BELSOMRA®

(suvorexant) 5, 10, 15, 20 mg tablets, for oral use, C-IV

Efficacy

Clinical Efficacy in Adults With Insomnia (Including Those ≥65 Years of Age)

In 2 clinical trials with the 15-mg and 20-mg doses, BELSOMRA helped insomnia patients stay asleep longer1

Patients met DSM-IV criteria for the diagnosis of primary insomnia2:

  • Waking up in the middle of the night, with difficulty getting back to sleep3

STUDY 1: DIFFERENCE IN TIME SPENT AWAKE AFTER SLEEP ONSET (WASO) AS MEASURED BY POLYSOMNOGRAPHY

Study 1 Shows Reduced Time Spent Awake After Sleep Onset as Measured by Polysomnography With BELSOMRA® (suvorexant) C-IV 15 mg or 20 mg Mean Change From Baseline (min) month 1 month 3 0 -10 -20 -30 -40 -50 Baseline (min) 115 120 115 120 0.05 at Month 1 and Month 3. PLACEBO (n=290) BELSOMRA 15 mg or 20 mg (n=193)
  • At Night 1, BELSOMRA 15 mg or 20 mg reduced WASO to 65 minutes, compared to 96 minutes with placebo (P<0.05)1
  • In Study 2, from a baseline of 119 minutes, BELSOMRA 15 mg or 20 mg (n=145) reduced WASO to 61 minutes at Night 1, 72 minutes at Month 1, and 63 minutes at Month 3 (compared with a baseline of 118 minutes, 98 minutes at Night 1, 95 minutes at Month 1, and 93 minutes at Month 3 for placebo; n=286); P values were comparable with Study 11

Study design for Studies 1 and 2:

  • Two similarly designed, 3-month, randomized, double-blind, placebo-controlled, parallel-group studies were conducted (Study 1 and Study 2). In both studies, non-elderly (ages 18–64) and elderly (ages ≥65) patients were randomized separately. For the studies together, non-elderly adults (mean age 46 years; 465 females, 275 males) were treated with BELSOMRA 20 mg (n=291) or placebo (n=449), and elderly patients (mean age 71 years; 346 females, 174 males) were treated with BELSOMRA 15 mg (n=202) or placebo (n=318).

In clinical trials, almost half of the patients were ≥65 years of age.

In the same 2 clinical trials, with BELSOMRA 15-mg dose in patients ≥65 years of age

STUDY 1: ELDERLY SUBGROUP (≥65 YEARS) — DIFFERENCE IN TIME SPENT AWAKE AFTER SLEEP ONSET (WASO) AS MEASURED BY POLYSOMNOGRAPHY4

Phase 3 efficacy studies were not powered for elderly-only subgroup analyses and were not part of the multiplicity-controlled hypotheses for the trials.4 These data show the effect of BELSOMRA on the elderly and should not be used in a comparative manner to the overall population.

Elderly Subgroup (≥65 Years) - Difference in Time Spent Awake After Sleep Onset as Measured by Polysomnography With BELSOMRA® (suvorexant) C-IV 15 mg Baseline,Night 1 (min) 126 135 126 135 Mean Change From Baseline (min) 0 -10 -20 -30 -40 -50 month 1 month 3 PLACEBO (n=123) BELSOMRA 15 mg (n=82)
  • At night 1, BELSOMRA 15 mg reduced WASO from baseline of 135 to 80 minutes vs reduction of 126 to 115 minutes for elderly patients receiving placebo4
  • In Study 2, from a baseline of 132 minutes, BELSOMRA 15 mg (n=63) reduced WASO to 81 minutes at Night 1, 96 minutes at Month 1, and 81 minutes at Month 3 (compared with a baseline of 128 minutes, 119 minutes at Night 1, 122 minutes at Month 1, and 113 minutes at Month 3 for placebo; n=122)4

Methodology of Elderly Subgroup Analysis

While elderly patients were randomized in both Studies 1 and 2, the studies were not powered for elderly-only subgroup analysis and were not part of the multiplicity-controlled hypotheses for the studies. For the studies together, elderly patients (mean age 71 years; 346 females, 174 males) were treated with BELSOMRA 15 mg (n=202) or placebo (n=318). Additional limitations include5:

  • Some patients were not evaluated for PSG4
  • The trials used 15 mg in elderly patients. Recommended dose is 10 mg. If the 10-mg dose is well-tolerated but not effective, the dose can be increased. The maximum recommended dose of BELSOMRA is 20 mg once daily4
  • Elderly patients (≥65 years old) were mostly 65–74 years of age (~80%). Patients were usually in good general health and had a diagnosis consistent with DSM-IV for primary insomnia. Patients with major depression or sleep-related breathing disorders, among others, were excluded4,5

In a clinical trial with the 10-mg dose, BELSOMRA improved sleep time vs placebo as measured by polysomnography6

