Protubetham^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J04AM03 (Ethambutol and Isoniazid)

Active Substances

Ethambutol (Rec.INN registered by WHO)

Isoniazid (Rec.INN registered by WHO)

Dosage Forms

	Protubetham®	Tablets 150 mg+400 mg: 100, 500 or 1000 pcs.
		Tablets 300 mg+800 mg: 100, 500 or 1000 pcs.

Dosage Form, Packaging, and Composition

500 pcs. – polymer jars.
500 pcs. – polypropylene jars.
100 pcs. – polypropylene jars.
1000 pcs. – polypropylene jars.

500 pcs. – polymer jars.
500 pcs. – polypropylene jars.
100 pcs. – polypropylene jars.
1000 pcs. – polypropylene jars.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Combined antitubercular agent

Pharmacological Action

Protubetham^® contains a combination of two antituberculosis drugs.

Isoniazid has a bactericidal effect on actively dividing cells of Mycobacterium tuberculosis. Its mechanism of action involves the inhibition of the synthesis of mycolic acids, which are a component of the mycobacterial cell wall. For Mycobacterium tuberculosis, the minimum inhibitory concentration of the drug is 0.025-0.05 mg/L. Isoniazid has a moderate effect on slowly and rapidly growing atypical mycobacteria.

Ethambutol. A bacteriostatic drug effective against typical and atypical Mycobacterium tuberculosis. The mechanism of action of the drug is associated with disruption of RNA synthesis in bacterial cells; it inhibits the synthesis of the cell wall by blocking the incorporation of mycolic acids into it. Ethambutol is active against rapidly and slowly growing atypical mycobacteria. The minimum inhibitory concentration of ethambutol is 0.78-2.0 mg/L. Ethambutol does not act on non-tuberculous pathogenic microorganisms.

Pharmacokinetics

Isoniazid

Isoniazid is rapidly and completely absorbed after oral administration; food reduces absorption and bioavailability. The bioavailability indicator is greatly influenced by the “first-pass” effect through the liver. T_max – 1-2 h, C_max after a single oral dose of 300 mg – 3-7 µg/ml. Protein binding is insignificant – up to 10%. Volume of distribution – 0.57-0.76 L/kg. It is well distributed throughout the body, penetrating all tissues and fluids, including cerebrospinal, pleural, and ascitic; high concentrations are created in lung tissue, kidneys, liver, muscles, saliva, and sputum. Penetrates the placental barrier and into breast milk.

It is metabolized in the liver by acetylation to form inactive products. In the liver, it is acetylated by N-acetyltransferase to form N-acetylisoniazid, which is then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect through the formation of an active intermediate metabolite during N-hydroxylation by the cytochrome P450 mixed oxidase system. The rate of acetylation is genetically determined; in people with “slow” acetylation, there is little N-acetyltransferase. It is an inhibitor of CYP2C9 and CYP2E1 isoenzymes in the liver. T_1/2 for “rapid acetylators” – 0.5-1.6 h; for “slow” ones – 2-5 h. In renal failure, T_1/2 can increase to 6.7 h. T_1/2 for children aged 1.5 to 15 years – 2.3-4.9 h, and in newborns – 7.8-19.8 h (which is explained by the imperfection of acetylation processes in newborns). Although the T_1/2 indicator varies significantly depending on the individual intensity of acetylation processes, the average T_1/2 is 3 h (oral administration of 600 mg) and 5.1 h (900 mg). With repeated administration, T_1/2 shortens to 2-3 h.

It is excreted mainly by the kidneys: 75-95% of the drug is excreted within 24 hours, mainly in the form of inactive metabolites – N-acetylisoniazid and isonicotinic acid. In this case, in “rapid acetylators” the content of N-acetylisoniazid is 93%, and in “slow” ones – no more than 63%. Small amounts are excreted in feces. The drug is removed from the blood during hemodialysis; 5 hours of hemodialysis can remove up to 73% of the drug from the blood.

Ethambutol

Absorption – high; bioavailability – 75-80%. After oral administration of a dose of 25 mg, the time to reach maximum concentration in the blood T_max – 2-4 h, maximum concentration in the blood C_max – 1-5 µg/ml. Plasma protein binding – 20-30%.

Penetrates well into tissues and organs, as well as into biological fluids, with the exception of ascitic and pleural fluids (in the cerebrospinal fluid only with meningitis). The highest concentrations are created in the kidneys, lungs, saliva, and urine. Penetrates into breast milk. Does not cross the intact blood-brain barrier.

Partially metabolized in the liver (15%) to form inactive metabolites. T_1/2 – 3-4 h, in case of renal dysfunction – 8 h. Excreted by the kidneys – 80-90% (50% – unchanged, 15% – in the form of inactive metabolites) through the gastrointestinal tract – 10-20% (unchanged). Removed by hemodialysis and peritoneal dialysis.

Indications

• Treatment of all forms and localizations of tuberculosis caused by mycobacteria sensitive to isoniazid and ethambutol;
• Can be used for chemoprophylaxis of tuberculosis and for anti-relapse therapy.

ICD codes

Dosage Regimen

The drug Protubetham^® is taken orally, 1-3 tablets once a day, after meals (based on 5-15 mg/kg/day of isoniazid; maximum dose – 900 mg/day). The drug is used daily during the intensive therapy period (3-4 months), and subsequently – every other day. The total course dose of the drug Protubetham^® is individual for each person and depends on the nature of the disease, the effectiveness of treatment and tolerability.

