Thiopental-vista

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIOFENTAL-VISTA (THIOPENTAL-VISTA)

Composition:

active substance: thiopental sodium;

1 vial contains 0.5 g or 1.0 g of thiopental sodium;

excipient: sodium carbonate.

Pharmaceutical form. Powder for solution for injection.

Main physicochemical properties: yellowish-white powder.

Pharmacotherapeutic group. General anesthetics. Barbiturates, single preparations. ATC code N01AF03.

Pharmacological Properties.

Pharmacodynamics.

Thiopental is a thiobarbiturate, a sulfur-containing analog of urea.

Thiopental is an ultra-short-acting central nervous system (CNS) depressant that induces hypnosis and anesthesia, but not analgesia. Due to its high lipophilicity, it rapidly crosses the blood-brain barrier and almost simultaneously inhibits the cerebral cortex and subcortical structures. The depth of anesthesia depends on the dose, with its effects spreading from the cortical level down to the medulla oblongata. Thiopental induces hypnosis within 30–40 seconds after intravenous injection. Recovery after a small dose is rapid, accompanied by drowsiness and retrograde amnesia.

Pharmacokinetics.

Absorption. Thiopental acts immediately after injection. A dose of 3–4 mg/kg of thiopental induces loss of consciousness. The onset time of injection is 30–40 seconds. Rapid awakening after injection is due to the redistribution of the drug from the brain to other tissues within the first 15–20 minutes. Distribution. The concentration in cerebrospinal fluid is slightly lower than in blood plasma. The distribution and fate of thiopental (as with other barbiturates) are primarily influenced by its lipid solubility (partition coefficient), protein binding, and degree of ionization. Thiopental has a partition coefficient of 580. Approximately 80% of the drug in blood is bound to plasma proteins. Repeated intravenous doses lead to prolonged anesthesia, as fatty tissues act as a reservoir: they accumulate thiopental at concentrations 6–12 times higher than in plasma and then slowly release the drug, resulting in prolonged anesthesia.

Biotransformation. Thiopental is extensively metabolized in the liver and, to a lesser extent, in other tissues, particularly the kidneys and brain. It has a pKa of 7.4. The metabolites of thiopental are pharmacologically inactive and are primarily excreted in urine.

Elimination. The elimination half-life after a single intravenous dose ranges from 3 to 8 hours. Thiopental is almost completely metabolized in the human body; only 0.3% of the administered dose is excreted unchanged in urine.

Clinical characteristics.

Indications.

Thiopental is indicated for use:

• as a sole anesthetic for short (15 minutes) surgical procedures;
• for induction of anesthesia prior to administration of other anesthetics;
• as an adjunct to regional anesthesia;
• to provide sedative effect during balanced anesthesia with other analgesic or muscle relaxant agents;
• for control of convulsive states during or after inhalation anesthesia, local anesthesia, or for other reasons;
• in neurosurgical patients with increased intracranial pressure, provided adequate lung ventilation is ensured.

Contraindications.

Absolute contraindications:

• hypersensitivity to thiopental or barbiturates;
• porphyria;
• anticipated difficulties in maintaining upper airway patency and lack of equipment for immediate resuscitation;
• asthmatic state;
• patients with history of difficult awakening.

Additionally, in case of rectal administration:

• intestinal cancer and inflammatory bowel diseases;
• local inflammation/irritation of the rectum;
• severe thrombocytopenia.

Relative contraindications:

• hypovolemia, especially associated with acute blood loss;
• cardiovascular diseases (myocardial disease, valvular stenosis, pericarditis, tamponade, congestive heart failure, ischemic heart disease, QT interval prolongation and heart block, high resting potential or myocardial ischemia) and other severe cardiovascular disorders (malignant hypertension);
• hypotension or shock;
• bronchial asthma and obstructive lung disease;
• respiratory function impairment, airway obstruction;
• acute hepatitis;
• kidney damage;
• neurological disorders (myasthenia gravis, myotonic dystrophy);
• metabolic disorders (myxedema, adrenal insufficiency);
• ophthalmoplegia;
• floor of mouth phlegmon;
• sepsis;
• obesity.

Interaction with other medicinal products and other types of interactions.

Thiopental enhances the effects of hypotensive and hypothermic agents. The drug potentiates the central nervous system (CNS) depressant effects of sedatives and hypnotics, ketamine, neuroleptics, magnesium sulfate, and ethanol. The activity of the drug is increased by H1-adrenoblockers and probenecid, and decreased by analeptics and certain antidepressants, aminophylline. Therefore, caution should be exercised when using the medicinal product Thiopental-Vista with the aforementioned medicinal products.

When thiopental sodium is used concomitantly with sulfafurazole, a reduced initial dose and the need for repeated doses to maintain anesthesia are indicated.

