Is It Safe to Combine Zopiclone and Alcohol?

Eszopiclone is a white or slightly yellowish powder with a molecular formula of C17H17ClN6O3, a molecular weight of 388.80800, a density of 1.54 g / cm3, a melting point of 202-204ºC, and a boiling point of 580.7ºC at 760 mmHg.

Chinese name: Eszopiclone
Foreign name: eszopiclone

CAS number: 138729-47-2
Molecular formula: C17H17ClN6O3

Introduction to eszopiclone compounds

Eszopiclone Basic Information

Chinese name dexzopiclone

English name: eszopiclone

English alias: [(7S) -6- (5-chloropyridin-2-yl) -5-oxo-7H-pyrrolo [3,4-b] pyrazin-7-yl] 4-methylpiperazine-1-carboxylate; Lunesta; Esopiclone; Estorra; UNII-UZX80K71OE;

CAS number: 138729-47-2

Molecular formula: C ₁₇ H ₁₇ ClN ₆ O ₃

Molecular weight: 388.80800

Structural formula:

Exact mass: 388.10500

PSA: 91.76000

LogP: 1.50880 ^[1]

Physicochemical properties of eszopiclone

Appearance and properties: white or slightly yellow powder

Density: 1.54 g / cm

Melting point: 202-204ºC

Boiling point: 580.7ºC at 760 mmHg

Flash point: 305ºC

Refractive index: 1.688

Vapor pressure: 1.78E-13mmHg at 25 ° C ^[1]

Eszopiclone Compound Related Drugs

Dexopiclone drug name:

[General name] eszopiclone

[Product Name] Wen Fei

[English name] Dexzopiclone tablets

[Chinese Pinyin] You Zuo Pi Ke Long Pian ^[2]

Eszopiclone ingredients:

The active ingredient of this product is eszopiclone. ^[2]

Dezopiclone traits:

This product is a white film-coated tablet, which appears white or almost white after removing the film coating. ^[2]

Eszopiclone indications:

Used to treat insomnia. ^[2]

Exozopiclone Specifications:

2mg, 3mg ^[2]

Dexopiclone usage and dosage:

This product should be administered individually. The recommended starting dose for adults is 2 mg before falling asleep. Since 3 mg can effectively extend sleep time, the starting dose can be increased or increased to 3 mg according to clinical needs.
The recommended starting dose for elderly patients complaining of difficulty falling asleep is 1 mg before bedtime, which can be increased to 2 mg if necessary. The recommended dose for elderly patients with sleep maintenance disorders is 2 mg before falling asleep (see notes).
For example, taking eszopiclone immediately after a high-fat diet may cause slow drug absorption, resulting in a decrease in the effect of eszopiclone on sleep latency (see Pharmacokinetics).
Special population: Patients with severe liver damage should use this product with caution, with an initial dose of 1 mg.
Concomitant CYP inhibitors: In combination with strong CYP3A4 inhibitors, the initial dose of this product should not be greater than 1 mg, and can be increased to 2 mg if necessary. ^[2]

Ezozopiclone adverse reactions:

According to reports from foreign clinical trials:
In a pre-marketing study of eszopiclone, approximately 400 normal subjects participated in a clinical pharmacology / pharmacokinetic study, and approximately 1500 patients participated in a placebo-controlled clinical efficacy study (equivalent to approximately 263 patient exposures). year). The conditions and duration of eszopiclone treatment in pre-marketing studies vary widely. Including open and double-blind trials, inpatients and outpatients, long-term and short-term trials, adverse reactions are evaluated by collecting adverse events, assessing physical examination, vital signs, weight, laboratory tests, ECG and other results.
Adverse events were recorded by interviews and clinical researchers using the terminology of their choice. Adverse reactions are reported in the table below using the COSTART term classification.
Adverse events observed in placebo-controlled trials lead to discontinuation of adverse events. In a placebo-parallel parallel controlled trial in older people, 3.8% of 208 patients received placebo and 215 of patients receiving 2mg eszopiclone In 2.3%, 1.4% of 72 patients taking 1 mg eszopiclone discontinued treatment due to adverse events. In a 6-week parallel controlled study of adults, none of the 3 mg eszopiclone was discontinued due to adverse events. In a 6-month long-term study of adult patients with insomnia, 7.2% of the 195 patients taking placebo and 12.8% of the 593 patients taking 3 mg eszopiclone discontinued the trial due to adverse events. The incidence of non-adverse event withdrawals was higher than 2%.
Adverse events with a rate of greater than 2% in controlled trials Table 1 shows the incidence of treatment-related adverse events in a 44-day phase III placebo-controlled clinical trial in which adult patients took 2 mg or 3 mg eszopiclone . This table only includes adverse events greater than 2% in the 2 or 3 mg eszopiclone group compared to the placebo group.
Table 1: Incidence of treatment-related adverse events in placebo-controlled clinical trials with eszopiclone for 6 weeks in adult patients

