Apaurin (Tablets, Solution) Instructions for Use

ATC Code

N05BA01 (Diazepam)

Active Substance

Diazepam (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anxiolytic (tranquilizer)

Pharmacotherapeutic Group

Anxiolytic agent (tranquilizer)

Pharmacological Action

Diazepam is a benzodiazepine derivative with a broad spectrum of activity. It exerts anxiolytic, hypnotic-sedative, muscle-relaxant, and anticonvulsant effects through specific benzodiazepine receptors, the largest number of which are located in the limbic system, hypothalamus, cerebellum, and corpus striatum. These receptors, along with GABA (gamma-aminobutyric acid) receptors, form an anatomical and functional unit. After diazepam binds to the receptor, GABAergic transmission is enhanced, leading to central nervous system depression. This results in the anticonvulsant and muscle-relaxant effects. By potentiating the effects of GABA, the stimulating influence of neurotransmitters such as serotonin, norepinephrine, or acetylcholine is reduced, which causes the anxiolytic, hypnotic, and sedative actions.

Pharmacokinetics

Absorption. Absorption of diazepam from the gastrointestinal tract (GIT) is rapid and complete. After oral administration, about 75% is absorbed. Bioavailability is 90%.

Food does not affect the absorption of diazepam.

Metabolism. It is metabolized in the liver with the participation of isoenzymes CYP2C19, CYP3A4, CYP3A5, and CYP3A7, forming three metabolites. The main metabolite is N-desmethyldiazepam, which is biologically active and has a longer T_1/2 than diazepam. The other two metabolites are oxazepam and temazepam, which are biologically active but do not significantly contribute to the pharmacodynamic effects of diazepam due to their shorter T_1/2 compared to the parent substance. It penetrates the blood-brain barrier and placental barrier, and is found in breast milk at concentrations corresponding to 1/10 of the plasma concentration. Plasma protein binding is 98%.

Distribution and Elimination. Diazepam is rapidly distributed in the human body. V_d is approximately 1.1 L/kg, indicating active binding to plasma proteins (98-99%). It is eliminated by the kidneys – 70% (as glucuronides), unchanged 1-2%, and less than 10% via the intestines. Elimination is biphasic: an initial phase of rapid and extensive distribution (T_1/2 – 3 h) is followed by a prolonged phase (T_1/2 – 20-70 h). T_1/2 of desmethyldiazepam is 30-100 h, temazepam is 9.5-12.4 h, and oxazepam is 5-15 h. With repeated use, accumulation of diazepam and its active metabolites is significant. It belongs to benzodiazepines with a long T_1/2; elimination after discontinuation of treatment is slow, as metabolites persist in the blood for several days or even weeks.

Indications

Anxiety disorders.

Dysphoria (as part of combination therapy as an additional medicinal product).

Insomnia (difficulty falling asleep).

Skeletal muscle spasm due to local injury; spastic conditions associated with damage to the brain or spinal cord (cerebral palsy, athetosis, tetanus); myositis, bursitis, arthritis, spondyloarthritis, rheumatoid arthritis; osteoarthritis accompanied by skeletal muscle tension; vertebral syndrome, angina pectoris, tension headache.

Alcohol withdrawal syndrome: anxiety, tension, agitation, tremor, transient reactive states.

Premedication before surgical interventions and endoscopic procedures, general anesthesia.

As part of complex therapy: arterial hypertension, gastric and duodenal ulcer; psychosomatic disorders in obstetrics and gynecology: menopausal and menstrual disorders, preeclampsia; eczema and other diseases accompanied by itching, irritability.

Ménière’s disease.

Convulsive syndrome in drug poisoning.

ICD codes

Dosage Regimen

Tablets

The dose is always determined by the physician.

The dosage regimen depends on the severity of symptoms, the patient’s age, and their condition.

Anxiety disorders, dysphoria From 2 mg to 10 mg 2-3 times daily.

