Pharmacological group: sleeping pills;
Systematic (IUPAC) name: (RS)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolopyrazin-5-yl-4-methylpiperazin-1-carboxylate
Trade names: Imovane, Zimovane
Legal status: Prescription only (Australia, UK, USA)
Application: 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 UK; brand name Zimovane in Europe) is a non-benzodiazepine hypnotic drug used in the treatment of insomnia. The substance is cyclopyrrolone, which increases 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 sleep aid. Its action is based on calming or suppressing the central nervous system. After prolonged use of zopiclone, tolerance and addiction to the drug may occur. When the dose is reduced or the drug is stopped, a withdrawal syndrome may develop, which may include a range of symptoms similar to those observed during benzodiazepine withdrawal. In the United States, zopiclone is not a commercially available drug, 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. In these countries, possessing the drug without a prescription may be illegal. Zopiclone is also called the "Z-drug". Other Z-drugs include Zaleplon (Sonata) and Zolpidem (Ambien and AmbienCR). These drugs are considered 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 chronic use of the drug is usually not recommended.

Medical use

Zopiclone is used for the short-term treatment of insomnia in which the prominent symptoms include difficulty 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 non-benzodiazepines, causes disturbances in body balance and standing stability in patients waking up at night or the next morning. Falls and hip fractures are frequently reported. Combination with alcohol increases the risk of such disorders. Partial, but incomplete, tolerance may develop towards such side effects. An extensive review of the medical literature regarding the treatment of insomnia in older adults found that there is sufficient evidence of the effectiveness and long-term benefits of non-drug treatments for insomnia. Compared with benzodiazepines, nonbenzodiazepine hypnotics and sedatives such as zopiclone offer few advantages in efficacy or tolerability in older adults. It has been found that new agents, such as melatonin agonists, may be more suitable and effective for the treatment of chronic insomnia in older adults. There is still insufficient evidence regarding the safety of long-term use of sedative hypnotics for insomnia. This use is not recommended for reasons that include concerns about possible adverse drug effects, including cognitive impairment (anterograde amnesia), daytime sedation, impaired motor coordination, and an increased risk of motor vehicle accidents and falls. In addition, the effectiveness 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

Side effects most often observed in clinical trials, there were changes in taste or dysgeusia (a bitter, metallic taste in the mouth that goes away quickly in most users, but may persist until the drug's half-life has expired in some). After stopping the drug, you may experience heart palpitations during the daytime, especially after long periods of use. Zopiclone, like Triazolam and Rohypnol, causes memory impairment 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 and is also observed with other sleeping pills. A study evaluating the effects of zopiclone on next-day driving performance found that the drug's detrimental effect on driving performance was twice that of alcohol. Zaleplon does not have a detrimental effect on driving performance the day after use. Daytime anxiety associated with discontinuation of nonbenzodiazepines such as Zopiclone.

Common side effects

Gastrointestinal: taste disturbances, including a metallic taste and dry mouth. Nervous system: REM sleep disturbances, double vision, drowsiness, memory impairment, visuospatial disturbances, dizziness, headaches and fatigue. Unexpected mood changes are also possible, and if they occur, you should stop taking the drug immediately.

Less common side effects

Gastrointestinal: heartburn, constipation, diarrhea, nausea, coating on the tongue, bad breath, anorexia or increased appetite, vomiting, epigastric pain, dyspepsia, dehydration, paravgesia. Cardiovascular: palpitations in elderly patients. Skin: urticaria, tingling in the arms and legs. Miscellaneous: Blurred vision, frequent urination, nocturnal enuresis, mild to moderate increases in serum transaminases and/or alkaline phosphatase, and interstitial nephritis (very rare). Reproductive system: impotence, delayed ejaculation, anorgasmia in men and women. Nervous system: excitement, anxiety, memory loss, including anterograde and retrograde amnesia, confusion, dizziness, weakness, drowsiness, asthenia, euphoria and / or dysphoria, feeling of intoxication, depression, sleepwalking, coordination problems, hypotension, speech impairment, hallucinations , as a rule, auditory and visual, behavioral disorders, aggression, tremors, relapse of insomnia, nightmares, hypomania. Delirium is mainly observed in older people.

