Belsomra(suvorexant)tab被美国食品和药物管理局FDA批准为新一代治疗失眠的新型途径
批准日期：2014年8月13日；公司：Merck，Sharpe & Dohme Corp.
近日，美国食品药品监督管理局(FDA)批准Belsomra(suvorexant)片为作为需要治疗难以入睡和保持睡眠(失眠)使用。
Belsomra是一种食欲素受体拮抗剂和是第一个被批准的这类型药物。食欲素是化学品涉及调整水母-觉醒循环和保持人们清醒起作用。Belsomra改变食欲素在脑中信号(作用)。
失眠是一种常见情况，其中人们难以入睡或维持睡眠。范围从轻至严重，取决于发生经常和如何长失眠可能至白天嗜睡和精神不振。也使人们柑橘焦虑，抑郁，或暴躁易怒。有失眠肯有警觉，学习和记忆麻烦。
FDA的药品评价和研究中心药品评价I室主任Ellis Unger，医学博士说：“帮助卫生保健专业人员和患者寻找对各个体患者失眠最佳治疗，FDA已批准Belsomra四种不同强度规格–5，10，15，and 20 mg，”“使用最低有效剂量可减低副作用风险，例如下一天嗜睡。”。
Belsomra应服用不要超过每夜1次，最睡前30分钟内，在计划苏醒时间前至少7个小时。总剂量不应超过20 mg每天1次。
服用Belsomra的临床试验参加者最常报告的不良反应是嗜睡。治疗失眠药物可致下一天嗜眠和损害驾驶和其他需要警觉的活动。即使人们感觉完全清醒，人们可能倍损害。
FDA要求药物制造商，Merck，Sharpe & Dohme 公司，研究服用Belsomra人们下一天驾驶体能状态。这个测试显示损害驾驶性能在男性和女性参加者当服用20 mg 规格时。患者用20 mg规格应谨慎对待下一天驾驶或需要完全精神警觉性活动。服用较低剂量患者也应意识到下一天驾驶受损，因为存在对药物敏感性的个体变异》
在三项临床试验涉及超过500例参加者研究Belsomra的有效性。在研究中，服用该药患者与服用无活性药丸(安慰剂)更快入眠和剩余夜期时间清醒时间花费较。Belsomra没有与其他被批准治疗失眠药物比较，所以不知道Belsomra和其他失眠药间是否存在安全性或有效性差别。
像其他睡眠药一样，有当没有完全清醒来自Belsomra睡眠-驾驶和其他复杂行为，例如准备和吃食物，打电话，或性活动的风险。如果一名人消耗酒精或或服用使他们睡眠的其他药这种活动机会增加。如发生这类活动，患者或他们的家庭应电话处方的卫生保健专业人员。
Belsomra将与一个FDA-批准的患者用药指南一起分发提供试验和重要安全性资料。Belsomra是一种受控物质(Schedule-IV)因为它可能被滥用或导致依赖性。.
Belsomra由新泽西州Whitehouse站Merck，Sharpe & Dohme公司制造。
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use BELSOMRA safely and effectively. See full prescribing information for BELSOMRA.
BELSOMRA ® (suvorexant) tablets, for oral use, C-IV
Initial U.S. Approval: 2014
INDICATIONS AND USAGE
BELSOMRA is an orexin receptor antagonist indicated for the treatment of insomnia, characterized by difficulties with sleep onset and/or sleep maintenance (1).
DOSAGE AND ADMINISTRATION
Use the lowest dose effective for the patient (2.1).
Recommended dose is 10 mg, no more than once per night taken 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, not to exceed 20 mg once daily (2.1, 2.2).
Time to effect may be delayed if taken with or soon after a meal (2.5).
DOSAGE FORMS AND STRENGTHS
Tablets, 5mg, 10mg, 15mg, 20mg (3).
CONTRAINDICATIONS
Do not use in patients with narcolepsy (4).
WARNINGS AND PRECAUTIONS
Daytime somnolence: 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).
Need to evaluate for co-morbid diagnoses: Reevaluate if insomnia persists after 7 to 10 days of treatment (5.2).
Nighttime "sleep-driving" and other complex behaviors while out of bed and not fully awake. Risk increases with dose, with use of CNS depressants, and with alcohol (5.3).
Depression: Worsening of depression or suicidal thinking may occur. Risk increases with dose. Immediately evaluate any new behavioral changes (5.4).
Compromised respiratory function: Effect on respiratory function should be considered (5.5, 8.6).
Sleep paralysis, hypnagogic/hypnopompic hallucinations, and cataplexy-like symptoms: Risk increases with dose (5.6).
ADVERSE REACTIONS
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 Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
CYP3A inhibitors: Recommended dose is 5 mg when used with moderate CYP3A inhibitors. Dose can be increased to 10 mg once daily 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).
USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm (8.1).
Patients with severe hepatic impairment: Not recommended (8.7).
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 8/2014
FULL PRESCRIBING INFORMATION: CONTENTS
1 INDICATIONS AND USAGE
BELSOMRA® (suvorexant) is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
2 DOSAGE AND ADMINISTRATION
2.1 Dosing Information
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 once daily.
2.2 Special Populations
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 [see Clinical Pharmacology (12.3)].
2.3 Use with CNS Depressants
When BELSOMRA is combined with other CNS depressant drugs, dosage adjustment of BELSOMRA and/or the other drug(s) may be necessary because of potentially additive effects [see Warnings and Precautions (5.1)].