Insomnia (difficulty falling asleep) From 4 mg to 10 mg in the evening, before bedtime.

Muscle spasms 2-10 mg 3 times daily.

Spastic conditions of central origin in degenerative neurological diseases, Ménière’s disease, convulsive syndrome 5-10 mg 2-3 times daily.

Musculoskeletal disorders 5 mg 1-4 times daily.

Alcohol withdrawal syndrome 10 mg 3-4 times daily in the first 24 hours, followed by a reduction to 5 mg 3-4 times daily.

Premedication on the eve of surgery, in the evening – 10-20 mg.

Angina pectoris and arterial hypertension, gastric and duodenal ulcer, eczema and other diseases accompanied by itching and irritability 2-5 mg 2-3 times daily.

Obstetrics and gynecology psychosomatic disorders, menopausal and menstrual disorders, preeclampsia: 2-5 mg 2-3 times daily.

Elderly, debilitated patients, and patients with atherosclerosis at the beginning of treatment 2 mg twice daily, if necessary, the dose can be increased to achieve the optimal effect.

Working patients 2 mg 1-2 times daily or 5 mg (main dose) in the evening.

Diazepam withdrawal syndrome 2 tablets (5 mg each) 3 times in the first 24 hours, then 1 tablet (5 mg) 3 times daily.

Children over 3 years 1 tablet (2 mg) 2-3 times daily.

Treatment is started with the recommended doses. After one or two weeks, the drug dose may be reduced if necessary so that the drug is taken once a day, preferably in the evening.

Treatment usually lasts from several days to several weeks.

With long-term use of benzodiazepines, tolerance to these drugs changes; signs of psychological and physical dependence may appear. The risk of developing dependence is higher with the use of high doses and with long-term use.

With long-term use, the drug Apaurin must be discontinued gradually, since abrupt cessation of therapy can cause withdrawal syndrome symptoms (tremor, abdominal and muscle cramps, vomiting, sweating).

Solution

Administered intramuscularly and intravenously. The single dose, frequency, and duration of use are determined individually, depending on the indications and clinical picture of the disease.

In adults, a single dose is 10 mg; in status epilepticus, the dose can be increased to 20 mg, and if necessary, repeated administration after 3-4 hours is possible.

In children (over 30 days old) IV slowly at 0.1-0.3 mg/kg body weight up to a maximum dose of 5 mg.

In children from 5 years and older IV slowly at 1 mg every 2 – 5 min up to a maximum dose of 10 mg.

Adverse Reactions

Classification of the frequency of adverse effects (WHO): very common (>1/10); common (from > 1/100 to < 1/10); uncommon (from > 1/1000 to < 1/100); rare (from >1/10000 to < 1/1000); very rare (< 1/10000), including isolated reports.

Hematopoietic system very rare – neutropenia (with long-term use, periodic blood count monitoring is recommended), leukopenia, agranulocytosis, anemia, thrombocytopenia;

Nervous system common – weakness, drowsiness, ataxia; uncommon – confusion, depression, dysarthria, incoherent speech, decreased activity, decreased libido, headache, dizziness, tremor, memory impairment, insomnia, hallucinations, anxiety; rare – headache, euphoria, depression, tremor, depressed mood, catalepsy, extrapyramidal reactions (uncontrolled body movements, including eyes), hyporeflexia; very rare – paradoxical reactions (aggressive outbursts, psychomotor agitation, fear, suicidal tendency, muscle spasm, irritability, acute agitation);

Cardiovascular system uncommon – palpitations, bradycardia, fainting, cardiovascular collapse;

Sensory organs uncommon – blurred vision, diplopia, nystagmus;

Digestive system uncommon – constipation, nausea, vomiting, dryness of the oral mucosa or hypersalivation, heartburn, hiccups, gastralgia, decreased appetite; very rare – jaundice (with long-term use, periodic liver function monitoring is recommended), impaired liver function, increased activity of “liver” transaminases and alkaline phosphatase;

Skin rare – urticaria, skin rash, itching;

Musculoskeletal system uncommon – muscle weakness;

Urinary system uncommon – urinary incontinence, urinary retention, impaired renal function;

Reproductive system uncommon – menstrual cycle disorders, increased or decreased libido.