  • Night 1 baseline values for sleep efficiency (SE) and total sleep time (TST) were 65.1% (5h13m) for the BELSOMRA 10 mg group and 65.9% (5h16m) for the placebo group
  • Baseline values at Month 1 were 65.7% (5h15m) for the BELSOMRA 10 mg group, and 65.4% (5h14m) for the placebo group
  • BELSOMRA improved SE (based on TST to 82.9% (6h38m) at Night 1 and 84.4% (6h45m) at Month 1. SE (based on TST) was 76.8% (6h9m) at Night 1 and 77.8% (6h13m) at Month 1 for placebo. P<0.01 vs placebo at Night 1 and Month 1

Study Design:

In a randomized, double-blind, placebo-controlled, 2-period (1 month per period with a single-blind washout between treatment periods 1 and 2) crossover polysomnography study, non-elderly adults with insomnia (ages 18-64) were treated with BELSOMRA at a dose of 10 mg (n=62) or 20 mg (n=61) in one period, and placebo in the other (n=249). The co-primary end points were SE, as derived from the PSG measure of TST, at Night 1 and at Month 1 of each period. (SE equals time asleep divided by time in bed multiplied by 100.)6

Clinical Efficacy for Insomnia in Patients With Mild to Moderate Alzheimer's Disease

Demonstrated efficacy and safety in an insomnia study in patients with mild to moderate Alzheimer’s disease (AD).

Patients treated with BELSOMRA exhibited a statistically significant improvement for both Total Sleep Time (TST) and Wake After Sleep Onset (WASO) measures, compared to those treated with placebo, as assessed by polysomnography at Week 4.

Patients Received 10 mg of BELSOMRA® (suvorexant) C-IV for Approximately 14 Days. 77% Had an Increase to 20 mg for Approximately 14 Additional Days

Patients received BELSOMRA 10 mg for approximately 14 days; of these, 77% had an increase to 20 mg for approximately 14 additional days.

  • Use the lowest dose effective for the patient. For all BELSOMRA doses, take no more than once per night within 30 minutes of going to bed (with at least 7 hours remaining prior to planned awakening). Time to effect of BELSOMRA may be delayed if taken with or soon after a meal.
  • The recommended dose for BELSOMRA is 10 mg, taken no more than once per night. If the 10 mg dose is well-tolerated but not effective, the dose can be increased. The maximum recommended dose of BELSOMRA is 20 mg taken no more than once per night.
  • Exposure to BELSOMRA is increased in obese compared to non-obese patients, and in women compared to men. Particularly in obese women, the increased risk of exposure-related adverse effects should be considered before increasing the dose.
Study Design

A randomized, double-blind, placebo-controlled, parallel-group, multi-site 4-week trial of BELSOMRA was conducted in patients with mild to moderate Alzheimer’s disease (n=285) for the treatment of insomnia. Male and female subjects aged 50-90 years (inclusive) were treated with BELSOMRA (n=142) or placebo (n=143).

References

1. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package US-IMA-01367.

2. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package US-IMA-01387.

3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.

4. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package US-IMA-01369.

5. Herring WJ, Connor KM, Snyder E, et al. Suvorexant in elderly patients with insomnia: pooled analyses of data from phase III randomized controlled clinical trials. Am J Geriatr Psychiatry. 2017;25:791-802.

6. Data available on request from Merck Professional Services-DAP, WP1, PO Box 4, West Point, PA 19486-0004. Please specify information package US-IMA-01363.

Indications and Usage

BELSOMRA® (suvorexant) is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.