When general anesthetics are used concomitantly with β-blockers, calcium channel blockers, ACE inhibitors, α-adrenoblockers, angiotensin II antagonists, phenothiazines, diazoxide, diuretics, methyldopa, moxonidine, nitrates, and peripheral vasodilators (hydralazine, minoxidil, nitroprusside), potentiation of their hypotensive effects may occur.

Analgesics

Data indicate increased activity of thiopental sodium with prior administration of acetylsalicylic acid. Due to the potential for respiratory depression, thiopental sodium should be used cautiously in combination with narcotic analgesics. Thiopental sodium may reduce the analgesic effect of meperidine.

Antibacterial medicinal products

Data indicate that general anesthetics may potentiate the hepatotoxicity of isoniazid. Increased sensitivity and adverse reactions may also occur with concomitant use of thiopental sodium and intravenous vancomycin.

Antidepressants

Concomitant use with tricyclic antidepressants increases the risk of arrhythmia and hypotension. Concomitant use of thiopental sodium with MAO inhibitors carries a risk of hypotension and arterial hypertension.

Antipsychotic medicinal products

Thiopental sodium may enhance the sedative properties of certain phenothiazines, particularly promethazine.

Benzodiazepines

Midazolam potentiates the anesthetic effect of thiopental sodium.

When thiopental sodium is used concomitantly with metoclopramide and droperidol, the dose of thiopental sodium should be reduced (these agents may enhance the hypnotic effect of thiopental).

When other CNS depressants are used concomitantly for premedication, synergistic effects may occur; therefore, in some cases, lower doses of general anesthetic agents may be required.

There are reports of bradycardia occurring during anesthesia induction with thiopental sodium in combination with fentanyl.

Sulfisoxazole has a higher affinity for plasma proteins than thiopental. It is recommended to reduce the amount of thiopental required for anesthesia.

Special precautions for use.

It is recommended to have resuscitation equipment and endotracheal intubation equipment, as well as readily available oxygen, wherever sodium thiopental is used. Patient airway patency must be monitored.

The medicinal product should be administered only by personnel qualified in the use of intravenous anesthetics.

Aseptic techniques must be observed during preparation and administration of the medicinal product solution.

When administering the drug to patients with relative contraindications, the dose should be reduced and the drug should be administered slowly.

Thiopental should be used with caution in patients with arterial hypotension or under conditions where the hypnotic effect may be prolonged or enhanced, such as in the presence of impaired liver or kidney function. Conditions in which the hypnotic effect may be prolonged or enhanced include excessive premedication, Addison's disease, impaired liver or kidney function, elevated blood urea levels, severe anemia, asthma, and myasthenia.

Extravasation

Extravascular infiltration should be avoided. Prior to thiopental injection, it must be confirmed that the needle is within the lumen of the vein.

Accidental intra-arterial administration

Intra-arterial administration should be avoided. Inadvertent intra-arterial injection may occur, particularly if an aberrant superficial artery is present on the medial side of the antecubital fossa. The site selected for intravenous administration should be palpated to detect any underlying pulsating vessel. Accidental intra-arterial injection may cause arterial spasm and severe pain along the course of the artery, accompanied by pallor of the hand and fingers.

Aseptic technique must always be observed when preparing and handling thiopental solutions.

Particular caution is required when administering this medicinal product to patients with cardiovascular and endocrine disorders, especially hyperfunction of the pituitary gland, thyroid gland, adrenal glands, or pancreas.

As with other barbiturates, thiopental administration may lead to dependence. Cases have been reported associating thiopental infusion with severe or refractory hypokalemia; after discontinuation of thiopental infusion, a rebound effect in the form of severe hyperkalemia may occur. When discontinuing thiopental therapy, the possibility of a rebound effect manifesting as pronounced hyperkalemia should be considered.

Important information about excipients

This medicinal product contains 3 mmol and 5 mmol of sodium per vial (according to dosage), which should be taken into account for patients on a low-sodium diet.

Use during pregnancy or breastfeeding.

Pregnancy

The safety of thiopental with regard to adverse effects on the fetus has not been established. Carcinogenicity, mutagenicity, and effects on fertility have not been evaluated in animal studies. Since thiopental readily crosses the placental barrier, the drug should not be administered to pregnant women, especially during early pregnancy, except when the expected benefit outweighs the potential risk to the fetus.

Breastfeeding period

Although thiopental rapidly crosses the placental barrier, no fetal harm has been observed after a single dose of 5 mg/kg body weight. Thiopental is excreted in breast milk; therefore, breastfeeding should be avoided for 24 hours following administration of the medicinal product.

