Zolpidem Sublingual Formulations

Abstract

The present chapter discusses the pharmacology, efficacy, and safety of two recently developed sublingual formulation of zolpidem that specifically target sleep-onset insomnia (Edluar, a standard dose of zolpidem, SL-SD) and middle-of-the-night (MOTN) insomnia (Intermezzo, a low dose of zolpidem, SL-LD). These two SL formulations are bioequivalent to the standard immediate oral release (IOR) form of zolpidem and have a comparable elimination half-life but a somewhat shorter Tmax than the standard oral form. Due to a gender effect on zolpidem metabolism, half-doses are recommended in women (i.e., 5 mg for SL-SD and 1.75 mg for SL-LD). Efficacy has been shown for SL-SD in three double-dummy crossover polysomnographic studies that could demonstrate the superiority of the acute administration of 10 mg SL-SD zolpidem over the same dose of IOR zolpidem in healthy subjects using models of transient insomnia and in patients with DSM-IV primary insomnia. Both 1.75 and 3.5 mg of SL-LD zolpidem have been found effective in 2 large placebo-controlled studies performed in DSM-IV primary insomniacs having middle-of-the-night insomnia. Most common adverse events were somnolence, fatigue, headache, and dysgeusia for SL-SD zolpidem and headache, nausea, and fatigue for SL-LD zolpidem. More generally types of adverse events for SL zolpidem were consistent with the adverse event profile of IOR zolpidem. Because of its middle-of-the-night way of administration, concern regarding the next-morning safety of the SL-LD was addressed in a highway driving performance study. Results indicate that SL-LD zolpidem 3.5 mg taken 3 h before driving may impair driving performance, but that there is a minimal risk of impairing driving performance if the drug is taken ≥ 4 h before driving. SL-SD zolpidem has been approved for the short-term treatment of sleep-onset insomnia at a dose of 10 mg in non-elderly man and at the dose of 5 mg in women or in special population including elderly patients. SL-LD zolpidem has been approved for the treatment of insomnia when MOTN awakening is followed by difficulty in returning to sleep. Recommended dosages are 3.75 mg for non-elderly man and 1.75 mg in women and in special population including elderly. It has to be stressed that, due to safety issue related to next-morning residual effects, the dose should be taken following MOTN awakenings only if the patient has at least 4 h of sleep remaining.