Zopiclone and its analogues in the treatment of insomnia and other disorders. Imovan - instructions for use Possible side effects and overdose

Round tablets, green, film-coated, biconvex shape.

Compound

Each Zopiclone-LF tablet contains:

active substance: zopiclone - 7.5 mg.

Excipients: microcrystalline cellulose, sodium starch glycolate (type A), magnesium stearate, calcium hydrogen phosphate dihydrate, lactose monohydrate, Opadry II (green) (partially hydrolysed polyvinyl alcohol, titanium dioxide E 171, macrogol/PEG, talc, indigo carmine aluminum hydroxide E 132, quinoline yellow aluminum varnish E 104).

Release form

Coated tablets.

Pharmacotherapeutic group

Psycholeptics. Sleeping pills and sedatives. benzodiazepine-like drugs.

The codeATX: N05CF01

Pharmacological properties

Zopiclone - hypnotic, which rapidly initiates and maintains sleep without reducing total REM sleep and preserves non-REM sleep. Little residual effects are observed the next morning after zopiclone application. Pharmacological properties zopiclone include hypnotic, sedative, anxiolytic, anticonvulsant and muscle relaxant actions.

Indications for use

Zopiclone is used to treat the following sleep problems in adults:

• difficulty falling asleep;
• night awakenings;
• early awakenings;
• severe sleep disorders.

Zopiclone can be used to treat both temporary and chronic insomnia. However, Zopiclone is not intended for daily use over a long period of time or for the treatment of depression.

If you have any doubts or questions, please consult your doctor.

Dosage and administration

Inside, without chewing and not dissolving, immediately before going to bed.

The dose should be selected depending on the patient's age, body weight, general health and type of insomnia. Treatment should begin with the lowest effective dose.

Adults under 65 years of age: 7.5 mg once daily.

Patients with impaired renal function: Accumulation of zopiclone and its metabolites has not been observed in the treatment of insomnia in patients with kidney failure. However, treatment of such patients is recommended to start with a dose of 3.75 mg.

Patients with hepatic impairment: Because zopiclone elimination may be reduced in patients with hepatic impairment, the recommended dose is 3.75 mg. The 7.5 mg dose should only be used with caution in exceptional cases, depending on efficacy and tolerability. medicinal product.

Patients with chronic lung failure: the recommended initial dose is 3.75 mg, if necessary, the dose can be increased to 7.5 mg.

In all cases, the dose should not exceed 7.5 mg per day.

Children

Zopiclone should not be used in children under 18 years of age. The safety and efficacy of zopiclone in children under 18 years of age have not been established.

Duration of treatment

Treatment should be as short as possible, ranging from a few days to 2-4 weeks (maximum), including a dose reduction period.

Situational insomnia (for example, during travel) - 2-5 days, short-term insomnia - 2-3 weeks.

If a low dose is required, the use of other medicinal products containing zopiclone is recommended.

Before starting the use of the drug, patients should be explained that therapy should not be long-term and how to gradually stop it. The gradual cessation of treatment reduces the risk of recurrence of insomnia.

To reduce anxiety possibly associated with discontinuation of the drug, the patient should be warned about the possibility of recurrence of insomnia after discontinuation of treatment.

If you miss the next dose of the drug, you must take it. But you should not use a double dose of the drug to replace the missed one. Continue taking the drug should be according to the doctor's recommendations.

If you have any doubts or questions, please contact your doctor.

Side effect

The most commonly observed adverse reaction is a bitter or metallic taste in the mouth. Other possible adverse reactions are listed below. Their appearance is associated with individual sensitivity, more often observed within an hour after application, if the patient does not immediately go to bed and does not fall asleep.

The following listed side effects ordered according to classification of organ system groups and MedDRA frequency: very often (>1/10), often (>1/100 to<1/10), нечасто (>1/1 000 to<1/100), редко (>1/10 000 up to<1/1 000), очень редко (<1/10 000), частота неизвестна (невозможно определить частоту по имеющимся данным).

Immune System Disorders: very rarely - angioedema, anaphylactic reactions.

Mental disorders: infrequently - nightmares, arousal; rarely - confusion, decreased libido, irritability, aggressiveness, hallucinations; frequency unknown - anxiety, delirium, anger, depressed mood, inappropriate behavior (possibly associated with amnesia) and somnambulism, dependence, withdrawal syndrome.

Nervous System Disorders: often - dysgeusia (bitter taste in the mouth), residual drowsiness; infrequently - dizziness, headache; rarely - antegrade amnesia (the risk increases with increasing dose; in some cases, behavioral disturbances can be observed additionally); frequency unknown - ataxia, paresthesia.

Violations of the organ of vision: frequency unknown - diplopia.

Respiratory, thoracic and mediastinal disorders: rarely - shortness of breath; frequency unknown - respiratory depression.

Gastrointestinal disorders: often - dry mouth, infrequently - nausea, vomiting; frequency unknown - dyspepsia.

Liver and biliary tract disorders: very rarely - a slight or moderate increase in the level of transaminases and / or alkaline phosphatase in plasma.

Skin and subcutaneous tissue disorders: rarely - urticaria or rash, itching.

Musculoskeletal and connective tissue disorders: frequency unknown - muscle weakness.

General disorders and disorders at the injection site: frequency unknown - weakness.

Injuries, intoxications, complications of manipulations: rarely - falls (mainly in elderly patients).

There are reports that after discontinuation of zopiclone, a withdrawal syndrome develops, the symptoms of which vary and can manifest as "rebound" insomnia, muscle pain, restlessness, tremors, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, hallucinations , nightmares, panic attacks, muscle cramps, gastrointestinal disturbances and irritability. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling in the extremities, increased sensitivity to light and noise, tactile hyperesthesia, hallucinations. In very rare cases, seizures may occur.

In the event of adverse reactions, including those not listed in this leaflet, you must stop taking the drug and consult a doctor.

Contraindications

• hypersensitivity to zopiclone or to any of the auxiliary components of the drug;
• severe respiratory failure;
• severe liver failure;
• sleep apnea syndrome;
• myasthenia gravis;
• pregnancy and lactation period;
• children's age up to 18 years;
• rare congenital lactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Overdose

Symptoms
Symptoms of an overdose depend on the dose of the drug taken and are manifested by signs of depression of the central nervous system (CNS), ranging from drowsiness to the development of a coma. In mild cases, an overdose is accompanied by drowsiness, confusion, lethargy; in more severe cases, there is ataxia, hypotension, methemoglobinemia, respiratory depression and coma. An overdose is not life threatening unless other CNS depressants, including alcohol, have been used concomitantly. Other risk factors, such as the patient's concurrent illness and debilitating state of health, may exacerbate symptoms and, in very rare cases, cause death.

Treatment
Within an hour after an overdose of zopiclone, it is necessary to wash the stomach, give activated charcoal. If necessary, symptomatic and supportive therapy is recommended in a hospital setting with monitoring of respiratory and cardiovascular activity.
In severe cases, the benzodiazepine receptor antagonist flumazenil can be used as an antidote. It has a short half-life (about an hour). Flumazenil should not be used in cases of mixed overdose or as a diagnostic tool.
In case of drug overdose, hemodialysis is not effective due to the large volume of distribution of zopiclone.

Precautionary measures

Whenever possible, the cause of insomnia should be identified and possible precipitating factors should be eliminated before prescribing a hypnotic.

Benzodiazepines and benzodiazepine-like drugs are not prescribed as the main drugs in the treatment of psychosis.

Treatment with zopiclone should be short-term or intermittent to reduce the risk of developing symptoms on drug withdrawal.

High risk groups

The greatest caution should be observed in cases where there is a history of alcoholism or addiction/dependence on other substances;

Patients with impaired liver function, tk. benzodiazepines and benzodiazepine-like drugs in severe liver failure can accelerate the development of encephalopathy, so in this case they are contraindicated;

Patients with respiratory failure, tk. benzodiazepines and their derivatives can depress the respiratory center (anxiety and anxiety can be harbingers of respiratory decompensation);

Elderly patients, tk. the muscle relaxant and sedative effects can lead to fall injuries.