2.4 Use with CYP3A Inhibitors
The recommended dose of BELSOMRA is 5 mg when used with moderate CYP3A inhibitors and the dose generally should not exceed 10 mg in these patients. BELSOMRA is not recommended for use with strong CYP3A inhibitors [see Drug Interactions (7.2)].
2.5 Food Effect
Time to effect of BELSOMRA may be delayed if taken with or soon after a meal.
3 DOSAGE FORMS AND STRENGTHS
5mg tablets are yellow, round, film-coated tablets with "5" on one side and plain on the other side.
10mg tablets are green, round, film-coated tablets with "33" on one side and plain on the other side.
15mg tablets are white, oval, film-coated tablets with the Merck logo on one side and "325" on the other side.
20mg tablets are white, round, film-coated tablets with the Merck logo and "335" on one side and plain on the other side.
4 CONTRAINDICATIONS
BELSOMRA is contraindicated in patients with narcolepsy.
5 WARNINGS AND PRECAUTIONS
5.1 CNS 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.
5.2 Need to Evaluate for Co-morbid Diagnoses
Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new cognitive or behavioral abnormalities may be the result of an unrecognized underlying psychiatric or physical disorder, and can emerge during the course of treatment with hypnotic drugs such as BELSOMRA.
5.3 Abnormal Thinking and Behavioral Changes
A variety of cognitive and behavioral changes (e.g., amnesia, anxiety, hallucinations and other neuro-psychiatric symptoms) have been reported to occur in association with the use of hypnotics such as BELSOMRA. Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after taking a hypnotic) and other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex), with amnesia for the event, have been reported in association with the use of hypnotics. These events can occur in hypnotic-naïve as well as in hypnotic-experienced persons. The use of alcohol and other CNS depressants may increase the risk of such behaviors. Discontinuation of BELSOMRA should be strongly considered for patients who report any complex sleep behavior.
5.4 Worsening 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 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.
The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
5.5 Patients with Compromised Respiratory Function
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) [see Use in Specific Populations (8.6)].
5.6 Sleep Paralysis, Hypnagogic/Hypnopompic Hallucinations, Cataplexy-like Symptoms
Sleep paralysis, an inability to move or speak for up to several minutes during sleep-wake transitions, and hypnagogic/hypnopompic hallucinations, including vivid and disturbing perceptions by the patient, can occur with the use of BELSOMRA. Prescribers should explain the nature of these events to patients when prescribing 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 (e.g., laughter or surprise).
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)]
Abnormal thinking and behavioral changes [see Warnings and Precautions (5.3)]
Worsening of Depression/Suicidal ideation [see Warnings and Precautions (5.4)]
Sleep paralysis, hypnagogic/hypnopompic hallucinations, cataplexy-like symptoms [see Warnings and Precautions (5.6)]
6.1 Clinical 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 treated for up to one month with BELSOMRA at doses of 10 mg, 20 mg, 40 mg (2 times the maximum recommended dose) or 80 mg (4 times the maximum recommended dose). In patients treated with BELSOMRA 10 mg (n=62), although no adverse reactions were reported at an incidence of ≥2%, the types of adverse reactions observed were similar to those observed in patients treated with BELSOMRA 20 mg. BELSOMRA was associated with a dose-related increase in somnolence: 2% at the 10 mg dose, 5% at the 20 mg dose, 12% at the 40 mg dose, and 11% at the 80 mg dose, compared to <1% for placebo. BELSOMRA was also associated with a dose-related increase in serum cholesterol: 1 mg/dL at the 10 mg dose, 2 mg/dL at the 20 mg dose, 3 mg/dL at the 40 mg dose, and 6 mg/dL at the 80 mg dose after 4 weeks of treatment, compared to a 4 mg/dL decrease for placebo.
7 DRUG INTERACTIONS
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 can be increased to 10 mg in these patients if necessary for efficacy [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 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no adequate and well-controlled studies in pregnant women. BELSOMRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Administration of suvorexant to pregnant rats throughout organogenesis in two separate studies at oral doses of 30, 150, and 1000 mg/kg or 30, 80, and 325 mg/kg resulted in a decrease in fetal body weight at doses greater than 80 mg/kg. Plasma exposures (AUC) at the no-effect dose were approximately 25 times that in humans at the maximum recommended human dose (MRHD) of 20 mg/day.
Administration of suvorexant to pregnant rabbits throughout organogenesis in two separate studies at oral doses of 40, 100, and 300 mg/kg or 50, 150, and 325 mg/kg resulted in no apparent adverse effects on embryo-fetal development. Excessive toxicity resulted in premature sacrifice of pregnant animals at 325 mg/kg. The highest maternal plasma exposures (AUC) for which there are fetal data were up to approximately 40 times that in humans at the MRHD.
Administration of suvorexant (oral doses of 30, 80, and 200 mg/kg) to pregnant rats throughout gestation and lactation resulted in decreased body weight in offspring at the highest dose tested. Plasma AUCs at the no-effect dose were approximately 25 times that in humans at the MRHD.
8.3 Nursing Mothers
Suvorexant and a hydroxyl-suvorexant metabolite were excreted in rat milk at levels higher (9 and 1.5 times, respectively) than that in maternal plasma. It is not known whether this drug is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when BELSOMRA is administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established
8.5 Geriatric Use
Of the total number of patients treated with BELSOMRA (n=1784) in controlled clinical safety and efficacy studies, 829 patients were 65 years and over, and 159 patients were 75 years and over. No clinically meaningful differences in safety or effectiveness were observed between these patients and younger patients at the recommended doses [see Clinical Pharmacology (12.3) and Clinical Studies (14)].
