Relanium (Solution) Instructions for Use

Marketing Authorization Holder

Warsaw Pharmaceutical Work Polfa, S.A. (Poland)

ATC Code

N05BA01 (Diazepam)

Active Substance

Diazepam (Rec.INN registered by WHO)

Dosage Form

Relanium

Solution for intravenous and intramuscular administration 5 mg/1 ml: amp. 2 ml 5, 10, or 50 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous and intramuscular administration transparent, from colorless to yellow-green.

Excipients: benzyl alcohol – 15 mg, sodium benzoate – 48.8 mg, propylene glycol – 450 mg, glacial acetic acid – 2.3 mg, 10% acetic acid – to pH 6.0-7.5, ethanol 96% – 104 mg, water for injection – to 1 ml.

2 ml – glass ampoules (5) – PVC holders (1) – cardboard packs.
2 ml – glass ampoules (5) – PVC holders (2) – cardboard packs.
2 ml – glass ampoules (5) – PVC holders (10) – cardboard packs.

Clinical-Pharmacological Group

Anxiolytic (tranquilizer)

Pharmacotherapeutic Group

Anxiolytic agent (tranquilizer)

Pharmacological Action

Anxiolytic drug (tranquilizer), a benzodiazepine derivative.

Diazepam has a depressant effect on the CNS, primarily realized in the thalamus, hypothalamus, and limbic system. It enhances the inhibitory effect of gamma-aminobutyric acid (GABA), which is one of the main mediators of pre- and postsynaptic inhibition of nerve impulse transmission in the CNS. It has anxiolytic, sedative, hypnotic, muscle relaxant, and anticonvulsant effects.

The mechanism of action of diazepam is determined by the stimulation of benzodiazepine receptors of the supramolecular GABA-benzodiazepine-chloride ionophore receptor complex, which leads to activation of the GABA receptor, causing a decrease in the excitability of subcortical brain structures and inhibition of polysynaptic spinal reflexes.

Pharmacokinetics

Absorption

After intramuscular administration, Diazepam is absorbed slowly and unevenly, depending on the injection site; when injected into the deltoid muscle, absorption is rapid and complete. Bioavailability is 90%. C_max after intramuscular administration is reached in 0.5-1.5 hours, after intravenous administration within 0.25 hours.

Distribution

With constant use, C_ss is reached in 1-2 weeks.

Plasma protein binding is 98%.

Diazepam and its metabolites penetrate the blood-brain barrier and placental barrier, and are excreted in breast milk in concentrations corresponding to 1/10 of the concentration in plasma.

With repeated use of the drug, pronounced accumulation of diazepam and its active metabolites is observed.

Metabolism

It is metabolized in the liver with the participation of isoenzymes CYP2C19, CYP3A4, CYP3A5, and CYP3A7 by 98-99% with the formation of a very active metabolite, desmethyldiazepam, and less active ones – temazepam and oxazepam.

Excretion

T_1/2 of desmethyldiazepam is 30-100 hours, temazepam – 9.5-12.4 hours, and oxazepam – 5-15 hours.

It is excreted by the kidneys – 70% (as glucuronides), unchanged – 1-2%, and less than 10% – with feces.

It belongs to benzodiazepines with a long T_1/2. After discontinuation of treatment, metabolites persist in the blood for several days or even weeks.

Pharmacokinetics in special clinical cases

T_1/2 may increase in newborns – up to 30 hours, in elderly patients – up to 100 hours, in patients with hepatic and renal insufficiency – up to 4 days.

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;
• Conditions accompanied by increased muscle tone (including tetanus, acute cerebrovascular accidents);
• Relief of withdrawal syndrome and delirium in alcoholism;
• For premedication and ataralgesia in combination with analgesics and other neurotropic drugs during various diagnostic procedures, in surgical and obstetric practice;
• In internal medicine: in the complex therapy of arterial hypertension (accompanied by anxiety, increased excitability), hypertensive crisis, vascular spasms, climacteric and menstrual disorders.

ICD codes

Dosage Regimen

For relief of psychomotor agitation associated with anxiety, 5-10 mg is administered intravenously slowly, if necessary, after 3-4 hours the drug is administered again in the same dose.