Addiction Risk

Treatment with benzodiazepines and their derivatives, especially long-term, even at therapeutic doses, can lead to physical and mental dependence.

The risk of addiction increases when the following factors are present:

Increase in duration of treatment (more than 4 weeks);

Alcohol abuse and / or taking other psychotropic drugs;

Anxiety.

If the patient has developed a physical dependence, then the sudden discontinuation of zopiclone can lead to the development of an abstinence syndrome: headache, muscle pain, anxiety, restlessness, tension, irritability, confusion. In more severe cases, symptoms may appear: derealization, depersonalization, numbness and tingling in the limbs, increased sensitivity to light, noise and touch, hallucinations or epileptic seizures.

After stopping treatment, withdrawal symptoms may occur within a few days. With the duration of treatment with zopiclone no more than 4 weeks, the likelihood of developing withdrawal symptoms is minimal. It is recommended to cancel the drug gradually.

Depression

Benzodiazepines and benzodiazepine-like drugs should not be used alone in the treatment of depression and in the treatment of anxiety caused by depression, as they may induce suicide.

Tolerance

With the use of benzodiazepines and their derivatives, after repeated use for several weeks, some loss of effectiveness is possible. In patients who took zopiclone for no more than 4 weeks, cases of addiction were not noted. With the development of tolerance, you can not increase the dose of the drug.

The phenomenon of "recoil"

With the termination of therapy with benzodiazepines and their derivatives in an enhanced form, insomnia may resume, anxiety, anxiety, and mood changes may appear. The appearance of the syndrome is facilitated by prolonged treatment or abrupt cessation of treatment. In this regard, at the end of treatment, it is recommended to gradually reduce the dose of the drug and inform the patient about this.

Amnesia

Rarely, antegrade amnesia may occur, especially when sleep is interrupted or after a long period of time between taking the pill and going to bed. To reduce the risk of antegrade amnesia, zopiclone should be taken just before bedtime and provided with conditions for 7-8 hours of uninterrupted sleep.

Psychomotor disorders

Like other sedative/hypnotics, zopiclone has a CNS depressant effect. The risk of developing psychomotor disorders, including impaired ability to drive vehicles, increases:

If zopiclone is taken within 12 hours before performing activities that require concentration of attention and speed of psychomotor reactions;

When using zopiclone in doses higher than recommended;

When zopiclone is co-administered with other CNS depressants, alcohol, or drugs that increase the blood concentration of zopiclone.

After taking zopiclone and, in particular, during the first 12 hours after taking it, patients should refrain from engaging in hazardous activities that require concentration of attention or speed of psychomotor reactions (such as working with mechanisms or driving vehicles).

Somnambulism and related behaviors

Sleepwalking and sleep-related behaviors (eg, cooking and eating, talking on the phone, driving) followed by amnesia have been reported in patients who have taken zopiclone and are not fully awake. Simultaneous use with zopiclone of drugs that depress the central nervous system, alcohol consumption, exceeding the recommended doses increases the risk of developing this disorder. In patients who report such conduct disorder, the drug should be discontinued.

Other mental and paradoxical reactions

In the treatment with zopiclone, some patients, mostly elderly, have been reported paradoxical reactions: increased insomnia, nightmares, anxiety, agitation, irritability, aggressiveness, fits of anger, delirium, hallucinations, oneiric delirium, confusion, psychotic symptoms, inappropriate behavior and others. behavioral disorders. If such reactions occur, the drug should be discontinued.

Risk of cumulation

Benzodiazepines and their analogues are in the body for a time equal to 5 half-lives. In patients with impaired liver function and the elderly, the half-life of zopiclone may increase significantly. With repeated doses, the concentration of zopiclone and its metabolites in the blood plasma is higher and the saturation stage is reached later. The efficacy and safety of the drug can be assessed after the saturation stage has been reached. Dose adjustment may be required.

Despite the fact that in patients with impaired renal function, no accumulation of zopiclone was detected during long-term use, the dose of the drug is reduced by 2 times.

During treatment with zopiclone, you should not drink alcohol, and you should also avoid taking medicines containing ethanol.

Use during pregnancy and lactation

Pregnancy

Experience with the use of zopiclone during human pregnancy is limited. Animal studies have not shown a negative effect on the course of pregnancy and fetal development. However, use during pregnancy is not recommended.

Patients should be warned by the attending physician about the need to discontinue the use of the drug if they are planning a pregnancy or suspect a pregnancy.

When prescribing the drug in the third trimester of pregnancy or during childbirth, symptoms such as hypothermia, hypotension, drowsiness and respiratory depression should be expected in the newborn.

Newborns whose mothers took benzodiazepines or their analogues in the last stages of pregnancy may develop physical dependence and the risk of withdrawal in the postnatal period.

lactation period

Zopiclone is excreted in breast milk. Despite the fact that the concentration of zopiclone in breast milk is low, the drug should be avoided during breastfeeding.

Influence on the ability to drive vehicles or potentially dangerous mechanisms

Due to its pharmacological properties and ability to affect the central nervous system, zopiclone may adversely affect the ability to drive vehicles or potentially dangerous machinery. The risk of developing psychomotor disorders, including the ability to drive vehicles, increases:

• if zopiclone is taken within 12 hours before performing activities that require concentration of attention and speed of psychomotor reactions;
• when using the drug in doses exceeding those recommended;
• when zopiclone is co-administered with drugs that depress the central nervous system, alcohol, or drugs that increase the concentration of zopiclone in the blood.

After taking zopiclone, especially during the first 12 hours after taking it, patients should refrain from engaging in hazardous activities that require concentration of attention or speed of psychomotor reactions (such as working with mechanisms or driving vehicles).

Interaction with other drugs

Always tell your doctor what medicines you are taking or have recently taken, even if they are over-the-counter medicines.

Alcohol

With the simultaneous use of zopiclone with alcohol, the sedative effect of benzodiazepines or benzodiazepine-like drugs is enhanced. Inhibited attention may affect the patient's ability to drive vehicles or operate machinery. Alcoholic beverages and medicines containing ethyl alcohol should be avoided.

Morphine derivatives (pain relievers, cough suppressants and replacement therapy), barbiturates- increased risk of respiratory depression; in case of overdose, a lethal outcome is possible.

Simultaneous use with drugs that depress the central nervous system: morphine derivatives (painkillers, cough suppressants and replacement therapy), barbiturates, antidepressants and H 1 antihistamines with sedative action, antianxiety drugs, antipsychotics, clonidine and its analogues, thalidomide- increased inhibitory effect on the central nervous system. Inhibited attention may affect the patient's ability to drive vehicles or operate machinery.

Clozapine

Increased risk of shock with respiratory arrest and/or cardiac arrest.

Erythromycin

The effect of erythromycin on the pharmacokinetics of zopiclone was studied in 10 healthy subjects.

In the presence of erythromycin, the AUC of zopiclone is increased by 80%, which indicates the ability of erythromycin to inhibit the metabolism of those drugs that are metabolized by CYP 3A4. As a result, the hypnotic effect of zopiclone may be enhanced.

Since zopiclone metabolizes the cytochrome P450 (CYP) 3A4 isoenzyme, co-administration with CYP 3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itraconazole and ritonavir may increase plasma levels of zopiclone. With simultaneous use with inhibitors of CYP 3A4, a dose reduction of zopiclone may be necessary.

Conversely, when co-administered with CYP3A4 inducers such as rifampicin, carbamazepine, phenobarbital, phenytoin and St. John's wort, plasma levels of zopiclone may decrease. With simultaneous use with inducers of CYP 3A4, it may be necessary to increase the dose of zopiclone.

Storage conditions

In a place protected from moisture and light at a temperature not exceeding 25 ºС.

Keep out of the reach of children.

