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Eszopiclone (Wen Fei)

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Indications: Used to treat insomnia.

Approval date: April 19, 2007

Date of revision: April 17, 2009 September 16, 2009 July 10, 2012 March 04, 2014 August 5, 2014 November 12, 2015 February 8, 2018

Please read the instructions carefully and use under the guidance of a physician.

【Drug Name】

Common name: eszopiclone

Product Name: Wenfei

English name: Dexzopiclone Tablets

Phonetic script: Youzuopikelong Pian

[Ingredients]

The active ingredient of this product is eszopiclone.

Chemical name: (+)-6- (5-chloropyridin-2-yl) -7-[(4-methylpiperazin-1-yl) carbonyloxy] 5,6-dihydropyrrole [3,4 -b] pyrazin-5-one

Molecular formula: C 17 H 17 C1N 6 O 3

Molecular weight: 388.81

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

[Specifications] 1mg, 2mg, 3mg

【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 Precautions).

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.

【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, and long-term and short-term trials. Adverse reactions were evaluated by collecting adverse events and evaluating the results of physical examination, vital signs, weight, laboratory tests, and ECG.

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 reactions observed in placebo-controlled trials

Adverse events leading to discontinuation

In a placebo-parallel controlled trial of older people, 3.8% of 208 patients who received placebo, 2.3% of 215 patients who took 2mg eszopiclone, and 72 patients who took 1mg eszopiclone In 1.4%, treatment was discontinued due to adverse events. In a 6-week parallel group controlled study of adults, none of the 3 mg eszopiclone-treated patients discontinued treatment 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 3mg eszopiclone were discontinued due to adverse events. The incidence of non-adverse event withdrawals was higher than 2%.

Adverse events with a rate 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 includes only 2% or more adverse events in the 2 mg or 3 mg eszopiclone group compared to the placebo group.

Note: Adverse events comparable to or less frequent than placebo included abnormal dreams, accidental trauma, stomach pain, diarrhea, flu, myalgia, pain, sore throat, and 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 (age 65-86 years) taking 1 mg or 2 mg eszopiclone for 14 days in a combined phase III placebo-controlled clinical trial. The table includes only events with an adverse event greater than 2% in the 1 mg or 2 mg eszopiclone group compared to the placebo group.

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.

[Taboo]

Those who are allergic to this product and its components, patients with decompensated respiratory insufficiency, patients with myasthenia gravis, and severe sleep apnea syndrome are prohibited.

【Precautions】

pay attention

Because sleep disorders may be a manifestation of physical and / or psychological disorders, 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 unrecognized psychological or physical 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 behavior, agitation, hallucinations, and loss of personality. It is unforeseeable that amnesia and other neuropsychiatric symptoms may occur. 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 sedative / hypnotic doses are rapidly decreased or abruptly discontinued, similar withdrawal signs or symptoms may occur 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 falling asleep. After taking the drug and the next day, patients should be careful about 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, alcohol, and other drugs that produce CNS inhibitory effects may produce additional CNS inhibitory effects. Eszopiclone cannot be taken with alcohol. Due to the potential for additive effects, eszopiclone in combination with other CNS inhibitors should be dose-adjusted.

Medication time

Eszopiclone should be taken just before bedtime. Taking sedative / hypnotic drugs may cause short-term memory impairment, hallucinations, coordination disorders, dizziness, and dizziness.

Use in elderly and / or frail patients

The use of sedative / hypnotic drugs in elderly patients and / or debilitated patients should take into account sports injury 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

Clinical experience with eszopiclone in patients with other diseases is limited. Patients with a disease that may have an impact on metabolism or hemodynamics should use eszopiclone with caution.

In a clinical study of healthy volunteers, taking twice the recommended dose (7 mg) of eszopiclone did not produce respiratory depression. However, if patients with respiratory disorders use eszopiclone, attention is advised.

Because patients with severe liver injury have twice the systemic exposure as those 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.

Used by depressed patients

Patients showing depressive symptoms should take sedative / hypnotic medication with caution. Such patients may be suicidal and protection may be required. These patients often take drugs deliberately. Therefore, the amount of each prescription should be as low as possible.

[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.

