Thiopental sodium (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Sintez PJSC (Russia)

ATC Code

N01AF03 (Thiopental sodium)

Active Substance

Thiopental sodium (Rec.INN)

Dosage Forms

	Thiopental sodium	Lyophilisate for preparation of solution for intravenous administration 1 g: vial 1 pc.
		Lyophilisate for preparation of solution for intravenous administration 500 mg: vial 1 pc.

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravenous administration in the form of a powder, white or almost white, or from yellowish-white to slightly greenish-yellow; hygroscopic.

1 g – glass vials with a capacity of 20 ml (1) – cardboard packs.

Lyophilisate for preparation of solution for intravenous administration in the form of a powder, white or almost white, or from yellowish-white to slightly greenish-yellow; hygroscopic.

500 mg – glass vials with a capacity of 10 ml (1) – cardboard packs.

Clinical-Pharmacological Group

Agent for non-inhalation anesthesia

Pharmacotherapeutic Group

Agent for non-inhalation general anesthesia

Pharmacological Action

It belongs to the list of potent substances (List No. 1).

An ultrashort-acting agent for non-inhalation general anesthesia, a derivative of thiobarbituric acid. It has a pronounced hypnotic effect and weak muscle relaxant and analgesic activity. It slows down the opening time of GABA-dependent channels on the postsynaptic membrane of brain neurons, prolongs the entry time of chloride ions into the nerve cell and causes membrane hyperpolarization. It suppresses the excitatory effect of amino acids (aspartate and glutamate). In large doses, by directly activating GABA receptors, it has a GABA-stimulating effect. It has anticonvulsant activity by increasing the excitability threshold of neurons and blocking the conduction and propagation of the convulsive impulse in the brain. It promotes muscle relaxation by suppressing polysynaptic reflexes and slowing conduction along the interneurons of the spinal cord. It reduces the intensity of metabolic processes in the brain. It has a hypnotic effect, which is manifested by accelerating the process of falling asleep and changing the structure of sleep. It depresses (dose-dependently) the respiratory center and reduces its sensitivity to carbon dioxide. It has a (dose-dependent) cardiodepressant effect: reduces stroke and minute blood volume, arterial pressure. It increases the capacity of the venous bed, reduces hepatic blood flow and glomerular filtration rate. It has an excitatory effect on the vagus nerve and can cause laryngospasm, profuse mucus secretion.

After intravenous administration, general anesthesia develops in 30-40 seconds; after rectal administration – in 8-10 minutes, characterized by short duration (after a single dose administration, general anesthesia lasts 10-30 minutes) and awakening with some drowsiness and retrograde amnesia. Upon recovery from general anesthesia, the analgesic effect ceases simultaneously with the patient’s awakening.

Pharmacokinetics

When administered intravenously, it quickly penetrates the brain, skeletal muscles, kidneys, liver, and adipose tissue. Time to reach C_max – within 30 seconds (brain), 15-30 minutes (muscles). In fat depots, the concentration of the drug is 6-12 times higher than in blood plasma. V_d – 1.7-2.5 l/kg, during pregnancy – 4.1 l/kg, in obese patients – 7.9 l/kg. Plasma protein binding – 76-86 %. It penetrates the placental barrier and is excreted in breast milk.

It is metabolized mainly in the liver, with the formation of inactive metabolites, 3-5% of the dose is desulfated to pentobarbital, a small part is inactivated in the kidneys and brain.

T_1/2 in the distribution phase – 5-9 minutes, in the elimination phase – 3-8 hours (possibly prolonged to 10-12 hours; during pregnancy – up to 26.1 hours, in obese patients – up to 27.5 hours), in children – 6.1 hours. Clearance – 1.6-4.3 ml/kg/min, during pregnancy – 286 ml/min. It is excreted mainly by the kidneys through glomerular filtration. With repeated administration, it accumulates (associated with accumulation in adipose tissue).

Indications

• General anesthesia for short-term surgical interventions, induction and basic general anesthesia (with subsequent use of analgesics and muscle relaxants);
• Grand mal epileptic seizures, status epilepticus;
• Prevention of brain hypoxia (during artificial circulation, neurosurgical operations).

ICD codes

Dosage Regimen

Intravenously slowly (to avoid collapse), in adults, 2-2.5% solutions are used (less commonly, a 5% solution – the fractional administration technique is used); in children and debilitated elderly patients – a 1% solution.

Solutions are prepared immediately before use with water for injections.

The prepared solution must be absolutely transparent. With rapid administration of solutions with a concentration of less than 2%, hemolysis may develop. Premedication with atropine or metacin is performed before administration.