8.6 Patients with Compromised Respiratory Function
Effects of BELSOMRA on respiratory function should be considered if prescribed to patients with compromised respiratory function.
Obstructive Sleep Apnea
The respiratory depressant effect of BELSOMRA was evaluated after one night and after four consecutive nights of treatment 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 difference (suvorexant – placebo) on Day 4 was 2.7 (90% CI: 0.22 to 5.09), but there was wide inter- and intra-individual variability such that clinically meaningful respiratory effects of BELSOMRA in obstructive sleep apnea cannot be excluded. BELSOMRA has not been studied in patients with severe obstructive sleep apnea [see Warnings and Precautions (5.5)].
Chronic Obstructive Pulmonary Disease
The respiratory depressant effect of BELSOMRA was evaluated after one night and after four consecutive nights of treatment in a randomized, placebo-controlled, 2-period crossover study in patients (n=25) with mild to moderate chronic obstructive pulmonary disease (COPD). BELSOMRA (40 mg in non-elderly, 30 mg in elderly) had no respiratory depressant effects in patients with mild to moderate COPD, as measured by oxygen saturation. There was 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 (5.5)].
8.7 Patients with Hepatic Impairment
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 [see Clinical Pharmacology (12.3)].
No dose adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].
8.8 Patients with Renal Impairment
No dose adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].
9 DRUG ABUSE AND DEPENDENCE
9.1 Controlled Substance
BELSOMRA contains suvorexant, a Schedule IV controlled substance
9.2 Abuse
Abuse of BELSOMRA poses an increased risk of somnolence, daytime sleepiness, decreased reaction time and impaired driving skills [see Warnings and Precautions (5.1)]. Patients at risk for abuse may include those with prolonged use of BELSOMRA, those with a history of drug abuse, and those who use BELSOMRA in combination with alcohol or other abused drugs.
Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may develop after repeated abuse of a prescription or over-the-counter drug, including: a strong desire to take the drug, difficulties in controlling drug use, persisting in drug use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, as well as the possibility of the development of tolerance or development of physical dependence (as manifest by a withdrawal syndrome). Drug abuse and drug addiction are separate and distinct from physical dependence and tolerance (for example, abuse or addiction are not always accompanied by tolerance or physical dependence).
In an abuse liability study conducted in recreational polydrug users (n=36), suvorexant (40, 80 and 150 mg) produced similar effects as zolpidem (15, 30 mg) on subjective ratings of "drug liking" and other measures of subjective drug 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.
9.3 Dependence
Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use. Physical dependence manifests by drug class-specific withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. In completed clinical trials with BELSOMRA, there was no evidence for physical dependence with the prolonged use of BELSOMRA. There were no reported withdrawal symptoms after discontinuation of BELSOMRA.
10 OVERDOSAGE
There is limited premarketing clinical experience with an overdosage of BELSOMRA. In clinical pharmacology studies, healthy subjects who were administered morning doses of up to 240 mg of suvorexant showed dose-dependent increases in the frequency and duration of somnolence.
General symptomatic and supportive measures should be used, along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. As in all cases of drug overdose, vital signs should be monitored and general supportive measures employed. The value of dialysis in the treatment of overdosage has not been determined. As suvorexant is highly protein-bound, hemodialysis is not expected to contribute to elimination of suvorexant.
As with the management of all overdosage, the possibility of multiple drug ingestion should be considered. Consider contacting a poison control center for up-to-date information on the management of hypnotic drug product overdosage.
11 DESCRIPTION
BELSOMRA tablets contain suvorexant, a highly selective antagonist for orexin receptors OX1R and OX2R.
Suvorexant is described chemically as:
[(7R)-4-(5-chloro-2-benzoxazolyl) hexahydro-7-methyl-1H-1,4-diazepin-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone
Its empirical formula is C23H23ClN6O2 and the molecular weight is 450.92. Its structural formula is:

Suvorexant is a white to off-white powder that is insoluble in water.
Each film coated tablet contains 5 mg, 10 mg, 15 mg, or 20 mg of suvorexant and the following inactive ingredients: polyvinylpyrrolidone/vinyl acetate copolymer (copovidone), microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, and magnesium stearate.
In addition, the film coating contains the following inactive ingredients: lactose monohydrate, hypromellose, titanium dioxide, and triacetin. The film coating for the 5 mg tablets also contains iron oxide yellow and iron oxide black, and the film coating for the 10 mg tablets also contains iron oxide yellow and FD&C Blue 1/Brilliant Blue FCF Aluminum Lake.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The mechanism by which suvorexant exerts its therapeutic effect in insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.
Antagonism of orexin receptors may also underlie potential adverse effects such as signs of narcolepsy/cataplexy. Genetic mutations in the orexin system in animals result in hereditary narcolepsy; loss of orexin neurons has been reported in humans with narcolepsy.
12.2 Pharmacodynamics
Evaluation of QTc Interval
The effects of suvorexant on the QTc interval were evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover study in healthy subjects (n=53). The upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc interval was below 10 ms based on analysis of suvorexant doses up to 240 mg, 12 times the maximum recommended dose. BELSOMRA thus does not prolong the QTc interval to any clinically relevant extent.
12.3 Pharmacokinetics
Suvorexant exposure increases in a less than strictly dose-proportional manner over the range of 10-80 mg because of decreased absorption at higher doses. Suvorexant pharmacokinetics are similar in healthy subjects and patients with insomnia.