Selected Safety Information

  • BELSOMRA is contraindicated in patients with narcolepsy.
  • BELSOMRA is a central nervous system (CNS) depressant and 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. 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. Caution patients taking BELSOMRA 20 mg against next-day driving and other activities requiring full mental alertness. Caution patients taking lower doses of BELSOMRA as well, because there is individual variation in sensitivity to BELSOMRA.
  • Coadministration with other CNS depressants (eg, benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Patients should be advised not to consume alcohol in combination with BELSOMRA due to additive effects. Dosage adjustments of BELSOMRA and of other 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.
  • 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 recommended dose is taken, if coadministered with other CNS depressants, or if coadministered with other drugs that increase blood levels of BELSOMRA. Patients should be cautioned against driving and other activities requiring complete mental alertness if taken in these circumstances.
  • Because BELSOMRA can cause drowsiness, patients, particularly the elderly, are at higher risk of falls.
  • 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 onset behavioral changes. In primarily depressed patients treated with sedative-hypnotics, worsening of depression or suicidal thinking, including suicidal thoughts and actions (including completed suicide), have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdose is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time.
  • Complex sleep behaviors, including sleep-walking, sleep-driving, and engaging in other activities while not fully awake (eg, preparing and eating food, making phone calls, having sex), have been reported to occur with the use of hypnotics such as BELSOMRA. These events can occur in hypnotic-naïve as well as in hypnotic-experienced persons. Patients usually do not remember these events. Complex sleep behaviors may occur following the first or any subsequent use of BELSOMRA, with or without the concomitant use of alcohol and other CNS depressants. Discontinue BELSOMRA immediately if a patient experiences a complex sleep behavior.
  • Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/hypnopompic hallucinations, including vivid perceptions by the patient, can occur with use of BELSOMRA.
  • Symptoms similar to mild cataplexy can occur, with risk increasing with the dose of BELSOMRA. Such symptoms can include periods of leg weakness lasting from seconds to a few minutes, can occur both at night and during the day, and may not be associated with an identified triggering event (eg, laughter or surprise).
  • The effect of BELSOMRA on respiratory function should be considered if prescribed to patients with compromised respiratory function. BELSOMRA has not been studied in patients with severe obstructive sleep apnea (OSA) or severe chronic obstructive pulmonary disease (COPD).
  • Symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. Reevaluate for comorbid conditions if insomnia persists after 7 to 10 days of treatment.
  • In pivotal clinical studies, the most common adverse reaction (reported in 5% or more of patients treated with 15 mg or 20 mg of BELSOMRA and at least twice the placebo rate) was somnolence (BELSOMRA 7%, placebo 3%).
  • In clinical studies, during the first 3 months of treatment, the adverse reactions reported in ≥2% of elderly patients treated with 15 mg or non-elderly patients treated with 20 mg of BELSOMRA and more commonly than in patients treated with placebo, were: diarrhea (BELSOMRA 2%, placebo 1%), dry mouth (2%, 1%), upper respiratory tract infection (2%, 1%), headache (7%, 6%), somnolence (7%, 3%), dizziness (3%, 2%), abnormal dreams (2%, 1%), and cough (2%, 1%).
  • At doses of 15 mg or 20 mg, the incidence of somnolence was higher in females (8%) than in males (3%). The incidence of headache, abnormal dreams, dry mouth, cough, and upper respiratory tract infection occurred in women at least twice that in men.
  • In the insomnia study in patients with mild to moderate Alzheimer’s disease receiving BELSOMRA, the adverse reactions occurring ≥2% and greater than placebo were somnolence (4% compared to 1% placebo), dry mouth (2% compared to 1% placebo), and falls (2% compared to 0% placebo).
  • When BELSOMRA was coadministered with alcohol, additive psychomotor impairment was demonstrated.
  • Concomitant use of BELSOMRA with strong inhibitors of CYP3A (eg, ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, conivaptan) is not recommended.
  • The recommended dose of BELSOMRA is 5 mg in subjects receiving moderate CYP3A inhibitors (eg, amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil). The dose generally should not exceed 10 mg in patients receiving moderate CYP3A4 inhibitors.
  • The efficacy of BELSOMRA may be reduced when coadministered with strong CYP3A inducers (eg, rifampin, carbamazepine, phenytoin).
  • Slightly increased levels of digoxin were seen with coadministration of BELSOMRA. Digoxin levels should be monitored when coadministering BELSOMRA with digoxin.
  • 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.
  • There are no data on the presence of suvorexant in human milk, the effects on the breastfed infant or the effects on milk production. Infants exposed to BELSOMRA through breastmilk should be monitored for excessive sedation. The benefits of breastfeeding should be considered along with the mother’s clinical need for BELSOMRA and any potential adverse effects on the breastfed infant.
  • Safety and effectiveness of BELSOMRA in pediatric patients have not been established.
  • Because BELSOMRA can increase drowsiness, patients, particularly the elderly, are at a higher risk of falls.
  • BELSOMRA contains suvorexant, a Schedule IV controlled substance.
  • 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, health care providers should follow such patients carefully when those patients are receiving BELSOMRA.
  • Use the lowest dose effective for the patient.
  • The recommended dose for BELSOMRA is 10 mg, taken no more than once per night, and within 30 minutes of going to bed, with at least 7 hours remaining before the planned time of awakening. If the 10-mg dose is well tolerated but not effective, the dose can be increased. The maximum recommended dose of BELSOMRA is 20 mg taken no more than once per night.
  • Exposure to BELSOMRA is increased in obese compared to non-obese patients, and in women compared to men. Particularly in obese women, the increased risk of exposure-related adverse effects should be considered before increasing the dose.
  • When BELSOMRA is combined with other CNS depressant drugs, dosage reduction of BELSOMRA and/or the other drug(s) may be necessary because of potentially additive effects. The recommended dosage of BELSOMRA is 5 mg taken no more than once per night when used with moderate CYP3A inhibitors (the dose generally should not exceed 10 mg).
  • BELSOMRA is not recommended for use with strong CYP3A inhibitors.
  • Time to effect of BELSOMRA may be delayed if taken with or soon after a meal.
  • No dose adjustment is required in patients with mild and moderate hepatic impairment. BELSOMRA has not been studied in patients with severe hepatic impairment and is not recommended for these patients.

Before prescribing BELSOMRA, please read the Prescribing Information. The Medication Guide also is available.

US-IMA-0224907/23