Ability to influence reaction speed when driving or operating machinery

Thiopental significantly impairs the ability to drive a car or operate machinery. Postoperative dizziness, disorientation, and sedative effects may persist for a prolonged period after administration of the drug. Therefore, patients should refrain from driving or performing work requiring heightened attention and rapid psychomotor reactions, especially during the first 24 hours after drug administration.

Administration and Dosage

The use of the medicinal product is permitted only under hospital conditions.

For slow intravenous and rectal administration in children. The use of the medicinal product is allowed only for specialist anesthesiologists. Preparation of Solutions

The medicinal product Thiopental-Vista is supplied as a yellowish powder in a vial. Solutions should be prepared aseptically using one of the following two solvents:

• Sterile water for injections;
• Infusion solution of sodium chloride (9 mg/mL).

Clinical concentrations used for intermittent intravenous administration range from 2% to 5%. A 2% or 2.5% solution is most commonly used. A 3.4% concentration in sterile water for injections is isotonic; concentrations below 2% in this solvent should not be used, as they may cause hemolysis. For continuous intravenous infusion, concentrations of 0.2% or 0.4% are used. Solutions may be prepared by adding thiopental to 5% aqueous dextrose solution or to 0.9% sodium chloride solution.

Maximum single dose: 1 g.

Maximum daily dose: 2 g.

Since the medicinal product does not contain an added bacteriostatic agent, extreme care should always be exercised during preparation and handling to prevent the introduction of microbial contaminants.

Solutions should be freshly prepared and used immediately; when diluted for administration to multiple patients, unused portions should be discarded within 24 hours. Thiopental cannot be re-sterilized. Thiopental is administered only intravenously. Individual response to thiopental is so variable that no fixed dosage can be given. The dose should be titrated according to the patient's needs depending on age, sex, and body weight. Younger patients require relatively higher doses than middle-aged or elderly individuals; the latter metabolize thiopental more slowly. Dosing by sex is similar, but adult women may require slightly lower doses than adult men. The dose is usually proportional to body weight, so obese patients require higher doses than relatively thin individuals.

Rectal administration (in children)

For general anesthesia, a 5% or 10% solution of thiopental is administered rectally in a dose of 25–40 mg/kg body weight.

Test dose

It is advisable to administer a small intravenous "test" dose of 25 to 75 mg (1–3 mL of a 2.5% solution) to assess tolerance or unusual sensitivity to thiopental, followed by a pause to observe the patient's reaction for at least 60 seconds. If unexpectedly deep anesthesia or respiratory depression occurs, this may indicate that:

1. The patient may be extremely sensitive to thiopental.
2. The solution may be more concentrated than intended.
3. The patient may have received excessive premedication.

Use for anesthesia induction

In healthy adults, 4–6 mg/kg body weight is administered; in infants and children, 5–7 mg/kg body weight; in elderly patients, 2–3 mg/kg body weight.

Use in anesthesia

Adults

The bolus dose for adults is 100–150 mg (maximum 5 mg/kg of total body weight or 4 mg/kg of lean body mass) administered over approximately 15 seconds. Subsequent doses (25–50 mg) may be given as needed depending on the patient's response, after 30–60 seconds.

Children

In healthy children who have received premedication, the induction dose should be reduced until adequate sedation is achieved, compared to children who have not received premedication. The induction dose of thiopental required to achieve sedation in newborns without premedication is only 3.4 mg/kg body weight.

Elderly patients

In patients aged 60 years and older, dosage requirements are significantly reduced, so a dose of 2–2.5 mg/kg may be sufficient.

Variability in adult dosage requirements depending on age and sex can be described by the following formula:

Dose (in mg) = 350 + body weight (kg) – 2 × age (years) – 50 (if the patient is female). The dose and rate of injection must be adjusted not only according to the patient's age but also according to their health status, premedication, and prior opioid treatment immediately before induction.

Use for the control of seizure activity

From 75 mg to 125 mg (from 3 mL to 5 mL of a 2.5% solution) should be administered immediately after the onset of seizures. Additional doses may be required to control seizures occurring after general anesthesia. Other regimens, such as rectal or intravenous administration of diazepam, may be used to control seizure activity.

Use in neurological patients for reduction of intracranial pressure

Administration of a dose of 1.5 to 3 mg/kg as intermittent boluses to reduce elevated intracranial pressure, provided controlled ventilation is ensured. The use of thiopental for this indication in children has not been studied.

Effect of the drug on liver function

Thiopental is known not to reduce liver function at usual doses. Impairment of liver function occurs after exceeding high recommended doses or in the presence of concomitant hypoxia. In these conditions, hepatic glycogen stores are depleted, prothrombin time is prolonged, and bilirubinemia increases. Hepatitis with hepatocellular damage reduces the elimination of the anesthetic, so fractionated dosing and reduced administered doses are necessary.

