Chemical formula: C₁₇H₁₇ClN₆O₃ Molecular mass: 388.808 g/mol PubChem compound: 5735
Zopiclone interacts in the following cases:
In combination with CNS depressants an enhancement of the central depressive effect may occur. The therapeutic benefit of co-administration with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic drugs, anaesthetics and sedative antihistamines should therefore be carefully weighed. In the case of narcotic analgesics, enhancement of euphoria may also occur leading to an increase in psychic dependence. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines and benzodiazepine-like agents.
The effect of erythromycin on the pharmacokinetics of zopiclone has been studied in 10 healthy subjects. The AUC of zopiclone is increased by 80% in presence of erythromycin which indicates that erythromycin can inhibit the metabolism of drugs metabolised by CYP 3A4. As a consequence, the hypnotic effect of zopiclone may be enhanced.
Since zopiclone is metabolised by the cytochrome P450 (CYP) 3A4 isoenzyme, plasma levels of zopiclone may be increased when co-administered with CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole and ritonavir. A dose reduction for zopiclone may be required when it is co-administered with CYP3A4 inhibitors. Conversely, plasma levels of zopiclone may be decreased when co-administered with CYP3A4 inducers such as rifampicin, carbamazepine, phenobarbital, phenytoin and St. John’s wort. A dose increase for zopiclone may be required when it is co-administered with CYP3A4 inducers.
Accumulation of zopiclone or its metabolites has not been seen during treatment of insomnia in patients with renal insufficiency. However, it is recommended that patients with impaired renal function should start treatment with 3.75 mg.
The sedative effect of zopiclone may be enhanced when used in combination with alcohol, concomitant use is therefore not recommended. In particular this could affect the patient’s ability to drive or use machines.
As elimination of zopiclone may be reduced in patients with hepatic dysfunction, a lower dose of 3.75 mg zopiclone nightly is recommended. The standard dose of 7.5 mg zopiclone may be used with caution in some cases, depending on effectiveness and acceptability.
Concomitant use of opioids with benzodiazepines or other sedative-hypnotic drugs, including zopiclone may result in sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of opioids and benzodiazepines for use in patients for whom alternative treatment options are inadequate.
If a decision is made to prescribe zopiclone concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation.
Use of zopiclone may lead to the development of abuse and/or physical and psychological dependence. The risk is greater in patients with a history of psychiatric disorders and/or alcohol, substance or drug abuse. Zimovane should be used with extreme caution in patients with current or a history of alcohol, substance or drug abuse or dependence.
In patients with chronic respiratory insufficiency, a starting dose of 3.75 mg zopiclone is recommended initially. The dosage subsequently may be increased to 7.5 mg.
The use of zopiclone is not recommended during pregnancy.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
Zopiclone crosses the placenta.
A large amount of data on pregnant women (more than 1000 pregnancy outcomes) collected from cohort studies has not demonstrated evidence of the occurrence of malformations following exposure to benzodiazepines or benzodiazepine-like substances during the first trimester of pregnancy. However, certain case-control studies reported an increased incidence of cleft lip and palate associated with benzodiazepines during pregnancy.
Cases of reduced fetal movement and fetal heart rate variability have been described after administration of benzodiazepines or benzodiazepine-like substances during the second and/or third trimester of pregnancy.
Administration of benzodiazepines or benzodiazepine-like substances, including zopiclone, during the late phase of pregnancy or during labour have been associated with effects on the neonate, such as hypothermia, hypotonia, feeding difficulties (‘floppy infant syndrome’), and respiratory depression, due to the pharmacological action of the product. Cases of severe neonatal respiratory depression have been reported.
Moreover, infants born to mothers who took sedative/hypnotics agents chronically during the latter stages of pregnancy may have developed physical dependence and may be at risk of developing withdrawal symptoms in the postnatal period.
Appropriate monitoring of the newborn in the postnatal period is recommended.
If zopiclone is prescribed to a woman of childbearing potential, she should be warned to contact her physician about stopping the product if she intends to become or suspects that she is pregnant.
Zopiclone is excreted in breast milk, although the concentration of zopiclone in the breast milk is low, use in nursing mothers must be avoided.
Because of its pharmacological properties and its effect on central nervous system, zopiclone may adversely affect the ability to drive or to use machines. The risk of psychomotor impairment, including impaired driving ability, is increased if:
Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle following administration of zopiclone and in particular during the 12 hours following that administration.
The following CIOMS frequency rating is used, when applicable: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Very rare: angiooedema, anaphylactic reaction
Uncommon: nightmare, agitation
Rare: confusional state, libido disorder, irritability, aggression, hallucination
Not known: restlessness, delusion, anger, abnormal behaviour (possibly associated with amnesia) and complex sleep behaviours including somnambulism, dependence, withdrawal syndrome (see below)
Common: dysgeusia (bitter taste), somnolence (residual)
Uncommon: dizziness, headache
Rare: anterograde amnesia
Not known: ataxia, paraesthesia, cognitive disorders such as memory impairment, disturbance in attention, speech disorder
Not known: diplopia
Rare: dyspnoea
Not known: respiratory depression
Common: dry mouth
Uncommon: nausea, vomiting
Not known: dyspepsia
Very rare: transaminases increased and/or blood alkaline phosphatase increased (mild to moderate)
Rare: urticaria or rash, pruritus
Not known: muscular weakness
Uncommon: fatigue
Not known: light headedness, incoordination
Rare: fall (predominantly in elderly patients)
Withdrawal syndrome has been reported upon discontinuation of zopiclone. Withdrawal symptoms vary and may include rebound insomnia, muscle pain, anxiety, tremor, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares, panic attacks, muscle aches/cramps, gastrointestinal disturbances and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations. In very rare cases, seizures may occur.
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