Tolerance, dependence and discontinuation

Zopiclone, a benzodiazepine-like drug, was initially presented as having a reduced risk of dependence and withdrawal symptoms compared with traditional benzodiazepine drugs. In reality, however, zopiclone may have an even slightly greater addiction potential than benzodiazepines. Tolerance to the effects of zopiclone may develop over several weeks. In most cases, long-term 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 cessation of use, especially when taking high doses of the drug for a long time, can cause seizures and delirium in severe cases. Publications in the British Medical Journal provide no evidence that zopiclone has a low potential for addiction. In fact, physical dependence, abuse, and withdrawal symptoms similar to those observed with benzodiazepine withdrawal often occur with the drug. Symptoms of withdrawal syndrome include restlessness, tachycardia, tremors, sweating, hot flashes, palpitations, derealization, and later insomnia. Withdrawal seizures have also been reported during Zopiclone detoxification, however in this case the person was abusing high doses of Zopiclone. The risk of developing dependence when taking zopiclone for less than 2 weeks or less is very low. However, this is disputed by one study of low-dose zopiclone taken over 7 nights. Stopping zopiclone has been found to cause a relapse of insomnia. Additionally, when midazolam was discontinued after continuous use for 7 nights, no relapse of insomnia was observed, suggesting that zopiclone may cause more significant problems of tolerance and dependence than benzodiazepines. After 3 weeks of use, mild to moderate symptoms of relapse occur when zopiclone is stopped. 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, to rarely use the drug for long periods of time. Long-term users of Zopiclone who have become physically dependent on the drug should not abruptly stop taking the substance as severe withdrawal symptoms such as delirium may be associated with it. If zopiclone has been taken for several weeks or more, discontinuation of the drug should be done by gradually reducing the dose or switching to an equivalent dose (Valium), which has a much longer half-life, making withdrawal easier, and then gradually tapering over several months dosage to avoid the development of extremely severe and unpleasant withdrawal symptoms (such as internal restlessness, psychomotor agitation, abdominal pain, hypertension, hallucinations, seizures, anxiety, depression, psychosis, etc.), which can last up to two years if you stop taking the drug too abruptly. After 4 weeks of using zopiclone at night, some users develop daytime anxiety associated with stopping the drug. This symptom, however, does not occur as intensely as with triazolam, which has a much shorter duration of action and produces more severe symptoms of daytime withdrawal anxiety in long-term users. According to the World Health Organization, Zopiclone, although not molecularly a benzodiazepine, is capable of binding non-selectively and with high affinity to the same benzodiazepine binding site as benzodiazepines. The World Health Organization has also stated that zopiclone is cross-tolerant with benzodiazepines and these drugs can replace each other. A World Health Organization review of zopiclone found that the onset of withdrawal symptoms tends to occur either with excessive drug abuse or with long-term use of zopiclone. Zopiclone withdrawal symptoms include anxiety, tachycardia, tremors, sweating, relapse of insomnia, derealization, seizures, palpitations and hot flashes. Zopiclone is cross-tolerant with benzodiazepines. Alcohol exhibits cross-tolerance with positive GABA receptor modulators such as benzodiazepines and non-benzodiazepines. 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 developing psychological dependence from zopiclone. Patients with alcoholism, drug abuse, or physical or psychological dependence on sedatives should avoid taking Zopiclone. Discontinuation of Zopiclone is recommended through switching to an equivalent dose, as diazepam is available in low dosages, is cross-tolerant to zopiclone and lasts longer than zopiclone, allowing for a smoother withdrawal and allowing the body to adjust to a constant dose. Although Zopiclone acts at the same benzodiazepine receptors as drugs in the benzodiazepine family, 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 non-benzodiazepine Z-drugs, at prescribed doses, are associated with an increased risk of cancer in humans. There were 15 epidemiological studies that showed that sleeping pills increase the risk of mortality, mainly due to increased mortality from cancer (brain, lung, colon, breast and Bladder). One possible explanation for the increase in cancer deaths is that Z-drugs have a negative effect on the immune system. The fact that increased disease rates were observed in clinical trials in patients taking other Z-drugs (zolpidem, zaleplon, and eszaleplon) may support this theory. Benzodiazepine sleeping pills are also associated with an increased risk of ovarian cancer. Development malignant tumor has been associated with the use of zolpidem, but nothing can yet be said about the relationship of zolpidem with the development of neoplasms. Indiplon, another nonbenzodiazepine drug, also demonstrated an increased risk of cancer in clinical trials. The review concluded: "The risk of developing cancer is significant and physicians and patients should be aware that sleeping pills may increase a patient's risk of developing cancer."

Contraindications

Zopiclone causes decreased driving skills, similar to benzodiazepines. Long-term users of hypnotics develop only partial resistance to the adverse effects of the drugs associated with negative effects on driving skills. Users who take sleeping pills for an entire year are still at risk of road traffic accidents. You should avoid driving while taking Zopiclone. Zopiclone causes deterioration of psychomotor function. The day after taking Zopiclone, an effect such as deterioration in hand-eye coordination may occur. Patients with a history of drug abuse should avoid using 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, interacting with people (quite convincingly), and even driving a car while actually asleep. Therefore, the drug is generally not used as a sedative (like benzodiazepines), since patients may make unfavorable decisions (as they are asleep) and engage in dangerous activities while the drug is active, without remembering any of this afterwards.