Absorption
Suvorexant peak concentrations occur at a median Tmax of 2 hours (range 30 minutes to 6 hours) under fasted conditions. The mean absolute bioavailability of 10 mg is 82%.
Ingestion of suvorexant with a high-fat meal resulted in no meaningful change in AUC or Cmax but a delay in Tmax of approximately 1.5 hours. Suvorexant may be taken with or without food; however for faster sleep onset, suvorexant should not be administered with or soon after a meal.
Distribution
The mean volume of distribution of suvorexant is approximately 49 liters. Suvorexant is extensively bound (>99%) to human plasma proteins and does not preferentially distribute into red blood cells. Suvorexant binds to both human serum albumin and α1-acid glycoprotein.
Metabolism
Suvorexant is mainly eliminated by metabolism, primarily by CYP3A with a minor contribution from CYP2C19. The major circulating entities are suvorexant and a hydroxy-suvorexant metabolite. This metabolite is not expected to be pharmacologically active.
Elimination
The primary route of elimination is through the feces, with approximately 66% of radiolabeled dose recovered in the feces compared to 23% in the urine. The systemic pharmacokinetics of suvorexant are linear with an accumulation of approximately 1- to 2-fold with once-daily dosing. Steady-state is achieved by 3 days. The mean t1/2 is approximately 12 hours (95% CI: 12 to 13).
Special Populations
Gender, age, body mass index (BMI), and race were included as factors assessed in the population pharmacokinetic model to evaluate suvorexant pharmacokinetics in healthy subjects and to predict exposures in the patient population. Age and race are not predicted to have any clinically meaningful changes on suvorexant pharmacokinetics; therefore, no dose adjustment is warranted based upon these factors.
Suvorexant exposure is higher in females than in males. In females, the AUC and Cmax are increased by 17% and 9%, respectively, following administration of BELSOMRA 40 mg. The average concentration of suvorexant 9 hours after dosing is 5% higher for females across the dose range studied (10-40 mg). Dose adjustment of BELSOMRA is generally not needed based on gender only.
Apparent oral clearance of suvorexant is inversely related to body mass index. In obese patients, the AUC and Cmax are increased by 31% and 17%, respectively. The average concentration of suvorexant approximately 9 hours after a 20 mg dose is 15% higher in obese patients (BMI > 30 kg/m2) relative to those with a normal BMI (BMI ≤ 25 kg/m2).
In obese females, the AUC and Cmax are increased by 46% and 25%, respectively, compared to non-obese females. The higher exposure to suvorexant in obese females should be considered before increasing dose [see Dosage and Administration (2.2)].
The effects of renal and hepatic impairment on the pharmacokinetics of suvorexant were evaluated in specific pharmacokinetic studies.
Suvorexant exposure after a single dose was similar in patients with moderate hepatic insufficiency (Child-Pugh category 7 to 9) and healthy matched control subjects; however, the suvorexant apparent terminal half-life was increased from approximately 15 hours (range 10 - 22 hours) in healthy subjects to approximately 19 hours (range 11 - 49 hours) in patients with moderate hepatic insufficiency [see Use in Specific Populations (8.7)].
Suvorexant exposure (expressed as total and unbound concentrations) was similar between patients with severe renal impairment (urinary creatinine clearance ≤30 mL/min/1.73m2) and healthy matched control subjects. No dose adjustment is required in patients with renal impairment [see Use in Specific Populations (8.8)].
Drug Interactions
CNS-Active Drugs
An additive effect on psychomotor performance was observed when a single dose of 40 mg of suvorexant was co-administered with a single dose of 0.7 g/kg alcohol. Suvorexant did not affect alcohol concentrations and alcohol did not affect suvorexant concentrations [see Warnings and Precautions (5.1, 5.3) and Drug Interactions (7.1)].
An interaction study with a single dose of 40 mg suvorexant and paroxetine 20 mg at steady-state levels in healthy subjects did not demonstrate a clinically significant pharmacokinetic or pharmacodynamic interaction.
Effects of Other Drugs on BELSOMRA
The effects of other drugs on the pharmacokinetics of suvorexant are presented in Figure 1 as change relative to suvorexant administered alone (test/reference). Strong (e.g., ketoconazole or itraconazole) and moderate (e.g., diltiazem) CYP3A inhibitors significantly increased suvorexant exposure. Strong CYP3A inducers (e.g., rifampin) substantially decreased suvorexant exposure [see Drug Interactions (7.2)].
Figure 1:
Effects of Co-administered Drugs on the Pharmacokinetics of Suvorexant

Effects of BELSOMRA on Other Drugs
In vitro metabolism studies demonstrate that suvorexant has the potential to inhibit CYP3A and intestinal P-gp; however, suvorexant is unlikely to cause clinically significant inhibition of human CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. In addition, no clinically meaningful inhibition of OATP1B1, BCRP and OCT2 transporters is anticipated. Chronic administration of suvorexant is unlikely to induce the metabolism of drugs metabolized by major CYP isoforms. Specific in vivo effects on the pharmacokinetics of midazolam, warfarin, digoxin and oral contraceptives are presented in Figure 2 as a change relative to the interacting drug administered alone (test/reference) [see Drug Interactions (7.3)].
Figure 2:
Effects of Suvorexant* on the Pharmacokinetics of Co-administered Drugs

Monitor digoxin concentrations as clinically indicated [see Drug Interactions (7.3)].
