Insomnia is a highly prevalent and potentially debilitating condition characterised by difficulty falling or staying asleep. It can occur as a result of another medical or psychiatric condition or environmental factor (secondary insomnia), or it can occur in the absence of an obvious cause (primary insomnia).

The Therapeutic Goods Administration (TGA) has recently approved a new medication, suvorexant. This agent belongs to a new class of drugs called dual orexin receptor antagonists (DORA). DORAs target orexin receptors OX1R and OX2R which are a group of hypothalamic neuropeptides that promote wakefulness via their actions on serotonin, histamine, acetylcholine, and dopamine. Suvorexant is indicated for treatment of insomnia characterised by difficulties with sleep onset and/or sleep maintenance, and has demonstrated its efficacy in improving sleep latency and total sleep time compared with placebo. Although there is a lack of long-term data, with its novel mechanism of action, suvorexant may prove to be a ground-breaking alternative for patients who cannot tolerate or do not gain relief from traditional sleep agents.

Suvorexant has been studied for insomnia in three phase III clinical trials which involved a total of 1784 patients. All three clinical trials compared suvorexant with placebo. Across the three phase III suvorexant studies in patients with insomnia, suvorexant demonstrated efficacy compared with placebo and was generally well tolerated.

Dose
Suvorexant was studied in humans at doses of 10–80mg. In Australia, the recommended dose is 20mg for non-elderly adults (65 years of age). This dose should not be exceeded as higher doses (30mg and 40mg) were found to have similar efficacy to lower doses (15mg and 20mg). However, significantly more adverse effects were reported at the higher doses. Also, as food ingestion can delay the action of suvorexant, it should not be administered with or soon after a meal if faster sleep onset is preferred.

Clinical trials on renally and hepatically impaired patients in comparison to healthy subjects have demonstrated that suvorexant does not require any renal- or hepatic-specific dose adjustments.

An increase in the average plasma concentration of suvorexant was detected in female subjects. The same effect was seen in patients with obesity regardless of the gender. While no sex-specific or weight-based dosing is recommended, caution should be exercised when considering a dose increase in an obese female patient.

Side effects
Somnolence (7% versus 3% for placebo) was the most commonly reported adverse reaction. Other commonly reported adverse events (⩾2% incidence and greater than placebo) were diarrhoea, xerostomia, upper respiratory tract infections, headache, dizziness, abnormal dreams, cough, dyspepsia, and peripheral oedema. Other dose-related adverse reactions included daytime impairment, additive central nervous system (CNS) depression when co-administered with other CNS depressants, abnormal thinking and behavioural changes, worsening depression or increases in suicidal ideation, and sleep paralysis.

Contraindications
With the exception of known hypersensitivity, the sole contraindication for the use of suvorexant is patients with narcolepsy. Up to 90% of patients with narcolepsy with cataplexy are orexin ligand deficient. Therefore, using a DORA to further antagonise their orexin receptors could exacerbate their condition.

Drug-drug interactions
Metabolism of suvorexant occurs predominantly through cytochrome P450 (CYP) 3A4, with a minor contribution from CYP219. Concomitant administration with moderate to strong CYP3A inhibitors is therefore not recommended as it prolongs suvorexant exposure. Suvorexant also inhibits intestinal P-glycoprotein. This may result in a slight increase in digoxin concentrations. Taking into consideration the narrow therapeutic index of digoxin, monitoring of digoxin concentrations is recommended when co-administered with suvorexant.

Conclusion
Suvorexant provides an alternative for patients with insomnia who do not tolerate or do not benefit from traditional sleep medications such as benzodiazepines. However, there may be safety and efficacy issues not yet identified through clinical trials of suvorexant that may be revealed with more wide-spread use.

References:

  1. Belsomra® (suvorexant) Australian approved product information. Macquarie Park: Merck Sharp & Dohme. Approved December 2016.
  2. Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, et al. Suvorexant in patients with insomnia: results from two 3-month randomized controlled clinical trials. Biol Psychiatry. 2016; 79(2): 136-48.
  3. Rhyne DN, Anderson SL. Suvorexant in insomnia: efficacy, safety and place in therapy. Ther Adv Drug Saf. 2015; 6(5): 189–95.

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