Shelf life

Do not use after the expiry date stated on the package.

Catad_pgroup Anxiolytics (tranquilizers)

Imovan - instructions for use

Registration number:

Tradename: Imovan ®

International non-proprietary name:

Dosage form:

Compound
One tablet contains: Active substance: zopiclone 7.5 mg.
Excipients: wheat starch, calcium hydrogen phosphate dihydrate, lactose monohydrate, sodium carboxymethyl starch (type A), magnesium stearate, hypromellose, titanium dioxide (E 171).

Description: White, oval, film-coated tablets scored on one side.

Pharmacotherapeutic group A sedative.

CodeATH: N05CF01.

Pharmacological properties
Pharmacodynamics
The drug belongs to the list number 1 potent PKKN substances.
Zopiclone is a hypnotic drug from the cyclopyrrolone group. It has the following pharmacological properties: hypnotic, sedative, tranquilizing, anticonvulsant and muscle relaxant. These effects of zopiclone are associated with a specific agonistic effect on omega receptors (formerly known as benzodiazepine type I and type II receptors), related to the GABA-omega macromolecular complex, which modulates the opening of neuronal ion channels for chloride.
Zopiclone has the ability to reduce the time to sleep and the frequency of nocturnal and early awakenings, increase the duration of sleep and improve the quality of sleep and awakening. These effects, when used at recommended doses, are combined with a characteristic electroencephalographic profile that differs from that recorded with benzodiazepines. Polysomnography data have demonstrated that in patients with insomnia, zopiclone shortens phase I and prolongs phase II sleep, along with maintenance or prolongation of deep sleep (III and IV) and REM sleep.
An objective study of the withdrawal syndrome using polysomnogram registration did not reveal significant rebound insomnia after 28 days of taking the drug. Other studies have shown no escape of the hypnotic effect when taking the drug for up to 17 weeks.

Pharmacokinetics
Absorption
Zopiclone is rapidly absorbed. Eating does not affect absorption. Maximum plasma concentrations are reached within 1.5-2 hours and are approximately 30 and 60 ng / ml after oral administration of 3.75 mg and 7.5 mg, respectively. The absorption of the drug does not depend on gender.
Distribution
Communication with blood plasma proteins is weak (approximately 45%) and unsaturated. The risk of interaction with other drugs at the level of protein binding is very low. The drug is rapidly distributed from the systemic circulation. The volume of distribution is 91.8-10.4 liters.
Concentrations of the drug in breast milk are similar to those in plasma. According to calculations, the intake of the drug in the body of a child with breast milk will not exceed 1% of the dose taken by the mother within 24 hours.
Metabolism
After repeated doses of the drug, cumulation of zopiclone and its metabolites does not occur.
Interindividual differences are minor.
In humans, zopiclone is extensively metabolized to two major metabolites: zopiclone N-oxide and zopiclone N-demethyl. In vitro studies have shown that cytochrome P450 (CYP) ZA4 is the main isoenzyme that metabolizes zopiclone and produces both metabolites. In addition, the CYP2C8 isoenzyme is involved in the metabolism of zopiclone, which also forms a second metabolite (N-demethyl zopiclone). The elimination half-life of these metabolites is estimated to be approximately 4.5 and 7.4 hours, respectively.
breeding
At recommended doses, the elimination half-life of unchanged zopiclone is approximately 5 hours. The low values ​​of renal clearance of unchanged zopiclone (8.4 ml/min) in comparison with the values ​​of its plasma clearance (232 ml/min) indicate that the clearance of zopiclone is predominantly metabolic.
Zopiclone is excreted in the urine mainly as free metabolites (derivatives of N-oxide and N-demethyl) (approximately 80%) and in feces (approximately 16%).
Separate groups of patients

Zopiclone is a synthetic drug of a non-benzodiazepine structure that has a hypnotic and sedative effect.

Release form and composition of Zopiclone

The drug is produced in the form of tablets, coated with a whitish-cream color, which are 10 pieces in a blister pack, placed 1 or 2 pieces in a cardboard box. Each Zopiclone tablet contains 7.5 mg of the active substance - zopiclone, as well as excipients, represented by: lactose monohydrate, magnesium stearate, hypromellose, titanium dioxide, potato starch, calcium dihydrogen phosphate.

Pharmacological properties

Zopiclone is a drug that is a derivative of cyclopyrrolone and differs in its structure from barbiturates and benzodiazepines, at the same time related to benzodiazepine receptor agonists. The agent increases the sensitivity of GABA receptors to the mediator (gamma-aminobutyric acid), which increases the frequency of opening channels in the neuron membrane for the entry of chloride ions and, as a result, slows down the transmission between neurons in the central nervous system. Zopiclone is characterized by rapid absorption from the gastrointestinal tract, the maximum concentration of the drug in the blood is observed 60-90 minutes after administration, approximately 40-45% binds to blood proteins. The drug is excreted mostly by the kidneys and partially through the intestines, with repeated doses it does not accumulate.

The use of Zopiclone, according to the instructions, helps to reduce the period of falling asleep, prevent early awakenings, improve the quality and duration of sleep (without changing its phase structure), and reduces the number of awakenings at night. After taking Zopiclone, according to reviews, sleep occurs in 20-30 minutes and lasts an average of 6-8 hours. The use of the drug is effective for excessive psycho-emotional stress, situational insomnia, provoked by a violation of the rhythm of life. Zopiclone also helps to reduce the frequency, intensity and duration of nocturnal attacks in patients suffering from bronchial asthma (when combined with taking methylxanthine drugs). This remedy, when used, is characterized by the absence of drowsiness after waking up, which is inherent in barbiturate and benzodiazepine drugs.

Indications for use

As indicated in the instructions for Zopiclone, the drug is indicated for use in:

• Sleep disturbances, manifested in problems falling asleep, early awakenings, frequent awakenings at night;
• Situational, chronic and transient insomnia;
• Insomnia on the background of mental disorders;
• Nocturnal asthma attacks.

Method of application and dosage of Zopiclone

Zopiclone, according to the instructions, should be taken orally one tablet (7.5 mg) without chewing, no more than 30-40 minutes before the desired onset of sleep. With manifestations of a severe form of insomnia, it is possible to prescribe a dose of 15 mg (2 tablets) once at bedtime. The duration of therapy with Zopiclone should not exceed 30 days due to the possible development of drug dependence, which, according to reviews of Zopiclone, may be persistent. The initial dosage for elderly patients, as well as for liver dysfunction, is 3.75 mg (1/2 tablet), the maximum dose does not exceed 7.5 mg (1 tablet). When using the drug, it is necessary to ensure a sleep duration of at least 6 hours, without interrupting it artificially - due to the possible occurrence of anterograde amnesia.

Contraindications

Zopiclone is contraindicated for use in:

• severe myasthenia gravis;
• Pregnancy and lactation period;
• Under the age of 18;
• severe respiratory failure;
• Breath holding syndrome (sleep apnea);
• Intolerance to the components of the drug;
• Liver failure (in severe form).

Also, with extreme caution, the drug is prescribed for manifestations of liver dysfunction.

Side effects of Zopiclone

According to Zopiclone reviews, the use of the drug strictly according to the instructions rarely leads to side effects, but in some cases the appearance of: dry mouth, metallic taste, vomiting, nausea, headache, confusion, irritability, muscle weakness, depressed mood, urticaria , rash. Upon awakening, it was also occasionally observed - a depressive state, drowsiness, unmotivated aggressiveness. Patient reviews sometimes mention as side effects such manifestations as memory impairment, impaired coordination of movements, anterograde amnesia, paradoxical reactions in the form of hallucinations, nightmares, nervousness, increased insomnia (most often observed in older people).

special instructions

It is not recommended to drink alcoholic beverages during treatment with the drug. The day after taking Zopiclone, you must stop driving a car, as well as activities that require increased attention or are potentially dangerous.