For tetanus, 10 mg is administered intravenously slowly or deep intramuscularly, then 100 mg of diazepam is administered intravenously by drip in 500 ml of 0.9% sodium chloride solution or 5% glucose solution at a rate of 5-15 mg/hour.

For status epilepticus, 10-20 mg is administered intramuscularly or intravenously, if necessary, after 3-4 hours the drug is administered again in the same dose.

For relief of skeletal muscle spasm – 10 mg intramuscularly 1-2 hours before the start of surgery.

In obstetrics, 10-20 mg is administered intramuscularly when the cervix is dilated by 2-3 fingers.

Newborns after the 5th week of life (older than 30 days) are administered 100-300 mcg/kg body weight intravenously slowly up to a maximum dose of 5 mg, if necessary, the administration is repeated after 2-4 hours (depending on clinical symptoms).

Children aged 5 years and older are administered the drug intravenously slowly, 1 mg every 2-5 minutes up to a maximum dose of 10 mg; if necessary, the administration can be repeated after 2-4 hours.

Adverse Reactions

From the CNS and peripheral nervous system at the beginning of treatment (especially in elderly patients) – drowsiness, dizziness, increased fatigue, impaired concentration, ataxia, disorientation, blunted emotions, slowed mental and motor reactions, anterograde amnesia (develops more often than with other benzodiazepines); rarely – headache, euphoria, depression, tremor, catalepsy, confusion, dystonic extrapyramidal reactions (uncontrolled movements), asthenia, muscle weakness, hyporeflexia, dysarthria; in some cases – paradoxical reactions (outbursts of aggression, psychomotor agitation, fear, suicidal tendencies, muscle spasm, confusion, hallucinations, anxiety, sleep disorders).

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

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 cardiovascular system arterial hypotension, tachycardia.

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

From the reproductive system increased or decreased libido, dysmenorrhea.

From the respiratory system respiratory depression (with too rapid administration of the drug).

Allergic reactions skin rash, itching.

Local reactions phlebitis or venous thrombosis (redness, swelling, pain) at the injection site.

Other habituation, drug dependence; rarely – respiratory center depression, visual impairment (diplopia), bulimia, weight loss.

With a sharp dose reduction or discontinuation of use – 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). When used in obstetrics in newborns – muscle hypotonia, hypothermia, dyspnea.

Contraindications

• Severe form of myasthenia gravis;
• Coma;
• Shock;
• Closed-angle glaucoma;
• History of dependence on narcotic 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 I and III trimesters);
• Lactation period (breastfeeding);
• Hypersensitivity to benzodiazepines.

With caution prescribe for absence seizures (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 ataxia, in hyperkinesis, tendency to abuse psychotropic drugs, in depression, organic brain diseases (paradoxical reactions are possible), in hypoproteinemia, elderly patients.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation.

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

When using Relanium in doses of more than 30 mg within 15 hours before delivery or during delivery, it can cause respiratory depression (up to apnea), decreased muscle tone, decreased blood pressure, hypothermia, weak sucking reflex (“floppy infant syndrome”) in the newborn.

Use in Hepatic Impairment

If it is necessary to use the drug in patients with liver diseases, the risk-benefit ratio of therapy should be assessed.

Use in Renal Impairment

If it is necessary to use the drug in patients with kidney diseases, the risk-benefit ratio of therapy should be assessed.

Pediatric Use

Newborns after the 5th week of life (older than 30 days) are administered 100-300 mcg/kg body weight intravenously slowly up to a maximum dose of 5 mg, if necessary, the administration is repeated after 2-4 hours (depending on clinical symptoms).

Children aged 5 years and older are administered the drug intravenously slowly, 1 mg every 2-5 minutes up to a maximum dose of 10 mg; if necessary, the administration can be repeated after 2-4 hours.

Geriatric Use

With caution prescribe to elderly patients.

Special Precautions

Diazepam should be prescribed with particular caution in severe depression, as the drug may be used to realize suicidal intentions.

The intravenous solution of Relanium should be administered slowly, into a large vein, for at least 1 minute for every 5 mg (1 ml) of the drug. Continuous intravenous infusions are not recommended – precipitation and adsorption of the drug by PVC infusion balloon and tube materials are possible.

In renal or hepatic insufficiency and with prolonged use, it is necessary to monitor the peripheral blood picture and the activity of liver enzymes.

