Esmirtazapine maleate

Esmirtazapine (1.5-4.5 mg) has demonstrated short-term sleep-promoting effects in nonelderly outpatients with chronic insomnia. This phase 3, randomized, double-blind study (NCT00631657) and its open-label extension (NCT00750919) investigated efficacy and safety of long-term esmirtazapine treatment in adult outpatients with chronic insomnia.

Participants were randomized to receive esmirtazapine 4.5 mg or placebo for 6 months; those receiving esmirtazapine were then rerandomized to esmirtazapine or placebo for an additional 7 days. Participants could enter the 6-month open-label extension with esmirtazapine 4.5 mg. The primary objective of the double-blind study was to assess long-term efficacy of esmirtazapine vs placebo on self-reported total sleep time. Assessing long-term safety and tolerability were secondary and primary objectives of the double-blind and extension studies, respectively.

Overall, 457 participants received treatment in the double-blind study (esmirtazapine, n = 342; placebo, n = 115) and 184 participants (prior esmirtazapine, n = 136; prior placebo, n = 48) received esmirtazapine in the extension. In the double-blind study, a 48.7-minute increase in average nightly total sleep time was observed for esmirtazapine vs placebo (95% confidence interval, 35.0-62.5; P < .0001) at months 4-6. There was no evidence of residual effects on next-day alertness or daytime functioning and no evidence of rebound insomnia or withdrawal symptoms upon treatment discontinuation. Esmirtazapine was generally well tolerated; somnolence and weight gain were the most common adverse events.

Esmirtazapine improved sleep duration vs placebo over at least 6 months. There was no evidence of next-day residual effects or of withdrawal symptoms or rebound insomnia following abrupt treatment discontinuation.

Registry: ClinicalTrials.gov; Name: A 6-Month Efficacy and Safety Study of Org 50081 in Adult Patients With Chronic Primary Insomnia (21106/P05701/MK-8265-002); URL: https://clinicaltrials.gov/ct2/show/NCT00631657; Identifier: NCT00631657; and Registry: ClinicalTrials.gov; Name: Twenty-Six Week Extension Trial of Org 50081 (Esmirtazapine) in Outpatients With Chronic Primary Insomnia (176003/P05721/MK-8265-007); URL: https://clinicaltrials.gov/ct2/show/NCT00750919); Identifier: NCT00750919.

Two identical 12-week, randomized, double-blind, placebo-controlled, multi-arm, parallel-group Phase III studies (Study P012, NCT00560833; Study P013, NCT00535288) evaluated the efficacy and safety of esmirtazapine, an investigational medicine, for the treatment of moderate to severe vasomotor symptoms (VMS) in postmenopausal women.

Participants were randomized to placebo or esmirtazapine (2.25, 4.5, 9.0, or 18.0 mg). Co-primary efficacy endpoints (daily frequency and severity of moderate to severe VMS, both at weeks 4 and 12) were based on participative LogPad daily diaries. Adverse events (AEs) were recorded.

In Studies P012 and P013, 942 and 946 participants were randomized, respectively. Compared with placebo, esmirtazapine significantly reduced the mean daily frequency by 1.4-2.2 moderate to severe VMS at weeks 4 and 12 (both ≥4.5 mg) and mean daily severity by 0.06-0.08 symptoms at weeks 4 (≥4.5 mg) and 12 (9.0 mg P012; 18.0 mg P013 only). Esmirtazapine was generally well tolerated with a more favorable safety profile at lower doses. Somnolence and fatigue were the most frequently reported AEs.

Esmirtazapine reduced the frequency and severity of moderate to severe VMS associated with menopause and was generally well tolerated in the study population.