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Zolpidem

An Update of its Pharmacology, Therapeutic Efficacy and Tolerability in the Treatment of Insomnia

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Summary

Abstract

Zolpidem is an imidazopyridine agent that is indicated for the short term (≤4 weeks) treatment of insomnia (recommended dosage 10 mg/day in adults and 5 or 10 mg/day in the elderly or patients with hepatic impairment).

Data have shown that the hypnotic efficacy of zolpidem is generally comparable to that of the benzodiazepines flunitrazepam, flurazepam, nitrazepam, temazepam and triazolam as well as nonbenzodiazepine hypnotic agents such as zopiclone and trazodone in the treatment of elderly and adult patients with insomnia. The comparative efficacy of a recently available nonbenzodiazepine hypnotic zaleplon and zolpidem has yet to be established. There was no evidence of tolerance developing to the hypnotic effects of zolpidem in a number of studies of up to 6 months’ duration. However, tolerance has been described in a few patients taking the drug at high dosages for periods of up to several years.

Zolpidem is well tolerated in patients with insomnia and the most common adverse events are generally nausea, dizziness and drowsiness. Although zolpidem produced some psychomotor and memory impairment over the first few hours after administration, it had few next-day effects (including effects on daytime well-being and morning coordination). In this respect, it was comparable or superior to flunitrazepam and flurazepam and comparable to other benzodiazepines in patients with insomnia. Zolpidem appears to have a low potential for abuse.

Conclusions: Zolpidem is effective and well tolerated in patients with insomnia, including the elderly. Studies have shown that zolpidem generally has similar efficacy to other hypnotics including benzodiazepines and zopiclone. Zolpidem appears to have minimal next-day effects on cognition and psychomotor performance when administered at bedtime. In addition, there is little evidence of tolerance to the hypnotic effects of zolpidem, or rebound insomnia or withdrawal symptoms after discontinuation of the drug when it is given as recommended (10 mg/day for >1 month) or over longer periods.

Pharmacodynamic Profile

Zolpidem is an imidazopyridine agent that is an agonist at the benzodiazepine receptor component of the γ-aminobutyric acid (GABA)A-receptor complex. Zolpidem has shown weaker anxiolytic, anticonvulsant and myorelaxant effects than benzodiazepines in animal models, and the sedative effects of zolpidem predominate.

The hypnotic effects of zolpidem, in addition to the lack of effects of the drug on sleep architecture, have been demonstrated in a large number of studies in healthy volunteers and patients with insomnia.

In patients with chronic insomnia, zolpidem 10 mg/day had psychomotor effects comparable to or less than those of flunitrazepam or flurazepam the morning after drug administration. Some psychomotor and memory impairment was observed with zolpidem in healthy volunteers during the first few hours after administration, but these effects were generally not observed from 6 hours after administration (a more relevant assessment time for ‘before bed’ use). The psychomotor and cognitive profile of zolpidem was comparable to that of temazepam and comparable to or better than that of other benzodiazepines including flunitrazepam and triazolam and the nonbenzodiazepine hypnotic zopiclone in healthy volunteers. Zolpidem produced greater psychomotor and memory impairment than another nonbenzodiazepine hypnotic, zaleplon, generally for a period of up to 5 hours after drug administration in volunteers; however, comparative data are not yet available in patients with insomnia.

Zolpidem has no significant effects on respiration in most patients other than negative effects in those with sleep apnoea.

Overview of Pharmacokinetic Properties

Zolpidem is rapidly absorbed: a mean maximum plasma concentration of 121 μg/L is reached 1.6 hours after a 10mg dose. The drug does not accumulate after multiple doses. Zolpidem is extensively metabolised by a range of cytochrome P450 isoenzymes, predominantly CYP3A4 (≈60%), to 3 inactive metabolites. Zolpidem has a short elimination half-life (t1/2) in healthy volunteers (2.5 hours after a 10mg dose).

Mean maximum plasma concentrations of zolpidem are increased and elimination is reduced in the elderly and in patients with hepatic impairment or chronic renal insufficiency altering dosage recommendations in the 2 former groups of patients (Dosage and Administration section).

Therapeutic Efficacy

The hypnotic efficacy of zolpidem is generally equivalent to that of the benzodiazepines flunitrazepam, flurazepam, nitrazepam and triazolam. In addition, zolpidem demonstrated better effects on sleep parameters than temazepam and similar efficacy to doxylamine, trazodone and zopiclone in single trials. The efficacy of a recently available nonbenzodiazepine hypnotic zaleplon relative to that of zolpidem has yet to be established: 2 large studies have been conducted but they predominantly compared results for active treatments against placebo and not each other.

