Relium (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

A tranquilizer, a benzodiazepine derivative. It has sedative, hypnotic, anticonvulsant, and central muscle relaxant effects. The mechanism of action is due to the stimulation of benzodiazepine receptors of the supramolecular GABA-benzodiazepine-chlorionophore receptor complex, leading to an enhancement of the inhibitory effect of GABA on nerve impulse transmission.

It stimulates benzodiazepine receptors located in the allosteric center of postsynaptic GABA receptors of the ascending activating reticular formation of the brainstem and interneurons of the lateral horns of the spinal cord, reduces the excitability of subcortical brain structures (limbic system, thalamus, hypothalamus), and inhibits polysynaptic spinal reflexes.

The anxiolytic effect is due to the influence on the amygdaloid complex of the limbic system and is manifested by a reduction in emotional tension, weakening of anxiety, fear, and restlessness.

The sedative effect is due to the influence on the reticular formation of the brainstem and nonspecific thalamic nuclei and is manifested by a reduction in symptoms of neurotic origin (anxiety, fear).

The main mechanism of the hypnotic action is the inhibition of cells of the reticular formation of the brainstem. The anticonvulsant action is realized by enhancing presynaptic inhibition. The spread of epileptogenic activity is suppressed, but the excited state of the focus is not relieved.

The central muscle relaxant effect is due to the inhibition of polysynaptic spinal afferent inhibitory pathways (and to a lesser extent, monosynaptic ones). Direct inhibition of motor nerves and muscle function is also possible.

Possessing moderate sympatholytic activity, it can cause a decrease in blood pressure and dilation of coronary vessels. It increases the pain sensitivity threshold. It suppresses sympathoadrenal and parasympathetic (including vestibular) paroxysms. It reduces nocturnal gastric acid secretion.

It has practically no effect on productive symptoms of psychotic origin (acute delusional, hallucinatory, affective disorders); a reduction in affective tension and delusional disorders is rarely observed.

In withdrawal syndrome in chronic alcoholism, it causes a weakening of agitation, tremor, negativism, as well as alcoholic delirium and hallucinations.

Pharmacokinetics

With intramuscular administration, the absorption of diazepam may be slow and inconsistent (depends on the injection site); when injected into the deltoid muscle, absorption is rapid and complete. Bioavailability is 90%. C_max in blood plasma is reached in 0.5-1.5 hours with intramuscular administration and within 0.25 hours with intravenous administration; C_ss is reached with constant use after 1-2 weeks.

Diazepam and its metabolites penetrate the blood-brain barrier and placental barrier, and are found in breast milk in concentrations corresponding to 1/10 of the concentrations in plasma. Plasma protein binding is 98%.

It is metabolized in the liver with the participation of the enzyme systems CYP2C19, CYP3A4, CYP3A5, and CYP3A7, forming pharmacologically very active derivatives (desmethyldiazepam) and less active ones (temazepam and oxazepam).

It is excreted by the kidneys – 70% (in the form of glucuronides), unchanged – 1-2%, and less than 10% – in feces. T_1/2 of desmethyldiazepam is 30-100 hours, temazepam – 9.5-12.4 hours, and oxazepam – 5-15 hours.

T_1/2 may be prolonged in newborns (up to 30 hours), elderly and senile patients (up to 100 hours), and in patients with hepatic-renal insufficiency (up to 4 days).

With repeated use, the 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

Treatment of neurotic and neurosis-like disorders with manifestations of anxiety; relief of psychomotor agitation associated with anxiety; relief of epileptic seizures and convulsive conditions of various etiologies; relief of conditions accompanied by increased muscle tone (tetanus, acute cerebrovascular accidents, etc.); relief of withdrawal syndrome and delirium in alcoholism; premedication and ataralgesia in combination with analgesics and other neurotropic drugs during various diagnostic procedures, in surgical and obstetric practice; as part of complex therapy for hypertension (accompanied by anxiety, increased excitability), hypertensive crisis, vascular spasms, climacteric and menstrual disorders.

ICD codes

Dosage Regimen

Tablets

Orally. The dose is calculated individually, depending on the indications and clinical picture of the disease.