Special Precautions

Alcohol should be avoided when using zopiclone because alcohol and zopiclone enhance each other's effects, which may increase the risk of addiction. 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 older adults, and also has cognitive effects side effects. Falls are one of the most common causes of death in older people. 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 diseases, or experiencing sleep apnea, should avoid the use of Zopiclone. Patients with untreated thyroid disease should also avoid using the drug.

EEG and sleep

Like other sedative-hypnotics, zopiclone causes a decrease in body temperature and is effective in reducing sleep latency. Zopiclone causes benzodiazepine-like changes in EEG and sleep architecture, and also causes disturbances in sleep structure when discontinued, as a rebound effect. Zopiclone reduces delta waves and the number of high-amplitude delta waves, while increasing the number of low-amplitude waves. Zopiclone reduces total time in REM sleep and also delays its onset. Cognitive behavioral therapy is more effective means in the treatment of insomnia than zopiclone, 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 act indiscriminately at the benzodiazepine-binding sites on the α1, α2, α3, and α5 GABA 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 addictive properties of these drugs. One study, however, demonstrated slight selectivity of zopiclone for the α1 and α5 subunits. It is believed, however, that zopiclone binds indiscriminately to the α1, α2, α3, and α5 GABA receptor benzodiazepine complexes. Desmethylzopiclone exhibits partial agonist properties, unlike zopiclone, which is a full agonist. The mechanism of action of zopiclone is similar to that of benzodiazepines, both substances have similar effects on motor activity and on the turnover of dopamine and serotonin. A meta-analysis of randomized controlled clinical trials comparing benzodiazepines and zopiclone or other Z-drugs such as zolpidem and zaleplon found that there were clear and consistent differences between zopiclone and benzodiazepines in terms of sleep onset latency, total sleep duration, number of awakenings, sleep quality, adverse effects, tolerance, relapse of insomnia and daytime activity. Zopiclone is part of the cyclopyrrolone family. Another drug in this class is Suriclone. Zopiclone, while molecularly different from 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 pharmachologic effect Zopiclone. In addition to its pharmacological properties, Zopiclone may act similar to barbiturates. In EEG studies, zopiclone has been shown to significantly increase beta frequency band energy and show high voltage slow wave characteristics, desynchronization of hippocampal theta waves, and increased energy in the delta frequency band. Zopiclone increases both REM sleep and NREM sleep, while zolpidem, an α1-selective compound, increases only NREM sleep and has no effect on REM sleep. Zopiclone is less selective at the α1 site and has a higher affinity for the α2 site than zaleplon. Therefore, pharmacologically, Zopiclone is 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 into 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 from 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 a racemic mixture, Cmax (time to maximum 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 lower volume of distribution (adjusted). on 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 the concentrations 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 increases its effects and adverse effects, including significantly increasing the potential for zopiclone overdose. |Erythromycin]] increases the rate of absorption of zopiclone and prolongs the half-life of zopiclone, which leads to increased plasma concentrations of the drug and more pronounced effects. Itraconazole has a similar effect on the pharmacokinetics of zopiclone. Older adults may be especially sensitive to drug interactions between itraconazole and zopiclone. A temporary dosage reduction may be necessary during combination therapy, especially in the elderly. Rifampicin causes a significant decrease in zopiclone half-life and peak plasma levels, resulting in a decrease in the hypnotic effects of zopiclone. Phenytoin and carbamazepine may also cause similar interactions. Ketoconazole and sulfaphenazole interfere with the metabolism of zopiclone. Nefazodone interferes with the metabolism of zopiclone, causing increased zopiclone levels and next-day sedation.

Story

Zopiclone was developed and first introduced in 1986 by Rhône-Poulenc S.A., now part of Sanofi-Aventis, the main manufacturer of Zopiclone worldwide. The drug was initially marketed as an improved version of benzodiazepines, but a recent meta-analysis showed that zopiclone has no particular advantage over benzodiazepines in any of the accrued aspects. On April 4, 2005, the US Drug Enforcement Administration designated zopiclone as a Schedule IV substance because the drug has addictive properties similar to benzodiazepines. Zopiclone, traditionally sold throughout the world, is a racemic mixture of two stereoisomers, only one of which is active. In 2005, the Marlborough, Massachusetts-based pharmaceutical company Sepracor began marketing the active stereoisomer of Eszopiclone under the name Lunesta in the United States. The consequence of this was the placement of this drug, which is a generic in most countries of the world, under patent control in the United States. Although the drug was expected to be available in generic form by 2010, no generic version of the drug has been brought to market to date. However, Zopiclone is currently available as a generic medicine in several European countries, as well as in Brazil, Canada and Hong Kong. The difference between Eszopiclone and Zopiclone is the dosage - the most active dose of the Eszopiclone 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 studied in comparative clinical trials to determine whether there are any potential clinical differences (in efficacy, side effects, dependence potential, safety, etc.)

