Zolpidem - instructions for use, dose, side effects, contraindications

Selective agonist omega-1subtype of benzodiazepine receptors of macromolecular GABA_A-receptor complex. Interacts with central omega₁-receptors localized mainly in the cerebellum, certain areas of the cortex (IV layer of the sensitive-motor cortical areas), black substance, lower hillock, olfactory bulb, ventral part of thalamic complex, bridge and pallid sphere in the central nervous system. Increases the sensitivity of GABA-receptors to the mediator (gamma-aminobutyric acid), which leads to an increase in the opening frequency in the cytoplasmic membrane of the neurons of the channels for the incoming currents of chloride ions, the hyperpolarization of the synaptic membrane, the enhancement of the inhibitory effect of GABA, and the suppression of neuronal activity in various parts of the central nervous system.

It is believed that the selective binding of zolpidem with omega₁-receptors cause the manifestation of hypnotic action, whereas anticonvulsant, myorelaxing and anxiolytic effects (associated, apparently, with a predominant effect on omega₂- and omega₅-receptors) are practically absent.

When taken in therapeutic doses, shortens the time of falling asleep, reduces the number of nocturnal awakenings, prolongs the duration of sleep, and improves its quality.

Pharmacokinetics:

After ingestion of zolpidem, tartrate is quickly and completely absorbed from the digestive tract. Bioavailability is about 70% (undergoing pre-systemic metabolism). Average value of C_max in healthy volunteers, when taking 5 mg was 59 ng / ml with a fluctuation of 29-113 ng / ml, while taking 10 mg - 121 ng / ml with fluctuations of 58-272 ng / ml. T_max - 0.5-2 hours (average 1.6 hours). Simultaneous food intake can reduce the rate and degree of absorption and increase T_max. Binding to plasma proteins - 92.5%. Penetrates into breast milk (in samples of milk taken 3 hours after ingestion of 20 mg, its amount was 0.004-0.019% of the dose). Metabolized in the liver with the formation of inactive metabolites. The half-life is 1.4-4.5 hours (an average of 2.6 hours) and 1.4-3.8 hours (an average of 2.5 hours) after taking 5 and 10 mg, respectively.The half-life is prolonged in elderly people and in patients with impaired hepatic and / or renal function. It is excreted as inactive metabolites with urine (56%) and with feces (37%). Trace amounts of unchanged zolpidem are detected in urine and feces.

A number of studies have shown that in elderly patients, the C_max, the half-life and AUC were significantly higher than those in adult young adults.

Do not cumulate in adults young people (20-40 years) after taking 20 mg for a night for 2 weeks. Do not cumulate in elderly patients after taking 10 mg overnight for 1 week.

In 8 patients with chronic hepatic insufficiency after taking a single dose of 20 mg of the C_max and AUC were 2 and 5 times higher than those in healthy people, in patients with cirrhosis the half-life was also increased.

Carcinogenicity, mutagenicity, effects on fertility

Carcinogenicity. The evaluation of the carcinogenicity of zolpidem was carried out in biennial studies in laboratory animals (mice, rats) who received zolpidem with food at doses of 4, 18 and 80 mg / kg per day. In mice, these doses exceed the dose of 10 mg per day recommended for humans, calculated in mg / kg or mg / m2,in 26-520 times or 2-35 times, respectively. In rats, these doses exceed the dose of 10 mg / day recommended for humans, calculated in mg / kg or mg / m², 43-876 times or 6-115 times, respectively. The mice showed no carcinogenic properties. In rats, cases of renal lipocarcinomas (4/100 rats receiving a dose of 80 mg / kg per day) and renal lipoma (in one rat receiving a dose of 18 mg / kg per day) were noted, with the incidence of lipomas and liposarcomas in the background Zolpidem was comparable to the incidence of spontaneous onset of tumors according to literature data.

Indications:Sleep disorders: difficulty falling asleep, early and nocturnal awakenings.

ICD-10

VI.G40-G47.G47.0 Disturbances of falling asleep and maintaining sleep [insomnia]

Contraindications:Hypersensitivity, children under 15 years of age (safety and efficacy in children are not defined).

Carefully:

Since sleep disorders can be manifestations of somatic and / or mental illness, symptomatic treatment of insomnia begins only after a detailed examination of the patient.

Zolpidem is indicated for short-term treatment of sleep disorders. The lack of effect after 7-10 days of treatment may indicate the presence of a primary mental and / or somatic disease, which must be diagnosed.The aggravation of insomnia or the appearance of new cognitive impairments or behavioral disorders may be the result of an unrecognized mental or somatic disease.