In adults, the daily therapeutic dose varies from 5 to 15 mg, frequency of administration – 2-3 times/day. In a hospital setting, the daily therapeutic dose can be increased to 30 mg for patients, and in case of exacerbation of the condition, if necessary and taking into account tolerance, up to 60 mg.

Solution

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

In adults, the 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 (older than 30 days) intravenously 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 intravenously slowly at 1 mg every 2 – 5 min up to a maximum dose of 10 mg.

Adverse Reactions

From the hematopoietic system: leukopenia, neutropenia, agranulocytosis (chills, hyperthermia, sore throat, unusual fatigue or weakness), anemia, thrombocytopenia.

From the nervous system at the beginning of treatment (especially in elderly patients) – drowsiness, dizziness, increased fatigue, impaired concentration, ataxia, disorientation, slowed mental and motor reactions, anterograde amnesia; rarely – headache, euphoria, depression, tremor, catalepsy, confusion, dystonic extrapyramidal reactions (uncontrolled body movements), asthenia, muscle weakness, hyporeflexia, dysarthria; extremely rarely – paradoxical reactions (aggressive outbursts, psychomotor agitation, fear, suicidal tendency, muscle spasm, confusion, hallucinations, anxiety, sleep disorders).

From the cardiovascular system: palpitations, tachycardia, decreased blood pressure.

From the digestive system dry mouth or hypersalivation, heartburn, hiccups, gastralgia, nausea, vomiting, decreased appetite, constipation; impaired liver function, increased activity of hepatic transaminases and alkaline phosphatase, jaundice.

From the reproductive system rarely – increased or decreased libido, dysmenorrhea.

From the urinary system rarely – urinary incontinence or retention, impaired renal function.

Allergic reactions rarely – skin rash, itching.

General disorders and administration site conditions phlebitis or venous thrombosis (redness, swelling or pain at the injection site). With rapid intravenous administration – hypotension, orthostatic collapse, respiratory center depression, hiccups, visual impairment (diplopia).

Other habituation, drug dependence, bulimia, weight loss.

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

When used in obstetrics: in newborns, muscle hypotonia, hypothermia, dyspnea.

With a sharp dose reduction or discontinuation of the drug: withdrawal syndrome (increased irritability, headache, anxiety, fear, psychomotor agitation, sleep disorders, dysphoria, spasm of smooth muscles of internal organs and skeletal muscles, depersonalization, increased sweating, depression, nausea, vomiting, tremor, perception disorders, including hyperacusis, paresthesia, photophobia, tachycardia, convulsions, hallucinations, rarely – psychotic disorders).

Contraindications

Hypersensitivity to benzodiazepine derivatives; severe form of myasthenia gravis; coma, shock; closed-angle glaucoma; history of dependence phenomena (drugs, alcohol, except for the treatment of alcohol withdrawal syndrome and delirium); sleep apnea syndrome; state of alcohol intoxication of varying severity; acute intoxication with drugs that have a depressant effect on the CNS (narcotic, hypnotic, and psychotropic drugs); severe chronic obstructive pulmonary diseases (risk of progression of respiratory failure), acute respiratory failure; children under 30 days of age inclusive; pregnancy (especially the first and third trimester); period of breastfeeding.

With caution

Absence (petit mal) or Lennox-Gastaut syndrome (with intravenous administration may provoke the development of tonic epileptic status); epilepsy or epileptic seizures in history (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; tendency to abuse psychotropic drugs, organic brain diseases (paradoxical reactions are possible); hypoproteinemia; elderly age; depression.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy, especially in the first and third trimester, and during breastfeeding.

Use in Hepatic Impairment

Should be used with caution in patients with hepatic insufficiency.

Use in Renal Impairment

Should be used with caution in patients with renal insufficiency.

Pediatric Use

Contraindicated for use in newborn infants (under 30 days of age inclusive).

Geriatric Use

Used with particular caution in elderly patients.

Special Precautions

Particular caution is required when prescribing diazepam for severe depression, as Diazepam may be used to realize suicidal intentions.

In renal/hepatic insufficiency, as well as during long-term treatment, monitoring of the peripheral blood picture and liver enzymes is necessary.

The risk of developing drug dependence increases with the use of high doses of diazepam, significant duration of treatment, in patients who have previously abused alcohol or drugs. Should not be used long-term without specific instructions. Abrupt discontinuation of treatment is unacceptable due to the risk of withdrawal syndrome. Due to the slow T_1/2 of diazepam, the manifestations of withdrawal syndrome are much weaker than with other benzodiazepines.