For adults for induction of general anesthesia: test dose – 25-75 mg, followed by observation for 60 seconds before administration of the main dose. Induction general anesthesia – 200-400 mg (50-100 mg at intervals of 30-40 seconds until the desired effect is achieved or as a single dose at the rate of 3-5 mg/kg). For maintenance of anesthesia – 50-100 mg.

For relief of convulsions – 75-125 mg IV over 10 minutes; with the development of convulsions during local anesthesia – 125-250 mg over 10 minutes.

For brain hypoxia, 1.5-3.5 mg/kg is administered over 1 minute until temporary circulatory arrest.

In renal impairment (creatinine clearance less than 10 ml/min) – 75% of the average dose.

The maximum single dose of the drug for adults IV is 1 g (50 ml of a 2% solution).

The IV solution should be administered slowly, at a rate not exceeding 1 ml/min. Initially, 1-2 ml is usually administered, and after 20-30 seconds – the remaining amount.

For children – IV bolus, slowly over 3-5 minutes, as a single dose at the rate of 3-5 mg/kg. Before inhalational anesthesia without prior premedication in newborns – 3-4 mg/kg, 1-12 months – 5-8 mg/kg, 1-12 years – 5-6 mg/kg; for general anesthesia in children weighing 30-50 kg – 4-5 mg/kg. Maintenance dose – 25-50 mg. In children with reduced renal function (creatinine clearance less than 10 ml/min) – 75% of the average dose. The use of the drug for basic anesthesia is especially indicated in children with increased nervous excitability and in patients with thyrotoxicosis.

Adverse Reactions

From the cardiovascular system decreased blood pressure, arrhythmia, tachycardia, collapse.

From the respiratory system cough, sneezing, hypersecretion of bronchial mucus, laryngospasm, bronchospasm, pulmonary hypoventilation, dyspnea, respiratory center depression, apnea.

From the nervous system: headache, muscle twitching, epileptic seizures, increased vagus nerve tone, dizziness, lethargy, ataxia, anterograde amnesia, drowsiness in the postoperative period, anxiety, especially with pain in the postoperative period; rarely – postoperative delirious psychosis.

From the digestive system hypersalivation, nausea, vomiting, abdominal pain in the postoperative period.

Allergic reactions skin hyperemia, rash, skin itching, urticaria, rhinitis, anaphylactic shock, rarely – hemolytic anemia with impaired renal function (pain in the lower back, legs and stomach, nausea, vomiting, loss of appetite, unusual weakness, fever, pale skin).

Other: hiccups.

Local reactions with IV administration – pain at the injection site, – thrombophlebitis (administration of solutions with a high concentration of the drug), vascular spasm and thrombosis at the injection site, tissue irritation at the injection site (skin hyperemia and peeling), necrosis; damage to nerves approaching the injection site.

Contraindications

• Hypersensitivity;
• Porphyria, including acute intermittent (including in the patient’s history or his immediate relatives);
• Intoxication with ethanol, narcotic analgesics, hypnotics and general anesthetics;
• Shock;
• Asthmatic status;
• Malignant hypertension;
• Lactation period.

With caution: chronic obstructive pulmonary diseases, bronchial asthma, severe impairment of myocardial contractile function, severe cardiovascular failure, arterial hypotension, collapse, hypovolemia, excessive premedication, hepatic and/or renal failure, Addison’s disease, myxedema, diabetes mellitus, anemia, myasthenia gravis, myotonia, muscular dystrophy, cachexia, febrile syndrome, inflammatory diseases of the nasopharynx, obesity, pregnancy, childhood.

Use in Pregnancy and Lactation

In pregnant women, the drug should be used only if the intended benefit to the mother outweighs the potential risk to the fetus.

The drug is contraindicated during lactation.

Use in Hepatic Impairment

With caution hepatic insufficiency.

Use in Renal Impairment

In renal impairment (creatinine clearance less than 10 ml/min) – 75% of the average dose.

Pediatric Use

Use with caution in children.

For children – IV bolus, slowly over 3-5 minutes, as a single dose at the rate of 3-5 mg/kg. Before inhalational anesthesia without prior premedication in newborns – 3-4 mg/kg, 1-12 months – 5-8 mg/kg, 1-12 years – 5-6 mg/kg; for general anesthesia in children weighing 30-50 kg – 4-5 mg/kg. Maintenance dose – 25-50 mg. In children with reduced renal function (creatinine clearance less than 10 ml/min) – 75% of the average dose. The use of the drug for basic anesthesia is especially indicated in children with increased nervous excitability.

Special Precautions

Use only in specialized departments by anesthesiologists-resuscitators, with means to maintain cardiac activity and ensure airway patency, artificial lung ventilation. It should be taken into account that achieving and maintaining general anesthesia of the required depth and duration depends both on the amount of the drug and on the individual sensitivity of the patient to it.