Recreational use

Zopiclone is a drug that has the potential for abuse and drug escalation, drug 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 dependence. After long-term use of the drug in normal doses, withdrawal symptoms may be observed, even after a gradual dose reduction. It is usually recommended to take Zopiclone no longer than 7-10 days, due to concerns about the possible development of dependence and tolerance to the drug. It is possible to develop two types of drug addiction: recreational abuse, when the drug is taken to achieve a “high,” or prolonged 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. Symptoms of addiction from Zopiclone abuse may include depression, dysphoria, feelings of hopelessness, slowed 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, including benzodiazepines and zolpidem, are also often found in such cases. In many drivers, blood levels of the drug significantly exceed 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 in prescribed doses causes mild side effects observed the day after use, increases the risk of road 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 sleeping pills are sometimes used to commit criminal acts such as sexual assault. Zopiclone is cross-tolerant to barbiturates and may suppress signs of barbiturate withdrawal. Zopiclone is often used intravenously and has been shown in studies in monkeys to be associated with a high risk of abuse. Zopiclone is among 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. The tablets are coated with a special layer of film to mask the taste when swallowed, but this film is destroyed when chewed. Additionally, a common side effect is a bitter, metallic taste after ingestion, which is why a person taking zopiclone will likely know they are under the influence of the drug.

Overdose

Zopiclone is sometimes used as a method of suicide. Zopiclone has a mortality rate similar to benzodiazepines (except temazepam, which is toxic in overdose). Deaths have been reported due to overdose of Zopiclone, when taken alone or in combination with other drugs. An overdose of zopiclone may 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. In case of an overdose of Zopiclone, you can take the benzodiazepine receptor antagonist flumazenil, which displaces zopiclone from the benzodiazepine binding site on the receptor, thereby helping to quickly eliminate the effects of zopiclone. Serious effects on the heart may also occur if Zopiclone is taken in combination with piperazine. Death certificates show an increase in Zopiclone overdose deaths. Zopiclone, when taken alone, is usually not fatal, but when combined with alcohol or other drugs such as opioids, or in patients with respiratory or liver disease, the risk of serious and fatal overdose increases.

APPROVED

By order of the chairman

Committee for Control of Medical and
pharmaceutical activities
Ministry of Health

Republic of Kazakhstan

From "__" ________ 20__

Instructions for medical use

Medicine

Tradename

International nonproprietary name

Zopiclone

Dosage form

Film-coated tablets 7.5 mg.

Compound

One tablet contains

active substance- zopiclone 7.5 mg,

Excipients: calcium hydrogen phosphate, anhydrous, potato starch, magnesium stearate, sodium starch glycolate (type A), silicon dioxide,

Shell composition: Opadry II white 33G28707 (hypromellose, titanium dioxide (E 171), lactose monohydrate, triacetin, macrogol 3000).

Description

White, film-coated tablets, round in shape with a biconvex surface, scored on one side.

Pharmacotherapeutic group

Sleeping pills and sedatives. Benzodiazepine-like drugs.

ATX code N05СF01

Pharmacological properties

Pharmacokinetics

After oral administration at a dose of 7.5 mg, zopiclone is rapidly absorbed. The maximum concentration in the blood plasma is achieved within 0.5-1.5 hours. 1 hour after administration, 95% of the drug is absorbed. In the dose range of 5-15 mg, a linear correlation is observed between the dose and the concentration of the drug in the blood plasma. The drug is characterized by first-order kinetics. The distribution volume is 100 l. About 45% of the drug is bound to plasma proteins. The elimination period of zopiclone and its active metabolite, N oxide, ranges from 3.5 to 6 hours. Minor and moderate renal dysfunction does not cause significant changes in the kinetics of zopiclone, and with severe renal failure, it is possible to increase the area under the concentration-time curve, the time to reach the maximum concentration (Tmax) and elimination period (T1/2). A slight increase in the half-life of elimination is also observed in elderly patients.

Only 4-5% of unchanged zopiclone is excreted in the urine. The 2 main metabolites (active zopiclone N-oxide and inactive desmethylzopiclone N) are excreted by the kidneys, while the others are excreted by the lungs.

After 24-48 hours, almost 100% of the administered dose of somnol is excreted from the body.

In case of liver failure, adjustment of the dosage regimen is required.

Special risk groups

Elderly patients: Despite a slight decrease in hepatic metabolism and an average half-life of 7 hours, no accumulation of the drug in plasma was found in various studies with repeated dosing.

Patients with renal failure: no accumulation of zopiclone or its metabolites was detected after long-term use. Zopiclone penetrates the dialysate membrane. Hemodialysis is not useful in treating overdose due to the large volume of distribution of the drug.

