Eszopiclone

Eszopiclone is the S-enantiomer of zopiclone, a non-benzodiazepine hypnotic (Z-drug) used for sleep onset and sleep maintenance insomnia. It is licensed mainly in the United States and is not available in many regions. It has a longer duration than zolpidem and carries a major warning for complex sleep behaviours.

Classification. Non-benzodiazepine hypnotic, cyclopyrrolone.

Mechanism. Positive allosteric modulation of GABA-A receptors, with activity at alpha-1, alpha-2, alpha-3 and alpha-5 subunits.

Pharmacokinetics. Rapid absorption, peak in about 1 hour; a high-fat meal delays peak. Metabolised by CYP3A4 and CYP2E1 to an inactive N-oxide and an active N-desmethyl metabolite. Half-life about 6 hours (about 9 hours in older adults).

All regimens are oral with no loading dose.

Insomnia, adults.

• Start 1 mg immediately before bed.
• Titration: may increase to 2 mg or 3 mg if needed.
• Maximum 3 mg daily. Use the lowest effective dose.
• Duration: short term, no longer than 2 to 4 weeks; reassess after 7 to 10 days.

Older adults and debilitated patients. Start 1 mg; maximum 2 mg.

Dose limits. Severe liver impairment: maximum 2 mg (start 1 mg). Strong CYP3A4 inhibitors (ketoconazole, ritonavir, clarithromycin): maximum 2 mg (start 1 mg). Kidney impairment: no adjustment.

Contraindications. Previous complex sleep behaviour with a hypnotic, hypersensitivity, severe sleep apnoea, myasthenia gravis, severe respiratory insufficiency. Major warning of complex sleep behaviours (sleep-walking, sleep-driving, eating), sometimes fatal.

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

Common adverse effects. Unpleasant or metallic taste, headache, drowsiness, dizziness, dry mouth, nausea.

Interactions. Alcohol, opioids and other sedatives add respiratory depression and sedation. Rifampicin lowers levels sharply; ketoconazole, ritonavir and clarithromycin raise them. Olanzapine can impair psychomotor performance.

Common prescribing errors. Dosing with or soon after a high-fat meal; prescribing 3 mg to older adults; long-term use; combining with alcohol.

Special groups.

• Pregnancy: avoid; neonatal sedation and withdrawal with late exposure.
• Breastfeeding: excreted in milk; avoid or monitor the infant.
• Children: not advised.
• Older adults: start 1 mg; maximum 2 mg.
• Kidney impairment: no adjustment.
• Liver impairment: maximum 2 mg in severe impairment.

Formulations. Tablets 1 mg, 2 mg and 3 mg. Swallow immediately before getting into bed, with at least 8 hours of sleep time available, and not with or soon after a high-fat meal.

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

Monitoring. Review within 7 to 10 days 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.

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