvorexant exposure can be substantially decreased when co-administered with strong CYP3A inducers(e.g.,use of BELSOMRA, those with a history of drug abuse, and those who use BELSOMRA in combination with alcohol or rifampin, carbamazepine and phenytoin). The efficacy of BELSOMRA may be reduced. other abused drugs.Effects of BELSOMRA on Other Drugs Drug abuse is the intentional non-therapeutic use of a drug, even once, for its desirable psychological or physiological Digoxin effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, Concomitant administration of BELSOMRA with digoxin slightly increased digoxin levels due to inhibition of intestinalgiving a higher priority to drug use than to other activities and obligations), and possible tolerance or physical P-gp. Digoxin concentrations should be monitored when co-administering BELSOMRA with digoxin. dependence. USE IN SPECIFIC POPULATIONS In an abuse liability study conducted in recreational polydrug users (n=36), suvorexant (40, 80 and 150 mg) produced Pregnancy similar effects as zolpidem (15, 30 mg) on subjective ratings of drug liking and other measures of subjective drug Risk Summary effects. Because individuals with a history of abuse or addiction to alcohol or other drugs may be at increased risk for abuse and addiction to BELSOMRA, follow such patients carefully.Available data from postmarketing reports with BELSOMRA use in pregnant women are insufficient to establish aDependencedrug-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 periodPhysical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, of organogenesis decreased maternal body weight and/or weight gain at doses30 and 28 times the maximummanifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. recommended human dose (MRHD) of 20 mg based on AUC in the rat and rabbit, respectively. Suvorexant causedIn completed clinical trials with BELSOMRA, there was no evidence for physical dependence with the prolonged use of decreased fetal weight at doses86 times the MRHD based on AUC in the rat and did not cause significant fetalBELSOMRA. There were no reported withdrawal symptoms after discontinuation of BELSOMRA. toxicity at doses up to 28 times the MRHD based on AUC in the rabbit. The no observed adverse effect levelsOVERDOSAGE(NOAELs) for fetal toxicity are 25 and 28 times the MRHD based on AUC in the rat and rabbit, respectively. OralThere is limited premarketing clinical experience with an overdosage of BELSOMRA. In clinical pharmacology studies, administration of suvorexant to pregnant rats during pregnancy and lactation caused decreased maternal andhealthy subjects who were administered morning doses of up to 240 mg of suvorexant showed dose-dependent pup body weight or weight gain at approximately 48 times the MRHD based on AUC. The NOAEL for developmentincreases in the frequency and duration of somnolence. toxicity in the rat is 25 times the MRHD based on AUC [see Data]. General symptomatic and supportive measures should be used, along with immediate gastric lavage where The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. Allappropriate. Intravenous fluids should be administered as needed. As in all cases of drug overdose, vital signs should pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population,be monitored and general supportive measures employed. The value of dialysis in the treatment of overdosage has the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 tonot been determined. As suvorexant is highly protein-bound, hemodialysis is not expected to contribute to elimination 4% and 15 to 20%, respectively. of suvorexant. Data As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. Consider Animal Data contacting a poison control center for up-to-date information on the management of hypnotic drug product Suvorexant was administered orally to pregnant rats during the period of organogenesis in two separate studiesoverdosage.at doses of 30, 150, and 1000 mg/kg/day or 30, 80, and 325 mg/kg/day, which are approximately 3 to 93 timesCLINICAL STUDIESthe MRHD based on AUC. Suvorexant decreased maternal weights at doses150 mg/kg/day and fetal weights atSpecial Safety Studiesdoses325 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. Effects on DrivingSuvorexant was administered orally to pregnant rabbits during the period of organogenesis in two separate studiesTwo randomized, double-blind, placebo- and active-controlled, four-period crossover studies evaluated the at doses of 40, 100, and 300 mg/kg/day or 50, 150, and 325 mg/kg/day, which are approximately 3 to 70 timeseffects of nighttime administration of BELSOMRA on next-morning driving performance 9 hours after dosing in 24 the MRHD based on AUC. Suvorexant decreased maternal body weight or weight gain at doses150 mg/kg/day.healthy elderly subjects (65 years old, mean age 69 years; 14 men, 10 women) who received 15 mg and 30 mg Suvorexant caused excessive maternal toxicity that led to premature deaths at 325 mg/kg/day, which precludedBELSOMRA and 28 non-elderly subjects (mean age 46 years; 13 men, 15 women) who received 20 mg and 40 mg fetal evaluation. Suvorexant did not cause significant fetal toxicity at doses up to 300 