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
eva luation of QTc Interval
The effects of suvorexant on the QTc interval were eva luated 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 app |