The risk of drug dependence increases with the use of Relanium in high doses, with significant duration of treatment in patients who have previously abused alcohol or drugs. Without special necessity, the drug should not be used for a long time. Abrupt discontinuation of treatment is unacceptable due to the risk of withdrawal syndrome, however, due to the slow elimination of diazepam, the manifestation of this syndrome is much weaker than with other benzodiazepines.

If patients develop such unusual reactions as increased aggressiveness, psychomotor agitation, anxiety, fear, suicidal thoughts, hallucinations, increased muscle cramps, difficulty falling asleep, shallow sleep, treatment should be discontinued.

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

Relanium should be used with particular caution and without exceeding the recommended doses in elderly patients.

If it is necessary to use the drug in patients with liver and kidney diseases, the risk-benefit ratio of therapy should be assessed.

Relanium is not administered intra-arterially due to the risk of gangrene.

With prolonged use of the drug, the development of tolerance is possible.

During treatment, alcohol consumption is prohibited.

Use in pediatrics

Children, especially young children, are very sensitive to the depressant effect of benzodiazepines on the CNS.

Newborns are not recommended to be prescribed drugs containing benzyl alcohol, as the development of a toxic syndrome is possible, manifested by metabolic acidosis, CNS depression, respiratory difficulty, renal failure, arterial hypotension and, possibly, epileptic seizures, as well as intracranial hemorrhage.

Effect on ability to drive vehicles and machinery

Patients receiving the drug should refrain from engaging in potentially hazardous activities that require increased attention and speed of psychomotor reactions.

Overdose

Symptoms drowsiness, depression of consciousness of varying severity, paradoxical agitation, decreased reflexes to areflexia, reduced response to painful stimuli, dysarthria, ataxia, visual disturbances (nystagmus), tremor, bradycardia, decreased blood pressure, collapse, depression of cardiac activity, respiratory depression, coma.

Treatment gastric lavage, forced diuresis, intake of activated charcoal; symptomatic therapy (maintenance of respiration and blood pressure), artificial ventilation.

Hemodialysis is not very effective.

The specific antidote is flumazenil, which should be used in a hospital setting. Flumazenil is not indicated for patients with epilepsy who have been treated with benzodiazepines. In such cases, the antagonistic effect against benzodiazepines may provoke the development of epileptic seizures.

Drug Interactions

MAO inhibitors, strychnine and corazole exhibit antagonism to the effects of Relanium.

With simultaneous use of Relanium with hypnotics, sedatives, opioid analgesics, other tranquilizers, benzodiazepine derivatives, muscle relaxants, general anesthetics, antidepressants, antipsychotics, as well as with ethanol, a sharp enhancement of the depressant effect on the CNS is observed.

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

Isoniazid, ketoconazole and metoprolol also slow down the metabolism of diazepam and increase its plasma concentration.

Propranolol and valproic acid increase the plasma concentration of diazepam.

Rifampicin may induce the metabolism of diazepam, leading to a decrease in its plasma concentration.

Inducers of liver microsomal enzymes reduce the effectiveness of Relanium.

Opioid analgesics enhance the depressant effect of Relanium on the CNS.

With simultaneous use with antihypertensive agents, an enhancement of the hypotensive effect is possible.

With simultaneous use with clozapine, an enhancement of respiratory depression is possible.

With simultaneous use of Relanium 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).

Relanium reduces the effectiveness of levodopa in patients with parkinsonism.

Omeprazole prolongs the elimination time of diazepam.

Respiratory analeptics and psychostimulants reduce the activity of Relanium.

Concomitant use with Relanium may increase the toxicity of zidovudine.

Theophylline (in low doses) may reduce the sedative effect of Relanium.

Premedication with Relanium allows for a reduction in the dose of fentanyl required for induction of general anesthesia and shortens the time to onset of general anesthesia.

Pharmaceutical Interactions

Relanium is incompatible in the same syringe with other drugs.

Storage Conditions

Relanium belongs to Schedule No. 1 of potent substances of the Permanent Committee for Narcotic Control of the Ministry of Health of the Russian Federation.

The drug should be stored out of the reach of children, in a light-protected place at a temperature between 15°C (59°F) and 25°C (77°F).

Shelf Life

The shelf life is 5 years.

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.