Terms and conditions of storage

Zopiclone should be stored away from light sources, out of the reach of children, at room temperature, with a shelf life of 36 months.

Released by prescription.

Name:

Zopiclone-FT

INN: Zopiclone

Analogues:

Sonnat, somnol, sonex, relaxon, imovan.

ATX code: N05CF01

Description:

white, round, biconvex, film-coated tablets with a score line on one side.

Compound:

Active substance:

zopiclone 7.5 mg.
Excipients:

corn starch, croscarmellose sodium, magnesium stearate, povidone, colloidal anhydrous silicon dioxide, microcrystalline cellulose, lactose monohydrate.
Shell composition: hypromellose, titanium dioxide, macrogol 400

Pharmacotherapeutic group:

Sleeping pills and sedatives. benzodiazepine-like drugs.

Pharmacological properties

Pharmacodynamics
Zopiclone is a hypnotic drug that is a derivative of cyclopyrrolone. It rapidly initiates and maintains sleep without reducing total REM sleep and preserves non-REM sleep. Little residual effects are observed the next morning after zopiclone application. Pharmacological properties of zopiclone include hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant actions. These effects are due to the high affinity and specific agonistic effect of the drug on the central receptors of the GABA macromolecular complex, which regulate the opening of chloride ion channels. however, compared to benzodiazepines, zopiclone and other cyclopyrrolones have been found to act at a different site in the receptor complex, including its various conformational changes.

Pharmacokinetics
Suction:
After oral administration at a dose of 7.5 mg, zopiclone is rapidly absorbed. The maximum plasma concentration is reached within 1.5-2 hours and is approximately 30 ng/ml and 60 ng-ml after administration of 3.75 mg and 7.5 mg, respectively. Bioavailability is approximately 80%. Absorption is not affected by the time of application, repeated doses and gender of the patient.

Distribution:
The drug is rapidly distributed throughout the body. Plasma protein binding is weak (approximately 45%) and unsaturable. the risk of drug interactions due to the association of zopiclone with proteins is very small. The volume of distribution is 91.8-104.6 liters. At the recommended doses, the elimination half-life of zopiclone is approximately 5 hours.
Repeated use of the drug does not cause accumulation; interindividual differences are minor.
Benzodiazepines and benzodiazepine-like drugs cross the blood-brain and placental barriers and are excreted into breast milk. During lactation, the pharmacokinetic properties of zopiclone in milk are the same as in plasma. It is calculated that with mother's milk, the infant absorbs no more than 1% of the dose of the drug that the mother took within 24 hours.

Metabolism:
Zopiclone is metabolized primarily in the liver. In humans, the main metabolins of zopiclone are N-oxide (pharmacologically active in animals) and N-desmethylzopiclone (pharmacologically inactive in animals). In vitro studies indicate that cytochrome P450 (CYP)3A4 is the most important isoenzyme involved in the formation of both metabolites of zopiclone; CYP2C8 is also involved in the formation of N-desmethylzopiclone.
The apparent half-life (calculated from urine values) is 4.5 hours and 7.4 hours, respectively. Even at high doses, no induction of the enzyme is observed in animals.

Derivation:
Comparing the low renal clearance of unchanged zopiclone (mean 8.4 ml/min) with its plasma clearance (232 ml/min) shows that clearance of zopiclone largely determines metabolism. the drug is mainly excreted in the urine (approximately 80%) as metabolites (N-oxide and N-demethylated derivatives) and in the feces (approximately 16%).

High risk groups
In elderly patients, liver metabolism is significantly reduced and the elimination half-life is approximately 7 hours. In various studies, after repeated use of zopiclone, its accumulation in the body has not been proven.
In renal failure, the accumulation of zopiclone and its metabolites with prolonged use of the drug has not been established. In the treatment of overdose, hemodialysis is not used due to the large volume of distribution of zopiclone.
In patients with cirrhosis of the liver, plasma clearance of zopiclone is reduced (approximately 40%) due to a slowdown in the demethylation process, therefore, such patients need to adjust the dose.

Indications for use

• For the treatment of transient short-term insomnia in adults (including difficulty falling asleep, nocturnal and early awakenings).
• For maintenance therapy of chronic insomnia, applying for a limited period of time.

Dosage and administration

Inside, without chewing and not dissolving, immediately before going to bed.
The dose should be selected depending on the patient's age, body weight, general health and type of insomnia.
Adults under the age of 65: 1 tablet (7.5 mg) once daily.
Patients over the age of 65: The recommended dose is 1/2 tablet (3.75 mg) per day. If necessary, the dose can be increased to 1 tablet (only in exceptional cases).
Patients with impaired liver function or respiratory failure: the recommended dose of the drug is 1/2 tablet (3.75 mg) per day.
Patients with impaired renal function: it is recommended to start treatment with 1/2 tablet (3.75 mg) per day, although the accumulation of zopiclone or its metabolites in case of renal insufficiency has not been established.
In all cases, the daily dose of ZOPICLONA-FT should not exceed 7.5 mg.
Duration of treatment:
Treatment should be as short as possible, ranging from a few days to 2-4 weeks (maximum), including a period of dose reduction:

• Transient insomnia (for example, during travel) - 2-5 days;
• Short-term insomnia - 2-3 weeks (for example, caused by stress).

Treatment should begin with the lowest recommended dose.
How to stop treatment
Before starting the use of the drug, patients should be explained that therapy should not be long-term and how to gradually stop it. The gradual cessation of treatment reduces the risk of recurrence of insomnia.
To reduce anxiety caused by possible symptoms of discontinuation of the drug, patients should be warned about the possibility of resumption of insomnia after discontinuation of treatment.

Side effects

The most common side effect with ZOPYCLONE-FT is a bitter or microtallic taste in the mouth.
From the immune system: rarely - angioedema, anaphylactic reactions.
Mental disorders: infrequently - nightmares, agitation; rarely - confusion, decreased libido, irritability, aggressiveness, hallucinations; frequency unknown - anxiety, delirium, anger, depressed mood, inappropriate behavior (possibly associated with amnesia) and somnambulism, dependence, withdrawal syndrome.
From the nervous system: often - dysgeusia (bitter taste in the mouth), residual drowsiness; infrequently - dizziness, headache; rarely - antegrade amnesia (risk increases with increasing dose; in some cases, behavioral disturbances can be observed additionally); frequency unknown - ataxia, paresthesia.
From the side of the organ of vision: frequency unknown - diplopia.
From the respiratory system, chest and mediastinum: rarely - shortness of breath, the frequency is unknown - respiratory depression.
From the gastrointestinal tract: often - dry mouth, infrequently - nausea, vomiting; frequency unknown - dyspepsia.
From the hepatobiliary system: very rarely - a slight or moderate increase in the level of transaminases and / or alkaline phosphatase in plasma.
From the skin and subcutaneous tissue: rarely - urticaria or rash, itching.
From the musculoskeletal system and connective tissue: frequency unknown - muscle weakness.
General disorders and disorders at the injection site: frequency unknown - weakness.
Injuries, intoxications, complications of manipulations: rare - falls (mainly in elderly patients).

There are reports that after discontinuation of zopiclone, a withdrawal syndrome develops, the symptoms of which vary and can manifest as "rebound" insomnia, muscle pain, restlessness, tremors, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, hallucinations , nightmares, panic attacks, muscle cramps, gastrointestinal disturbances and irritability. In severe cases, the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling in the extremities, increased sensitivity to light and noise, tactile hyperesthesia, hallucinations. In very rare cases, seizures may occur.

Contraindications

• Hypersensitivity to zopiclone or any of the excipients;
• myasthenia;
• severe respiratory failure;
• sleep apnea syndrome;
• severe liver failure;
• The period of breastfeeding;
• Children's age up to 18 years;
• Congenital lactose intolerance, Lapp lactose deficiency, glucose-galactose malabsorption.

