BELSOMRA (Page 4 of 7)

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, impaired 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 a drug, even once, for its desirable psychological or physiological 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, giving a higher priority to drug use than to other activities and obligations), and possible 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, manifested by withdrawal signs and 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, an orexin receptor antagonist.

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 C23 H23 ClN6 O2 and the molecular weight is 450.92. Its structural formula is:

Chemical Structure
(click image for full-size original)

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: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polyvinylpyrrolidone/vinyl acetate copolymer (copovidone).

In addition, the film coating contains the following inactive ingredients: hypromellose, lactose monohydrate, titanium dioxide, and triacetin. The film coating for the 5 mg tablets also contains iron oxide black and iron oxide yellow, and the film coating for the 10 mg tablets also contains FD&C Blue #1/Brilliant Blue FCF Aluminum Lake and iron oxide yellow.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The mechanism of action of suvorexant in the treatment of insomnia is presumed to be through antagonism of orexin receptors. The orexin neuropeptide signaling system plays a role in wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R is thought to suppress wake drive.

12.2 Pharmacodynamics

Suvorexant binds to orexin receptors, OX1R and OX2R (Ki= 0.55 and 0.35 nM, respectively).

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.

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%.

Effect of Food

Ingestion of BELSOMRA with a high-fat meal resulted in no meaningful change in AUC or Cmax but a delay in Tmax of approximately 1.5 hours [see Dosage and Administration (2.1)].

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.

Elimination

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.

Excretion

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).

Specific 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 Interaction Studies

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

Figure 1
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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)].

# 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.
Figure 2: Effects of Suvorexant * on the Pharmacokinetics of Co-Administered Drugs

Figure 2
(click image for full-size original)

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