Note: Adverse events comparable to or less frequent than placebo include abnormal dreams, accidental trauma, stomach pain, diarrhea, flu, myalgia, pain, sore throat, rhinitis,
Table 1 shows that dose-related adverse events in adult patients include viral infections, dry mouth, dizziness, hallucinations, infections, rashes, and abnormal taste. Among them, the dose correlation of abnormal taste is the most obvious.
Table 2 shows the incidence of treatment-related adverse events in elderly patients (aged 65-86 years) taking 1 mg or 2 mg eszopiclone for 14 days in combination with a phase III placebo-controlled clinical trial. The table includes only placebo and placebo. Adverse events were greater than 2% in the 1 mg or 2 mg eszopiclone group compared with the agent group.
Table 2 Incidence of treatment-related adverse events in placebo-controlled clinical trials of eszopiclone for 2 weeks in elderly patients (age 65-80 years)

Note: Adverse events comparable to or less frequent than placebo included abdominal pain, weakness, nausea, rash, and lethargy.
Table 2 shows that dose-related side effects in elderly patients include: pain, dry mouth, and abnormal taste. Among them, the abnormality of taste is most significantly related to the dose.
Due to differences in patient characteristics and other factors in clinical trials, these data cannot be used to predict the incidence of adverse events in normal medical practice. Similarly, due to differences in therapeutic drugs and methods of use with clinical evaluators, the data cited in this trial are incomparable with data from other clinical trials. But these numbers can provide some references for clinicians. ^[2]

Ezozopiclone contraindications:

Those who are allergic to this product and its ingredients, patients with decompensated respiratory insufficiency, and patients with myasthenia gravis and severe sleep apnea syndrome are prohibited. ^[2]

Precautions for eszopiclone :

Special attention is given to the fact that sleep disorders may be a manifestation of physical and / or psychological disorders, and symptomatic treatment is only taken after careful evaluation of the patient. The presence of insomnia after 7-10 days of treatment indicates the presence of a primary psychological and / or medical disorder. The worsening of insomnia or the emergence of new ideas and behavioral abnormalities may be the result of cognitive or psychological disorders. This may occur during sedative / hypnotic medication, including eszopiclone treatment. Because some of the side effects of eszopiclone are dose-dependent, it is important to use the lowest effective dose, especially for elderly patients.
It has been reported that taking sedative / hypnotic drugs can cause a series of abnormal thoughts and behavior changes. Some changes resemble the effects of alcohol and other central nervous system inhibitors, such as aggressiveness and extraversion that is incompatible with personality. Other reported behavioral changes include strange behaviors, agitation, hallucinations, and loss of personality, unforeseen potential for amnesia and other neuropsychiatric symptoms. Depression patients have reported worsening depression, including suicidal thoughts, when taking sedative / hypnotic medications.
It is difficult to determine whether the above-mentioned abnormal behaviors are caused by drugs, spontaneous or psychological or physiological disorders. However, any new signs or symptoms of behavior should be carefully evaluated.
When the amount of sedative / hypnotic drugs drops rapidly or is suddenly stopped, there may be similar withdrawal signs or symptoms with other CNS inhibitors.
Like other hypnotic drugs, eszopiclone has a central inhibitory effect. Due to its rapid onset of action, eszopiclone should only be taken before going to bed or if you have been in bed but have difficulty sleeping. After taking the drug and the next day, patients should be careful of dangerous tasks (such as operating an instrument or driving a car) that require complete alertness or behavioral coordination. Like other hypnotic drugs, eszopiclone in combination with other psychiatric drugs, anticonvulsants, antihistamines, ethanol, and other drugs that produce CNS inhibitory effects may produce additional CNS inhibitory effects. Eszopiclone cannot be taken with alcohol. Due to the additive effect that may occur, the dose adjustment of eszopiclone and other CNS inhibitors should be adjusted.
The time of taking eszopiclone should be taken before going to bed. Taking sedative / hypnotic drugs may cause short-term memory impairment, hallucinations, coordination disorders, dizziness, and dizziness.
Use of sedative / hypnotic drugs in elderly and / or frail patients should take into account motor impairment and / or cognitive impairment caused by repeated use or sensitivity to the drug. The recommended starting dose for such patients is 1 mg.
Patients with other diseases have limited clinical experience in taking eszopiclone in patients with other diseases. Caution should be taken when taking eszopiclone for diseases that may affect metabolism or hemodynamics.
In a clinical study of healthy volunteers, taking zozopiclone at twice the recommended dose (7 mg) did not produce respiratory-suppressive effects. However, if patients with respiratory disorders use eszopiclone, attention is advised.
Because patients with severe liver injury have twice the systemic exposure as patients with normal liver function, the dose of eszopiclone should be reduced to 1 mg. No dose adjustment is necessary for patients with mild or moderate hepatic impairment. Because less than 10% of eszopiclone is metabolized by urine as the original drug, there is no need for dose adjustment in patients with renal impairment. When combined with a strong inhibitor of CYP3A4, such as ketoconazole, the dose of eszopiclone should be reduced. It is also recommended to reduce the dose of eszopiclone in combination with CNS inhibitory drugs.
Patients with depression should use sedative / hypnotic drugs with caution. Such patients may be suicidal and protection may be required. These patients often take drugs deliberately overdose, so the number of prescriptions should be as low as possible. ^[2]

