Eszopiclone

DEA NFLIS-Drug Category -> Depressants and Tranquilizers

Pharmaceuticals -> Hypnotics

soluble in water

Slightly soluble in ethanol and soluble in phosphate buffer (pH 3.2)

8.85e-01 g/L

Breast Feeding; Lactation; Milk, Human; Hypnotics and Sedatives

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Danger

H300 (14.3%): Fatal if swallowed [Danger Acute toxicity, oral]

P203, P261, P264, P264+P265, P270, P271, P273, P280, P301+P316, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 7 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl eszopiclone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

An additive effect on psychomotor performance was seen with coadministration of eszopiclone and ethanol 0.70 g/kg for up to 4 hours after ethanol administration.

CYP3A4 is a major metabolic pathway for elimination of eszopiclone. The AUC of eszopiclone was increased 2.2-fold by coadministration of ketoconazole, a potent inhibitor of CYP3A4, 400 mg daily for 5 days. C max and t 1/2 were increased 1.4-fold and 1.3-fold, respectively. Other strong inhibitors of CYP3A4 (eg, clarithromycin, nefazodone, troleandomycin, ritonavir, nelfinavir) would be expected to behave similarly.

Racemic zopiclone exposure was decreased 80% by concomitant use of rifampicin, a potent inducer of CYP3A4. A similar effect would be expected with eszopiclone.

/The authors/ studied the possible interaction between itraconazole, a potent inhibitor of CYP3A, and zopiclone, a short-acting hypnotic. A double-blind, randomized, two-phase crossover design was used. Ten healthy young subjects received daily either 200 mg itraconazole or placebo for 4 days. On day 4 they ingested a single 7.5-mg oral dose of zopiclone. Plasma concentrations of zopiclone and itraconazole were determined and pharmacodynamic responses were measured up to 17 hr. Itraconazole significantly increased the Cmax of zopiclone from 49 to 63 ng.mL-1. The t1/2 of zopiclone was prolonged from 5.0 to 7.0 hr. The AUC(0-inifinity) of zopiclone was increased from 415 to 719 ng.mL-1 hr by itraconazole. No statistically significant differences were observed in the pharmacodynamic responses between the groups. Itraconazole has a statistically significant pharmacokinetic interaction with zopiclone but this is only of limited clinical importance, at least in young adults.

For more Interactions (Complete) data for ESZOPICLONE (6 total), please visit the HSDB record page.

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 Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl eszopiclone, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

N - Nervous system

QN - Nervous system

Eszopiclone rapidly induces sleep and decreases sleep latency. It also aids in the maintenance of sleep, preventing frequent awakenings. This drug has shown anticonvulsant and muscle relaxant properties in animals but is used in humans for its sedating effects. Eszopiclone is a central nervous system depressant with various effects. These include changes in alertness and motor coordination and the risk of next morning impairment, increasing with the amount of eszopiclone administered. Exercise caution and advise against driving a motor vehicle or activities that require full mental alertness the next morning. Complex sleep behaviors may result from eszopiclone use. Eszopiclone should be discontinued in these cases. Avoid the use of alcohol and other CNS depressants when eszopiclone is administered. Advise patients to skip the eszopiclone dose if alcohol has been consumed before bed or during the evening. Use the smallest dose of eszopiclone as possible, especially in elderly patients, who may experience exaggerated drug effects. Though the potential for dependence and abuse with eszopiclone is lower than for other hypnotic drugs, this drug has been abused and is known to cause dependence.

The exact mechanism of action of eszopiclone is unknown at this time but is thought to occur via binding with the GABA receptor complexes at binding sites located near benzodiazepine receptors, possibly explaining its hypnotic and sedative effects. It has particular affinity for GABA-A (or GABAA) receptor subunits 1, 3 and 5. Eszopiclone increases GABA-A channel currents significantly. GABA-A channels are major inhibitory channels that cause CNS depression when their receptors are activated.

Eszopiclone, the S-enantiomer of zopiclone (not commercially available in the US), is a sedative and hypnotic agent that is structurally unrelated to benzadiazepines and other sedative and hypnotic agents that are commercially available in the US, including barbiturates, imidazopyridines (e.g., zolpidem), and pyrazolopyrimidines (e.g., zaleplon). Eszopiclone is pharmacologically similar to zaleplon and zolpidem; all of these agents have been shown to interact with the CNS gamma-aminobutyric acid (GABA) receptor complex at binding domains located close to or allosterically coupled to benzodiazepine receptors.

The precise mechanism of action of eszopiclone as a hypnotic is unknown. Its pharmalogic effect is believed to result from its interaction with GABA-receptor complexes at binding domains located close to or allosterically coupled to benzodiazepine receptors.

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.

Treatment of insomnia

For the treatment of insomnia