Patients with liver cirrhosis: plasma clearance of zopiclone is greatly reduced as a result of delayed dimethylation; therefore, the dose for such patients needs to be adjusted.

Pharmacodynamics

Somnol (zopiclone) is a hypnotic drug of the group psychotropic drugs- cyclopyrrolone derivatives. It has high affinity and selectivity for omega-1 and omega-2 benzodiazepine receptors, which are part of the macromolecular complex of the chloride ion channel and gamma-aminobutyric acid A receptors. The drug has virtually no effect on omega-5 benzodiazepine peripheral receptors.

Zopiclone binds to sites of benzodiazepine receptors specific to cyclopyrrolone derivatives and causes characteristic changes in the conformation of benzodiazepine receptors, leading to activation of the chloride channel.

Indications for use

Transient, situational insomnia

Directions for use and doses

Somnol 7.5 mg tablets are prescribed orally.

Adults are prescribed 1 tablet shortly before going to bed.

The duration of continuous treatment is no more than 4 weeks.

Somnol is not prescribed to children and adolescents under 18 years of age.

In patients with impaired renal function, treatment is recommended to begin with a dose of 3.75 mg, although accumulation of the drug in this group of patients was not observed.

In patients with impaired liver function, treatment is recommended to begin with a dose of 3.75 mg, since the elimination of the drug in this group of patients is reduced. If necessary, the dose can be carefully increased to 7.5 mg, taking into account the sensitivity of the patient.

Elderly patients are initially prescribed 3.75 mg of the drug. If necessary, the dose of the drug can be gradually increased, taking into account the individual sensitivity of the patient.

The maximum single and daily dose of somnol is 7.5 mg.

Side effects

There are known cases of withdrawal syndrome when stopping therapy with Somnol®. Withdrawal symptoms vary and may include rebound insomnia, muscle pain, restlessness, tremors, sweating, agitation, confusion, headache, palpitations, tachycardia, delirium, nightmares, irritability. In severe cases, possible following symptoms: derealization, depersonalization, hyperacusis, numbness and tingling sensation in the extremities, hypersensitivity to light, noise and physical contact, hallucinations. In very rare cases, seizures are possible.

Dry mouth

Dysgeusia (bitter taste), residual drowsiness

Headache, dizziness

Nausea

Fatigue

Nightmares, agitation

Anterograde amnesia

Rash, itching

Confusion, irritability, aggressiveness, hallucinations

Libido disturbance

Falls (mostly in adult patients)

Very rarely

Angioedema, anaphylactic reactions

Increased levels of transaminases and/or alkaline phosphatase in the blood (mild to moderate)

Frequency unknown

Dyspepsia

Diplopia

Anxiety, delirium, irritability, abnormal behavior for the patient (possibly associated with amnesia) and somnambulism, addiction, withdrawal syndrome

Ataxia

Muscle weakness

Contraindications

Hypersensitivity to the drug

Myasthenia Gravis

Severe liver dysfunction

Severe sleep apnea

Respiratory failure

Congenital galactose intolerance, Lapp lactase deficiency, glucose-galactose malabsorption

Pregnancy and lactation

Children and teenagers up to 18 years of age

Drug interactions

Alcohol

The sedative effect of benzodiazepines and related drugs is enhanced by alcohol. If vigilance is reduced, driving or operating machinery can become dangerous.

Patients should avoid taking alcoholic beverages and medications containing alcohol.

Combinations requiring precautions during use

Rifampicin

Reduced plasma concentrations and reduced efficacy of zopiclone due to increased hepatic metabolism. Clinical monitoring. If necessary, you can use another sleeping pill.

Combinations to Consider

Other central nervous system depressants

Morphine derivatives (analgesics, antitussives and replacement therapy agents, except buprenorphine), antipsychotics, barbiturates, sedatives, anxiolytics, other hypnotics, sedative antidepressants, sedative H1 antihistamines, centrally acting antihypertensives, baclofen, thalidomide, pizotifen. Central nervous system (CNS) suppression increases. Reduced alertness can make driving or operating machinery dangerous.

Moreover, with the simultaneous use of zopiclone with morphine derivatives (analgesics, antitussives and replacement therapy) and barbiturates, the risk of respiratory depression increases, which in case of overdose can be fatal.

Buprenorphine

When used as replacement therapy, the risk of fatal respiratory depression increases. The balance of benefits and harms of this combination should be carefully weighed. The patient should be warned about the need to strictly adhere to the prescribed dose.

Clozapine

Increased risk of acute vascular insufficiency with respiratory and/or cardiac arrest.

Clarithromycin, ketoconazole, itraconazole, voriconazole, nelfinavir, ritonavir

Slightly increased sedative effect of zopiclone.

special instructions

Drug addiction

Taking sedative/hypnotics like zopiclone can lead to physical and mental drug dependence or abuse.