Adverse Reactions

Isoniazid

From the central nervous system: headache, dizziness, rarely – unusual fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of the extremities, peripheral neuropathy, optic neuritis, polyneuritis, psychoses, mood changes, depression. In patients with epilepsy, seizures may become more frequent.

From the cardiovascular system: palpitations, angina pectoris, increased blood pressure.

From the digestive system: nausea, vomiting, gastralgia, toxic hepatitis.

Allergic reactions: skin rash, itching, hyperthermia, arthralgia.

Other: very rarely – gynecomastia, menorrhagia, tendency to bleeding and hemorrhages.

Ethambutol

From the nervous system and sensory organs: weakness, headache, dizziness, impaired consciousness, disorientation, hallucinations, depression, peripheral neuritis (paresthesia in the extremities, numbness, paresis, itching), optic neuritis (decreased visual acuity, impaired color perception, mainly green and red colors, color blindness, scotoma).

From the digestive system: decreased appetite, nausea, vomiting, gastralgia, impaired liver function – increased activity of “hepatic” transaminases (ALT, AST, alkaline phosphatase).

Allergic reactions: dermatitis, skin rash, itching, arthralgia, fever, anaphylaxis.

Other: hyperuricemia, exacerbation of gout.

Contraindications

• Epilepsy and other diseases accompanied by a tendency to convulsions;
• Stage II-III arterial hypertension;
• Coronary heart disease;
• Liver cirrhosis;
• Acute hepatitis;
• Myxedema;
• Optic neuritis;
• Cataract;
• Diabetic retinopathy;
• Childhood (under 13 years);
• Pregnancy;
• Lactation period;
• Hypersensitivity to isoniazid and ethambutol.

Use with caution in persons with chronic renal failure.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

Contraindicated in liver cirrhosis, acute hepatitis.

Use in Renal Impairment

Use with caution in persons with chronic renal failure.

Pediatric Use

Contraindicated in children under 13 years of age.

Special Precautions

During treatment, it is necessary to refrain from taking ethanol. Protubetham^® may have a hepatotoxic effect, so use with caution in patients with impaired liver function, in persons suffering from chronic alcoholism.

For the prevention and treatment of peripheral neuropathy, additional administration of pyridoxine (vitamin B₆) is recommended. In some cases, especially in patients with a history of gout attacks, it is recommended to periodically monitor the level of uric acid in the blood serum. It is necessary to check the visual acuity of each eye separately and both eyes together. Visual acuity is checked before starting treatment and periodically during treatment. If any change in visual acuity occurs, patients should immediately consult a doctor. If a decrease in visual acuity is detected, the drug is discontinued. Vision usually normalizes after timely discontinuation.

Effect on the ability to drive vehicles and mechanisms

When taken in high doses, adverse reactions from the nervous system may develop, for example, peripheral neuropathy, which affects the ability to drive a car and work with complex equipment.

Overdose

Isoniazid

Symptoms: dizziness, dysarthria, lethargy, disorientation, hyperreflexia, peripheral polyneuropathy, impaired liver function, metabolic acidosis, hyperglycemia, glucosuria, ketonuria, convulsions (1-3 hours after drug use), coma.

Treatment: peripheral polyneuropathy (vitamins: pyridoxine, thiamine, glutamic acid, nicotinamide; massage, physiotherapeutic procedures); convulsions (IM pyridoxine hydrochloride – 200-250 mg, IM 25% magnesium sulfate solution – 10 ml, diazepam); impaired liver function (methionine, thioctic acid, cyanocobalamin).

Ethambutol

Symptoms: nausea, vomiting, hallucinations, polyneuritis.

Treatment: symptomatic.

Drug Interactions

Isoniazid

When combined with paracetamol, hepatotoxicity and nephrotoxicity increase; Isoniazid induces the cytochrome P450 system, resulting in increased metabolism of paracetamol to toxic products.

Ethanol increases the hepatotoxicity of isoniazid and accelerates its metabolism.

Reduces the metabolism of theophylline, which can lead to an increase in its concentration in the blood.

Cycloserine and disulfiram enhance the adverse central effects of isoniazid.

Combination with pyridoxine reduces the risk of developing peripheral neuritis.

It should be combined with caution with potentially neuro-, hepato- and nephrotoxic drugs due to the risk of increased side effects.

Enhances the effect of coumarin and indandione derivatives, benzodiazepines, carbamazepine, as it reduces their metabolism by activating the cytochrome P450 system.

Glucocorticosteroids accelerate metabolism in the liver and reduce active concentrations in the blood.

Suppresses the metabolism of phenytoin, leading to an increase in its concentration in the blood and an increase in the toxic effect (correction of the phenytoin dosage regimen may be required, especially in patients with slow acetylation of isoniazid).

Ethambutol

Aluminum hydroxide reduces the absorption of ethambutol.

Taking ethambutol with aminoglycosides, ciprofloxacin, imipenem, carbamazepine, lithium salts, and quinine increases the risk of neurotoxic effects of the drug.

Ethambutol enhances the antimicrobial activity of other antituberculosis drugs.

Storage Conditions

List B. In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

Shelf life – 2 years.

Dispensing Status

For hospitals.

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.