mg/kg/day. The NOAELs forBELSOMRA. Testing was conducted after one night and after 8 consecutive nights of treatment with BELSOMRA at maternal and fetal toxicities are 100 mg/kg/day and 300 mg/kg/day, respectively, which are approximately 10 andthese doses.28 times the MRHD based on AUC, respectively. The primary outcome measure was change in Standard Deviation of Lane Position (SDLP), a measure of driving Suvorexant was administered orally to pregnant rats during pregnancy and lactation at doses of 30, 80, and performance, assessed using a symmetry analysis. The analysis showed clinically meaningful impaired driving 200 mg/kg/day, which are approximately 8 to 48 times the MRHD based on AUC. Suvorexant causedperformance in some subjects. After one night of dosing, this effect was observed in non-elderly subjects after either maternal toxicity of decreased body weight and weight gain and food consumption at 200 mg/kg/day. At thisa 20 mg or 40 mg dose of BELSOMRA. A statistically significant effect was not observed in elderly subjects after amaternally toxic dose, suvorexant caused decreased weight gain in offspring pups. The NOAEL for maternal and15 mg or 30 mg dose of BELSOMRA. Across these two studies, five subjects (4 non-elderly women on BELSOMRA;developmental toxicity is 80 mg/kg/day, which is approximately 25 times the MRHD based on AUC. 1 elderly woman on placebo) prematurely stopped their driving tests due to somnolence. Patients using the 20 mg Lactation dose of BELSOMRA should be cautioned against next-day driving and other activities requiring full mental alertness. Patients taking lower doses of BELSOMRA should also be cautioned about the potential for driving impairment Risk Summary because there is individual variation in sensitivity to BELSOMRA [see Warnings and Precautions].There are no data on the presence of suvorexant in human milk, the effects on the breastfed infant or the effectsEffects on Next-Day Memory and Balance in Elderly and Non-Elderlyon milk production. Suvorexant and hydroxyl-suvorexant are present in rat milk. When a drug is present in animalFour placebo-controlled trials evaluated the effects of nighttime administration of BELSOMRA on next-day memory milk, it is likely that the drug will be present in human milk. Infants exposed to BELSOMRA through breastmilkand balance using word learning tests and body sway tests, respectively. Three trials showed no significant effects should be monitored for excessive sedation. The developmental and health benefits of breastfeeding should beon memory or balance compared to placebo. In a fourth trial in healthy non-elderly subjects, there was a significant considered along with the mothers clinical need for BELSOMRA and any potential adverse effects on the breastfeddecrease in word recall after the words were presented to subjects in the morning following a single dose of 40 mg infant from BELSOMRA or from the underlying maternal condition. BELSOMRA, and there was a significant increase on body sway area in the morning following a single dose of 20 mg Pediatric Use or 40 mg BELSOMRA. Safety and effectiveness in pediatric patients have not been established. Middle of the Night Safety in Elderly SubjectsGeriatric Use A double-blind, randomized, placebo-controlled trial evaluated the effect of a single dose of BELSOMRA on balance, Of the total number of patients treated with BELSOMRA (n=1784) in controlled clinical safety and efficacy studies,memory and psychomotor performance in healthy elderly subjects (n=12) after being awakened during the night. 829 patients were 65 years and over, and 159 patients were 75 years and over. No clinically meaningful differencesNighttime dosing of BELSOMRA 30 mg resulted in impairment of balance (measured by body sway area) at 90 in safety or effectiveness were observed between these patients and younger patients at the recommended doses. minutes as compared to placebo. Memory was not impaired, as assessed by an immediate and delayed word recall Because BELSOMRA can increase drowsiness, patients, particularly the elderly, are at a higher risk of falls [seetest at 4 hours post-dose. Warnings and Precautions]. PATIENT COUNSELING INFORMATIONPatients with Compromised Respiratory Function Advise the patient to read the FDA-approved patient labeling (Medication Guide).Effects of BELSOMRA on respiratory function should be considered if prescribed to patients with compromisedFor patent information: www.merck.com/product/patent/home.htmlrespiratory function. For more detailed information, please read the Prescribing Information.Obstructive Sleep Apnea uspi-mk4305-t-2205r009The respiratory depressant effect of BELSOMRA was evaluated after one night and after four consecutive nights ofRevised: 05/2022treatment in a randomized, placebo-controlled, 2-period crossover study in patients (n=26) with mild to moderate obstructive sleep apnea. Following once-daily doses of 40 mg, the mean Apnea/Hypopnea Index treatment differenceCopyright2022 Merck & Co., Inc., Rahway, NJ, USA and its affiliates.(suvorexantplacebo) on Day 4 was 2.7 (90% CI: 0.22 to 5.09), but there was wide inter- and intra-individualAll rights reserved.US-IMA-01985 09/22'