The risk of dependence or abuse increases:

With dose and duration of treatment

If there is a history of alcohol and/or drug abuse

When taken with alcohol or other psychotropic drugs.

Sudden cessation of treatment when physical dependence develops may be accompanied by withdrawal symptoms.

Rebound insomnia

A transient syndrome in which the symptoms for which sedative/hypnotic drugs were prescribed may return in an intensified form when the latter are discontinued.

Since the risk of such a phenomenon is higher after stopping treatment with Somnol®, especially after long-term therapy, it is recommended to gradually reduce the dosage and inform the patient accordingly.

Tolerance

After repeated doses, a decrease in the effectiveness of other sleeping pills may occur. However, there is no significant tolerance in patients treated for periods of up to 4 weeks.

Anterograde amnesia may occur, especially after interrupted sleep or if there is a delay in going to bed after taking the pill. To reduce this risk, patients should:

Take the tablet immediately before going to bed, that is, in bed

Take care of the conditions that are most conducive to a good night's sleep.

Other psychiatric and paradoxical reactions

There are known cases of other psychiatric and paradoxical reactions, such as anxiety, agitation, irritability, aggressiveness, delirium, irritation, nightmares, hallucinations, abnormal behavior for the patient and other adverse behavioral effects that have occurred when taking sedative/hypnotics such as zopiclone. If such reactions occur, zopiclone should be discontinued. Such reactions are more common in adults.

Somnambulism and associated behavior

Sleepwalking and other associated behaviors such as drowsy driving, preparing and eating food, or making telephone calls with post-event amnesia have been reported in patients treated with zopiclone who were in a state of incomplete awakening after taking it. Concomitant use of alcohol and other CNS depressants with zopiclone increases the risk of such behavior, as does taking zopiclone in doses exceeding the maximum recommended dose. It is strongly recommended that discontinuation of zopiclone be considered for patients who have experienced such disorders.

Depression

Like other sleeping pills, Somnol® is not part of the treatment of depression and may mask its symptoms.

The shell of Somnol tablets contains a dye that includes lactose, so this medicine should not be prescribed to patients with rare congenital galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Features of the effect of the drug on the ability to drive a vehicle or potentially dangerous mechanisms.

Since somnol belongs to the group of sedatives that cause drowsiness, after taking the drug you cannot control vehicles or perform the work of an operator of various devices and mechanisms.

Overdose

Symptoms: CNS depression, in which a complex of symptoms from drowsiness to coma is observed. Typically, this CNS depression is not life-threatening for the patient. However, when somnol is used together with drugs that have a depressant effect on the central nervous system, an overdose can be severe and life-threatening for the patient.

Treatment: symptomatic treatment, paying special attention to normalizing breathing and heart activity. The benzodiazepine receptor antagonist flumazenil can be used as an antidote. If an overdose is diagnosed soon after taking the drug, it is advisable to perform gastric lavage. In case of an overdose of somnol, the use of hemodialysis does not provide a therapeutic effect.

Address of the organization receiving claims on the territory of the Republic of Kazakhstan from consumers regarding product quality

A Zopiclone tablet contains 7.5 milligrams of the active drug compound of the same name. In addition, such auxiliary components as: microcrystalline cellulose, lactose monohydrate, potato starch, anhydrous colloidal silicon dioxide, magnesium stearate , and talc, aerosil and povidone .

Release form

This drug is produced in the form of tablets, on top of which a special coating is applied, as well as powder, packaged in special sachets.

pharmachologic effect

The drug belongs to sedative and hypnotic drugs, members of the group pyrrolopyrazinamide .

Pharmacodynamics and pharmacokinetics

Since Zopiclone is hypnotic cyclopyrrolone derivative, the drug is effective agonists, so-called benzodiazepine receptors . This medicine is distinguished by its pronounced anxiolytic, and sedative effect . In addition, the drug stands out for its amnestic, anticonvulsant and muscle-relaxing properties.

Due to the chemical characteristics of the medicinal substance included in the preparation zopiclone , there is an increase GABAergic processes in the brain person, thereby increasing the threshold of sensitivity to GABA receptor mediator due to the interaction of active components with benzodiazepine receptors. Taking this medication reduces the number of times you wake up during the night.

In addition, the drug has a beneficial effect on the process of falling asleep and significantly increases the duration of sleep. It is worth noting that the drug does not have a negative effect on the sleep structure itself, i.e. does not change its stages, for example, does not reduce the duration of REM sleep, and so on. The drug dissolves quickly enough in stomach and reaches its maximum concentration after just a few hours after taking it.

