indication

For the short-term treatment of insomnia.

pharmacology

Zopiclone is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class and is indicated for the short-term treatment of insomnia. While Zopiclone is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties, it interacts with the gamma-aminobutyric acid-benzodiazepine (GABA_BZ) receptor complex. Subunit modulation of the GABA_BZ receptor chloride channel macromolecular complex is hypothesized to be responsible for some of the pharmacological properties of benzodiazepines, which include sedative, anxiolytic, muscle relaxant, and anticonvulsive effects in animal models. Zopiclone binds selectively to the brain alpha subunit of the GABA A omega-1 receptor.

mechanism of action

Zopiclone exerts its action by binding on the benzodiazepine receptor complex and modulation of the GABA_BZ receptor chloride channel macromolecular complex. Both zopiclone and benzodiazepines act indiscriminately at the benzodiazepine binding site on α1, α2, α3 and α5 GABAA containing receptors as full agonists causing an enhancement of the inhibitory actions of GABA to produce the therapeutic (hypnotic and anxiolytic) and adverse effects of zopiclone.

toxicity

Rare individual instances of fatal outcomes following overdose with racemic zopiclone have been reported in European postmarketing reports, most often associated with overdose with other CNS-depressant agent. Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing.

biotransformation

Extensively metabolized in the liver via decarboxylation (major pathway), demethylation, and side chain oxidation. Metabolites include an N-oxide derivative (weakly active; approximately 12% of a dose) and an N-desmethyl metabolite (inactive; approximately 16%). Approximately 50% of a dose is converted to other inactive metabolites via decarboxylation. Hepatic microsomal enzymes are apparently not involved in zopiclone clearance.

absorption

Rapidly absorbed following oral administration.

half life

Elimination half life is approximately 5 hours (range 3.8 to 6.5 hours) and is prolonged to 11.9 hours in patients with hepatic insufficiency.

drug interactions

Amprenavir: Amprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if amprenavir is initiated, discontinued or dose changed.

Atazanavir: Atazanavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if atazanavir is initiated, discontinued or dose changed.

Clarithromycin: Clarithromycin, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if clarithromycin is initiated, discontinued or dose changed.

Conivaptan: Conivaptan, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if conivaptan is initiated, discontinued or dose changed.

Darunavir: Darunavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if darunavir is initiated, discontinued or dose changed.

Delavirdine: Delavirdine, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if delavirdine is initiated, discontinued or dose changed.

Erythromycin: The macrolide antibiotic, erythromycin, may increase the serum concentration of zopiclone. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if erythromycin is initiated, discontinued or dose changed.

Fosamprenavir: Fosamprenavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if fosamprenavir is initiated, discontinued or dose changed.

Imatinib: Imatinib, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if imatinib is initiated, discontinued or dose changed.

Indinavir: Indinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if indinavir is initiated, discontinued or dose changed.

Isoniazid: Isoniazid, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if isoniazid is initiated, discontinued or dose changed.

Itraconazole: Itraconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if itraconzole is initiated, discontinued or dose changed.

Ketoconazole: Ketonconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if ketoconazole is initiated, discontinued or dose changed.

Lopinavir: Lopinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if lopinavir is initiated, discontinued or dose changed.

Methotrimeprazine: Additive CNS depressant effects. Reduce zopiclone dose by half upon initiation of methotrimeprazine. Zopiclone dose may be adjusted once methotrimeprazine dose has been established. Monitor for increased CNS depression.

Nefazodone: Nefazodone, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if nefazodone is initiated, discontinued or dose changed.

Nelfinavir: Nelfinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if nelfinavir is initiated, discontinued or dose changed.

Nicardipine: Nicardipine, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if nicardipine is initiated, discontinued or dose changed.

Posaconazole: Posaconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if posaconazole is initiated, discontinued or dose changed.

Quinidine: Quinidine, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if quinidine is initiated, discontinued or dose changed.

Ritonavir: Ritonavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if ritonavir is initiated, discontinued or dose changed.

Saquinavir: Saquinavir, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if saquinavir is initiated, discontinued or dose changed.

Telithromycin: Telithromycin, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if telithromycin is initiated, discontinued or dose changed.

Tolbutamide: Tolbutamide, a strong CYP2C9 inhibitor, may decrease the metabolism and clearance of Zopiclone. Consider alternate therapy or monitor for changes in Zopiclone therapeutic and adverse effects if Tolbutamide is initiated, discontinued or dose changed.

Triprolidine: The CNS depressants, Triprolidine and Zopiclone, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of zopiclone by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zopiclone if voriconazole is initiated, discontinued or dose changed.