Zolpidem

When ATH:
N05CF02

Characteristic.

Non-benzodiazepine hypnotic patterns (Group imidazopyridines).

Zolpidem tartrate - white or almost white crystalline powder, sparingly soluble in water, alcohol and propylene glycol. Molecular weight 764,88.

Pharmacological action.
Snotvornoe, sedation.

Application.

Sleep disorders: difficulty falling asleep, early and nocturnal awakening.

Contraindications.

Hypersensitivity, childhood (to 15 years) (safety and effectiveness in children have not identified).

Restrictions apply.

Sleep apnea, acute and / or severe respiratory insufficiency, myasthenia, depression, alcoholism, drug abuse or drug dependence, severe liver and / or kidney, advanced age.

Pregnancy and breast-feeding.

Teratogenic effects. Studies evaluating the effect of zolpidem on reproductive ability and intrauterine development in humans have not performed.

Teratogenicity study zolpidem was conducted in rats and rabbits. Experimental data show, that in rats, dose that gave 20 and 100 mg / kg (in 25 and 125 times the recommended human, calculated in mg / m²), The following adverse effects were observed: dozozavisimыe zatormozhennosty and ataxia in samok and dozozavisimaya trend k nepolnomu okosteneniyu Costea fetal skull (reduced ossification of various bones in the fetus due to delayed maturation, often observed in the offspring of rats under the influence of sedative / hypnotic drugs).

The rabbits were observed a dose-dependent sedative effect and decreased body weight gain in female (throughout the range of doses studied). Rabbits, receiving high-dose zolpidem (16 mg base / kg, in 28 times the recommended human dose, calculated in mg / m²), The observed increase in the frequency of postimplantation fetal death and incomplete ossification of sternum segments in viable fetuses (these effects are considered secondary, associated with a decrease in body weight gain in females). Obvious teratogenic properties were found. At a dose of 4 mg base / kg (in 7 times the MRDC, calculated in mg / m²) toxic effects on the fetus have been identified.

Nonteratogenic effects. Studies evaluating the effect of zolpidem on children, whose mothers received zolpidem during pregnancy, not performed. However, in newborns, whose mothers received during pregnancy other sedative-hypnotics, observed weakness and withdrawal symptoms.

When pregnancy is possible, if the expected benefit to the mother outweighs the potential risk to the fetus (adequate and well-controlled studies in pregnant women were not conducted).

Category actions result in FDA - C. (The study of reproduction in animals has revealed adverse effects on the fetus, and adequate and well-controlled studies in pregnant women have not held, However, the potential benefits, associated with drugs in pregnant, may justify its use, in spite of the possible risk.)

Breast-feeding. Displaying, that in rats a dose of zolpidem 4 mg / kg (in 6 times the recommended human dose, calculated in mg / kg) inhibit the secretion of breast milk.

At the time of treatment should stop breastfeeding (in small quantities into breast milk). According to one study in 5 nursing mothers, after oral administration of a single dose to human milk penetrates less 0,02% dose, but the effect of zolpidem on the body of the baby is unknown.

Side effects.

Side effects, led to discontinuation of treatment

According to the results of clinical trials premarketingovyh in the US about 4% from 1701 patients, receiving at doses of zolpidem 1,25 to 90 mg, discontinued treatment due to the occurrence of clinically significant side effects, among which were marked daytime sleepiness (0,5%), dizziness (0,4%), headache (0,5%), nausea (0,6%), vomiting (0,5%).

According to the results of other similar foreign trials, about 4% from 1959 patients, receiving at doses of zolpidem 1 to 50 mg, discontinued treatment because of side effects, among which were marked daytime sleepiness (1,1%), dizziness of varying severity (0,8%), amnesia (0,5%), nausea (0,5%), headache (0,4%), drop (0,4%).

According to clinical studies, in which patients, prinimavšim SIOZS, given zolpidem (n=95), in 4 from 7 patients during the double-blind study treatment discontinuation zolpidem was associated with impaired concentration, ongoing or worsening depression, mania.

Side effects, observed with a frequency ≥1% in controlled clinical trials

The most common adverse effects, observed in clinical trials

For short (to 10 nights) zolpidem tartrate treatment at doses up to 10 mg of the most commonly observed adverse effects, associated with taking zolpidem and statistically significantly different from placebo, We were: drowsiness (to 2%), dizziness (1%), diarrhea (1%). Long-term treatment (28-35 Days) zolpidem at doses up to 10 mg of the most commonly observed adverse effects, associated with its reception and statistically significantly different from placebo, We were: dizziness (5%) and feeling drugged (3%).