Effect on the fetus teratogenicity (especially the first trimester), CNS depression, respiratory depression and suppression of the sucking reflex in newborns whose mothers used the drug.

During and after therapy with diazepam, minor, clinically insignificant changes on the electroencephalogram (most often, low-voltage fast activity) are possible.

With long-term use of benzodiazepines, tolerance to these drugs changes; signs of mental or physical dependence may develop. The risk of developing dependence is higher with the use of high doses and long-term use of the drugs.

Upon abrupt discontinuation of diazepam, withdrawal syndrome symptoms develop (convulsions, tremor, abdominal and muscle cramps, vomiting, sweating). Most often, these symptoms develop after long-term use of high doses. Milder symptoms (dysphoria, insomnia) are noted after sudden withdrawal of benzodiazepines taken in therapeutic doses for several months.

Thus, rapid discontinuation of the drug should be avoided during long-term use, and the daily dose should be reduced gradually.

If severe adverse effects develop, treatment should be discontinued.

Contraindications

Hypersensitivity, coma, shock, acute alcohol intoxication with depression of vital functions, acute intoxication with drugs that have a depressant effect on the CNS (including narcotic analgesics and hypnotic drugs), myasthenia gravis, closed-angle glaucoma (acute attack or predisposition); severe chronic obstructive pulmonary disease (risk of progression of respiratory failure), acute respiratory failure, pregnancy, lactation period, children under 3 years of age, lactase and/or sucrase/isomaltase deficiency, fructose or lactose intolerance, glucose-galactose malabsorption.

With caution. Epilepsy or history of epileptic seizures (initiation of diazepam treatment or its abrupt withdrawal may accelerate the development of seizures or status epilepticus), hepatic and/or renal insufficiency, cerebral and spinal ataxias, hyperkinesis, history of drug dependence, tendency to abuse psychoactive drugs, organic brain diseases, hypoproteinemia, sleep apnea (established or suspected), elderly age.

Use in Pregnancy and Lactation

The drug Apaurin is not recommended for pregnant women. Its use before childbirth can cause decreased blood pressure, respiratory depression, and cause withdrawal syndrome in the newborn.

The drug Apaurin is secreted into breast milk, so it should not be used during breastfeeding. If it is necessary to use the drug Apaurin, breastfeeding should be discontinued.

Use in Hepatic Impairment

Use with caution in hepatic insufficiency.

Use in Renal Impairment

Use with caution in renal insufficiency. Patients with severe kidney disease should be under particularly careful supervision. With long-term use of benzodiazepines, tolerance to these drugs changes.

Pediatric Use

Contraindicated in children under 3 years of age. In children, treatment with the drug Apaurin should be started cautiously and gradually, due to large differences in individual tolerance.

Geriatric Use

With caution: elderly age. In elderly patients, treatment with the drug Apaurin should be started cautiously and gradually, due to large differences in individual tolerance.

Special Precautions

In elderly patients, children, and patients with organic CNS lesions, treatment with the drug Apaurin should be started cautiously and gradually, due to large differences in individual tolerance.

Caution is also necessary in chronic lung diseases, as respiratory failure may worsen.

Patients with severe kidney disease, severe heart failure, psychoses, and a tendency to alcohol dependence, psychotropic drugs, or illicit psychoactive substances should be under particularly careful supervision. With long-term use of benzodiazepines, tolerance to these drugs changes.

Mental or physical drug dependence may sometimes develop, especially with long-term use of high doses (more than 3 months). Therefore, individuals prone to developing dependence, such as those suffering from alcoholism or dependence on other psychotropic substances, and patients with personality disorders, should be under careful supervision during treatment.

