Tetram

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TETURAM (TETURAM)

Composition:

Active substance: disulfiram;

1 tablet contains disulfiram (calculated as 100% and dry substance) – 150 mg;

Excipients: hypromellose, microcrystalline cellulose, sodium croscarmellose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: tablets are white or white with a slightly yellowish-greenish tint, round-shaped, with flat surface and beveled edges (chamfer) and a score line.

Pharmacotherapeutic group. Agents used in alcohol dependence. ATC code N07BB01.

Pharmacological Properties

Pharmacodynamics

Teturan is a specific agent for the treatment of chronic alcoholism. The action of disulfiram is due to its ability to disrupt alcohol metabolism. In the body, disulfiram is converted into N,N-diethyldithiocarbamic acid and other metabolites that chelate metal ions and block sulfhydryl groups of enzymes involved in alcohol detoxification. Ethanol in the body undergoes oxidative transformation via the acetaldehyde and acetic acid stages. By inhibiting the enzymatic biotransformation of alcohol by alcohol dehydrogenase, disulfiram promotes the accumulation of acetaldehyde in the blood after alcohol consumption, leading to characteristic toxic effects (nausea, vomiting, skin hyperemia, flushing of the face and upper body, chest pain, dyspnea, headache, palpitations, dizziness, fear sensation, chills, hypotension). Administration of alcohol during disulfiram therapy induces a stable negative conditioned reflex to the taste and smell of alcohol, and with prolonged treatment, leads to partial or complete alcohol intolerance.

Pharmacokinetics

After oral administration, disulfiram is rapidly but incompletely absorbed (70–90%) in the gastrointestinal tract. The duration of action is 48 hours. Disulfiram is rapidly metabolized by reduction to diethyldithiocarbamate, which is excreted as conjugates, or to diethylamine and carbon disulfide (from 4% to 53%). Carbon disulfide is excreted via the lungs.

Clinical characteristics.

Indications.

Adjuvant therapy for the prevention of relapse of alcohol dependence.

Contraindications.

• Hypersensitivity to disulfiram or any component of the drug, as well as to thiuram compounds;
• cardiovascular disorders;
• diabetes mellitus;
• psychiatric and behavioral disorders: severe personality disorders, suicidal risk, psychoses;
• epilepsy and epileptiform syndromes (except alcohol-related epilepsy);
• severe respiratory insufficiency;
• severe hepatic and/or renal insufficiency;
• consumption of alcoholic beverages or use of medicinal products containing alcohol within the last 24 hours before taking disulfiram.

Interaction with other medicinal products and other forms of interaction.

Not recommended combinations of Teturom:

• with alcohol (as a beverage or excipient) − development of disulfiram-like reaction (flushing, warmth sensation, vomiting, tachycardia). Alcoholic beverages or medicinal products, foodstuffs, perfumes, and cosmetics containing ethanol must be avoided until the drug is completely eliminated from the body. For this purpose, data on elimination half-life should be considered. Also, avoid using medicinal products containing large amounts of propylene glycol;
• with isoniazid, paraldehyde – possible acute disturbances in behavior and motor coordination;
• with nitroimidazoles (metronidazole, ornidazole, secnidazole, tinidazole, omeprazole) – possible acute toxic psychosis (delirium tremens), disturbances of consciousness, catatonia, which are reversible after discontinuation of the drug; metronidazole should be avoided for 14 days after stopping disulfiram therapy;
• with hydantoins (phenytoin, by extrapolation, fosphenytoin) – possible significant and rapid increase in plasma levels of hydantoins, including phenytoin (due to inhibition of metabolism), with toxic manifestations; if combination cannot be avoided, clinical monitoring and plasma phenytoin level control during and after disulfiram treatment are required;
• with hepatotoxic drugs – increased risk of hepatotoxicity; therefore, concomitant use with disulfiram should be avoided.

Combinations requiring cautious use:

• with vasodilators, alpha- and beta-adrenergic blockers, sympathomimetics – expect pharmacodynamic interactions with potentially serious clinical consequences;
• with warfarin and other oral anticoagulants − due to reduced hepatic metabolism, increased plasma concentrations of anticoagulants and enhanced anticoagulant effect (risk of bleeding) may occur. Prothrombin time or international normalized ratio (INR) should be monitored more frequently, and anticoagulant doses adjusted during disulfiram treatment and for at least 8 days after its discontinuation;
• with theophylline – possible reduction in theophylline metabolism and increased plasma concentration. The theophylline dose should be adjusted based on clinical signs and plasma drug levels;
• with benzodiazepines – possible potentiation of sedative effects and CNS-related adverse reactions due to inhibition of oxidative metabolism of benzodiazepines (especially chlordiazepoxide and diazepam). Under the influence of diazepam, the intensity of the disulfiram-alcohol reaction may decrease. Potentially increased temazepam toxicity. Benzodiazepine dosing should be adjusted according to clinical signs;
• with barbiturates, morphine, pentazocine – enhanced therapeutic effect and adverse reactions of these substances due to increased plasma concentrations, leading to toxic reactions;
• with buspirone − potentially possible development of psychiatric disorders (mania);
• with tricyclic antidepressants (desipramine, imipramine, amitriptyline) – possible increased intolerance to alcohol, potentiation of antabuse reaction, development of acute organic brain syndrome; patient's mental status should be monitored;
• with pimozide – possible potentiation of organic brain syndrome and choreoathetosis;
• with phenothiazine derivatives (including perphenazine, chlorpromazine) and MAO inhibitors − risk of serious adverse reactions (including psychotic reactions, enhanced arterial hypotension) related to drug interaction;
• with chlorzoxazone − increased risk of CNS-related adverse reactions;
• with cocaine − disulfiram may inhibit its metabolism, leading to significantly increased cocaine blood concentration and increased risk of cardiovascular adverse effects of cocaine, including QT interval prolongation;
• with caffeine − concomitant use of disulfiram and high doses of caffeine increases the risk of cardiovascular reactions and excitation. Use of caffeine-containing drugs and products should be monitored;
• with ascorbic acid – high doses of ascorbic acid may interfere with the disulfiram-alcohol reaction;
• with rifampicin – disulfiram inhibits oxidation and renal excretion of rifampicin.

