Zopiclone

Introduction Overview

Generic Name

zopiclone

Brand Name

Imovane, Zimovane, Zimovane LS, Imoclone, Imrest, Lyzop, Ziclone, Zolinox, Zolium, Zopicon, Zopitran and more

Dosage Form

oral tablet, oral solution

Drug Class

Non-benzodiazepine hypnotic

Pharmacokinetics

Absorption: Zopiclone is rapidly absorbed from the gastrointestinal tract following oral administration, with an onset of action typically occurring within approximately one hour. The bioavailability is high, ensuring effective plasma concentrations are reached to exert its hypnotic effects. Its absorption can be influenced by factors such as gastric pH and motility, but these effects remain minimal clinically. Peak plasma concentrations (Cmax) are typically achieved within 1 to 2 hours post-dose, correlating with onset of sedation and sleep induction.

Distribution: Zopiclone exhibits moderate protein binding in plasma (about 45-80%) and is widely distributed in body tissues, including the central nervous system (CNS), which is its primary site of action. The distribution volume (Vd) reflects moderate tissue penetration, allowing effective receptor binding in the brain to facilitate its hypnotic properties. Importantly, zopiclone crosses the blood-brain barrier efficiently due to its lipophilic nature. It is also known to cross the placenta and is excreted into breast milk, warranting caution during pregnancy and lactation.

Metabolism: The drug undergoes extensive hepatic metabolism primarily via cytochrome P450 enzymes, especially CYP3A4 and to a lesser extent CYP2E1. The major metabolic pathways include demethylation and hydroxylation resulting in inactive metabolites. The parent compound and metabolites are subject to phase II conjugation reactions before elimination. The metabolic rate can be affected by liver function, age, and concomitant use of enzyme-inducing or inhibiting drugs, which may alter plasma levels and therapeutic effects or increase toxicity risk.

Elimination: Zopiclone and its inactive metabolites are predominantly excreted via the kidneys, with around 80% eliminated in the urine and the remainder through feces. The elimination half-life ranges from approximately 5 to 7 hours in healthy adults, but this can be prolonged in elderly patients or those with hepatic or renal impairment. Clearance is reduced in these populations, requiring dose adjustments to avoid accumulation and adverse effects. The drug's elimination profile supports once-daily dosing, ideally shortly before bedtime, to optimize hypnotic efficacy while minimizing residual next-day sedation.

Dosage Forms

Available Dosage Forms: Zopiclone is commercially available in the form of oral tablets and, in certain countries, as an oral solution to accommodate patients who experience difficulty swallowing tablets. The tablets are available in two main strengths: 7.5 mg (standard dose) and 3.75 mg (low strength, often designated LS) formulations.

Dosages for Adults and Adolescents: Standard adult dosing for the treatment of insomnia involves taking one 7.5 mg tablet orally just before bedtime. In elderly patients aged over 65 years, or in individuals with compromised liver or kidney function, treatment typically starts at a lower dose of 3.75 mg or half of a 7.5 mg tablet, which may be increased cautiously to the full 7.5 mg dose based on therapeutic response and tolerability. Zopiclone is not recommended for use in children and adolescents under 18 years due to lack of established safety and efficacy data.

Specific Patient Populations: Dose reduction is critical in patients with hepatic or renal impairment, as metabolism and clearance may be impaired, increasing the risk of accumulation and toxicity. For these patients, the low-strength 3.75 mg tablet or half of a 7.5 mg dose is recommended. Elderly patients also require cautious dosing to mitigate the risks of cognitive impairment, falls, and prolonged sedation. Pregnant and breastfeeding women should avoid zopiclone due to potential fetal risks and drug passage into milk.

Oral Tablet Strengths: 3.75 mg (Zimovane LS, Imovane low strength), 7.5 mg (Zimovane, Imovane, and other branded versions).

Oral Solution: Available in select countries for patients with swallowing difficulties; concentration and dosing to be individually determined by the prescribing physician.