Suvorexant 40 mg was evaluated in all studies, except midazolam where 80 mg suvorexant was administered. 
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In a 26-week study in Tg.rasH2 mice, there was no evidence of suvorexant-induced neoplasms at oral doses of 25, 50, 200, and 650 mg/kg/day.
In a 2-year study in rats (oral suvorexant doses of 80, 160, and 325 mg/kg/day), increases in thyroid (follicular cell adenoma and combined adenoma/carcinoma in high-dose females; follicular cell adenoma in mid- and high-dose males) and liver (hepatocellular adenoma in high-dose males) neoplasms were observed. These findings were consistent with increased TSH and hepatic enzyme induction, respectively, which are mechanisms believed to be rodent-specific. Plasma exposures (AUC) at doses not associated with drug-induced neoplasms in rats were approximately 7 times that in humans at the maximum recommended human dose (MRHD) of 20 mg.
Mutagenesis
Suvorexant was negative in in vitro (bacterial reverse mutation and chromosomal aberration) and in vivo (mouse and rat micronucleus) assays.
Impairment of Fertility
In two separate studies, male and female rats were treated with suvorexant prior to and during mating and continuing in females to gestation day 7. Increases in peri-implantation loss and resorptions, resulting in a decrease in live fetuses, were observed at the highest doses tested (1200 or 325 mg/kg) when treated males and females were mated with untreated animals. At the no-effect dose for adverse effects on fertility in males and females, plasma AUCs were approximately 20 times that in humans at the MRHD.
13.2 Animal Toxicology and/or Pharmacology
In dogs, daily oral administration of suvorexant (5, 30 mg/kg) for 4-7 days resulted in behavior characteristic of cataplexy (e.g., transient limb buckling, prone posture) when presented with food enrichment, a stimulus demonstrated to induce cataplexy in dogs with hereditary narcolepsy.
In the 2-year carcinogenicity study in rats, an increased incidence of retinal atrophy was observed at all doses. Plasma AUCs at the lowest dose tested were approximately 7 times that in humans at the MRHD.
In subsequent studies of suvorexant in albino and pigmented rats, retinal atrophy was delayed in onset and, after approximately one year of dosing, was of lower incidence and severity in pigmented rats.
14 CLINICAL STUDIES
14.1 Controlled Clinical Studies
BELSOMRA was evaluated in three clinical trials in patients with insomnia characterized by difficulties with sleep onset and sleep maintenance.
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 (age 18-64) and elderly (age ≥ 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). Elderly patients (mean age 71 years, 346 females, 174 males) were treated with BELSOMRA 15 mg (n=202) or placebo (n=318).
In Study 1 and Study 2, BELSOMRA 15 mg or 20 mg was superior to placebo for sleep latency as assessed both objectively by polysomnography (Table 3) and subjectively by patient-estimated sleep latency (Table 4). BELSOMRA 15 mg or 20 mg was also superior to placebo for sleep maintenance, as assessed both objectively by polysomnography (Table 5) and subjectively by patient-estimated total sleep time (Table 6). The effects of BELSOMRA at night 1 (objective) and week 1 (subjective) were generally consistent with later time points. The efficacy of BELSOMRA was similar between women and men and, based on limited data, between Caucasians and non-Caucasians. Twenty seven percent of patients treated with BELSOMRA 15 mg or 20 mg in Study 1 and Study 2 were non-Caucasians. The majority (69%) of the non-Caucasian patients was Asian.
Table 3: Polysomnographic Assessment of Time to Sleep Onset in Studies 1 and 2 

Mean Baseline and Change from Baseline† After 1 and 3 Months (minutes)		Difference† Between BELSOMRA and Placebo (minutes)
Change from baseline and treatment differences based upon estimated means.
15 mg in elderly and 20 mg in non-elderly patients
p<0.05; **p<0.01; ***p<0.001
Study 1
	Placebo (n=290)	BELSOMRA 15-20 mg‡ (n=193)
Baseline	66	69
Change from Baseline
Month 1	- 23	- 34	- 10***
Month 3	- 27	- 35	- 8**
Study 2
	Placebo (n=286)	BELSOMRA 15-20 mg‡ (n=145)
Baseline	69	65
Change from Baseline
Month 1	- 25	- 33	- 8*
Month 3	- 29	- 29	0

Change from baseline and treatment differences based upon estimated means. 
15 mg in elderly and 20 mg in non-elderly patients
p<0.05; **p<0.01; ***p<0.001
Table 4: Patient-estimated Time to Sleep Onset in Studies 1 and 2

Mean Baseline and Change from Baseline† After 1 and 3 Months (minutes)		Difference† Between BELSOMRA and Placebo (minutes)
Change from baseline and treatment differences based upon estimated means.
15 mg in elderly and 20 mg in non-elderly patients
p<0.05; **p<0.01; ***p<0.001
Study 1
	Placebo (n=382)	BELSOMRA 15-20 mg‡ (n=251)
Baseline	67	64
Change from Baseline
Month 1	- 12	- 17	- 5
Month 3	- 17	- 23	- 5*
Study 2
	Placebo (n=369)	BELSOMRA 15-20 mg‡ (n=231)
Baseline	83	86
Change from Baseline
Month 1	- 14	- 21	- 7*
Month 3	- 21	- 28	- 8*

Table 5: Polysomnographic Assessment of Sleep Maintenance (Wake After Sleep Onset) in Studies 1 and 2

Mean Baseline and Change from Baseline† After 1 and 3 Months (minutes)		Difference† Between BELSOMRA and Placebo (minutes)
Change from baseline and treatment differences based upon estimated means.