Since many side effects of zolpidem are dose-dependent, it is important to use zolpidem in minimally effective doses, especially in elderly patients. When taking zolpidem by elderly patients, confusion and cases of falling are more likely; careful monitoring is recommended.

In order to minimize the possibility of developing anterograde amnesia and an unstable state, zolpidem Should be used only if the patient's regime allows him to sleep through the night (7-8 hours).

Use with caution in depression, alcohol and drug dependence in history.

Before discontinuing use after 1-2 weeks, consult a physician; To avoid the development of withdrawal symptoms, a gradual dose reduction may be required.

Since the action of zolpidem develops rapidly, after taking the drug, the patient must be ready to go to sleep.Do not take it concurrently or immediately after a meal (eating can slow the onset of action).

During the treatment period, it is necessary to refrain from taking alcoholic beverages (additive depressant effect is possible). Caution is necessary when taking concomitantly with other drugs that depress the central nervous system (potentially potentiating the effect).

During the treatment period, one should refrain from potentially dangerous activities (driving, working with machinery).

During the period of treatment, it is necessary to strive to create favorable conditions for sleep. Non-compliance with this recommendation or frequent uncontrolled use of high doses increases the risk of drug dependence.

Pregnancy and lactation:

Teratogenic effects. Studies on the evaluation of the effect of zolpidem on reproductive capacity and intrauterine development in humans have not been conducted.

Zolpidem teratogenicity was studied in rats and rabbits. Experimental data show that in rats given doses of 20 and 100 mg / kg (25 and 125 times higher than that recommended for humans, calculated in mg / m²), the following adverse effects were observed: dose-related inhibition and ataxia in females and a dose-dependent tendency to incomplete ossification of the skull bones in the fetus (reduced ossification of different bones in the fetus is due to delay in maturation, often observed in offspring of rats under the influence of sedative / hypnotic drugs).

Rabbits had a dose-dependent sedative effect and a decrease in weight gain in females (in the whole range of doses studied). In rabbits who received zolpidem in high doses (16 mg base / kg, 28 times higher than the recommended dose for humans, calculated in mg / m²), an increase in the frequency of postimplantation death of the fetus and incomplete ossification of the sternal segments in viable fetuses (these effects are considered secondary, associated with a decrease in weight gain in females). No apparent teratogenic properties were found. At a dose of 4 mg base / kg (7 times the recommended dose for humans, calculated in mg / m²) no toxic effects on the fetus were detected.

Nonteratogenic effects. Studies to assess the effect of zolpidem on children whose mothers were receiving zolpidem during pregnancy, did not. However, in newborns, whose mothers received other sedative-hypnotic drugs during pregnancy, weakness and withdrawal symptoms were observed.

When pregnancy is possible, if the intended benefit for the mother exceeds the potential risk to the fetus (adequate and strictly controlled studies in pregnant women are not conducted).

The action category for fetus by FDA is C.

Breast-feeding. It was shown that in rats the dose of zolpidem more than 4 mg / kg (6 times higher than the recommended dose for a person, calculated in mg / kg) suppress the secretion of breast milk.

For the duration of treatment, breastfeeding should cease (in small amounts it penetrates into breast milk). According to one study in 5 nursing mothers, after taking a single dose in breast milk penetrates less than 0.02% of the dose, but the effect of zolpidem on the body of an infant is unknown.

Dosing and Administration:Inside, immediately before going to bed or lying in bed, once. The dose and duration of the course of treatment are set individually. Treatment begins with a minimum effective dose.The average single dose for adults under the age of 65 years is 10 mg, the maximum dose is 15-20 mg. For patients older than 65 years, weakened patients, patients with impaired liver and / or kidney function, the initial single dose is 5 mg, the maximum (if necessary) is not more than 10 mg.

Side effects:

Organism as a whole: often - asthenia; sometimes - edema, falls, fever, malaise, trauma; rarely - an allergic reaction, an exacerbation of allergies, a feeling of abdominal pain, anaphylactic shock, face swelling, a feeling of heat, an increase in the rate of erythrocyte sedimentation, pain, restless legs syndrome, chills, weight loss.

The cardiovascular system: sometimes - cardiovascular diseases, hypertension, tachycardia; rarely - angina pectoris, arrhythmia, arteritis, circulatory disorders, extrasystole, hypertension, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.