Mechanism Of Action

Zopiclone is classified as a non-benzodiazepine hypnotic agent, structurally distinct from benzodiazepines but with a similar pharmacodynamic profile. Its primary mechanism of action involves modulation of the gamma-aminobutyric acid type A (GABAA) receptor complex in the central nervous system. Specifically, zopiclone binds allosterically to a unique site on the GABAA receptor complex, enhancing the affinity of the receptor for the neurotransmitter gamma-aminobutyric acid (GABA), which is the principal inhibitory neurotransmitter in the brain. This enhancement facilitates increased chloride ion influx into neurons, leading to hyperpolarization and decreased neuronal excitability.

By potentiating GABAergic neurotransmission, zopiclone induces sedative, anxiolytic, muscle relaxant, and anticonvulsant effects, with hypnotic effects being most prominent clinically. This action reduces sleep latency, increases total sleep duration, and decreases nocturnal awakenings, thus improving overall sleep quality in patients with insomnia. Notably, zopiclone preferentially targets the alpha-1 subunit-containing GABAA receptors, which underlies its pronounced hypnotic effects with comparatively less anxiolytic and muscle relaxant action than classical benzodiazepines.

Compared to benzodiazepines, zopiclone has a lower risk profile for dependence and tolerance at therapeutic doses but can still cause these phenomena with prolonged use. It differs from benzodiazepines structurally, belonging to the cyclopyrrolone class, enabling a somewhat distinct side effect profile though with overlapping clinical benefits. Clinical studies have demonstrated that zopiclone’s hypnotic effects manifest rapidly, usually within an hour, and its half-life supports once-daily dosing before bedtime.

Ongoing research continues to elucidate the nuanced interactions of zopiclone with various GABAA receptor subtypes, including potential allosteric modulation that may contribute to its efficacy and side effect profile. Clinically, this mechanism translates to effective short-term treatment of insomnia with reduced risks of next-day sedation and cognitive impairment when dosed appropriately.

Pharmacological Actions

Potentiation of GABAergic inhibitory neurotransmission in the CNS by positive allosteric modulation of GABAA receptors.
Reduction of sleep latency facilitating faster onset of sleep.
Increase in total sleep duration and improvement of sleep maintenance by decreasing nocturnal awakenings.
Sedative and hypnotic effects with anxiolytic, muscle relaxant, and anticonvulsant actions to a lesser extent.
Rapid onset of action, typically within one hour after oral administration.
Metabolism primarily by hepatic cytochrome P450 enzymes, influencing pharmacokinetic interactions.
Demonstrates moderate protein binding and extensive tissue distribution including CNS penetration.
Produces dose-dependent CNS depression without significant respiratory depression at therapeutic doses.
Potential for development of physical and psychological dependence with prolonged use beyond recommended duration.
Exhibits muscle relaxation by attenuating polysynaptic reflexes mediated through the CNS.
Ability to cause anterograde amnesia in some patients when therapeutic doses are exceeded.
Reduced impact on sleep architecture compared to traditional benzodiazepines, preserving deep sleep stages better.
Oral bioavailability allows convenient dosing in tablet or oral solution forms.
Distinct stereoisomer eszopiclone exhibits similar mechanism but with potentially differing pharmacodynamic profiles.

Therapeutic Or Clinical Uses

Short-term management of insomnia characterized by difficulties in sleep initiation.
Treatment of sleep maintenance disorders presenting with frequent nocturnal awakenings.
Use in cases of premature awakening where sleep duration is reduced.
Management of severe or distressing sleep problems associated with mood or mental health disorders.
Improvement of sleep quality and daytime functioning in adults requiring hypnotic therapy.
Used to facilitate onset of sleep in situations requiring rapid sedation onset.
Administered to elderly patients with appropriate dose adjustments to mitigate sleep disturbances.
Alternative hypnotic agent for patients intolerant to benzodiazepine therapies.
Off-label short-term therapy in select cases of transient insomnia due to situational stressors.
Useful in clinical scenarios where a shorter half-life hypnotic is preferred to minimize next-day sedation.
May be utilized prior to procedures requiring sedation though not primarily approved for procedural sedation.
Supportive therapy in mental health disorders with concomitant sleep disruption under careful supervision.
Replacement option in patients displaying benzodiazepine-related adverse effects or interactions.