Abrupt discontinuation of therapy can cause transient intensification of anxiety (withdrawal anxiety) or insomnia.

After long-term use, the drug Apaurin should be discontinued gradually, since abrupt cessation of therapy can cause withdrawal symptoms (tremor, muscle and abdominal cramps, vomiting, sweating).

Treatment usually lasts from several days to a maximum of 12 weeks, including the period of gradual dose reduction. Treatment can be continued only after a thorough re-evaluation of the patient’s condition.

When using any benzodiazepines, a paradoxical reaction may develop in individual cases. It develops more often in the elderly and in children. If agitation, aggressiveness, anxiety, confusion, increased muscle spasms, or insomnia appear, treatment with the drug Apaurin must be discontinued.

Special information about some components of the drug.

Sucrose may have a damaging effect on teeth.

Azo dyes E110 (2 mg tablets) may cause allergic reactions.

Effect on the ability to drive vehicles and operate machinery: The drug may affect psychophysical activity, especially when alcohol or other CNS depressants are consumed simultaneously. During the use of the drug Apaurin, it is necessary to refrain from driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms include drowsiness, dizziness, weakness, dysarthria, respiratory failure; in more severe cases – loss of consciousness, hyporeflexia or areflexia, respiratory depression, especially when combined with alcohol or other substances that depress the CNS.

Treatment involves gastric lavage, forced diuresis, and administration of activated charcoal. The patient requires active monitoring in an intensive care unit; in severe cases, especially with respiratory depression, the specific benzodiazepine receptor antagonist flumazenil is prescribed. The half-life of flumazenil is approximately 1 hour, which is shorter than the half-life of diazepam. Therefore, to maintain the desired level of consciousness, repeated administration of flumazenil is necessary, preferably as an infusion. The recommended initial dose of flumazenil is 0.3 mg intravenously. If the desired effect is not achieved within 60 seconds, additional doses of 0.1 mg can be administered repeatedly until a total dose of 2 mg is reached or until the patient regains consciousness. If the patient’s consciousness is impaired again after recovery, the same doses are usually administered. In such cases, intravenous administration of flumazenil at a rate of 0.1 mg to 0.4 mg/hour is possible, depending on the desired level of consciousness.

Although flumazenil is an effective antidote for benzodiazepine intoxications, it should not be administered for benzodiazepine intoxications in patients with epilepsy, as it may provoke the development of seizures. Hemodialysis is not very effective.

Drug Interactions

During diazepam therapy, alcohol consumption should be avoided due to the possibility of potentiating its effects.

When diazepam is used concomitantly with sedative drugs, antidepressants, antipsychotics, barbiturates, narcotic analgesics, anesthetics, MAO inhibitors (MAOIs), antiepileptic drugs, and antihistamines, its depressant effect on the CNS is enhanced. Concomitant use of erythromycin or rifampicin also enhances the effects of diazepam. Diazepam reduces the effect of levodopa.

Cimetidine reduces the clearance of diazepam and enhances its effect.

Omeprazole slows down the metabolism of diazepam and increases its duration of action and elimination. Concomitant use of antifungal agents (itraconazole, fluconazole, and ketoconazole) may increase the plasma concentrations of diazepam and cause adverse effects. Oral contraceptives may slow down the metabolism of diazepam.

Rifampicin may enhance the elimination of diazepam and lower its plasma concentrations. Theophylline (used in low doses) may reduce or even reverse the sedative effect of diazepam.

Storage Conditions

The drug belongs to Schedule No. 1 of potent substances of the Permanent Committee for Narcotic Control of the Ministry of Health and Social Development.

Store at a temperature not exceeding 25°C (77°F), in the original packaging. Keep out of reach of children.

Shelf Life

5 years. Do not use the drug after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.