In the table 1 and Table 2 presents side effects, observed, A survey in the United States, placebo-controlled trials, in 1% and more cases in patients with insomnia, receiving zolpidem tartrate. Adverse effects are classified using a modified WHO terminology dictionary.

It will be appreciated, that the data on adverse effects, obtained in the placebo-controlled studies, They can not be used to predict the occurrence of side effects in normal medical practice, tk. condition of the patient and other factors may differ from those, that prevailed in the clinical trials. Similarly, the tables provided in the incidence of side effects (in percents) may differ from that obtained by other investigators clinical, tk. Each test drug can be performed with a different set of conditions. However, these figures give the doctor an idea of ​​the relative contribution of the substance and other factors (non-PM), in the development of side-effects of drugs in the population.

In the table 1 presents side effects according 11 short-term placebo-controlled trials of zolpidem at doses of 1,25-10 mg (10 mg is the highest recommended dose).

Table 1

Side effects, observed with short-term treatment (Placebo-controlled trials)

In the table 2 presented side effects of a set of data 3 placebo-controlled trials of long-term patients with chronic insomnia with zolpidem tartrate appointment for 28-35 nights at doses 5 and 10 mg (10 mg is the highest recommended dose); It includes only those side effects, which were observed in patients, receiving zolpidem, a frequency, at least, 1%.

Table 2

Side effects, observed during long-term treatment (Placebo-controlled trials)

The dependence of the side effects of the dose

When comparative tests provided data, indicating dose-dependent nature of many side effects, especially some of the effects of the central nervous system and gastrointestinal tract.

Pobochnye phenomenon, observed in all clinical studies

Zolpidem tartrate is used in 3660 Patients in clinical trials, held in the USA, Canada and Europe. In order to provide comparable estimates of the results, similar types of adverse events were grouped into a smaller number of standard categories and classified using the modified WHO terminology dictionary. Said rate represents the proportion of all 3660 patients, receiving zolpidem, at all doses, in which the side effect mentioned type was observed at least 1 time while receiving zolpidem. Taking into account all the cases, except those already listed in the tables (the results of placebo-controlled trials), and formulated in general terms and does not reasonably associated with the use of drugs. It is important to note, that although the following side effects were observed during treatment zolpidem tartrate, they are not necessarily caused by it.

Adverse events were divided by body system and are presented in order of decreasing frequency of occurrence using the following definitions: often the effects, observed in at least 1 from 100 patients; sometimes from 1 from 100 to 1 from 1000; rarely — less than 1 from 1000 patients.

Autonomic nervous system: sometimes excessive sweating, paleness, postural hypotension, syncope; rarely, the ccomodation eye, changes in the secretion of saliva, flushing, glaucoma, gipotenziya, impotence, tenesmus.

Body as a Whole: often fatigue; sometimes edema, drop, fever, malaise, trauma; rarely, allergic reaction, aggravation of allergies, a feeling of abdominal pain, anaphylactic shock, swelling of the face, feeling the heat, increased erythrocyte sedimentation rate, pain, syndrome of "restless legs", chills, weight loss.

Cardiovascular system: sometimes — cardiovascular diseases, hypertension, tachycardia; seldom-angina, arrhythmia, arteritis, disturbed circulation, arrythmia, increased hypertension, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, phlebeurysm, ventricular tachycardia.

Central and peripheral nervous system: often, ataxia, confusion, euphoria, insomnia, vertigo; sometimes ajitation, cognitive decline, difficulty concentrating, dysarthria, emotional lability, gipesteziya, hallucinations, migraine, paraesthesia, drowsiness (after a day reception), stupor, tremor; rarely is the gait, violation of the thinking process, aggressive reactions, apathy, increased appetite, decreased libido, delirium, dementia, depersonalization, disfazija, strange sensations, gipokineziya, hypotension, vapors, feeling poisoning, manic reactions, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, zevota.

Gastrointestinal tract: often the hiccups; sometimes constipation, dysphagia, flatulence, gastroenteritis; seldom-enteritis, belching, esophagism, gastritis, hemorrhoids, kishechnaya obstruction, rectal bleeding, caries.

Blood and lymphatic system: rare anemia, incl. macrocytic, gipergemoglobinemiâ, leukopenia, lymphadenopathy, purpura, thrombosis.

The immune system: rarely is an abscess, herpes infection (herpes simplex, herpes zoster).