Central and peripheral nervous system: often - ataxia, confusion, euphoria, insomnia, vertigo; sometimes - agitation, decreased cognitive ability, difficulty concentrating, dysarthria, emotional lability,hypesthesia, hallucinations, migraine, paresthesia, drowsiness (after the daytime intake), stupor, tremor; rarely - gait disturbance, disturbance of thought processes, aggressive reaction, lethargy, increased appetite, decreased libido, delusion, dementia, depersonalization, dysphasia, strange sensations, hypokinesia, hypotonia, hysteria, poisoning feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis , panic attacks, paresis, personality disorder, somnambulism, suicidal attempts, tetany, yawning.

Gastrointestinal tract: often - hiccough; sometimes - constipation, dysphagia, flatulence, gastroenteritis; rarely - enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal bleeding, caries.

Blood and lymphatic system: rarely - anemia, including macrocytic, hyperhemoglobinaemia, leukopenia, lymphadenopathy, purpura, thrombosis.

The immune system: rarely - abscess, herpetic infection (Herpes simplex, Herpes zoster).

Liver and biliary system: sometimes - a violation of the liver, increased SGP-transaminases; rarely - bilirubinemia, aspartate aminotransferase.

Metabolism: sometimes hyperglycemia, thirst; rarely - gout, hypercholesterolemia, hyperlipidemia, increased alkaline phosphatase, increased blood urea nitrogen, periorbital edema.

Musculoskeletal system: sometimes - arthritis, spasms in the legs; rarely - arthrosis, muscle weakness, sciatica, tendonitis.

Reproductive system: sometimes - menstrual disorders, vaginitis; rarely - breast fibroadenosis, breast tumor, pain in the mammary gland.

Respiratory system: sometimes - bronchitis, cough, dyspnea; rarely - bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.

Skin and its appendages: sometimes itching; rarely - acne, bullous rash, dermatitis, furunculosis, inflammation at the injection site, photosensitivity reactions, urticaria.

Sense organs: often - diplopia, impaired vision; sometimes - eye irritation, pain in the eyes, sclerite, taste distortion, tinnitus; rarely - corneal ulceration, tearing, parosmia, photopsy, external otitis media, otitis media.

Genitourinary system: sometimes - cystitis, urinary incontinence; rarely - acute renal failure, dysuria, frequent urination, nocturia, polyuria, pyelonephritis, pain in the kidney, retention of urination.

Overdose:

Symptoms. European post-marketing reports on zolpidem overdose report a violation of consciousness (from drowsiness to mild coma). Fixed one case of cardiovascular and respiratory disorders.There was a complete recovery after taking doses of zolpidem tartrate to 400 mg (40 times higher than the recommended dose for a person).

Cases of overdose caused by the simultaneous administration of many drugs depressing the central nervous system, including zolpidem, led to more severe consequences, up to lethal outcomes.

Treatment: induction of emesis or immediate gastric lavage (depending on the condition), the purpose of activated charcoal. It shows the monitoring of vital functions (breathing, pulse, blood pressure, etc.), if necessary - symptomatic and supportive therapy. It should be abandoned the use of any sedatives (even with pronounced stimulation). Hemodialysis is ineffective. A specific antidote, a benzodiazepine receptor antagonist flumazenil.

Interaction:With the simultaneous use of zolpidem with drugs that depress the central nervous system (including tranquilizers, barbiturates, antipsychotics, other hypnotics, antidepressants and antihistamines with sedative component, alcohol), mutual enhancement of effects is possible (caution,the dose of one or all of the medicines should be reduced). The benzodiazepine-type anxiolytics increase the risk of drug dependence. When combined with imipramine zolpidem reduces C_max imipramine, it is possible to increase drowsiness and increase the frequency of anterograde amnesia, in combination with chlorpromazine, an extension of the half-life of chlorpromazine is possible.

Special instructions:

Not recommended for myasthenia gravis.

Use with caution in patients with respiratory failure. If the liver function is insufficient, it may be necessary to reduce the dose.

If you cancel therapy, the dose should be reduced gradually. The likelihood of developing addiction increases with prolonged use of zolpidem.

During the treatment period against the background of therapy, do not allow alcohol.

Impact on the ability to drive vehicles and manage mechanisms

During the treatment period, one should refrain from potentially dangerous activities requiring concentration of attention and high speed of psychomotor reactions.

Instructions

Zolpidem (Zolpidemum)