15 mg in elderly and 20 mg in non-elderly patients
p<0.05; **p<0.01; ***p<0.001
Study 1
	Placebo (n=290)	BELSOMRA 15-20 mg‡ (n=193)
Baseline	115	120
Change from Baseline
Month 1	- 19	- 45	- 26***
Month 3	- 25	- 42	- 17***
Study 2
	Placebo (n=286)	BELSOMRA 15-20 mg‡ (n=145)
Baseline	118	119
Change from Baseline
Month 1	- 23	- 47	- 24***
Month 3	- 25	- 56	- 31***

Change from baseline and treatment differences based upon estimated means. 
15 mg in elderly and 20 mg in non-elderly patients
p<0.05; **p<0.01; ***p<0.001
Table 6: Patient-estimated Total Sleep Time in Studies 1 and 2

Mean Baseline and Change from Baseline† After 1 and 3 Months (minutes)		Difference† Between BELSOMRA and Placebo (minutes)
Change from baseline and treatment differences based upon estimated means.
15 mg in elderly and 20 mg in non-elderly patients
p<0.05; **p<0.01; ***p<0.001
Study 1
	Placebo (n=382)	BELSOMRA 15-20 mg‡ (n=251)
Baseline	315	322
Change from Baseline
Month 1	23	39	16***
Month 3	41	51	11*
Study 2
	Placebo (n=369)	BELSOMRA 15-20 mg‡ (n=231)
Baseline	307	299
Change from Baseline
Month 1	22	43	21***
Month 3	38	60	22***

Change from baseline and treatment differences based upon estimated means. 
15 mg in elderly and 20 mg in non-elderly patients
p<0.05; **p<0.01; ***p<0.001
In the 1-month crossover study (Study 3), non-elderly adults (age 18-64 years, mean age 44 years) were treated with placebo (n=249) and BELSOMRA at a dose of 10 mg (n=62), 20 mg (n=61), or up to 80 mg. BELSOMRA 10 mg and 20 mg were superior to placebo for sleep latency and sleep maintenance, as assessed objectively by polysomnography.
BELSOMRA was also evaluated at doses of 30 mg and 40 mg in the 3-month placebo-controlled trials (Study 1 and Study 2). The higher doses were found to have similar efficacy to lower doses, but significantly more adverse reactions were reported at the higher doses.
14.2 Special Safety Studies
Effects on Driving
Two randomized, double-blind, placebo- and active-controlled, four-period crossover studies evaluated the effects of nighttime administration of BELSOMRA on next-morning driving performance 9 hours after dosing in 24 healthy elderly subjects (≥65 years old, mean age 69 years; 14 men, 10 women) who received 15 mg and 30 mg BELSOMRA, and 28 non-elderly subjects (mean age 46 years; 13 men, 15 women) who received 20 mg and 40 mg BELSOMRA. Testing was conducted after one night and after 8 consecutive nights of treatment with BELSOMRA at these doses.
The primary outcome measure was change in Standard Deviation of Lane Position (SDLP), a measure of driving performance, assessed using a symmetry analysis. The analysis showed clinically meaningful impaired driving performance in some subjects. After one night of dosing, this effect was observed in non-elderly subjects after either a 20 mg or 40 mg dose of BELSOMRA. A statistically significant effect was not observed in elderly subjects after a 15 mg or 30 mg dose of BELSOMRA. Across these two studies, five subjects (4 non-elderly women on BELSOMRA; 1 elderly woman on placebo) prematurely stopped their driving tests due to somnolence. 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 [see Warnings and Precautions (5.1)].
Effects on Next-day Memory and Balance in Elderly and Non-elderly
Four placebo-controlled trials evaluated the effects of nighttime administration of BELSOMRA on next-day memory and balance using word learning tests and body sway tests, respectively. Three trials showed no significant effects on memory or balance compared to placebo. In a fourth trial in healthy non-elderly subjects, there was a significant decrease in word recall after the words were presented to subjects in the morning following a single dose of 40 mg BELSOMRA, and there was a significant increase on body sway area in the morning following a single dose of 20 mg or 40 mg BELSOMRA.
Middle of the Night Safety in Elderly Subjects
A double-blind, randomized, placebo-controlled trial evaluated the effect of a single dose of BELSOMRA on balance, memory and psychomotor performance in healthy elderly subjects (n=12) after being awakened during the night. Nighttime dosing of BELSOMRA 30 mg resulted in impairment of balance (measured by body sway area) at 90 minutes as compared to placebo. Memory was not impaired, as assessed by an immediate and delayed word recall test at 4 hours post-dose.
Rebound Effects
In 3-month controlled safety and efficacy trials (Study 1, Study 2), rebound insomnia was assessed following discontinuation of BELSOMRA relative to placebo and baseline in non-elderly adult patients receiving BELSOMRA 40 mg or 20 mg and in elderly patients receiving BELSOMRA 30 mg or 15 mg. No clear effects were observed on measures of sleep onset or maintenance.
Withdrawal Effects
In 3-month controlled safety and efficacy trials (Study 1, Study 2), withdrawal effects were assessed following discontinuation in non-elderly adult patients who received BELSOMRA 40 mg or 20 mg and elderly patients who received BELSOMRA 30 mg or 15 mg. The analysis showed no clear evidence of withdrawal in the overall study population based on assessment of patient responses to the Tyrer Withdrawal Symptom Questionnaire or assessment of withdrawal-related adverse events following the discontinuation of BELSOMRA.
