BELSOMRA suvorexant 10 mg Tablet, Film Coated

5 WARNINGS AND PRECAUTIONS CNS Depressant Effects and Daytime Impairment: Risk of impaired alertness and motor coordination, including impaired driving; risk increases with dose; caution patients taking 20 mg against next-day driving and other activities requiring complete mental alertness ( 5.1 ). Worsening of Depression/Suicidal Ideation: Worsening of depression or suicidal thinking may occur. Risk increases with dose.

Immediately evaluate any new behavioral changes ( 5.2 ). Complex Sleep Behaviors: Behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur. Discontinue immediately if a complex sleep behavior occurs ( 5.3 ).

Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, and Cataplexy-like Symptoms: May occur with the use of BELSOMRA. Risk increases with dose ( 5.4 ). Compromised Respiratory Function: Effect on respiratory function should be considered ( 5.5 , 8.6 ).

Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of treatment ( 5.6 ).

5.1CNS Depressant Effects and Daytime Impairment BELSOMRA is a central nervous system (CNS) depressant that can impair daytime wakefulness even when used as prescribed. Prescribers should monitor for somnolence and CNS depressant effects, but impairment can occur in the absence of symptoms, and may not be reliably detected by ordinary clinical exam (i.e., less than formal testing of daytime wakefulness and/or psychomotor performance). CNS depressant effects may persist in some patients for up to several days after discontinuing BELSOMRA.

BELSOMRA can impair driving skills and may increase the risk of falling asleep while driving. Discontinue or decrease the dose in patients who drive if daytime somnolence develops. In a study of healthy adults, driving ability was impaired in some individuals taking 20 mg BELSOMRA [see Clinical Studies (14.2) ].

Although pharmacodynamic tolerance or adaptation to some adverse depressant effects of BELSOMRA may develop with daily use, patients using the 20 mg 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 because there is individual variation in sensitivity to BELSOMRA. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression.

Patients should be advised not to consume alcohol in combination with BELSOMRA because of additive effects [see Drug Interactions (7.1) ] . Dosage adjustments of BELSOMRA and of concomitant CNS depressants may be necessary when administered together because of potentially additive effects. The use of BELSOMRA with other drugs to treat insomnia is not recommended [see Dosage and Administration (2.3) ].

The risk of next-day impairment, including impaired driving, is increased if BELSOMRA is taken with less than a full night of sleep remaining, if a higher than the recommended dose is taken, if co-administered with other CNS depressants, or if co-administered with other drugs that increase blood levels of BELSOMRA. Patients should be cautioned against driving and other activities requiring complete mental alertness if BELSOMRA is taken in these circumstances. Because BELSOMRA can cause drowsiness, patients, particularly the elderly, are at higher risk of falls.

5.2Worsening of Depression/Suicidal Ideation In clinical studies, a dose-dependent increase in suicidal ideation was observed in patients taking BELSOMRA as assessed by questionnaire. Immediately evaluate patients with suicidal ideation or any new behavioral sign or symptom. In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides) have been reported.

Suicidal tendencies may be present in such patients and protect…

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections: CNS Depressant Effects and Daytime Impairment [see Warnings and Precautions (5.1) ] Worsening of Depression/Suicidal Ideation [see Warnings and Precautions (5.2) ] Complex Sleep Behaviors [see Warnings and Precautions (5.3) ] Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, Cataplexy-Like Symptoms [see Warnings and Precautions (5.4) ] Patients with Compromised Respiratory Function [see Warnings and Precautions (5.5) ] The most common adverse reaction (reported in 5% or more of patients treated with BELSOMRA and at least twice the placebo rate) with BELSOMRA was somnolence ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 clinical practice. In 3-month controlled efficacy trials (Study 1 and Study 2), 1263 patients were exposed to BELSOMRA including 493 patients who received BELSOMRA 15 mg or 20 mg (see Table 1 ). In a long-term study, additional patients (n=521) were treated with BELSOMRA at higher than recommended doses, including a total of 160 patients who received BELSOMRA for at least one year.

Table 1: Patient Exposure to BELSOMRA 15 mg or 20 mg in Study 1 and Study 2 Patients Treated BELSOMRA 15 mg BELSOMRA 20 mg For ≥ 1 Day (n) 202 291 Men (n) 69 105 Women (n) 133 186 Mean Age (years) 70 45 For ≥ 3 Months (n) 118 172 The pooled safety data described below (see Table 2 ) reflect the adverse reaction profile during the first 3 months of treatment. Adverse Reactions Resulting in Discontinuation of Treatment The incidence of discontinuation due to adverse reactions for patients treated with 15 mg or 20 mg of BELSOMRA was 3% compared to 5% for placebo.

No individual adverse reaction led to discontinuation at an incidence ≥1%. Most Common Adverse Reactions In clinical trials of patients with insomnia treated with BELSOMRA 15 mg or 20 mg, the most common adverse reaction (reported in 5% or more of patients treated with BELSOMRA and at least twice the placebo rate) was somnolence (BELSOMRA 7%; placebo 3%). Table 2 shows the percentage of patients with adverse reactions during the first three months of treatment, based on the pooled data from 3-month controlled efficacy trials (Study 1 and Study 2).

At doses of 15 or 20 mg, the incidence of somnolence was higher in females (8%) than in males (3%). Of the adverse reactions reported in Table 2, the following occurred in women at an incidence of at least twice that in men: headache, abnormal dreams, dry mouth, cough, and upper respiratory tract infection. The adverse reaction profile in elderly patients was generally consistent with non-elderly patients.

The adverse reactions reported during long-term treatment up to 1 year were generally consistent with those observed during the first 3 months of treatment. Table 2: Percentage of Patients with Adverse Reactions Incidence ≥2% and Greater than Placebo in 3-Month Controlled Efficacy Trials (Study 1 and Study 2) Placebo BELSOMRA (20 mg in non-elderly or 15 mg in elderly patients) n=767 n=493 Gastrointestinal Disorders Diarrhea 1 2 Dry mouth 1 2 Infections and Infestations Upper respiratory tract infection 1 2 Nervous System Disorders Headache 6 7 Somnolence 3 7 Dizziness 2 3 Psychiatric Disorders Abnormal dreams 1 2 Respiratory, Thoracic and Mediastinal Disorders Cough 1 2 Dose Relationship for Adverse Reactions There is evidence of a dose relationship for many of the adverse reactions associated with BELSOMRA use, particularly for certain CNS adverse reactions.

In a placebo-controlled crossover study (Study 3), non-elderly adult patients were…

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 ).

7.1CNS-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) ].

7.2Effects 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) ].

7.3Effects 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) ].