Studies in elderly patients with insomnia suggested that zolpidem has equivalent efficacy to flunitrazepam, temazepam and triazolam in this group.

There was no evidence of tolerance developing to the hypnotic effects of zolpidem in a number of clinical studies of 3 to 6 months’ duration that generally considered patients’ self assessments. However, case reports have described tolerance to the hypnotic effects of zolpidem in patients, usually with psychiatric disorders, taking the drug at high dosages for periods of up to several years.

Discontinuous or ‘as needed’ use of zolpidem 10 mg/day over 2 to 8 weeks was found to be effective for the treatment of chronic insomnia based on subjective ratings in 3 randomised, double-blind, parallel studies, 1 of which has been published in full.

Tolerability

Zolpidem is well tolerated in patients with insomnia, including the elderly. The most common adverse events generally include nausea, dizziness and drowsiness.

In patients with insomnia, the next-day effects and adverse events profile of zolpidem were generally comparable to those of benzodiazepine and non-benzodiazepine hypnotics. Findings were similar in elderly patients.

There was no evidence of rebound insomnia after sudden withdrawal of zolpidem 10 mg/day after up to 6 months’ treatment in all but a few clinical trials. In addition, zolpidem appears to have a low potential for abuse.

Drowsiness or somnolence was the most common symptom of zolpidem overdose. Fatalities have been reported in patients taking an overdose of zolpidem: where full details are available there was usually a concomitant overdose of other drugs.

Drug Interactions

No pharmacokinetic interactions have been observed between zolpidem and cimetidine, ranitidine, haloperidol or imipramine. However, cimetidine, chlorpromazine and imipramine increased the sedative effects of zolpidem. Rifampicin reduced the plasma concentration and pharmacodynamic effects of zolpidem. Ketoconazole and itraconazole increased the area under the plasma concentration-time curve of zolpidem. Ketoconazole also increased the t1/2 of zolpidem and enhanced zolpidem-related impairment of psychomotor function, whereas itraconazole had no such effect. Fluconazole did not affect the pharmacokinetics of zolpidem.

No clinically significant drug interactions were observed between zolpidem and the SSRIs fluoxetine and sertraline in studies in healthy volunteers.

Dosage and Administration

It is recommended that zolpidem is given orally immediately before bedtime for the treatment of insomnia. The maximum recommended dosage of zolpidem is currently 10 mg/day in adults. Each course of zolpidem should not exceed 4 weeks.

In patients with hepatic impairment and the elderly, zolpidem should be initiated at a dosage of 5 mg/day and these patients should be closely monitored. The maximum recommended dosage of zolpidem in the elderly is 10 mg/day (5 mg/day in the UK). No dosage reduction is required in patients with renal impairment, although this group should also be closely monitored. It may be necessary for lower than recommended dosages of zolpidem to be given when the drug is coadministered with drugs having depressant effects on the CNS, because of potential additive effects. Zolpidem is contraindicated in patients with severe hepatic impairment, obstructive sleep apnoea, acute pulmonary impairment or respiratory depression. The use of zolpidem during pregnancy and in women who are breast feeding is not recommended.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 10, New Zealand

    Kristin J. Holm & Karen L. Goa

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Correspondence to Kristin J. Holm.

Additional information

Various sections of the manuscript reviewed by: R. Cluydts, Department of Psychology, Free University of Brussels, Brussels, Belgium; G. Hajak, Department of Psychiatry, Sleep Disorder Center, University of Gottingen, Gottingen, Germany; M.H. Lader, Institute of Psychiatry, Department of Psychiatry, London, England; J.M. Monti, Department of Pharmacology, Clinics Hospital, Montevideo, Uruguay; R.G. Priest, Iver, Bucks, England; T. Roth, Sleep Disorders Center, Henry Ford Hospital, Detroit, Michigan, USA; M.G. Terzano, Istituto di Neurologia, University of Parma, Parma, Italy; M. Wagner, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.

Data Selection

Sources: Medical literature published in any language since 1966 on zolpidem, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand) and Medline. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: AdisBase search terms were ‘zolpidem’ or ‘SL-80-0750-23N’. Medline search terms were ‘zolpidem’. Searches were last updated 21 February 2000.

Selection: Studies in patients with insomnia who received zolpidem. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: zolpidem, insomnia, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.

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Holm, K.J., Goa, K.L. Zolpidem. Drugs 59, 865–889 (2000). https://doi.org/10.2165/00003495-200059040-00014

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