If reactions such as increased aggressiveness, psychomotor agitation occur during the use of diazepam, treatment should be discontinued.

Initiation of diazepam treatment or its abrupt withdrawal in patients with epilepsy or a history of epileptic seizures may accelerate the development of seizures or status epilepticus.

It has a toxic effect on the fetus and increases the risk of developing congenital malformations when used in the first trimester of pregnancy. Taking therapeutic doses in later stages of pregnancy may cause CNS depression in the fetus. Continuous use during pregnancy can lead to physical dependence – withdrawal symptoms in the newborn are possible.

Use in doses above 30 mg within 15 hours before delivery or during delivery may cause respiratory depression (up to apnea), decreased muscle tone, decreased blood pressure, hypothermia, weak sucking act (floppy infant syndrome) in the newborn.

Children, especially at a young age, are very sensitive to the CNS depressant effect of benzodiazepins.

Diazepam should be prescribed to elderly patients with particular caution and the recommended doses should not be exceeded.

The risk-benefit ratio should be carefully assessed when use is necessary in patients with kidney and liver diseases.

Alcohol consumption is prohibited during treatment with diazepam.

Intra-arterial administration of diazepam is contraindicated due to the possible development of gangrene.

Risk of concomitant use with opioids

Concomitant use of diazepam and opioids may lead to enhanced sedative effect, respiratory depression, coma, and death. Given the above risks, concomitant use of benzodiazepines or related compounds with opioids should only be considered in cases where alternative treatment options are not possible. When diazepam is used concomitantly with opioids, the lowest therapeutic dose of the drug should be used, the duration of treatment should be as short as possible, and patients should be closely monitored.

Effect on ability to drive vehicles and operate machinery

Diazepam may cause a slowing of psychomotor reactions, which should be taken into account by patients engaged in potentially hazardous activities.

Drug Interactions

With simultaneous use with MAO inhibitors, respiratory analeptics, psychostimulants, strychnine, and corazole, a decrease in the effects of diazepam is observed.

With simultaneous use with hypnotics, sedatives, narcotic analgesics, other tranquilizers, benzodiazepine derivatives, muscle relaxants, general anesthetics, antidepressants, antipsychotics, alcohol, the depressant effect on the CNS is enhanced.

Concomitant use of diazepam with opioids increases the sedative effect, increases the risk of respiratory depression, coma, and death due to an additive depressant effect on the CNS. Dosage and duration of treatment should be strictly controlled by a physician.

With simultaneous use with cimetidine, disulfiram, erythromycin, fluoxetine, oral contraceptives, and estrogen-containing drugs, which competitively inhibit metabolism in the liver, a slowdown in the metabolism of diazepam and an increase in its plasma concentration are possible.

With simultaneous use with isoniazid, ketoconazole, and metoprolol, a slowdown in the metabolism of diazepam and an increase in its concentration in blood plasma are possible.

With simultaneous use with propranolol and valproic acid, an increase in the level of diazepam in blood plasma is possible.

With simultaneous use with rifampicin, an increase in the metabolism of diazepam and, as a result, a decrease in its concentration in blood plasma are possible.

With simultaneous use with inducers of liver microsomal enzymes, a decrease in the effectiveness of diazepam is possible.

With simultaneous use with antihypertensive agents, an increase in arterial hypotension is possible.

With simultaneous use with clozapine, severe arterial hypotension, respiratory depression are possible.

With simultaneous use with cardiac glycosides, an increase in the concentration of the latter in the blood serum and the development of digitalis intoxication are possible (as a result of competitive binding to plasma proteins).

With simultaneous use with levodopa, suppression of the antiparkinsonian effect is possible.

With simultaneous use with zidovudine, an increase in the toxicity of zidovudine is possible.

With simultaneous use, omeprazole prolongs the elimination time of diazepam.

With simultaneous use with theophylline in low doses, a decrease in the sedative effect of diazepam is possible.

Premedication with diazepam allows reducing the dose of fentanyl required for induction of general anesthesia and shortens the time to onset of general anesthesia.

Diazepam is pharmaceutically incompatible in the same syringe with other drugs.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.