Merck & Co., Inc.: Suvorexant

We have concluded that you have submitted substantial evidence of effectiveness for suvorexant for the treatment of insomnia characterized by difficulty with sleep onset and/or sleep maintenance, at doses of 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, and 80 mg.

We conclude that you have not demonstrated that suvorexant is safe for use, even at the revised lower doses you proposed on May 14, 2013: 15 mg for elderly patients and 20 mg for nonelderly adult patients.

Specifically, for reasons described below, we conclude that suvorexant has not been demonstrated to be adequately safe even if the starting dose is 15 mg for both nonelderly and elderly adult patients.

We find that suvorexant is associated with a dose-related risk of the following potentially serious and life-threatening adverse effects:

Two patients on suvorexant vs. none on placebo experienced unconscious, out-of-bed nighttime activity, including a 65 year-old man on the 30 mg dose who lunged out of bed and hit his face against a wall.

Whereas falls or injuries from these events were not reported in suvorexant studies, we remain concerned that risk of falls from these events has not been adequately investigated to permit approval of the 30 and 40 mg doses.

We are also concerned that hallucinations and sleep paralysis, which were reported more frequently in patients taking suvorexant than placebo, can cause clinically meaningful psychological harm in patients with insomnia.

We believe that labeling can be written to allow safe use of the 15 mg and 20 mg doses in patients in whom the 10 mg dose is well tolerated but not effective.