Liver and biliary system: Sometimes the liver, SGP-raising transaminases; rarely — bilirubinemiâ, AST increase.

Metabolism: sometimes-hyperglycemia, thirst; rarely — gout, hypercholesterolemia, hyperlipidemia, increase in AP, increase in blood urea nitrogen, periorbital edema.

Musculoskeletal System: sometimes arthritis, cramps in the legs; rarely is osteoarthritis, muscular weakness, işialgija, Tendinitis.

Reproductive system: sometimes menstrual disorders, vaginitis; rarely is a breast fibroadenoz, mastoncus, pain in the breast.

Respiratory system: sometimes bronchitis, cough, dyspnoea; rarely, bronchospasm, nose bleed, gipoksiya, laringit, pneumonia.

The skin and its appendages: sometimes itching; rarely, acne, bullous rash, dermatitis, furunculosis, inflammation at the injection site, photosensitivity reaction, hives.

Senses: often, diplopia, blurred vision; sometimes eye irritation, sore eyes, scleritis, dysgeusia, tynnyt; rarely, corneal ulceration, violation of lacrimation, parosmija, photopsia, otitis externa, otitis media.

Genito-urinary system: sometimes cystitis, urinary incontinence; rarely, acute renal failure, dizurija, frequent urination, nocturia, polyuria, pyelonephritis, pain in the kidneys, urinary retention.

Cooperation.

With simultaneous use of zolpidem with means, CNS depressants (incl. trankvilizatorы, barbiturates, neuroleptics, other hypnotics, antidepressants and antihistamines drugs with sedative component, alcohol) possible mutual reinforcement effects (Caution is advised, dose of one or all of the PM should be reduced). Benzodiazepine anxiolytics increase the risk of drug dependence. When combined with imipramine zolpidem reduces C_max imipramine, may increase drowsiness and increase the frequency of anterograde amnesia, in combination with chlorpromazine may elongation T_1/2 chlorpromazine.

Overdose.

Symptoms. In European postmarketing reports of overdose zolpidem reported abuse awareness (from drowsiness to light coma). Recorded one case of cardiovascular and respiratory disorders. There was a full recovery after receiving doses of zolpidem tartrate to 400 mg (in 40 times higher than MRDC).

Cases of overdose, due to the simultaneous reception of many tools, CNS depressants, including zolpidem, It led to more serious consequences, until death.

Treatment: induction of vomiting or gastric lavage immediately (depending on the condition), appointment of activated carbon. Showed monitoring vital functions (breathing, pulse, BP and others.), If necessary, symptomatic and supportive therapy. Should renounce the use of any sedatives (even with an excited expression). Hemodialysis nyeeffyektivyen. Specific antidote-BZ antagonist Flumazenil receptors.

Dosing and Administration.

Inside, just before going to bed or lying down in bed, single. The dose and duration of treatment set individually. Treatment started with a minimum effective dose. The average single dose for adults under the age of 65 years - 10 mg, maximum is 15-20 mg. For patients older 65 years, debilitated patients, patients with impaired liver and/or kidney initial single dose — 5 mg, maximum (if necessary) -not more than 10 mg.

Precautions.

Because sleep disturbances may be manifestations of physical and / or mental illness, symptomatic treatment of insomnia begin only after a detailed examination of the patient.

Zolpidem is indicated for short-term treatment of sleep disorders. Lack of effect after 7-10 days of treatment may indicate the presence of a primary psychiatric and / or medical illness, which is necessary to diagnose. Worsening of insomnia or the emergence of new cognitive impairments or behavioral disorders may be due to unrecognized mental or physical illness.

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

In order to minimize the possibility of anterograde amnesia and unstable state, Zolpidem should be used only in the event, if the regime of the patient allows him to sleep through the night (7-8).

To use caution in depression, alcohol and drug dependency history.

Before discontinuation after application for 1-2 weeks should consult a doctor; to prevent the development of withdrawal symptoms may require a gradual reduction of the dose.

Since the effect of zolpidem develops rapidly, after taking the drug the patient should be ready to go to sleep. Do not be taken simultaneously with or immediately after a meal (meal may delay onset of action).

During treatment should abandon admission alcohol (possible additive inhibitory effect). Care should be taken when taken with other drugs, CNS depressants (possible potentiation effect).

During the period of treatment should refrain from potentially hazardous activities (driving, using machinery).

In the period of treatment should strive to create favorable conditions for sleep. Failure to comply with this recommendation, or uncontrolled frequent use of high doses increase the risk of drug dependence.