Eszopiclone

In multiple premarketing randomized controlled trials, eszopiclone was not associated with an increased rate of serum enzyme elevations in comparison to placebo therapy, and no instance of clinically apparent liver injury was reported. Since its approval and widescale use, eszopiclone has not been implicated in causing clinically apparent liver disease, although hepatitis and liver injury are listed as a rare adverse reactions in the product label. Eszopiclone is metabolized in the liver by the cytochrome P450 system (predominantly CYP 3A4 and 2E1). Nevertheless, drug-drug interactions appear to be uncommon. Thus, eszopiclone induced liver injury must be rare, if it occurs at all.

/SIGNS AND SYMPTOMS/ Signs and symptoms of overdose effects of CNS depressants can be expected to present as exaggerations of the pharmacological effects noted in preclinical testing. Impairment of consciousness ranging from somnolence to coma has been described. 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 agents.

/CASE REPORTS/ A case of an elderly lady who was admitted for congestive heart failure /is reported/. She developed delirium during the course of her hospital stay. Multiple investigations were performed but were unremarkable. Finally, a diagnosis of abrupt zopiclone withdrawal causing delirium was made. Zopiclone was resumed at a lower dose and delirium resolved completely.

/CASE REPORTS/ The death of a 72-year-old man is described who overdosed himself while in hospital. The man was being treated for lung cancer and ingested 90 mg of zopiclone in a suicide attempt. He died between 4 and 10 h after the ingestion. Zopiclone, quantitated by GC-MS in the femoral blood, cardiac blood, vitreous humor, urine and bile was found to be 254, 408, 94, 7,330, and 114,700 ng/mL, respectively. Considering the man's weakened physical condition, 90 mg could represent a minimum lethal zopiclone dose. /Zopiclone/

/CASE REPORTS/ Zopiclone, a relatively new nonbenzodiazepine short-acting hypnotic medication is prescribed frequently for insomnia. The authors report a case of zopiclone-induced acute interstitial nephritis in a young, otherwise healthy man. The patient presented with anuric acute renal failure requiring hemodialysis. Kidney biopsy results showed acute interstitial nephritis with a prominent eosinophilic infiltrate in the interstitium. He recovered his renal function after stopping the medication and receiving corticosteroids. /Zopiclone/

For more Human Toxicity Excerpts (Complete) data for ESZOPICLONE (7 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Eszopiclone

vLess-DILI-concern

3

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Eszopiclone did not increase tumors in a p53 transgenic mouse bioassay at oral doses up to 300 mg/kg/day.[Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 3140]

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a carcinogenicity study in B6C3F1 mice in which racemic zopiclone was given in the diet, an increase in pulmonary carcinomas and carcinomas plus adenomas in females and an increase in skin fibromas and sarcomas in males were seen at the highest dose of 100 mg/kg/day. The skin tumors were due to skin lesions induced by aggressive behavior, a mechanism that is not relevant to humans.[Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 3140]

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ In a carcinogenicity study in Sprague-Dawley rats in which eszopiclone was given by oral gavage, no increases in tumors were seen; plasma levels (AUC) of eszopiclone at the highest dose used in this study (16 mg/kg/day) are estimated to be 80 (females) and 20 (males) times those in humans receiving the maximum recommended human dose (MRHD). However, in a carcinogenicity study in Sprague-Dawley rats in which racemic zopiclone was given in the diet, and in which plasma levels of eszopiclone were reached that were greater than those reached in the above study of eszopiclone, an increase in mammary gland adenocarcinomas in females and an increase in thyroid gland follicular cell adenomas and carcinomas in males were seen at the highest dose of 100 mg/kg/day. ... The mechanism for the increase in mammary adenocarcinomas is unknown. The increase in thyroid tumors is thought to be due to increased levels of TSH secondary to increased metabolism of circulating thyroid hormones...[Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 3140]

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Eszopiclone administered by oral gavage to pregnant rats and rabbits during the period of organogenesis showed no evidence of teratogenicity up to the highest doses tested (250 and 16 mg/kg/day in rats and rabbits...). In the rat, slight reductions in fetal weight and evidence of developmental delay were seen at maternally toxic doses of 125 and 150 mg/kg/day, but not at 62.5 mg/kg/day... .[Physicians Desk Reference 60th ed, Thomson PDR, Montvale, NJ 2006., p. 3140]

For more Non-Human Toxicity Excerpts (Complete) data for ESZOPICLONE (9 total), please visit the HSDB record page.

Patients 65 years of age and older may be more sensitive to pharmacologic and adverse effects of sedative and hypnotic agents. Systemic exposure to eszopiclone may be increased in geriatric patients compared with younger adults. Reduction of initial and maximum dosages is recommended.

While data specific to eszopiclone were not located(SRC, 2006), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils(1).

The half-life is 6.1 hours in healthy patients but is prolonged in various patients, including those with hepatic impairment, elderly patients, in addition to those taking CYP3A enzyme inhibiting drugs.

Eszopiclone has an intermediate duration of action (i.e., possesses a half-life of approximately 5-7 hours).

Following oral administration, eszopiclone is extensively biotransformed and the major metabolites are S-desmethylzopiclone and zopiclone-N-oxide, which are largely inactive.. The enzymes involved in the metabolism of eszopiclone are CYP3A (the primary metabolizing enzyme), CYP2C8, and CYP2E1. The N-oxide derivative shows weak pharmacological activity in animals. The N-desmethyl metabolite is pharmacologically active.

Extensively metabolized by CYP3A4 and CYP2E1 via oxidation and demethylation. The two primary metabolites are (S)-zopiclone-N-oxide (inactive) and (S)-N-demethylzopiclone which binds to GABA receptors with lower potency then eszopiclone.

Eszopiclone has known human metabolites that include N-desmethyl-zopiclone and N-oxide-zopiclone.

Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. Route of Elimination: Up to 75% of an oral dose of racemic zopiclone is excreted in the urine, primarily as metabolites. Half Life: 6 hours

Eszopiclone is rapidly absorbed and the peak concentration is reached within about 1 hour after oral administration. The mean AUC after a 3 mg dose of eszopiclone was 278 ng/mL × h. The consumption of a high-fat has been shown to slow absorption. Steady-state concentrations of eszopiclone are reached within 24-48 hours.

Only about 10% of an eszopiclone dose is found excreted in the urine as the parent drug. As much as 75% of an orally administered dose of racemic zopiclone as is found to be excreted in the urine in the form of metabolites. Eszopiclone, the S-isomer of racemic zopiclone, would likely show the same excretion pattern.

The volume of distribution of eszopiclone is estimated at 89.9L

The mean clearance of eszopiclone in young, healthy volunteers was 184 mL/min in one pharmacokinetic study.

Eszopiclone is rapidly absorbed following oral administration. Peak plasma concentrations are achieved within approximately 1 hour after oral administration. Eszopiclone is weakly bound to plasma protein (52-59%). The large free fraction suggests that eszopiclone disposition should not be affected by drug-drug interactions caused by protein binding. The blood-to-plasma ratio for eszopiclone is less than one, indicating no selective uptake by red blood cells.

Onset of action may be reduced if taken with or immediately after a high-fat or heavy meal.