Effect of the drug on kidney function

Diuresis is slightly reduced, but renal toxicity is minimal. In patients with azotemia, excretion is somewhat delayed.

Rectal administration in children

A 5–10% solution of thiopental in a dose of 25–40 mg/kg body weight is administered rectally to a child during induction of anesthesia. The child lies on their side. The solution is warmed to body temperature and administered over 2 minutes via a thin catheter inserted through the sphincter. Before connecting the syringe to the drug, 1–2 mL of air may be drawn into a clean syringe. The anesthetic effect develops gradually over 10–15 minutes and lasts longer than after intravenous administration. After anesthesia is achieved, any remaining solution can be aspirated using a thin catheter. Anesthesia lasts 30–40 minutes and gradually diminishes during the last 10 minutes.

Thiopental is a drug that is a very strong tissue irritant and, in extreme cases, may lead to gangrene or necrosis (in case of intra-arterial administration or extravasation), especially in solutions with a concentration above 5%.

Children

The drug may be used from the first days of life (see section "Administration and dosage").

Overdose

Overdose may occur due to too rapid or repeated administration of the drug.

Symptoms

Rapid administration may be accompanied by a drop in arterial blood pressure. Respiratory depression up to apnea, laryngospasm, coughing, collapse, tachycardia, cardiac arrest, cardiovascular collapse, pulmonary edema, and post-anesthetic delirium may occur. Apnea, periodic laryngospasm, coughing, and other respiratory disturbances may result from excessive or too rapid administration of the drug. Cardiovascular collapse may occur, and treatment should be directed toward restoring normal blood volume through appropriate measures: increasing fluid volume and/or administering vasoconstrictors.

Treatment

In case of suspected or evident overdose, administration of the drug should be discontinued, the airway should be cleared (intubation if necessary) or maintained as needed, and oxygen should be administered via artificial ventilation of the lungs.

Respiratory depression (hypoventilation, apnea)

Respiratory depression may result from increased sensitivity to thiopental or overdose. The procedure described above is required. It should be recognized that thiopental has the same potential for respiratory depression as an inhalational agent; therefore, airway patency must be continuously maintained.

Laryngospasm

Laryngospasm may occur with light anesthesia induced by thiopental, both during and without intubation. The cause of laryngospasm is most often the presence of secretions or other substances irritating the respiratory tract. Coughing and bronchial reflex resulting from stimulation of the vagus nerve (most often due to excessive secretion) can be minimized by premedication with an anticholinergic agent (e.g., atropine or scopolamine); deeper anesthesia will be achieved with the same dose of thiopental after prior administration of a benzodiazepine or opioid. The use of skeletal muscle relaxants or oxygen administration during positive pressure ventilation usually relieves laryngospasm. In difficult cases, tracheostomy may be indicated.

Myocardial depression

Myocardial depression may occur, proportional to the amount of drug administered that directly contacts the heart, and may cause arterial hypotension, especially in patients with diseased myocardium. Arrhythmias may occur if pCO2 is elevated, but they are uncommon with adequate ventilation. Treatment of myocardial depression is the same as for overdose. Thiopental does not cause sensitization of the heart to epinephrine or other sympathomimetic amines.

Adverse reactions.

All adverse reactions are listed by system organ classes and frequency: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1000 – < 1/100), rare (≥ 1/10000 – < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data). Coughing and sneezing may occur during induction with thiopental, as with the use of any barbiturate.

Latent and clinical porphyria are permanent and absolute contraindications to the use of thiopental, as well as other barbiturates; administration of the drug may disrupt CNS function and cause severe paralysis and nerve demyelination.

Adverse effects with rectal administration: irritation of the anal opening, involuntary defecation; prolonged drowsiness; nausea, vomiting; ataxia. The severity of local adverse reactions increases when using solutions of higher concentration.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of this medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of drug efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

No special storage conditions required. Keep out of reach of children.

Incompatibility.

The stability of thiopental solutions depends on several factors, including the solvent used, storage temperature, and the amount of carbon dioxide from ambient air that comes into contact with the solution. Any factor or condition that tends to lower the pH (increase acidity) of thiopental solutions increases the likelihood of precipitation of thiopentone acid. Such factors include the use of overly acidic solvents and absorption of carbon dioxide, which can combine with water to form carbonic acid. Solutions of suxamethonium, tubocurarine, or other agents with acidic pH must not be mixed with thiopental solutions. Any incompatibility with thiopental manifests as the formation of a visible precipitate. A medicinal product solution showing visible precipitate must not be used.

Packaging.

0.5 g or 1 g of powder in a vial; 1 vial per cardboard box.

Prescription category. Prescription only.

Manufacturer.

VUAB Pharma a.s.

Manufacturer's address and location of its business operations.

Vltavska 53, Roztoky, 252 63, Czech Republic.