Side Or Adverse Effects

Commonly reported mild bitter or metallic taste in the mouth (dysgeusia) and dry mouth.
Drowsiness or excessive somnolence the following day, especially if adequate sleep duration is not maintained.
Headache and dizziness, sometimes leading to impaired coordination and increased fall risk especially in the elderly.
Gastrointestinal disturbances including nausea and vomiting less frequently noted.
Rare allergic reactions manifesting as rash, urticaria, and in severe cases angioedema or anaphylaxis.
Potential anterograde amnesia and impaired memory function, particularly with insufficient uninterrupted sleep.
Confusional states, hallucinations, and psychomotor impairment reported in sensitive individuals or overdose.
Sleepwalking and complex sleep-related behaviors such as driving, eating, or making phone calls while not fully awake.
Mood alterations including depression, agitation, and irritability.
Respiratory depression in cases of overdose or when combined with other CNS depressants, notably opioids.
Dependence and withdrawal symptoms including anxiety, agitation, tremors, seizures upon abrupt cessation after prolonged use.
Ataxia and impaired motor coordination increasing fall and injury risk particularly in frail or elderly patients.
Reduced libido or sexual dysfunction reported less commonly.
Double vision, muscle weakness, and unusual sensations such as paraesthesia.
Potential for respiratory issues, including exacerbation of sleep apnea or breathing difficulties.

Precautions

Use with caution in patients with a history of substance abuse or dependence due to risk of zopiclone abuse.
Ensure patients have at least 7 to 8 hours available for uninterrupted sleep to reduce residual sedation and amnesia risks.
Dose reductions recommended in elderly patients and those with hepatic or renal impairment to avoid accumulation.
Avoid concomitant use with other CNS depressants, such as opioids, sedative antihistamines, and alcohol.
Monitor patients for signs of depression or suicidal ideation during therapy, particularly in those with pre-existing mental illness.
Advise patients to report any unusual behaviors such as sleepwalking or complex nocturnal activities immediately.
Gradual tapering recommended when discontinuing therapy after prolonged use to minimize withdrawal symptoms.
Avoid use in patients with respiratory insufficiency or sleep apnea syndrome due to risk of respiratory depression.
Screen for hypersensitivity to zopiclone or components of formulations to prevent allergic reactions.
Not recommended in patients under 18 years old due to lack of safety and efficacy data.
Pregnant and breastfeeding women should avoid zopiclone due to potential fetal and neonatal adverse effects.
Regularly reassess need for continued therapy beyond recommended duration of 7 to 14 days.
Caution when operating machinery or driving for at least 12 hours after dosing due to sedation and impaired alertness.
Baseline evaluation of liver and kidney function advised before initiating therapy in at-risk populations.
Monitor for signs of tolerance, dependence, or abuse, especially with prolonged or high-dose use.

Warnings

Risk of physical and psychological dependence increases with duration and dosage; prolonged use beyond four weeks is not advised.
Concomitant use with opioids increases risk of profound sedation, respiratory depression, coma, and death.
Potential for serious adverse effects such as coma and respiratory depression in overdose situations.
Reports of increased suicidal ideation and attempts with sedatives including zopiclone necessitate careful patient monitoring.
Abrupt discontinuation can cause withdrawal symptoms including anxiety, irritability, hallucinations, seizures.
Possible occurrence of complex sleep-related behaviors (e.g., sleepwalking, nocturnal eating, driving) with no memory of events.
Use contraindicated in myasthenia gravis due to muscle weakness exacerbation.
Avoid use in patients with severe hepatic impairment or respiratory failure due to impaired drug metabolism and respiratory risk.
Contraindicated in patients with sleep apnea syndrome as zopiclone may worsen respiratory compromise.
Not suitable for pediatric use under 18 due to safety and efficacy not established.
May impair cognitive and motor function the next day; patients should avoid hazardous tasks during this period.
Use during pregnancy may cause congenital malformations and neonatal withdrawal symptoms.
Caution advised regarding potential for abuse in patients with a history of drug or alcohol dependence.
Concomitant use with other CNS depressants should be limited or avoided to prevent additive adverse effects.
Zopiclone can alter liver enzyme levels, potentially complicating interpretation of liver function tests.