​Overdose

Symptoms

overdoses depend on the dose of ZOPICLONA-FT taken and are manifested by signs of depression of the central nervous system from drowsiness to the development of a coma. In mild cases, an overdose is accompanied by drowsiness, confusion, lethargy; in more severe cases, ataxia, hypotension, methemoglobinemia, respiratory depression and coma appear. An overdose does not pose a threat to life, except for the situation of combination with alcohol and drugs that depress the central nervous system.
The presence of comorbidities and the weakened state of the patient can contribute to the severity of symptoms, which in rare cases can lead to death.
Treatment

Within an hour after an overdose of zopiclone, it is necessary to wash the stomach, give activated charcoal. If necessary, symptomatic and supportive therapy is recommended in a hospital setting with monitoring of respiratory and cardiovascular activity.
In severe cases, the benzodiazepine receptor antagonist flumazenil can be used as an antidote. It has a short half-life (about an hour). Flumazenil should not be used in cases of mixed overdose or as a diagnostic tool. Hemodialysis in overdose is not effective due to the large volume of distribution of zopiclone.

Interaction with other drugs

Alcohol
With simultaneous use with alcohol, the sedative effect of benzodiazepines or benzodiazepine-like drugs is enhanced. Inhibited attention may affect the patient's ability to drive vehicles or operate machinery. Alcoholic beverages and preparations containing ethyl alcohol should be avoided.
Morphine derivatives (pain relievers, cough suppressants and replacement therapy), barbiturates
Increased risk of respiratory depression; in case of overdose, a lethal outcome is possible.
Simultaneous use of m drugs that depress the central nervous system- morphine derivatives (painkillers, antitussives and replacement therapy), barbiturates, antidepressants and sedative H1 antihistamines, anti-anxiety agents, neuroleptics, clonidine and its analogues, thalidomide
Strengthening the inhibitory effect of the central nervous system. Inhibited attention may affect the patient's ability to drive vehicles or operate machinery.
Closatin
Increased risk of shock with respiratory arrest and/or cardiac arrest.
Erythromycin
The effect of erythromycin on the pharmacokinetics of zopiclone was studied in 10 healthy volunteers. In the presence of erythromycin, the AUC of zopiclone is increased by 80%, which indicates the ability of erythromycin to inhibit the metabolism of those drugs that are metabolized under the influence of CYP3A4. As a result, the hypnotic effect of zopiclone may be enhanced.
Since zopiclone is metabolized by the cytochrome P450 system, when co-administered with CYP3A4 inhibitors such as erythromycin, clarithromycin, ketoconazole, itracolnasol and ritonavir, plasma levels of zopiclone may increase. With simultaneous use with CYP3A4 inhibitors, a dose reduction of zopiclone may be necessary.
Conversely, with simultaneous use with CYP3A4 inducers, such as rifampicin, phenobarbital, carbamazepine, phenytoin, St. John's wort, plasma levels of zopiclone may decrease. With simultaneous use with CYP3A4 inducers, an increase in the dose of zopiclone may be required.

special instructions

Whenever possible, the cause of insomnia should be identified and possible precipitating factors should be eliminated before prescribing a hypnotic. Benzodiazepines and benzodiazepine-like drugs are not prescribed as the main drugs in the treatment of psychosis.
To reduce the risk of withdrawal symptoms, treatment with zopiclone should be short-term or intermittent.
High risk groups:

• The greatest caution should be observed in cases where there is a history of alcoholism or addiction/dependence on other substances;
• Patients with impaired liver function, tk. benzodiazepines and benzodiazepine-like drugs in severe liver failure can accelerate the development of encephalopathy, so in this case they are contraindicated;
• Patients with respiratory failure, tk. benzodiazepines and their derivatives have a depressing effect on the respiratory center (anxiety and anxiety can be harbingers of respiratory decompensation);
• Elderly patients, tk. the muscle relaxant and sedative effects can lead to fall injuries.

Addiction Risk
Treatment with benzodiazepines and their derivatives, especially long-term, even at therapeutic doses, can lead to physical and mental dependence.
The risk of addiction increases when the following factors are present:

• Exceeding the recommended dose of zopiclone (7.5 mg);
• Increase in duration of treatment (more than 4 weeks);
• Alcohol abuse and / or taking other psychotropic drugs;
• Anxiety.

If the patient has developed a physical dependence, then the sudden discontinuation of ZOPICLONA-FT may lead to the development of an abstinence syndrome: headache, muscle pain, anxiety, restlessness, tension, irritability, confusion. In more severe cases, symptoms may appear: derealization, depersonalization, numbness and tingling in the limbs, increased sensitivity to light, noise and touch, hallucinations or epileptic seizures.
After stopping treatment, withdrawal symptoms may occur within a few days. With a duration of treatment with ZOPICLON-FT of no more than 4 weeks, the likelihood of developing withdrawal symptoms is minimal. It is recommended to cancel the drug gradually.

Depression
Benzodiazepines and benzodiazepine-like drugs should not be used as monotherapy for depression and anxiety associated with depression, as they may induce suicide.

tolerance
With the use of benzodiazepines and their derivatives, after repeated use for several weeks, some loss of effectiveness is possible. in patients taking zopiclone for no more than 4 weeks, cases of addiction were not noted. With the development of tolerance, you can not increase the dose of the drug.

The phenomenon of "recoil"
With the termination of therapy with benzodiazepines and their derivatives in an enhanced form, insomnia may resume, anxiety, anxiety, and mood changes may appear. The appearance of the syndrome is facilitated by prolonged treatment or abrupt cessation of treatment. In this regard, at the end of treatment, it is recommended to reduce the dose of the drug gradually and inform the patient about this.

Amnesia
Rarely, antegrade amnesia may occur, especially when sleep is interrupted or after a long period of time between taking the pill and going to bed. to reduce the risk of antegrade amnesia, ZOPICLON-FT should be taken immediately before bedtime and provided with conditions for 7-8 hours of uninterrupted sleep.

Somnambulism and related behaviors
Sleepwalking and sleep-related behaviors (eg, cooking and eating, talking on the phone, driving) followed by amnesia have been reported in patients who have taken zopiclone and are not fully awake. Simultaneous use with zopiclone of drugs that depress the central nervous system, alcohol consumption, exceeding the recommended doses increases the risk of developing this disorder. Patients who report such conduct disorder should discontinue the drug.

Other mental and paradoxical reactions:
In the treatment with zopiclone, some patients, mostly elderly, have been reported paradoxical reactions: increased insomnia, nightmares, anxiety, agitation, irritability, aggressiveness, fits of anger, dilirium, hallucinations, oneiric delirium, confusion, psychotic symptoms, inappropriate behavior and others. behavioral disorders. If such reactions occur, ZOPICLON-FT is canceled.

Risk of cumulation
Benzodiazepines and their analogues are in the body for a time equal to 5 half-lives. In patients with impaired liver function and the elderly, T1 / 2 may increase significantly. With repeated doses, the concentration of zopiclone and its metabolites in the blood plasma is higher and the saturation stage is reached later. The efficacy and safety of the drug can be assessed after reaching the saturation stage. Dose adjustment may be required.

Despite the fact that in patients with impaired renal function, no accumulation of zopiclone was detected during long-term use, the dose of the drug is reduced by 2 times.

During treatment with ZOPICLON-FT, alcohol should not be consumed, and medications containing ethanol should be avoided.

Use during pregnancy and lactation
Available data are insufficient to assess the safety of zopiclone during pregnancy and lactation.
Pregnancy:
Experience with the use of zopiclone during human pregnancy is limited. Animal studies have not revealed a negative effect on the course of pregnancy and fetal development. However, results obtained in animals do not always correlate with effects in humans. Therefore, the use of the drug during pregnancy is contraindicated.
If ZOPICLON-FT is prescribed to women of childbearing age, they should be aware of the need to consult a doctor if pregnancy is suspected or planned to stop the drug.
When prescribing the drug in the third trimester of pregnancy or during childbirth, it should be expected that the newborn will develop symptoms such as hypotemia, hypotension, drowsiness and respiratory depression.
Newborns whose mothers took benzodiazepines or their analogues in the last stages of pregnancy may develop physical dependence and the risk of withdrawal in the postnatal period.
Lactation:
Despite the fact that the concentration of zopiclone in breast milk is low, the drug should be avoided during breastfeeding.