Concomitant use of antacids containing divalent cations may reduce disulfiram absorption. Similarly, high doses of iron salts block absorption.

Effect on laboratory test results.

Disulfiram may interfere with determination of blood cholesterol levels (increased values).

Disulfiram slightly reduces urinary excretion of vanillylmandelic acid, but not to an extent that would interfere with diagnosis of pheochromocytoma.

Disulfiram may increase urinary homovanillic acid concentration due to inhibition of beta-dopamine hydroxylase.

Special precautions for use.

Precautions specific to disulfiram.

Cases of severe hepatotoxicity leading to liver transplantation or fatal outcomes have been reported.

If asthenia, anorexia, nausea, vomiting, abdominal pain, jaundice, or darkening of urine occur, disulfiram administration must be discontinued immediately, and the patient should undergo clinical evaluation, including assessment of liver function laboratory tests (see section "Adverse reactions").

Precautions related to the disulfiram-alcohol combination.

Patients must be warned about the risk of developing a disulfiram reaction of varying severity, including fatal outcomes in rare cases, if the drug is taken concomitantly with alcoholic beverages—even in minimal amounts—or if abstinence is not maintained for up to 2 weeks after discontinuation of treatment (see sections "Interaction with other medicinal products and other forms of interaction", "Adverse reactions").

Patients should be cautious about ethanol content in certain other medicinal products (especially oral solutions) or food products, as well as when using perfumery and cosmetic products such as aftershave lotions, mouthwashes, and perfumes.

The disulfiram reaction (symptoms: flushing, erythema, nausea, vomiting, general malaise, tachycardia, and arterial hypotension) develops within 10 minutes after ingestion of alcohol-containing products and may last from 30 minutes to several hours.

Reactions upon alcohol consumption may occur for up to 2 weeks after stopping disulfiram treatment. More severe reactions have been reported, including cardiac arrhythmias, angina attacks, cardiovascular collapse, myocardial infarction, respiratory depression, neurological symptoms (confusion, encephalopathy, seizures), and sudden death.

Disulfiram should not be used with the following substances:

• Alcoholic beverages and medicinal products containing ethanol;
• Isoniazid;
• Metronidazole;
• Phenytoin, fosphenytoin (see section "Interaction with other medicinal products and other forms of interaction").

Precautionary measures during use.

Disulfiram should only be administered in specialized healthcare facilities (inpatient units, medical centers, outpatient clinics) with qualified personnel experienced in its use.

Due to the potential for significant adverse effects, disulfiram should only be used when alternative treatment methods are unavailable or ineffective.

Disulfiram treatment must be initiated only after a thorough medical evaluation (including general physical examination and laboratory tests), in the absence of contraindications, and under physician supervision. The patient must be fully informed about the nature of the therapy and explicitly instructed to avoid alcohol consumption during treatment.

Disulfiram must never be administered to patients without their knowledge, to insufficiently informed patients, or to patients under the influence of alcohol.

Prior to initiating treatment, alcohol withdrawal symptoms must be fully resolved, and detoxification, general supportive, and symptomatic therapy should be completed. Rational psychotherapy is advisable.

Sedatives, tranquilizers, antidepressants, and neuroleptics should be discontinued 1–3 days before starting disulfiram.

Liver function tests, including serum transaminase levels, should be performed before initiating disulfiram treatment (see section "Contraindications") and periodically thereafter, at least once a month, particularly during the first 3 months of treatment. A threefold or greater elevation of serum transaminase levels above the upper normal limit requires immediate and permanent discontinuation of disulfiram. Close monitoring of the patient is necessary until liver function parameters return to normal.

Disulfiram should be used with caution in patients with nickel dermatitis/eczema due to an increased risk of developing hepatitis.

Arterial blood pressure should be closely monitored in patients with hypertension receiving disulfiram; dose reduction is recommended.