Dexopiclone medication for pregnant and lactating women:

Due to its proper lipophilicity, this product can easily enter the brain, and eszopiclone and its metabolites can partially pass through the placental barrier. At the same time, this product may have a higher concentration in milk. Therefore, pregnant women and lactating women should use this medicine with caution. ^[2]

Dexopiclone for children:

The safety and effectiveness of the drug for children under the age of 18 have not been established, and this drug is not recommended. ^[2]

Eszopiclone for elderly:

When taking the medicine, you can start with a small dose and gradually increase it in order to get a dose suitable for the patient, see the [Usage and Dosage] item. ^[2]

Dexopiclone Drug Interactions:

CNS-active drug ethanol: eszopiclone combined with 0.70 g / kg ethanol can have an additive effect on neuromotor function for 4 hours.
Paroxetine: 3 mg of dexzopiclone and 2 mg of paroxetine were used daily for 7 days. There was no interaction between pharmacokinetics and pharmacodynamics.
Lorazepam: The combination of 3mg eszopiclone and 2mg lorazepam has no clinically relevant pharmacodynamic and pharmacokinetic effects.
Olanzapine: The combination of 3 mg eszopiclone and 10 mg olanzapine reduced the DSST score. The interaction is a change in pharmacodynamics rather than a change in pharmacokinetics.
Drugs that inhibit CYP3A4 (ketoconazole)
CYP3A4 is the main metabolic channel eliminated by eszopiclone. Combined with 400 mg of ketoconazole (a strong inhibitor of CYP3A4) for 5 days, the AUC of eszopiclone increased by 2.2 times. Cmax and t1 / 2 increased by 1.4 and 1.3 times, respectively. Other strong inhibitors of CYP3A4 may produce similar effects (for example: itraconazole, clarithromycin, nefazodone, ambomycin, ritonavir, nelfinavir).
Drugs that induce CYP3A4 (rifampin)
The combination with rifampin, a strong inducer of CYP3A4, can reduce the exposure rate of mesozopiclone by 80%. Eszopiclone may have a similar effect.
Drugs with strong plasma protein binding ability eszopiclone plasma protein binding rate is not strong (52% -59%); therefore, the distribution of eszopiclone should not be sensitive to protein binding. Patients taking 3mg eszopiclone and strong protein binding drugs should not change the free concentration of the two drugs.
Digoxin with a narrow therapeutic index: 0.5 mg twice a day on the first day of taking digoxin, and 0.25 mg a day for the next 6 days does not affect the pharmacokinetic parameters of a single dose of 3 mg eszopiclone.
Warfarin; taking 3mg eszopiclone for 5 days does not affect the pharmacokinetic parameters of (R) and (S) warfarin: oral 25mg warfarin does not affect the pharmacodynamic parameters of eszopiclone. ^[2]

