Zaleplon

Abstract

Zaleplon is a pyrazolopyrimidine hypnotic agent which is indicated for the short term (2 to 4 weeks) management of insomnia. Zaleplon 5 and 10mg at bedtime (usual recommended doses) significantly reduced sleep latency compared with placebo in clinical trials in nonelderly and elderly patients with insomnia. In general, sleep maintenance (sleep duration and number of awakenings) and sleep quality were not significantly different from placebo with zaleplon 5 and 10 mg/night. Zaleplon 20 mg/night significantly improved sleep latency and duration in nonelderly patients, but effects on number of awakenings were inconsistent and sleep quality generally did not improve. The relative hypnotic efficacy of zaleplon compared with that of triazolam and zolpidem is not yet clearly established. Tolerance to the hypnotic effects of zaleplon generally did not occur during 5 weeks’ treatment, or during long term treatment (6 or 12 months) according to a small number of studies presented as abstracts. Zaleplon was well tolerated in clinical trials. The most common event was headache but the incidence was similar to that observed with placebo. Zaleplon 5 and 10mg did not impair psychomotor function or memory even immediately after the dose in studies in volunteers or patients with insomnia. Zaleplon 20mg, however, impaired psychomotor function and memory immediately after the dose but next-day effects were not observed. The psychomotor profile of zaleplon appears to be better than that of comparator agents. Rebound insomnia was not observed after sudden discontinuation of up to 12 months’ treatment with zaleplon 5 and 10 mg/night and up to 4 weeks’ treatment with zaleplon 20 mg/night. In addition, the potential for withdrawal syndrome with zaleplon appears to be low according to limited data. In conclusion, zaleplon 5, 10 and 20mg administered at bedtime, or later if patients have difficulty sleeping, is an effective and well tolerated hypnotic agent. There was no evidence of next-day residual effects with the 5 and 10mg dosages, and the incidence of withdrawal effects with zaleplon 5, 10 and 20mg did not differ significantly to that observed with placebo. In addition, tolerance to the effects of zaleplon is unlikely to develop when administered for the recommended treatment period. The comparative efficacy and tolerability of zaleplon with other short acting nonbenzodiazepine hypnotics is difficult to establish. However, on the basis of current efficacy evidence and the lower incidence of residual effects with zaleplon 5 and 10mg relative to comparator agents, this drug represents a useful option in the management of patients with insomnia who have difficulties initiating sleep. Zaleplon is a selective agonist at the benzodiazepine ω₁ (type 1) receptor subtype. Sleep efficiency significantly improved with zaleplon 5 and 10mg compared with placebo during the first 4 hours, but not over an entire 8-hour period after administration, in a study in healthy volunteers using a phase-advanced sleep model of transient insomnia. In healthy volunteers, no significant residual sedation was observed with zaleplon 5,10 and 20mg compared with placebo during the 4 hours after the dose. In volunteers and patients with insomnia, dosages of ≤10 mg/night had no adverse effects on sleep architecture. Next-day sedation does not occur with zaleplon 5 to 20mg as observed in studies in healthy volunteers and patients with insomnia. In addition, zaleplon 5 and 10mg did not significantly impair psychomotor function or memory as shown predominantly in healthy volunteers but also in patients with insomnia. The 20mg dosage, however, impairs psychomotor function and some parameters of memory immediately after administration but generally no next-day effects were observed. The psychomotor profile of zaleplon 10mg appears to be better than that of zolpidem 10mg, zopiclone 7.5mg and flurazepam 30mg while that of zaleplon 5mg appears to be better than that of zopiclone 7.5mg. The cognitive profile of zaleplon 10mg appears to be significantly better than that of zolpidem 10mg. Although higher than the recommended dose, the psychomotor profile of zaleplon 20mg seems to be better than that of zolpidem 20mg, lorazepam 2mg and flurazepam 30mg and the cognitive profile better than that of zolpidem 20mg and lorazepam 2mg. Zaleplon (1 to 60mg) did not appear to have any abuse potential in patients with no history of drug abuse. However, the abuse potential of zaleplon (at 2.5 to 7.5 times the therapeutic dose) was similar to that of triazolam (1 to 3 times the therapeutic dose) in volunteers with a history of drug abuse. Zaleplon does not appear to affect mood in healthy volunteers. Respiratory parameters are not adversely affected by zaleplon 10mg according to a single dose study in patients with insomnia and chronic obstructive pulmonary disease. The pharmacokinetic parameters of oral single dose zaleplon (5 to 20mg) were assessed in healthy volunteers. The maximum plasma concentration (C_max) and area under the plasma concentration-time curve (AUC) increased proportionally with increasing dose. The time to Cmaxis about 1 hour after zaleplon 5, 10 and 20mg, the volume of distribution of zaleplon 10 and 20mg is 276L and the bioavailability of zaleplon 5mg is 30.6%. The rate, but not the extent, of absorption is increased if zaleplon is administered with or immediately after a high-fat meal. Concentrations of zaleplon in the breast milk of lactating mothers were lower than those in plasma, and maximum exposure of the infant to zaleplon 10mg during a single feed was estimated to be minimal in this study. However, the manufacturer does not recommend the use of zaleplon during breastfeeding. Zaleplon undergoes first pass metabolism. It is metabolised to inactive metabolites, primarily by oxidative metabolism, and then predominantly renally eliminated. Clearance parameters are independent of dose;...