Disulfiram should be used cautiously in patients with renal impairment or hypothyroidism due to the potential risk of an inadvertent disulfiram reaction.

Disulfiram is not recommended during pregnancy, regardless of the stage, or in women of childbearing potential who are not using effective contraception (see section "Use during pregnancy or breastfeeding").

Use during pregnancy or breastfeeding.

Animal studies have not provided conclusive evidence, and clinical data are insufficient. Therefore, disulfiram is not recommended during pregnancy, regardless of gestational stage, or in women of childbearing potential who do not use contraception.

The development of a disulfiram reaction upon concomitant use of the drug and alcohol may have serious consequences for the fetus.

Disulfiram is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Patients should refrain from driving or operating machinery, as visual disturbances, confusion, and somnolence may occur during treatment.

Dosage and Administration

Treatment should be initiated only after at least 24 hours of alcohol abstinence, under the supervision of physicians experienced in its use, and preferably in a specialized medical facility.

The drug is intended for oral administration. The recommended dose for adults is 150–450 mg once daily in the morning with breakfast, for 7–10 days.

After 7–10 days of treatment, the first disulfiram-ethanol test should be performed: following morning administration of the drug at a dose of 450–750 mg, the patient should ingest 20–30 mL of 40% ethyl alcohol solution (e.g., vodka or another suitable alcoholic beverage). If the reaction is mild, the alcohol dose may be increased by 10–20 mL in subsequent tests, up to a maximum of 100–120 mL. Repeat tests should be conducted in a hospital setting every 1–2 days, or on an outpatient basis every 3–5 days.

The total duration of treatment is determined individually by the physician.

Children

There is no experience with the use of this drug in the treatment of children.

Overdose

Symptoms: Disulfiram overdose may lead to serious neurological complications, including encephalopathy, disturbances of consciousness such as confusion, coma, convulsions, and extrapyramidal symptoms.

Disulfiram overdose in combination with alcohol may result in coma or delirium, cardiovascular failure, and sometimes neurological complications.

Treatment: Symptomatic.

Side effects.

Side effects associated with disulfiram.

Nervous system and psychiatric disorders: peripheral neuropathies, neuritis including optic neuritis, polyneuritis, usually of the lower limbs; psychoneurological disorders (including impaired/loss of memory, confusion, disorientation, paranoia), asthenia; headache, drowsiness, feeling of increased fatigue (usually at the beginning of treatment). Encephalopathy, seizures/epileptiform attacks, and catatonia may occasionally develop, usually reversible upon discontinuation of treatment.

Psychoneurological reactions usually occurred with high doses (more than 500 mg/day), concomitant use with metronidazole or isoniazid (potentiation of toxicity), or in patients with alcohol withdrawal syndrome.

Gastrointestinal tract: metallic or garlic-like taste in the mouth, unpleasant breath odor (halitosis), unpleasant odor in patients with colostomy, loss of appetite, gastralgia, nausea, vomiting, diarrhea. These reactions usually occur within the first two weeks and resolve spontaneously with continued therapy or upon dose reduction.

Hepatobiliary system: elevated levels of transaminases and bilirubin; cases of jaundice and hepatitis (predominantly cytolytic) have been reported, sometimes accompanied by eosinophilia and skin rash; severe cases were associated with fulminant hepatitis, liver necrosis, and hepatic failure, sometimes requiring liver transplantation or leading to fatal outcomes. Some cases of hepatitis occurred in patients with nickel eczema. Disulfiram should be discontinued immediately if liver function deteriorates (see section "Special precautions").

Skin and subcutaneous tissues: allergic dermatitis, pruritus, skin rashes, including acneiform and maculopapular eruptions. Cross-sensitivity to disulfiram may occur in patients sensitized to tetramethylthiuram disulfide present in rubber products. Cases of erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported.

Reproductive system: decreased libido, potency, erectile dysfunction.

Immune system: hypersensitivity reactions.

Side effects associated with the combination of disulfiram and alcohol (disulfiram-alcohol reactions).

These may occur up to two weeks after discontinuation of disulfiram and are characterized by:

• intense vasodilation of the face and neck, causing facial flushing, hot flashes, pulsating sensation in the head and neck; hyperthermia, sweating, nausea, vomiting, thirst, skin itching, urticaria, anxiety, malaise, dizziness, headache, blurred vision, dyspnea, palpitations, tachycardia, arterial hypotension, hyperventilation;
• in more severe cases – respiratory depression, chest pain, QT interval prolongation, ST segment depression, arrhythmias, angina attacks, syncope, cyanosis of lips and nails, myocardial infarction, cardiovascular insufficiency, cardiovascular collapse, neurological complications (confusion, loss of consciousness, cerebral edema, hemorrhage into meninges, hemorrhagic stroke, encephalopathy, seizures/epileptiform attacks), coma, sudden death. Rare complications include arterial hypertension, bronchospasm, and methemoglobinemia.

Shelf life. 4 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets per blister pack, 1 or 5 blister packs per carton.

Prescription status. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant".

Manufacturer's name and address of the place of business.

17 Myru Street, Kyiv, 03134, Ukraine.