Dezopiclone overdose:

High-dose pre-marketing clinical trials using eszopiclone are limited. A clinical trial of eszopiclone reported a complete recovery in a patient using a 36 mg overdose of eszopiclone. Patients who used racemic zopiclone overdose 340mg also fully recovered (equivalent to 56 times the maximum recommended dose of zozopiclone).
Symptoms and signs Amplification of preclinical drug effects can be considered as signs and symptoms of excessive CNS inhibitor use. The degree of impairment of consciousness ranges from hesitancy to coma. After racemic zopiclone was marketed in Europe, there have been reports of overdose lethality, but such events are often combined with other central nervous system inhibitors.
The recommended treatment after overdose is gastric lavage, symptomatic and supportive treatment as soon as possible. Flumazenil may be useful when given intravenous fluids. In all cases of overdose use of drugs, the patient's breathing, pulse and blood pressure should be monitored, and some systemic supportive therapies should be used. Cases of hypotension and central nervous system depression should be monitored and appropriate treatment measures taken. The value of dialysis is unknown. ^[2]

Dexopiclone Pharmacology and Toxicology:

1. Toxicology research:
Genotoxicity The chromosomal aberration test results of zozopiclone mouse lymphoma cells were positive, and the chromosomal aberration test results of CHO cells were unclear. The Ames test, UDS test, and nuclear transfer test of mice were all negative. Test results of dexazopiclone metabolite (S) -N-demethyl-zopiclone CHO cells and human lymphocytes were positive for chromosomal aberration test, Ames test, 32P-terminally labeled DNA addition test, mouse bone marrow cells in vivo Chromosome aberration test and micronucleus test results were negative.
Reproductive toxicity In fertility and early embryonic developmental toxicity tests, male and female rats orally administered eszopiclone at 45 and 180 mg / Kg / day, respectively. Fertility of both sexes of animals was reduced. At the time of administration, no pregnancy occurred in the female animals, and no effect dose was found to be 5 mg / Kg / day (calculated as mg / m, which is equivalent to 16 times the maximum recommended human dose). Other effects include increased preimplantation loss (25mg / Kg at no effect), abnormal estrous cycle (25mg / Kg at no effect), and decreased sperm count and activity, and increased morphological abnormality (no effect at 5mg / Kg).
In the embryo-fetal developmental toxicity test, pregnant rats and rabbits were orally administered during the organogenesis period, and no teratogenicity was seen at the highest dose tested (250 and 16 mg / Kg / day, respectively, mg / m estimates are equivalent to 800 and 100 times the maximum recommended human dose, respectively). In rats, at the doses of 125 and 150 mg / Kg / day for maternal toxicity, the fetal weight was slightly reduced and the development was retarded. 200 times).
In the perinatal toxicity test, rats were given orally dexazopiclone 180 mg / Kg / day during pregnancy and lactation. It can be seen that the loss after implantation increased in each dose group, the weight and survival rate of the pups decreased, and the scared response of the pups increased. The minimum dose is 60 mg / Kg / day, and the extrapolation based on mg / m is equivalent to 200 times the maximum recommended human dose. There was no obvious maternal toxicity in the test, and it had an impact on other behavioral indicators or reproductive function.
In the carcinogenicity test of carcinogenic SD rats given eszopiclone by mouth, the incidence of tumors was increased, the high dose was 16 mg / Kg / day, and the plasma level (AUC) was estimated as the plasma level at the recommended dose for large amounts of humans. 80 times (female) and 20 times (male). However, in the carcinogenicity test of racemic zopiclone given to SD rats by admixture, at a dose of 100 mg / Kg / day, the plasma level of dexazopiclone was higher than that achieved in the dexazopiclone carcinogenicity test described above. Level, it can be seen that the incidence of breast cancer in females and thyroid adenoma and cancer in males has increased. At this time, the plasma level of eszopiclone was estimated to be 150 times (female) and 70 times the level at the maximum recommended human dose. (Female). The pathogenesis of breast cancer is unclear. The increase in the incidence of thyroid tumors is thought to be caused by increased thyroid hormone metabolism in the circulation and elevated levels of TSH in the hair, which is believed to be unrelated to humans.
In the carcinogenicity test of B6C3F1 mice, racemic zopiclone was administered in an admixture method. At the highest dose of 100 mg / Kg / day, the incidence of lung tumors in females increased, and the incidence of cutaneous fibromas and endomas in males increased. Plasma levels of eszopiclone at these doses were 8 times (female) and 20 times (male) the highest recommended human dose. The occurrence of skin tumors is caused by aggressive behavior in animals and has no correlation with humans. In a carcinogenicity test of CD-1 mice, dexazopiclone was administered orally up to 100 mg / Kg / day. Increased incidence of skin swelling and cancer. The plasma level at the highest dose in this trial was estimated to be 90 times the level at the maximum human recommended dose. That is 12 times the exposure in the racemate test. In the P53 transgenic mouse test, when the oral dose reached 300 mg / Kg / day, no increase in tumor incidence was seen.
2. Pharmacological effects:
Dexopiclone is a non-benzodiazepine hypnotic. The exact mechanism of dextropiclone's hypnotic effect is unknown, but it is thought to be caused by the action of GABA receptor complexes coupled to benzodiazepine receptors. of. ^[2]