The drug easily overcomes histohematic barrier and is evenly distributed in tissues and organs human body, including in the brain. When repeating a course of treatment with Zopiclone cumulation does not appear. Within half an hour after using the drug, a sound sleep occurs, the duration of which is a maximum of eight hours.

It is worth noting that when taking Zopiclone and medications containing theophylline , patients with a significantly reduced duration, and, in addition, the intensity of asthmatic attacks in the early morning hours.

Indications for use

As a rule, the drug is prescribed for the following sleep disorders:

• difficulty falling asleep;
• constant night or morning awakenings;
• , including chronic, short-term or situational types of illness;
• restless sleep;
• sleep disorders associated with various types mental disorders.

Contraindications

TO absolute contraindications relate:

• respiratory failure;
• age under 18 years;

In addition, patients with liver failure, at at malabsorption of galactose and glucose, with congenital galactosemia , at , and also at lactase deficiency .

Side effects

With the correct dosage of the drug, there are usually no side effects of Zopiclone. However, if the dosage is significantly exceeded, the following ailments may occur:

• behavioral disorders;
• aggressiveness;
• somnambulism;
• confusion or changes in consciousness;
• psychological or physiological dependence;
• speech disorders;
• lack of coordination;
• decreased sex drive;
• skin rashes;
• diplopia;
• hypotension;
• and other manifestations of allergies;
• asthenia;
• dispersion;
• hypotension;
• vomit;
• weight loss.

It is worth noting that in case of overdose, patients feel dry mouth and bitter taste . In some cases it may intensify liver enzyme activity .

Instructions for use of Zopiclone (Method and dosage)

The therapeutic (average) dose of the drug in accordance with the instructions for Zopiclone is 7.5 mg, which corresponds to one tablet. The medicine is taken immediately before bedtime. For severe forms insomnia the dosage can be doubled. However, elderly patients and people suffering from disorders liver functions should not take more than 3.75 mg. Zopiclone per day.

Overdose

An overdose of the drug occurs when the recommended average therapeutic doses of the drug are exceeded and can threaten the patient’s life. As a rule, in case of overdose occurs depression of the central nervous system (CNS). Signs of an overdose can be considered the patient's lethargic condition , and , confusion, respiratory depression, hypotension and hypotension.

If no more than an hour has passed since taking the drug, then you can call the patient vomiting . In other cases, you should immediately gastric lavage , while paying particular attention to the protection respiratory organs . In order to reduce absorption patients are prescribed zopiclone contained in the drug.

Gross formula

C 17 H 17 ClN 6 O 3

Pharmacological group of the substance Zopiclone

Nosological classification (ICD-10)

CAS code

43200-80-2

Characteristics of the substance Zopiclone

Non-benzodiazepine hypnotic (cyclopyrrolone derivative).

Pharmacology

pharmachologic effect- sleeping pills, sedatives.

It is a benzodiazepine receptor agonist. Interacts with central receptors (omega 1 and omega 2 benzodiazepine receptor subtypes) of the macromolecular GABA-benzodiazepine-chlorionophore complex and does not interact with peripheral benzodiazepine receptors. Increases the sensitivity of GABA receptors to the mediator (GABA), which causes an increase in the frequency of opening channels in the cytoplasmic membrane of neurons for incoming currents of chlorine ions. As a result, the inhibitory effect of GABA is enhanced and interneuronal transmission is inhibited in various parts of the central nervous system.

Rapidly absorbed from the gastrointestinal tract. Cmax is reached after 1-1.5 hours. Binding to blood plasma proteins is about 45%. Easily passes through histohematic barriers, including the BBB, and is distributed throughout organs and tissues, incl. brain. Passes through the placental barrier, penetrates into breast milk (breast milk contains 2 times lower concentrations than in blood plasma). Metabolized in the liver to form N-oxide, which has little pharmacological activity, and 2 inactive metabolites. T1/2 - 3.5-6 hours, with severe insufficiency of liver function increases to 11 hours. It is excreted mainly by the kidneys in the form of metabolites (80%), as well as through the intestines (16%). There is evidence of excretion of small amounts by the salivary glands. Repeated doses are not accompanied by accumulation of zopiclone and its metabolites.

Shortens the period of falling asleep, reduces the number of night awakenings, improves sleep quality, and does not change the phase structure of sleep. Effective for situational insomnia associated with psycho-emotional stress, changes in the usual rhythm of life (for example, during hospitalization), desynchronosis, incl. when changing time zones, shift work. Sleep occurs within 20-30 minutes after administration and lasts 6-8 hours.

In patients with nocturnal manifestations of bronchial asthma, in combination with methylxanthine drugs (theophylline), it reduces asthma attacks in the early morning hours, reduces their intensity and duration.

Use of the substance Zopiclone

Sleep disturbances (difficulty falling asleep, frequent night and/or early morning awakenings), incl. situational, short-term, chronic insomnia; secondary sleep disorders with mental disorders.

