Zopiclone

Generic Name: Zopiclone

Brand Names (examples)

– Imovane (Canada, Europe)

– Zimovane (UK)

– Dopareel (India)

– Ximovan

– Hypnite

– Somnite

Class

Cyclopyrrolone derivative (non-benzodiazepine hypnotic agent)

Pharmacologically distinct from benzodiazepines but shares some of their receptor-binding properties

Mechanism of Action

Zopiclone acts as a GABA-A receptor agonist by selectively binding to the benzodiazepine receptor site located on the GABA-A complex, specifically targeting omega-1 (BZ1) and omega-2 (BZ2) receptor subtypes. This binding enhances the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), resulting in neuronal hyperpolarization and central nervous system (CNS) depression

It shortens sleep latency, reduces nocturnal awakenings, and increases total sleep time with minimal effect on sleep architecture at therapeutic doses

Indications / Uses

Short-term treatment of insomnia, including:

Difficulty falling asleep (sleep-onset insomnia)

Frequent nocturnal awakenings

Early morning awakenings

Poor sleep quality

Zopiclone is primarily indicated for short-term use (2 to 4 weeks) due to concerns about tolerance, dependence, and withdrawal

Dosage & Administration

Adults

Standard dose: 7.5 mg orally at bedtime

Elderly or hepatic impairment: 3.75 mg at bedtime, may be titrated based on response and tolerability

Renal Impairment

No dosage adjustment generally required but caution is advised

Pediatric Use

Not approved in children

Geriatric Use

Start at 3.75 mg due to increased sensitivity and risk of sedation-related falls

Note: Should be taken immediately before bedtime and not with or immediately after food (food delays absorption)

Pharmacokinetics

Absorption: Rapidly absorbed; peak plasma concentration in 1.5–2 hours

Bioavailability: ~80%

Half-life: ~5 hours (can be longer in elderly or those with hepatic impairment)

Protein binding: ~45%

Metabolism: Primarily hepatic via CYP3A4, forming inactive metabolites

Excretion: Urinary (main route), with minor fecal elimination

Contraindications

Known hypersensitivity to zopiclone or any ingredient in the formulation

Myasthenia gravis

Severe respiratory insufficiency

Sleep apnea syndrome

Severe hepatic impairment (risk of hepatic encephalopathy)

Concomitant use with alcohol or other CNS depressants

Pregnancy and lactation (category C – not recommended)

Warnings & Precautions

Dependence and withdrawal: Risk of physical and psychological dependence especially with prolonged use

Next-day impairment: Residual sedation, drowsiness, and impairment of psychomotor function the following morning (especially at higher doses)

Complex sleep behaviors: May include sleepwalking, sleep-driving, preparing and eating food while not fully awake (blackout activities)

Depression: Use cautiously in patients with a history of depression or suicidal ideation

Rebound insomnia: Possible upon discontinuation

Elderly patients: Higher risk of cognitive decline, falls, and sedation

Side Effects

Common (≥1%)

Bitter or metallic taste

Dry mouth

Drowsiness, sedation

Headache

Dizziness

Less Common

Nausea

Fatigue

Muscle weakness

Ataxia

Rare / Serious

Anaphylaxis or angioedema

Hallucinations

Depression or suicidal ideation

Amnesia

Complex sleep behaviors

Respiratory depression (especially with other depressants)

Hypersensitivity reactions (rash, urticaria)

Overdose

Symptoms

CNS depression

Confusion, drowsiness, ataxia, hypotonia

Respiratory depression (especially in combination with alcohol, opioids, or other sedatives)

Management:

Supportive care and symptomatic treatment

Activated charcoal if within 1 hour of ingestion

Flumazenil (benzodiazepine antagonist) is not routinely recommended for zopiclone due to uncertain efficacy and seizure risk

Drug Interactions

Pharmacodynamic Interactions (Additive CNS Effects):

Alcohol – potentiates sedative effects; contraindicated

Opioids – enhanced respiratory depression and sedation

Antipsychotics, antidepressants, antihistamines (sedating), benzodiazepines – increased sedation risk

Muscle relaxants – potentiated muscle weakness

Antiepileptics (e.g., valproate, phenytoin) – additive CNS effects

Pharmacokinetic Interactions

CYP3A4 inhibitors (e.g., ketoconazole, erythromycin, ritonavir) – ↑ zopiclone levels and effects

CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) – ↓ zopiclone efficacy

Tolerance, Dependence, and Withdrawal

Tolerance:

May develop with continued use beyond 2–4 weeks

Dependence

Physical and psychological dependence risk increases with:

Higher doses

Prolonged use

History of substance use disorder

Withdrawal Symptoms

Rebound insomnia

Anxiety, restlessness

Tremor

Rare: seizures (especially with abrupt cessation)

Discontinuation should be gradual, tapering over days to weeks if used longer than a few weeks.

Use in Special Populations

Pregnancy:

Category C (risk of neonatal respiratory depression, hypotonia, and withdrawal)

Not recommended unless potential benefits justify potential risks

Lactation:

Excreted in breast milk

Avoid use in breastfeeding mothers

Geriatrics

Increased sensitivity; start at lowest effective dose

Use caution due to fall risk, confusion, prolonged sedation

Hepatic Impairment

Dose reduction necessary in moderate impairment

Contraindicated in severe hepatic dysfunction

Renal Impairment

No adjustment usually required, but monitor closely in severe cases

Comparative Profile with Similar Hypnotics

While zopiclone is often grouped with other Z-drugs like zolpidem and eszopiclone, there are pharmacokinetic and clinical differences:

Zopiclone vs. Zolpidem

Zopiclone has a slightly longer half-life (~5 hours vs. 2–3 hours for zolpidem), potentially increasing risk of next-day drowsiness

Both show similar efficacy in inducing sleep, but zolpidem has more evidence for reduced next-morning residual effects at lower doses

Zopiclone vs. Eszopiclone (the S-enantiomer of zopiclone)

Eszopiclone has a longer half-life (~6 hours) and is approved for long-term use in the U.S.

Eszopiclone is more associated with metallic taste and next-day effects at higher doses.

Zopiclone vs. Benzodiazepines (e.g., temazepam, diazepam)

Zopiclone preserves sleep architecture better (minimal REM suppression)

Lower risk of dependence and withdrawal, though still present

Fewer next-day psychomotor effects compared to long-acting benzodiazepines

Formulations Available

Zopiclone 3.75 mg and 7.5 mg tablets (immediate release)

Some countries have orodispersible tablets and film-coated tablets

Regulatory & Legal Status

Controlled Substance in many jurisdictions:

Schedule IV (U.S., under similar Z-drugs like eszopiclone)

Class C drug in the UK under Misuse of Drugs Act

Prescription-only medicine

Not recommended for use beyond 4 weeks due to safety concerns

Monitoring Parameters

Evaluate sleep latency and duration

Monitor for signs of misuse or dependency

Monitor daytime alertness and cognitive function

Liver function in prolonged therapy

Educate patients on avoiding alcohol, driving, or operating machinery