Zopiclone

Zopiclone is a short-acting non-benzodiazepine hypnotic (Z-drug) used for short-term insomnia. It is the racemic mixture of which eszopiclone is the active S-enantiomer. A bitter or metallic taste is typical, and it carries the same risks as other hypnotics: next-day impairment, complex sleep behaviours and dependence. It is not marketed in the United States.

Classification. Non-benzodiazepine hypnotic, cyclopyrrolone.

Mechanism. Positive allosteric modulation of GABA-A receptors, with less subtype selectivity than zolpidem.

Pharmacokinetics. Rapid absorption, peak in about 1.5 to 2 hours. Metabolised by CYP3A4 and CYP2C8 to an inactive N-oxide and an active N-desmethyl metabolite. Half-life about 5 hours (7 to 9 hours in older adults).

All regimens are oral with no loading dose.

Insomnia, adults (short term).

• 7.5 mg at night.
• Maximum 7.5 mg daily. Use the lowest effective dose.
• Duration: no longer than 2 to 4 weeks, including the taper.

Older adults. Start 3.75 mg; may increase to 7.5 mg with caution.

Dose limits. Liver impairment and chronic respiratory insufficiency: start 3.75 mg. Kidney impairment: start 3.75 mg. Strong CYP3A4 inhibitors (erythromycin, ketoconazole, ritonavir): start 3.75 mg. Rifampicin and other strong inducers: higher doses may be needed.

Contraindications. Severe sleep apnoea, myasthenia gravis, severe respiratory insufficiency, severe liver impairment, previous complex sleep behaviour with a hypnotic, hypersensitivity. Major warning of complex sleep behaviours in some regions.

Serious adverse effects. Complex sleep behaviours, next-day impairment of driving and alertness, anterograde amnesia, hallucinations, depression and suicidality, respiratory depression (with other sedatives), dependence and withdrawal, falls and fractures.

Common adverse effects. Metallic taste, dry mouth, drowsiness, dizziness, headache, nausea.

Interactions. Alcohol, opioids and other sedatives add respiratory depression and sedation. Rifampicin, carbamazepine and phenytoin lower levels; erythromycin, ketoconazole, ritonavir and clarithromycin raise them.

Common prescribing errors. Prescribing 7.5 mg to older adults; long-term use; combining with alcohol; prescribing to patients who need to be alert within 8 hours.

Special groups.

• Pregnancy: avoid; neonatal sedation and withdrawal with late exposure.
• Breastfeeding: excreted in milk; avoid or use with infant monitoring.
• Children: not advised.
• Older adults: start 3.75 mg; high risk of falls and confusion.
• Kidney impairment: start 3.75 mg.
• Liver impairment: start 3.75 mg; avoid in severe disease.

Formulations. Tablets 3.75 mg and 7.5 mg. Swallow immediately before getting into bed, with at least 7 to 8 hours of sleep time available.

Baseline. Sleep history and sleep hygiene, alcohol and sedative use, respiratory status, depression and suicide risk, driving requirements, medicines list.

Monitoring. Review at 1 to 2 weeks and at the end of the planned course. Ask about complex sleep behaviours, next-day impairment and escalating use.

Stopping. After more than 2 weeks of nightly use, reduce the dose by 5 to 10% every 1 to 2 weeks or reduce frequency; abrupt stopping can cause rebound insomnia and withdrawal.

Referral and escalation. Stop the drug at once for complex sleep behaviours. Refer to addiction or psychiatric services for dependence.