Contraindications

Hypersensitivity, severe respiratory failure, pregnancy (especially the first and third trimester), breastfeeding, age under 18 years.

Restrictions on use

Sleep apnea, myasthenia gravis, severe liver failure.

Use during pregnancy and breastfeeding

Contraindicated during pregnancy (especially in the 1st and 3rd trimester). When zopiclone is used by a woman in the third trimester of pregnancy, the newborn may experience nervous system disorders and withdrawal syndrome. If a woman, as prescribed by a doctor, took zopiclone immediately before the onset of labor and childbirth, constant medical monitoring of the newborn is necessary. Treatment should be stopped during treatment breast-feeding(zopiclone passes into breast milk).

Side effects of Zopiclone

From the nervous system and sensory organs: drowsiness, lethargy, fatigue, headache, dizziness, irritability, confusion (more often in the elderly), depressed mood, muscle weakness, impaired coordination of movements, diplopia, memory impairment, paradoxical reactions (increased insomnia, nightmares, nervousness, agitation, aggressiveness, attacks of anger, hallucinations).

Other: bitter or metallic taste in the mouth, dry mouth, nausea, vomiting, skin allergic reactions, changes in libido, anterograde amnesia.

Possible addiction, drug dependence, withdrawal syndrome, incl. rebound insomnia (see "Precautions").

Interaction

When zopiclone is used together with other drugs that depress the central nervous system (including antipsychotics, other hypnotics, antiepileptic drugs, some antihistamines, alcohol), mutual enhancement of the effects is possible.

Zopiclone reduces plasma concentrations of trimipramine.

Overdose

Symptoms: depression of the central nervous system of varying severity (from drowsiness to loss of consciousness).

Treatment: gastric lavage, taking activated carbon; if necessary, symptomatic therapy. The benzodiazepine receptor antagonist flumazenil is used as a specific antidote (in a hospital setting). Hemodialysis is ineffective.

Routes of administration

Inside.

Precautions for the substance Zopiclone

Due to the possibility of developing drug dependence, long-term use may be prescribed by a doctor in exceptional cases. If insomnia does not disappear within 4 weeks, you should inform your doctor. The likelihood of addiction, physical or psychological dependence increases if the prescribed dosage is violated or the duration of treatment exceeds 4 weeks.

Cancellation should be carried out gradually, because with abrupt cessation of treatment, resumption of insomnia, frequent awakenings, headache and muscle pain, anxiety, agitation, absent-mindedness, and irritability are possible.

Paradoxical reactions are more often observed in elderly patients. If paradoxical reactions occur, zopiclone should be discontinued.

International name

Zopiclone

Group affiliation

Sleeping pill

Dosage form

Tablets, film-coated tablets

pharmachologic effect

A hypnotic from the group of cyclopyrrolones, which are structurally different from benzodiazepines and barbiturates. It has a sedative and hypnotic effect, which is due to a high degree of affinity for binding sites on the GABA receptor complex in the central nervous system. Quickly induces sleep without reducing the REM sleep phases in its structure, and then maintains sleep while maintaining normal phase composition. Does not cause post-somnia disorders: there are no feelings of weakness and drowsiness the next morning.

Sleep occurs within 30 minutes and lasts 6-8 hours. Reduces headaches. In patients with nocturnal attacks of bronchial asthma, in combination with methylxanthine drugs (theophylline), it reduces asthma attacks in the early hours of the morning, reduces their intensity and duration.

Indications

Sleep disorders: difficulty falling asleep, night awakenings, early awakening; transient, situational and chronic insomnia; sleep disturbances in mental disorders, bronchial asthma with nocturnal attacks (in combination with a single daily dose of theophylline).

Contraindications

Hypersensitivity, severe respiratory failure, myasthenia gravis, severe liver failure, sleep apnea syndrome, age under 18 years, pregnancy, lactation. With caution. Liver failure.

Side effects

“Metallic” taste in the mouth, nausea, vomiting, mental disorders (irritability, confusion, depressed mood), allergic reactions (urticaria, rash).

When waking up - drowsiness, dizziness, impaired coordination of movements, sometimes depressive states, aggressiveness, anterograde amnesia.

Application and dosage

Orally, 7.5 mg, 30-40 minutes before expected sleep, if necessary - up to 15 mg ( maximum dose). The starting dose for the elderly and the maximum recommended dose for liver failure is 3.75 mg. Duration of continuous use – no more than 1 month.

special instructions

Long-term use is not recommended (due to the possible development of drug dependence); the course of treatment should not exceed 4 weeks. Patients should drive a car and operate machinery with caution the day after taking the drug.

Interaction

Reduces plasma concentrations of trimipramine and its effect. Strengthens the effect of drugs that depress the central nervous system (including ethanol).

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