[Child medication]

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

[Medicine for the elderly]

The dosage can be gradually increased from a small dose in order to obtain a dose suitable for the patient. See [Usage and Dosage].

【medicine interactions】

1. CNS active drugs

Ethanol: The combination of eszopiclone and 0.70g / kg alcohol can have an additive effect on neuromotor function, which can last for 4 hours.

Paroxetine: 3 mg of dexazopiclone and 2 mg of paroxetine were used daily for 7 days without pharmacokinetic and pharmacodynamic interactions.

Lorazepam: There is no clinically relevant pharmacodynamic and pharmacokinetic effect of 3 mg eszopiclone and 2 mg lorazepam.

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.

2. Drugs that inhibit CYP3A4 (ketoconazole)

CYP3A4 is the main metabolic channel eliminated by eszopiclone. Co-administration with 400 mg of ketoconazole, a strong inhibitor of CYP3A4, for 5 days increased the AUC of eszopiclone by 2.2 times. 和t 1/2分别增加1.4倍和1.3倍。 C max and t 1/2 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).

3. Drugs that induce CYP3A4 (rifampin)

Combined with rifampin, a strong inducer of CYP3A4, the exposure of racemic zopiclone was reduced by 80%. Eszopiclone may have a similar effect.

4. Drugs with strong plasma protein binding

The plasma protein binding rate of eszopiclone is not very 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.

5. Drugs with a narrow therapeutic index

Digoxin: 0.5 mg twice a day on the first day of taking digoxin, and 0.25 mg a day for the next 6 days, without affecting 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; taking 25mg warfarin orally. Does not affect the pharmacodynamic parameters of eszopiclone.

[Drug 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 took an overdose of 340 mg of racezopiclone also recovered completely (equivalent to 56 times the maximum recommended dose of zozopiclone).

Symptoms and signs

Amplification of preclinical pharmacological effects can be considered as symptoms and signs of excessive CNS inhibitor use. The degree of impairment of consciousness ranges from drowsiness to unconsciousness. 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.

Recommended treatment after overdose

Stomach 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.

[Pharmacology and Toxicology]

Pharmacological action

Dexopiclone is a non-benzodiazepine hypnotic. The exact mechanism of eszopiclone's hypnotic effect is unknown, but it is thought to be caused by the action of the GABA receptor complex coupled to the benzodiazepine receptor.

Toxicology research

Genotoxicity

The chromosomal aberration test results of eszopiclone mouse lymphoma cells were positive, the CHO cell chromosome aberration test results were unclear, and the Ames test, UDS test, and mouse micronucleus test results were all negative. Test results of dextropiclone metabolite (S) -N-demethyl-zopiclone in CHO cells and human lymphocytes were positive, Ames test, 32P-terminally labeled DNA addition test, mouse bone marrow in vivo Cell chromosome aberration test and micronucleus test were negative.

Reproductive toxicity

In fertility and early embryonic developmental toxicity tests, male and female rats were given orally dexazopiclone at 45 and 180 mg / kg / day, respectively. Fertility of both sexes of animals was reduced, and male and female animals were administered at high doses. At that time, no pregnancy occurred in the female animal, and no effect dose was found to be 5 mg / Kg / day (calculated as mg / m 2 , 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), reduced sperm count and motility, and increased morphological abnormal sperm count (no effect at 5mg / Kg).

In the embryo-fetal developmental toxicity test, pregnant rats and rabbits were administered orally during the period of organogenesis, and no teratogenicity was seen at the highest doses tested (250 and 16 mg / Kg / day, respectively, mg / m2 projections 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, but the dose was 62.5 mg / Kg / day (equivalent to the maximum recommended human dose based on mg / m 2) 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 lowest dose is 60mg / Kg / day, and the extrapolation based on mg / m 2 is equivalent to 200 times the maximum recommended human dose. There was no obvious maternal toxicity in the test, and it had no effect on other behavioral indicators or reproductive function of the offspring.

Carcinogenicity

No increase in tumor incidence was observed in the carcinogenicity test of SD rats given dexazopiclone orally. The highest dose was 16 mg / Kg / day, and the plasma level (AUC) was estimated to be 80 times the human maximum plasma level (female). Animals) and 20-fold (male animals). 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 female animals and thyroid adenoma and cancer in male animals increased. At this time, plasma levels of eszopiclone were estimated to be 150 times (female) and 70 times (male) at the maximum human recommended dose. The pathogenesis of breast cancer is unclear. The increase in the incidence of thyroid tumors is thought to be caused by an increase in circulating thyroid hormone metabolism secondary to an increase in TSH levels, which is believed to be unrelated to humans.