Application in children.
Zopiclone is contraindicated in children and adolescents under 18 years of age, as the safety and efficacy of zopiclone in this group of patients has not been established.

Ability to influence driving

ZOPYCLONE-FT significantly affects the ability to drive and operate machinery. because it causes sedation, reduced ability to concentrate, blurred vision and impaired muscle activity. This risk increases the simultaneous use with alcohol. Therefore, it is not recommended to drive vehicles and maintain mechanisms while using zopiclone and alcohol. the risk of impaired attention is increased if the patient's sleep duration was insufficient.

Release form

Film-coated tablets in blisters No. 10x1, No. 10x2, No. 10x3 and in jars No. 20 and No. 30 in package No. 1.
Each 1, 2 or 3 blister packs or a jar, together with a leaflet, is placed in a pack of cardboard.

Storage conditions

Store in a place protected from moisture and light at a temperature not exceeding 25 0 C.

Shelf life - 2 years

Manufacturer

LLC "Pharmtechnology"

Pharmacological group: sleeping pills;
Systematic (IUPAC) name: (RS) -6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo pyrazin-5-yl-4-methylpiperazin-1-carboxylate
Trade names: Imovane, Zimovane
Legal status: Prescription only (Australia, UK, US)
Usage: oral tablets, 3.75 mg (UK), 5 or 7.5 mg
Bioavailability: 52-59% bound to plasma proteins
Metabolism: various liver cytochrome P450 enzymes
Half-life: ~ 6 hours
Excretion: urine
Formula: C 17 H 17 ClN 6 O 3
Mol. mass: 388.808 g/mol

Zopiclone (brand name Imovane in Canada, Australia, Sweden, Finland, Norway, Russia, and the United Kingdom; brand name Zimovane in Europe) is a nonbenzodiazepine hypnotic drug used in the treatment of insomnia. The substance is cyclopyrrolone, which increases the normal transmission of the neurotransmitter GABA in the central nervous system, in the same way as benzodiazepines, but in a different way. Zopiclone is a sedative and is sold as a sleeping pill. Its action is based on sedation or depression of the central nervous system. After prolonged use of zopiclone, tolerance and addiction to the drug may occur. With dose reduction or discontinuation of the drug, an abstinence syndrome may develop, which may include a number of symptoms similar to those observed with the withdrawal of benzodiazepines. In the United States, zopiclone is not commercially available, but its active stereoisomer, Eszopiclone, is sold under the brand name Lunesta. Zopiclone is under regulatory control in countries such as the United States, Japan, Brazil, and some European countries. Possession of the drug without a prescription may be illegal in these countries. Zopiclone is also called the "Z-drug". Other Z-drugs include Zaleplon (Sonata) and Zolpidem (Ambien and AmbienCR). These drugs are thought to be less addictive than benzodiazepines. However, in recent years, reports of cases of dependence and addiction developing when taking Z-drugs have become more frequent. Zopiclone is recommended to be taken on a short-term basis, usually for a week or less. Daily or continuous use of the drug is usually not recommended.

Medical use

Zopiclone is used for the short-term treatment of insomnia, in which severe symptoms are problems initiating or maintaining sleep. Long-term use of Zopiclone is not recommended, as tolerance and dependence may develop with prolonged use of the drug.

Elderly patients

Zopiclone, like other benzodiazepines and nonbenzodiazepines, causes disturbances in body balance and standing stability in patients on nocturnal awakenings or the next morning. Falls and hip fractures are often reported. The combination with alcohol increases the risk of such disorders. In relation to such side effects, partial, but incomplete, tolerance may develop. An extensive review of the medical literature regarding the treatment of insomnia in the elderly found that there is sufficient evidence for the effectiveness and long-term benefits of non-drug treatments for insomnia. Compared with benzodiazepines, nonbenzodiazepine hypnotics and sedatives such as zopiclone offer little advantage in efficacy or tolerability in the elderly. It has been found that newer agents, such as melatonin agonists, may be more suitable and effective for the treatment of chronic insomnia in the elderly. There is still not enough evidence to support the safety of long-term use of sedative-hypnotics for insomnia. Such use is not recommended for reasons that include concerns about the possible adverse effects of drugs, including cognitive impairment (anterograde amnesia), daytime sedation, impaired motor coordination, and an increased risk of traffic accidents and falls. In addition, the efficacy and safety of long-term use of nonbenzodiazepine hypnotics remains to be determined. Further research is needed to evaluate the long-term effects of treatment and find the most appropriate treatment strategy for older adults with chronic insomnia.

Adverse reactions

The side effects most commonly seen in clinical trials were changes in taste or dysgeusia (a bitter, metallic taste in the mouth that disappears quickly in most users, but may persist until the drug's half-life has elapsed in some). Daytime palpitations may occur after discontinuation of the drug, especially after prolonged periods of use. Zopiclone, like Triazolam and Rohypnol, causes memory impairments such as amnesia. The most significant side effect is impaired driving skills and an increased risk of traffic accidents. This side effect is not unique to Zopiclone but has also been observed with other sleeping pills. A study evaluating the effects of zopiclone on next-day driving skills found that the drug's detrimental effect on driving skills was twice as strong as that of alcohol. Zaleplon does not adversely affect driving skills the day after application. Daytime anxiety associated with discontinuation of nonbenzodiazepines such as Zopiclone.

Common Side Effects

Gastrointestinal: Taste disturbances including metallic taste and dry mouth. Nervous system: REM sleep disturbances, double vision, drowsiness, memory disturbances, visuospatial disturbances, dizziness, headaches and fatigue. Unexpected mood changes are also possible, in the event of which you should immediately stop taking the drug.

More rare side effects

Gastrointestinal: heartburn, constipation, diarrhea, nausea, plaque on the tongue, bad breath, anorexia or increased appetite, vomiting, epigastric pain, dyspepsia, dehydration, paragesia. Cardiovascular: palpitations in elderly patients. Skin: urticaria, tingling in the arms and legs. Miscellaneous: blurred vision, frequent urination, nocturnal enuresis, mild to moderate increase in serum transaminases and/or alkaline phosphatase, and interstitial nephritis (very rare). Reproductive system: impotence, delayed ejaculation, anorgasmia in men and women. Nervous system: agitation, restlessness, memory loss including anterograde and retrograde amnesia, confusion, dizziness, weakness, drowsiness, asthenia, euphoria and/or dysphoria, sensation of intoxication, depression, sleepwalking, coordination problems, hypotension, speech disturbance, hallucinations , as a rule, auditory and visual, behavioral disorders, aggression, tremor, relapse of insomnia, nightmares, hypomania. Delusions are mostly seen in the elderly.