Respiratory Safety
Use in Healthy Subjects with Normal Respiratory Function
A randomized, placebo-controlled, double-blind, crossover trial in healthy non-elderly subjects (n=12) evaluated the respiratory depressant effect of BELSOMRA (40 mg and 150 mg) after one night of treatment. At the doses studied, BELSOMRA had no respiratory depressant effect as measured by oxygen saturation [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6)].
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How SuppliedNo. 3062 — BELSOMRA tablets, 5 mg, are yellow, round, film-coated tablets, with "5" on one side and plain on the other side. They are supplied as follows: NDC 0006-0005-30 unit-of-use blisters of 30
No. 3063 — BELSOMRA tablets, 10 mg, are green, round, film-coated tablets, with "33" on one side and plain on the other side. They are supplied as follows: NDC 0006-0033-30 unit-of-use blisters of 30
No. 3981 — BELSOMRA tablets, 15 mg, are white, oval, film-coated tablets with the Merck logo on one side and "325" on the other side. They are supplied as follows: NDC 0006-0325-30 unit-of-use blisters of 30
No. 3982 — BELSOMRA tablets, 20 mg, are white, round, film-coated tablets with the Merck logo and "335" on one side and plain on the other side. They are supplied as follows: NDC 0006-0335-30 unit-of-use blisters of 30
16.2 Storage and HandlingStore at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F), [see USP Controlled Room Temperature]. Store in the original package until use to protect from light and moisture.
----------------------------------------------
New Drugs Online Report for suvorexant
Information
Generic Name: suvorexant  
Trade Name: Belsomra 
Synonym: MK-4305 
Entry Type: New molecular entity  
Developmental Status
UK: Phase III Clinical Trials 
EU: Phase III Clinical Trials 
US: Approved (Licensed) 
UK launch Plans: Available only to registered users
Actual UK launch date:  
Comments
Aug 14: Licensed in US at doses between 5 and 20mg [17].
14/08/2014 20:24:41 
Apr 14: FDA accepts Merck´s resubmitted NDA [16].
19/06/2014 16:21:19 
Jul 13: The company has received a Complete Response Letter from the FDA advising: the efficacy of suvorexant has been established at doses of 10mg to 40mg in elderly and non-elderly adult patients but the safety data do not support the approval of the 30mg and40 mg does; 10mg should be the starting dose for most patients, and must be available before suvorexant can be approved; 15mg and 20mg doses would be appropriate in patients in whom the 10mg dose is well-tolerated but not effective; for patients taking concomitant moderate CYP3A4 inhibitors, a 5mg dose would be necessary. Merck has determined that additional clinical studies of suvorexant 10mg will not be necessary. However, manufacturing studies will be required to advance the 10mg dosage form. Merck will discuss with the FDA whether additional studies will be required to support the 5mg dose [14]
02/07/2013 08:43:26 
May 13:US FDA advisory committee has found clear evidence that suvorexant is quite effective in promoting sleep, but multiple safety issues call for lower doses. The FDA´s peripheral and central nervous system advisory committee reportedly agreed that the drug was generally safe and effective for treating sleep maintenance and latency. The panel voted 13-3, recommending lower starting doses of 15 mg for elderly and 20 mg for non-elderly. The panel delivered a split recommendation, seven for and eight against, on the safety of the higher doses of the product. [13] 
24/05/2013 12:02:38 
May 13: FDA is concerned that suvorexant may only be safe at doses lower than proposed: doses as much as 40mg are effective in helping the sleep deprived but may not be safe. Lower doses may work just as well with better safety, but more information may be needed. Currently the lowest strength proposed for marketing is 15mg; if a lower dose was unavailable, the FDA would need to consider if the drug could be marketed safely at all, because they believe that a substantial proportion of the indicated population needs a lower dose. [12]
21/05/2013 08:11:27 
Nov 12: Filed and accepted for standard review by the FDA [11].
09/11/2012 08:52:05 
Feb 12: Merck report that the two pivotal PIII efficacy trials for suvorexant have been completed and, based on the positive results, they plan to file in the US in 2012 [6].
07/02/2012 21:55:14 
Nov 11: US filing planned for 2012-13 [5].
14/11/2011 13:56:55 
EU filing planned for 2012 [4].
21/05/2010 17:45:13 
Feb 10: Listed as PIII in Merck´s pipeline [1].
03/03/2010 08:09:29 
Trial or other data
Mar 14: PIII study (NCT01021813) published in The Lancet Neurology. 322 (62%) of 522 patients randomly assigned to receive suvorexant and 162 (63%) of 259 assigned to receive placebo completed the 1-year phase. Over 1 year, 362 (69%) of 521 patients treated with suvorexant experienced any adverse events compared with 164 (64%) of 258 treated with placebo. Serious adverse events were recorded in 27 patients (5%) who received suvorexant and 17 (7%) who received placebo. The most common adverse event, somnolence, was reported for 69 patients (13%) who received suvorexant and seven (3%) who received placebo. At month 1, suvorexant (517 patients in the efficacy population) showed greater efficacy than placebo (254 in the efficacy population) in improving sTST (38·7 min vs 16·0 min; difference 22·7, 95% CI 16·4 to 29·0; p<0·0001) and sTSO (—18·0 min vs −8·4 min, difference −9·5, −14·6 to −4·5; p=0·0002) [15].