In inflammatory diseases of the upper respiratory tract, it is necessary to ensure the patency of the upper respiratory tract, up to tracheal intubation.

Unintentional intra-arterial administration causes instantaneous vascular spasm, accompanied by impaired circulation distal to the injection site (thrombosis of the main vessel with subsequent development of necrosis and gangrene is possible). The first sign in conscious patients: complaints of a burning sensation spreading along the artery; in patients under general anesthesia, the first symptoms are transient pallor, mottled cyanosis, or dark discoloration of the skin.

Treatment: stop the administration; intra-arterially inject a heparin solution into the affected site followed by anticoagulant therapy; a glucocorticosteroid solution followed by systemic therapy; perform sympathetic blockade or brachial plexus blockade (intra-arterial administration of procaine).

In case of chemical irritation of tissues (associated with the high pH value of the solution (10-11) if the solution gets under the skin, a local anesthetic is administered to quickly resolve the infiltrate and warming is performed (activation of local blood circulation). A sign of extravasation is subcutaneous swelling.

In case of intravenous bolus administration to children under 18 years of age, careful monitoring of the patient’s condition is necessary for timely detection of symptoms of respiratory depression, hemolysis, decreased blood pressure, and extravasations.

The anesthetic effect is unreliable in persons who abuse alcohol.

The dose should be reduced in patients taking digoxin, diuretics; in patients who received morphine in premedication, as well as after administration of atropine, diazepam.

Premedication – with any of the commonly used drugs, except for phenothiazine derivatives.

During prolonged anesthesia, when the hypnotic effect caused by sodium thiopental is maintained by intravenous administration of long-acting anesthetics and/or inhalational anesthetics, due to the danger of a cumulative effect, the dose of sodium thiopental should not exceed 1 g.

Can be used in combination with muscle relaxants provided that artificial lung ventilation is performed.

Thiopental sodium does not affect the tone of the pregnant uterus. After IV administration, the maximum concentration in the umbilical cord is noted after 2-3 minutes. The maximum allowable dose is 250 mg. When used in obstetric and gynecological surgery, it can cause CNS depression in newborns.

Overdose

Symptoms CNS depression, convulsions, muscle hyperreactivity, respiratory depression up to apnea, laryngospasm, water-electrolyte disturbances, pronounced decrease in blood pressure, decrease in total peripheral vascular resistance (toxic effect in overdose begins from the first seconds), tachycardia; post-anesthetic delirium. With a very high dose: pulmonary edema, circulatory collapse, cardiac arrest.

Treatment: antidote – bemegride. In case of respiratory arrest – artificial lung ventilation, 100% oxygen; in case of laryngospasm – muscle relaxants and 100% oxygen under pressure; in case of collapse or pronounced decrease in blood pressure – plasma-substituting solutions, administration of vasopressor drugs and/or drugs with positive inotropic action. For convulsions – IV administration of diazepam; if ineffective – artificial lung ventilation and muscle relaxants.

Drug Interactions

Concomitant use with ethanol and drugs that depress the central nervous system leads to mutual enhancement of pharmacological action (both to significant depression of the central nervous system, respiratory function, enhancement of the hypotensive effect, and the degree of anesthesia); with magnesium sulfate – enhancement of the depressant effect on the central nervous system; with ganglion blockers, diuretics and other hypotensive drugs – enhancement of the hypotensive effect; with methotrexate – enhancement of the toxic effect of the latter.

Reduces the effect of indirect anticoagulants (coumarin derivatives), griseofulvin, contraceptives, glucocorticosteroids.

Enhances the effect of drugs that promote the development of hypothermia. Shows antagonism with bemegride.

Ketamine increases the risk of decreased blood pressure and respiratory suppression, prolongs the time of functional recovery after emergence from general anesthesia.

Drugs that block tubular secretion (probenecid) and H₁-histamine blockers enhance the effect; aminophylline, analeptics, some antidepressants – weaken it.

Diazoxide increases the risk of decreased blood pressure.

Pharmaceutically incompatible with antibiotics (amikacin, benzylpenicillin, cefapirin), anxiolytic drugs (tranquilizers), muscle relaxants (suxamethonium, tubocurarine), narcotic analgesics (codeine, morphine), ephedrine, epinephrine, ascorbic acid, dipyridamole, chlorpromazine, ketamine, atropine, scopolamine and tubocurarine chloride (should not be mixed in the same syringe and administered through the same needle with acidic solutions).

Storage Conditions

List No. 1 of potent substances. In a dry, light-protected place, out of reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life 2 years. Do not use 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.