Tolerance, dependence and discontinuation

Zopiclone, a benzodiazepine-like drug, was originally introduced as having a reduced risk of dependence and withdrawal compared to traditional benzodiazepine drugs. In reality, however, zopiclone may even have a slightly greater dependence potential than benzodiazepines. Tolerance to the effects of zopiclone may develop within a few weeks. In most cases, prolonged use of the drug should be avoided. Successful treatment of patients with severe insomnia due to anxiety can be achieved within a few months. Abrupt discontinuation, especially with prolonged use of high doses of the drug, can cause convulsions and delirium in severe cases. Publications in the British Medical Journal provide no evidence that zopiclone has a low addiction potential. In fact, physical dependence, abuse, and withdrawal symptoms similar to those seen with benzodiazepine withdrawal often develop when taking the drug. Withdrawal symptoms include restlessness, tachycardia, tremors, sweating, hot flashes, palpitations, derealization, and later insomnia. Seizures have also been reported on withdrawal during Zopiclone detox, however in this case the person was abusing high doses of Zopiclone. The risk of addiction when taking zopiclone for less than 2 weeks or less is very low. However, this is disputed in one study of low doses of zopiclone given over 7 nights. Stopping zopiclone has been found to cause relapse of insomnia. In addition, no relapses of insomnia were observed when midazolam was discontinued after continuous use for 7 nights, suggesting that zopiclone may cause more significant tolerance and dependence problems than benzodiazepines. After 3 weeks of use, mild to moderate relapse symptoms occur when zopiclone is discontinued. Due to the risk of developing tolerance and physical dependence, zopiclone is recommended to be used for a short period of time (maximum 1-4 weeks), or, conversely, rarely use the drug for long periods of time. Long-term users of Zopiclone who have become physically dependent on the drug should not discontinue the substance abruptly, as severe withdrawal symptoms such as delirium may be associated with this. If zopiclone has been taken for several weeks or more, stopping the drug should be done by gradually reducing the dose or switching to an equivalent dose (Valium), which has a much longer half-life, which makes it easier to withdraw, and then gradually reduce over several months. dosage to avoid the development of extremely severe and unpleasant withdrawal symptoms (such as restlessness, psychomotor agitation, abdominal pain, hypertension, hallucinations, convulsions, anxiety, depression, psychosis, etc.), which can last up to two years with too abrupt discontinuation of the drug. After 4 weeks of using zopiclone at night, some users develop daytime anxiety associated with discontinuation of the drug. This symptom, however, is not as intense as with triazolam, which has a much shorter duration of action and produces more severe symptoms of daytime discontinuation anxiety in long-term users. According to the World Health Organization, Zopiclone, although not a molecular benzodiazepine, is able to non-selectively and with high affinity bind to the same benzodiazepine binding site as benzodiazepines. The World Health Organization has also stated that zopiclone has cross-tolerance with benzodiazepines, and these drugs can substitute for each other. A World Health Organization review of zopiclone found that the onset of withdrawal symptoms is usually observed either when the drug is abused in excessive doses or when zopiclone is used for a long time. palpitations and flushes. Zopiclone is cross-tolerant to benzodiazepines. Alcohol has cross-tolerance with positive GABA receptor modulators such as benzodiazepines and nonbenzodiazepines. For this reason, alcoholics or recovering alcoholics may be at increased risk of physical dependence on zopiclone. In addition, alcoholics and drug addicts may be at increased risk of abuse and/or psychological dependence on zopiclone. Patients with alcoholism, drug abuse, or physical or psychological dependence on sedatives should avoid taking Zopiclone. Zopiclone discontinuation is recommended through switching to an equivalent dose because diazepam is available at low dosages, is cross-tolerant to zopiclone, and lasts longer than zopiclone, allowing smoother withdrawal and allowing the body to adjust to a constant dose. Although Zopiclone acts on the same benzodiazepine receptors as the benzodiazepine family of drugs, it is not classified as a benzodiazepine (although it shares a number of characteristics and effects with them) due to differences in molecular structure. Zopiclone is classified as a cyclopyrrolone derivative.

Carcinogenicity

A recent analysis of US FDA data and clinical trial results suggests that nonbenzodiazepine Z-drugs at prescribed doses cause an increased risk of cancer in humans. There have been 15 epidemiological studies that have shown that sleeping pills increase the risk of mortality, mainly by increasing mortality from cancer (brain, lung, colon, breast, and bladder). One possible explanation for the increase in cancer mortality is that Z-drugs have a negative effect on the immune system. The fact that in clinical trials, patients taking other Z-drugs (zolpidem, zaleplon and eszaleplon) had an increased incidence of disease may support this theory. Benzodiazepine hypnotics are also associated with an increased risk of ovarian cancer. The development of a malignant tumor has been associated with the use of zolpidem, but so far nothing can be said about the association of zolpidem with the development of neoplasms. Indiplon, another non-benzodiazepine drug, has also been shown to increase the risk of cancer in clinical trials. The review concluded: "The chance of developing cancer is high enough that clinicians and patients should be aware that hypnotics may increase the risk of cancer in patients."

Contraindications

Zopiclone causes a decrease in driving skills, similar to benzodiazepines. Long-term users of hypnotic drugs develop only partial resistance to the adverse effects of drugs associated with negative effects on driving skills. Users who take sleeping pills for an entire year are still at risk for road traffic accidents. You should not drive a car while taking Zopiclone. Zopiclone causes impairment of psychomotor function. The day after taking Zopiclone, there may be an effect such as a deterioration in hand-eye coordination. Patients with a history of drug abuse should avoid the use of Zopiclone as the substance has a very high abuse potential. Zopiclone can in some cases induce a state of amnesia associated with sleepwalking, which can progress to the point where the person is eating, talking to people (quite convincingly), and even driving a car while actually in a dream. Therefore, the drug is generally not used as a sedative (like benzodiazepines) because patients may make poor decisions while the drug is in effect (because they are asleep) and engage in hazardous activities, remembering none of this afterwards.

Special Precautions

Alcohol should be avoided when using zopiclone, as alcohol and zopiclone enhance each other's effects, which may increase the risk of dependence. In patients with liver disease, zopiclone is eliminated from the body much more slowly than in normal patients. Such patients experience more pronounced pharmacological effects of the drug. Zopiclone reduces stability and increases the risk of falls in the elderly, and also has cognitive side effects. Falls are one of the most common causes of death in the elderly. Patients suffering from muscle weakness as a result of myasthenia gravis or having poor respiratory reserves due to severe chronic bronchitis, emphysema or other lung disorders, or experiencing sleep apnea should avoid the use of Zopiclone. The use of the drug should also be avoided in patients with untreated thyroid disease.

EEG and sleep

Like other sedative-hypnotics, zopiclone causes a decrease in body temperature and is effective in reducing sleep latency. Zopiclone induces benzodiazepine-like changes in EEG and sleep architecture, and also causes disturbances in sleep patterns upon discontinuation, as a relapse effect. Zopiclone reduces delta waves and the number of high amplitude delta waves, while increasing the number of low amplitude waves. Zopiclone reduces the total amount of time in REM sleep and also delays its onset. Cognitive behavioral therapy is more effective than zopiclone in the treatment of insomnia and has a long-term effect on sleep quality for at least a year after therapy.

Pharmacology

Zopiclone acts as a hypnotic, anxiolytic, anticonvulsant and muscle relaxant. Zopiclone and benzodiazepines randomly act on benzodiazepine-binding sites on α1, α2, α3 and α5 GABA-containing receptors as full agonists, causing an increase in GABA action, resulting in the therapeutic and adverse effects of zopiclone. The metabolite of zopiclone is called desmethylzopiclone. The substance is also pharmacologically active and exhibits predominantly anxiolytic properties. Like benzodiazepines, zopiclone and its active metabolite, desmethylzopiclone, also inhibit N-methyl-D-aspartate (NMDA) receptors and nicotinic acetylcholine receptors, which may contribute to the fact that these drugs are addictive. In one study, however, zopiclone showed little selectivity for the α1 and α5 subunits. However, zopiclone is believed to non-selectively bind to α1, α2, α3 and α5 GABA receptor benzodiazepine complexes. Desmethylzopiclone exhibits partial agonist properties, in contrast to zopiclone, which is a full agonist. The mechanism of action of zopiclone is similar to that of benzodiazepines, both substances have similar effects on locomotor activity and on the turnover of dopamine and serotonin. A meta-analysis of randomized controlled trials comparing benzodiazepines and Zopiclone or other Z-drugs such as zolpidem and zaleplon showed that there are clear and consistent differences between zopiclone and benzodiazepines in terms of sleep onset delay, total sleep duration, number of awakenings, sleep quality, adverse effects, tolerance, recurrence of insomnia and daytime activity. Zopiclone is a member of the cyclopyrrolone family. Another drug in this class is Suriclone. Zopiclone, while molecularly different from the benzodiazepines, has an almost identical pharmacological profile, including anxiolytic properties. It acts through binding to the benzodiazepine site as a full agonist, which in turn positively modulates benzodiazepine-sensitive GABA receptors and enhances GABA binding at these GABA receptors, providing the pharmacological action of Zopiclone. In addition to its pharmacological properties, Zopiclone may act similarly to barbiturates. In EEG studies, zopiclone has been shown to significantly increase beta band energy and exhibit high voltage slow wave characteristics, hippocampal theta wave desynchronization, and increased delta band energy. Zopiclone increases both second-phase sleep and non-REM sleep, while zolpidem, an α1-selective compound, only increases non-REM sleep and has no effect on second-phase sleep. Zopiclone is less selective at the α1 site and has a higher affinity for the α2 site than zaleplon. Zopiclone is therefore pharmacologically very similar to benzodiazepines.