28/03/2014 10:54:56
Nov 12: Study published early online in Neurology (November 28, 2012, doi: 10.1212/WNL.0b013e31827688ee). In the randomized, double-blind, 2-period (4 weeks per period) crossover polysomnography study, 254 patients received suvorexant (10mg, 20 mg, 40mg or 80mg) in one period and placebo (n = 249) in the other. Polysomnography was performed on night 1 and at the end of week 4 of each period. Suvorexant showed significant (p <0.01) dose-related improvements vs placebo on the co-primary end points of sleep efficiency at night 1 and end of week 4. Dose-related effects were also observed for sleep induction (latency to persistent sleep) and maintenance (wake after sleep onset). Suvorexant was generally well tolerated.
30/11/2012 08:33:55
Sept 12: New results from the two-month discontinuation phase of the 12-month PIII RCT showed that, after daily use of a consistent dose of suvorexant for one year, patients who stopped taking the medicine experienced a return of their sleeping difficulties to levels similar to those reported by patients who received placebo over the course of the trial. Patients who continued to receive suvorexant for the additional two months experienced mean improvements in their ability to fall asleep and stay asleep that were consistent with those seen over the first 12 months compared to placebo. Adverse experiences reported in the two-month discontinuation phase were generally consistent with those reported during the 12-month study. [10] 
10/09/2012 17:06:15
Jun 12: Results from two (n=1,021 and 1,009) pivotal PIII RCTs reported. Patients with primary insomnia were randomized to high dose suvorexant (40mg for 18-64 year olds or 30mg for ≥65 year olds), low dose suvorexant (20mg or 15mg based on age), or to placebo, for 3 months. In both trials, patients on suvorexant fell asleep faster and stayed asleep longer vs placebo at months 1 and 3 (p<0.003) (patient-reported primary outcomes). Specifically, in trial 1 at 3 months, suvorexant reduced the time to fall asleep by 25.7 minutes (vs. 17.3 minutes with placebo) and sleep lasted 60.3 minutes longer (vs. 40.6 minutes) compared to baseline. On objective primary outcomes (polysomnographic, sleep lab-based), in both trials suvorexant reduced the time it took patients to fall into continuous sleep at month 1 and decreased the time patients spent awake during the night at 1 and 3 months. In trial 1, patients on suvorexant entered into continuous sleep 36 minutes faster (vs. 26.6 minutes with placebo) and spent less time awake during the night by 47.9 minutes (vs. 25.0 minutes) compared to baseline. The most common AEs with high dose of suvorexant vs placebo were sleepiness (10.7% vs. 3.4% in Trial 1) and headache (6.8 vs. 6%). In the overall study population, there were no statistically significant next day objective residual effects vs placebo as measured by the Digit Symbol Substitution Test [9].
13/06/2012 21:35:23
July 11: Long-term PIII trial (NCT01021813) completed. The randomised, double-blind, placebo-controlled trial investigated the efficacy, safety and tolerability of suvorexant administered for up to 14 months in patients with primary insomnia. The trial enrolled 782 patients in the US. [8]
20/04/2012 15:26:03
June 10: PIIb trial results. 254 patients were randomised to MK 4305 at 10 mg (n=62), 20 mg (n=61), 40 mg (n=59) or 80 mg (n=61) and 249 randomised to placebo. MK4305 was significantly more effective than placebo in improving overall sleep efficiency at night one and at end of wk 4. All doses of MK 4305 improved objectively measured sleep maintenance, as evidenced by significant reductions in the secondary endpoint of baseline-adjusted wake-after-sleep-onset vs. placebo both at night one and at the end of week four. MK 4305 significantly improved objectively-measured sleep onset (80mg dose). Data was presented at the SLEEP 2010 24th Annual Meeting of the Associated Professional Sleep Societies. (4)
11/06/2010 08:52:28
Apr 10: A PIII, multicentre, randomized, double-blind, placebo-controlled, parallel group study (NCT01097629, Study B) is due to start May 10 and is expected to complete Jun 12. The study will investigate the efficacy and safety of MK4305 in high (40mg if <65 years old and 30mg if >65) and low dose (20 and 15mg, respectively) in 945 patients with primary insomnia. The primary co-endpoints are subjective total sleep time and time to sleep onset, wake time after persistent sleep onset, and latency to onset of persistent sleep at 1 and 3 months [3].
06/04/2010 09:08:33
Apr 10: A PIII, multicentre, randomized, double-blind, placebo-controlled, parallel group study (NCT01097616, Study A) is due to start May 10 and expected to complete Sep 12. The study will investigate the efficacy and safety of MK4305 in high (40mg if <65 years old and 30mg if >65) and low dose (20 and 15mg, respectively) in 960 patients with primary insomnia. The primary co-endpoints are subjective total sleep time and time to sleep onset, wake time after persistent sleep onset, and latency to onset of persistent sleep at 1 and 3 months. Patients who complete the initial 3-month treatment period may participate in an optional 3-month extension period [3].
06/04/2010 09:08:19
NCT01021813: This 12 month US PIII randomised, double-blind, placebo-controlled trial started in Dec 09. The study will investigate the efficacy, safety and tolerability of MK in patients with primary insomnia. An estimated 750 patients will be enrolled. Primary outcome measures are: the proportion of patients who experience (1) narcolepsy-like events, including cataplexy (2) complex sleep-related behaviour, (3) falls, and (4) suicidal ideation and/or behaviours. The trial is scheduled for completion Nov 11 [2]
03/03/2010 08:18:39
Evidence Based Evaluations
FDA doc 
References  
Available only to registered users