In the carcinogenicity test of B6C3F1 mice, racemic zopiclone was administered by admixture. At the highest dose of 100 mg / Kg / day, the incidence of lung tumors in females increased, and the incidence of cutaneous fibroma and sarcoma in males increased. Plasma levels of eszopiclone at the above doses are 8 times (female) and 20 times (male) at 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, and there was no increase in the incidence of lung and skin tumors. The plasma level at the highest dose in this test is estimated to be 90 times the level at the maximum human recommended dose, which is 12 times the exposure in the racemate test described above. In the P53 transgenic mouse test, when the oral dose reached 300 mg / Kg / day, no increase in tumor incidence was seen.

【Pharmacokinetics】

Pharmacokinetic studies were performed on healthy volunteers (adults and elderly) and those with liver and kidney disease. In healthy subjects, the single dose reached a maximum of 7.5 mg, and a 7-day continuous dosing trial was conducted at doses of 1, 3, and 6 mg, respectively. ),消除半衰期大约为6小时。 This product can be quickly absorbed, reaching the peak (t max ) in about 1 hour, and the elimination half-life is about 6 hours. Healthy adults continue to take this product without accumulation, at 1-6mg, the distribution has a linear relationship with the dose.
Absorption and distribution

This product is quickly absorbed after oral administration. Peak plasma concentrations were reached approximately 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 through oxidation and demethylation. The main plasma metabolites are N-oxidized zozopiclone and N-desmethyl zozopiclone. 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 closely. In vitro experiments show that the metabolism of eszopiclone 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.

eliminate

After oral absorption, the elimination half-life of eszopiclone is approximately 6 hours. Oral racemic 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

降低21%,t max延迟1小时。 After taking high-fat foods orally to healthy adults, 3 mg of eszopiclone was administered orally. The AUC did not change, the average C max was reduced by 21%, and the t max was delayed by 1 hour. The half-life did not change, about 6 hours. If eszopiclone is taken during and immediately after eating high-fat foods, the effect of eszopiclone on sleep latency may be reduced.

Medication for special populations

age

未发生明显变化。 Compared with adults, patients over 65 years of age had a 41% increase in AUC, a half-life of approximately 9 hours, and no significant change in Cmax .

gender

Male and female pharmacokinetic parameters are similar.

race

Analysis of data from all subjects in the Phase I clinical trials showed similar pharmacokinetic results for all races.

liver damage

Sixteen healthy volunteers and eight patients with mild, moderate, and severe liver disease underwent pharmacokinetic studies with 2 mg eszopiclone. 与t max未发生变化。 Compared with healthy volunteers, patients with severe liver injury experienced a two-fold increase in exposure, and C max and t max did not change. 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 pay attention to taking eszopiclone (see [Dosage and Administration] item).

Kidney injury

Pharmacokinetic studies were performed in 24 patients with mild, moderate or severe renal impairment. 相似。 Compared to healthy controls, AUC was similar to Cmax . Because less than 10% of oral eszopiclone is excreted through urine, there is no need for dose adjustment in patients with renal impairment.

[Storage] Sealed and stored in a dry place.

[Packaging] Aluminum plastic blister pack

1mg: 6 tablets / plate, 1 plate / box; 10 tablets / plate, 2 plates / box;

2mg: 6 tablets / plate, 1 plate / box; 10 tablets / plate, 2 plates / box;

3mg: 6 tablets / plate, 1 plate / box; 7 tablets / plate, 1 plate / box; 10 tablets / plate, 2 plates / box;

[Validity] 24 months

[Executive standards] The first supplement of the 2015 edition of the Chinese Pharmacopoeia

[Approval number] Approval number: 1mg: Sinopharm standard word H20090210

2mg: National Medicine Standard H20090209

3mg: National Medicine Standard H20070069

Designated production batch number: 1mg: Su 201603

2mg: Su 201301

3mg: Su 201301

【manufacturer】