Contraindication

Known hypersensitivity or allergic reaction to zopiclone or any inactive ingredients in the formulation.
Patients suffering from myasthenia gravis due to risk of worsening muscle weakness.
Severe respiratory failure or insufficiency including conditions causing compromised breathing function.
Sleep apnea syndrome where respiratory pauses during sleep would be exacerbated by CNS depressant effects.
Severe hepatic impairment where metabolism of zopiclone is significantly decreased.
Pediatric patients under 18 years due to unestablished safety and efficacy.
History of sleepwalking or similar complex sleep behaviors associated with prior zopiclone use.
Concomitant use with strong inhibitors of CYP3A4 like ketoconazole or itraconazole may be contraindicated or require dose adjustment.
Patients with a history of substance abuse or dependency without careful assessment and monitoring.
Concomitant use with opioids except under strict medical supervision.
Pregnancy especially in the first and third trimesters due to teratogenicity and neonatal risks.
Breastfeeding women because of excretion in breast milk and potential infant exposure.

Drug Interactions

Increased sedative and respiratory depressive effects when combined with opioids such as morphine, codeine, methadone, oxycodone, pethidine, or tramadol.
Enhanced CNS depressant effects when co-administered with anxiolytics, hypnotics, antipsychotics, or sedative antihistamines (e.g., chlorphenamine, promethazine).
Drugs that inhibit CYP3A4 enzymes (e.g., clarithromycin, erythromycin, ketoconazole, itraconazole, ritonavir) can increase plasma concentrations of zopiclone, increasing toxicity risk.
Inducers of CYP3A4 such as carbamazepine, phenobarbital, phenytoin, rifampicin, and St John’s Wort decrease zopiclone plasma levels, reducing therapeutic efficacy.
Potential alteration of liver enzyme levels by zopiclone can interfere with interpretation of hepatic function tests during concurrent treatments.
Concomitant use with other CNS depressants, including alcohol, results in additive sedative and respiratory depressive effects.
Use with anesthetics may potentiate CNS depression during and post-surgical procedures.
Interaction with antidepressants may increase CNS depressive effects or alter metabolism.
Zopiclone may enhance hypnotic effects of anticonvulsants, necessitating dose adjustments.
Medications affecting renal or hepatic function may impact zopiclone pharmacokinetics.
Drugs with serotonergic properties require caution due to potential neurological adverse effects when combined.
Concurrent use with other hypnotics should be avoided or closely monitored to prevent excessive sedation.
Opioid analgesics co-administration requires careful dosing and monitoring to minimize risk of coma and death.
Zopiclone’s metabolism interference may increase plasma levels of other drugs metabolized by CYP3A4.
Potential interactions with herbal supplements like St John’s Wort can reduce effectiveness of zopiclone.

Preparations Of The Drug

Imovane 7.5 mg tablets containing zopiclone and inactive ingredients such as lactose monohydrate, calcium hydrogen phosphate dihydrate, wheat starch (gluten), sodium starch glycollate, magnesium stearate, and a hypromellose-based coating with titanium dioxide and macrogol 6000.
Zimovane 7.5 mg and Zimovane LS 3.75 mg tablets with excipients including lactose monohydrate, calcium hydrogen phosphate dihydrate, wheat starch, sodium starch glycollate, magnesium stearate, hypromellose, titanium dioxide, and macrogol 6000.
Generic formulations with similar inactive ingredient profiles to branded forms, with specific excipient composition varying by manufacturer.
Oral solutions containing zopiclone formulated for patients with swallowing difficulties, dosing to be individualized based on clinical need.
Tablets formulated for oral administration with non-crushable coating to ensure extended-release properties and stability.
Available in blister packs or bottles depending on manufacturer and country of distribution.
Some branded versions may contain gluten, lactose, and other excipients potentially relevant for patients with allergies or intolerances.
Storage recommendations include keeping drug below 25-30°C (77-86°F), in a dry place away from moisture, heat, and direct sunlight.
Packaging designed to maintain drug stability and prevent contamination during shelf life.
Certain brands may market low-strength formulations (3.75 mg) specifically for elderly or patients with dose adjustment needs.
Products distributed by Sanofi and other pharmaceutical companies under the various brand names mentioned.
Inactive ingredients designed to optimize dissolution, bioavailability, and patient tolerability.
Manufacturing standards comply with regulatory requirements for quality and purity.
Dosage forms and preparations undergo rigorous stability and efficacy testing prior to market release.
Some formulations include coatings to mask bitter taste and improve patient compliance.