Dexopiclone pharmacokinetics:

Pharmacokinetic studies were performed on healthy volunteers (adults and the elderly) and those with liver and kidney disease. Among healthy subjects, the highest single dose reached 7.5mg, and a 7-day continuous administration test was performed, the doses were 1 , 3 and 6mg, this product can be quickly absorbed, peak (tmax) in about 1 hour, terminal half-life is about 6 hours, healthy adults continue to take this product does not accumulate, at 1-6mg; distribution is linear with the amount .
Absorption and distribution This product is quickly absorbed after oral administration, and reaches the peak plasma concentration about 1 hour after oral administration. The plasma protein binding rate is low, ranging from 52% to 59%. Non-selective absorption of red blood cells.
Metabolism After oral administration, this product is mainly metabolized by oxidation and demethylation. The main plasma metabolites are N-oxidized zozopiclone and N-desmethylzozopiclone. N-desmethyl zozopiclone has a lower binding rate to GABA receptor than zozopic clone, and N-oxidized zozopic clone does not bind to GABA receptor tightly. In vitro experiments show that eszopiclone metabolism is related to CYP3A4 and CYP2E1. Eszopiclone did not show any inhibitory effect on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4 on cryopreserved hepatocytes.
After oral absorption is eliminated, the elimination half-life of dexazopiclone is about 6 hours. Oral zopiclone, 75% of the dose is excreted in the form of metabolites in the urine. Elimination of eszopiclone is similar to zopiclone, with less than 10% oral dose of eszopiclone eliminated from urine with the original drug.
Food healthy adults, taking 3mg eszopiclone orally after taking high diet, the AUC did not change, the average Cmax decreased by 21%, and the Tmax was delayed by 1 hour. The half-life did not change, about 6 hours. If eszopiclone is taken immediately after high fat / excessive food, the effect of eszopiclone on sleep latency may be reduced.
Compared with adults, the age of medication in special populations increased by 41% in patients over 65 years of age, with a half-life of approximately 9 hours and no significant change in Cmax.
Gender males and females have similar pharmacokinetic parameters.
Race analyzed data from all subjects in the Phase I clinical trials, and all pharmacokinetic results were similar.
Liver injury 162 healthy volunteers and 8 patients with mild, moderate, and severe liver disease underwent pharmacokinetic studies with 2 mg eszopiclone. Compared with healthy volunteers, patients with severe liver injury experienced a two-fold increase in exposure, and Cmax and tmax beams were induced. The maximum dose for patients with severe liver injury should be 2 mg. No dose adjustment is necessary in patients with mild to moderate liver damage. Patients with liver injury should take caution when taking eszopiclone (see [Dosage and Administration] section).
Renal Injury Pharmacokinetic studies were performed in 24 patients with mild, moderate or severe renal impairment. AUC was similar to Cmax compared to healthy controls. Because less than 10% of oral eszopiclone is metabolized by urine, there is no need for dose adjustment in patients with renal impairment. ^[2]