Pharmacokinetics

After oral administration, zopiclone is rapidly absorbed, its bioavailability is about 80%. Plasma protein binding of zopiclone ranges from 45 to 80%. Zopiclone is rapidly and widely distributed in body tissues, including the brain, and is excreted in urine, saliva and breast milk. Zopiclone is partially metabolized in the liver to form an inactive N-demethylated derivative and its active N-oxide metabolite. In addition, approximately 50% of the administered dose is decarboxylated and excreted through the lungs. In urine, N-demethyl and N-oxide metabolites account for 30% of the initial dose. 7-10% of zopiclone is excreted in the urine, indicating extensive metabolism of the drug prior to excretion. The terminal half-life (t1/2z) of zopiclone ranges from 3.5 to 6.5 hours. The pharmacokinetics of zopiclone in humans are stereoselective. Following oral administration of the racemic mixture, Cmax (time to peak plasma concentration), AUC (area under the plasma time-concentration curve) and t1/2z values ​​are higher for the dextrorotatory enantiomer due to slower complete elimination and smaller volume of distribution (adjusted for bioavailability) compared to the levorotatory enantiomer. In urine, the concentrations of the dextrorotatory enantiomers of the N-demethyl and N-oxide metabolites are higher than those of the corresponding antipodes. The pharmacokinetics of zopiclone varies with age and is influenced by renal and hepatic function.

Interactions

Zopiclone also interacts with trimipramine and. Alcohol in combination with zopiclone enhances its effect and adverse effects, including significantly increasing the potential for overdose of zopiclone. |Erythromycin]] increases the rate of absorption of zopiclone and prolongs the half-life of zopiclone, which leads to an increase in the concentration of the drug in the blood plasma and more pronounced effects. Itraconazole has a similar effect on the pharmacokinetics of Zopiclone. The elderly may be particularly sensitive to drug interactions between itraconazole and zopiclone. Temporary dosage reductions may be required with combination therapy, especially in the elderly. Rifampicin causes a significant reduction in Zopiclone's half-life and peak plasma levels, resulting in a decrease in the hypnotic effect of Zopiclone. Phenytoin and carbamazepine may also induce similar interactions. Ketoconazole and sulfafenazole interfere with the metabolism of zopiclone. Nefazodone interferes with the metabolism of zopiclone, causing an increase in zopiclone levels and sedation the next day.

Story

Zopiclone was developed and first introduced in 1986 by Rhône-Poulenc S.A., now part of Sanofi-Aventis, the world's leading manufacturer of Zopiclone. The drug was originally marketed as an improved version of the benzodiazepines, however a recent meta-analysis has shown that zopiclone has no particular advantage over the benzodiazepines in any of the assessed aspects. On April 4, 2005, the US Drug Enforcement Administration placed zopiclone on Schedule IV because the drug has addictive properties similar to benzodiazepines. Zopiclone, traditionally sold worldwide, is a racemic mixture of two stereoisomers, only one of which is active. In 2005, the pharmaceutical company Sepracor of Marlborough, Massachusetts, began marketing the active stereoisomer of Essopiclone under the name Lunesta in the United States. The consequence of this was the formulation of this drug, which is generic in most countries of the world, under patent control in the United States. While it was expected that the drug would be available in generic form by 2010, no generic drug has yet been introduced to the market. However, Zopiclone is currently available as a generic drug in several European countries, as well as in Brazil, Canada and Hong Kong. The difference between Essopiclone and Zopiclone is the dosage - the most active dose of the Essopiclone derivative contains 3 mg of the therapeutic stereoisomer, while the highest dose of zopiclone (7.5 mg) contains 3.75 mg of the active stereoisomer. These two substances have not yet been tested in comparative clinical trials to determine if there are any potential clinical differences (efficacy, side effects, dependence potential, safety, etc.)

recreational use

Zopiclone is a drug with the potential for abuse and drug escalation, addiction and drug dependence. Zopiclone is well known among drug addicts as an addictive drug. The drug is taken orally and sometimes intravenously and often in combination with alcohol to achieve a combined sedative hypnotic-alcoholic euphoria. Patients who abuse the drug are at risk of developing addiction. After long-term use of the drug at usual doses, withdrawal symptoms can be observed, even after a gradual dose reduction. It is usually recommended to take Zopiclone for no longer than 7-10 days, due to the possible development of dependence and tolerance to the drug. Two types of drug addiction may develop: recreational abuse, when the drug is taken to achieve a "high", or long-term use of the drug without medical advice. Zopiclone may have a greater dependence potential than benzodiazepines. Patients with a history of substance abuse or psychiatric disorders may be at increased risk for abuse of high doses of Zopiclone. Dependence symptoms of Zopiclone abuse may include depression, dysphoria, feelings of hopelessness, slowing of thoughts, social isolation, anxiety, sexual anhedonia, and nervousness. Zopiclone and other sedative-hypnotics are often found in cases where drivers are suspected of driving under the influence. Other drugs are often found in such cases, including benzodiazepines and zolpidem. In many drivers, blood levels of the drug are significantly higher than the therapeutic dose and are often observed in combination with alcohol and other drugs. Benzodiazepines, zolpidem, and zopiclone are associated with a high risk of abuse. Zopiclone, which, when taken at prescribed doses, causes mild side effects observed the day after use, increases the risk of traffic accidents by 50 percent. To reduce the risk of traffic accidents, it is recommended to use zaleplon or drugs instead of zopiclone. Zopiclone and other sleep aids are sometimes used to commit criminal acts such as sexual assault. Zopiclone is cross-tolerant with barbiturates and may suppress the withdrawal symptoms of barbiturates. Zopiclone is often administered intravenously and has been shown in monkey studies to be associated with a high risk of abuse. Zopiclone is one of the top ten drugs obtained using false prescriptions in France. However, due to the distinctly bitter taste of the drug, it is unlikely to be used for criminal purposes such as robbery and sexual assault. Tablets are coated with a special layer of film to mask the taste when swallowed, but this film is destroyed by chewing. In addition, a bitter, metallic taste after ingestion is a common side effect, making a person taking zopiclone more likely to know they are under the influence of the drug.

Overdose

Zopiclone is sometimes used as a suicide method. Zopiclone has a similar mortality rate to benzodiazepines (except temazepam, which is toxic in overdose). Deaths have been reported as a result of an overdose of Zopiclone, either alone or in combination with other medicinal products. An overdose of zopiclone can result in excessive sedation and decreased respiratory function, leading to coma and possibly death. Zopiclone in combination with alcohol, opiates or other CNS depressants can lead to a fatal overdose. Zopiclone overdose can be treated with the benzodiazepine receptor antagonist flumazenil, which displaces zopiclone from the benzodiazepine binding site on the receptor, thereby rapidly reversing the effects of zopiclone. Overdose of Zopiclone in combination with piperazine may also cause serious effects on the heart. Death certificates show an increase in Zopiclone overdose deaths. Zopiclone, when taken alone, is not usually fatal, but when combined with alcohol or other drugs such as opioids, or in patients with respiratory or liver disease, there is an increased risk of serious and fatal overdoses.