Isozid Comp. (Tablets) Instructions for Use

Marketing Authorization Holder

Fatol Arzneimittel, GmbH (Germany)

Promotion

SVICH, LLC (Russia)

ATC Code

J04AC51 (Isoniazid in combination with other drugs)

Active Substances

Pyridoxine (Rec.INN registered by WHO)

Isoniazid (Rec.INN registered by WHO)

Dosage Form

Isozid Comp.

Film-coated tablets, 300 mg+60 mg: 100 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, round, biconvex, with a score on one side and a stamp “300” on the other.

Excipients: microcrystalline cellulose – 30 mg, macrogol 6000 – 6 mg, copovidone – 12 mg, crospovidone – 6 mg, talc – 4 mg, calcium hydrogen phosphate – 2 mg.

Shell composition hypromellose (hydroxypropyl methylcellulose) – 3.4 mg, titanium dioxide (E171) – 1.8 mg, macrogol 6000 – 1.8 mg.

100 pcs. – polypropylene containers (1) – cardboard packs.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Combined antitubercular agent

Pharmacological Action

[I] – Instructions for medical use approved by the Pharmacological Committee of the Ministry of Health of the Russian Federation

Isoniazid acts bactericidally, inhibits the synthesis of mycolic acids, which are the most important component of the mycobacterial cell wall. It is especially active against rapidly multiplying microorganisms (including those located intracellularly).

Pyridoxine plays an important role in metabolism; it is necessary for the normal functioning of the central and peripheral nervous systems. In its phosphorylated form, Pyridoxine is a coenzyme for a large number of enzymes acting on the non-oxidative metabolism of amino acids. It plays an important role in histamine metabolism. It helps to normalize lipid metabolism.

Pharmacokinetics

Isoniazid is rapidly and completely absorbed when taken orally; food reduces absorption and bioavailability. However, 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 into all tissues and fluids, including cerebrospinal, pleural, and ascitic fluids; high concentrations are created in lung tissue, kidneys, liver, muscles, saliva, and sputum. It 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 by forming an active intermediate metabolite during N-hydroxylation by the cytochrome P450 mixed oxidase system. The rate of acetylation is genetically determined; people with slow acetylation have little N-acetyltransferase. It is an inhibitor of the CYP2C9 and CYP3A2E1 enzyme systems in the liver. T_1/2 for “fast acetylators” — 0.5 -1.6 h; for slow ones — 2-5 h. In renal failure, T_1/2 can increase to 6.7 h. 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 “fast acetylators” the content of N-acetylisoniazid is 93%, while in “slow” ones it is 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.

Indications

• Tuberculosis of any location in adults and children: treatment and prevention, including as part of combination therapy.

ICD codes

Dosage Regimen

Orally. Isozid Comp. should be taken on an empty stomach, without chewing and with a small amount of water.

The daily dose for adults is 5 mg (3-8 mg) of isoniazid per kilogram of the patient’s body weight daily. On average, this corresponds to a daily dose of 300 mg. For intermittent, periodic treatment, the dose is 15 mg/kg of body weight per week.

For children, Isoniazid is prescribed at a rate of 20 mg/m² of body surface area, or approximately 10 mg/kg of body weight.

Adverse Reactions

Associated with isoniazid

From the digestive system nausea, vomiting, constipation, transient increase in the activity of “liver” transaminases in blood plasma during the first month of treatment, gastralgia, toxic hepatitis. Rarely – persistent increase in enzyme activity.

From the CNS headache, dizziness, rarely – unusual fatigue or weakness, irritability, euphoria, mood changes, depression. In patients with epilepsy, seizures may become more frequent. When using high doses of isoniazid – peripheral neuropathy, manifested by paresthesia of the skin of the hands and feet; hyperreflexia, tremor, convulsions, toxic encephalopathy, psychosis, insomnia; neuritis and optic nerve atrophy.

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

From the hematopoietic system hemolytic, sideroblastic and aplastic anemia; thrombocytopenia, eosinophilia.

From the homeostasis system acidosis.

Allergic reactions “lupus-like” syndrome, skin rash, purpura, lymphadenopathy, vasculitis, itching, hyperthermia, arthralgia.

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

Associated with pyridoxine

With irregular use or when resuming treatment after a break, flu-like syndrome (fever, chills, headache, dizziness, myalgia), skin reactions, hemolytic anemia, thrombocytopenic purpura, acute renal failure are possible.

Contraindications

• Hypersensitivity;
• Epilepsy;
• Epileptic syndrome;
• Poliomyelitis (including in history);
• Bronchial asthma;
• Psoriasis;
• Chronic renal failure;
• Macrohematuria;
• Hepatitis;
• Liver cirrhosis;
• Phlebitis.

With caution severe form of heart failure, arterial hypertension, coronary artery disease, widespread atherosclerosis, diseases of the nervous system, hypothyroidism, pregnancy (do not prescribe in a dose above 10 mg/kg).

Simultaneous consumption of alcohol contributes to increased hepatotoxic reactions.

Use in Pregnancy and Lactation

Use with caution during pregnancy (do not prescribe in a dose above 10 mg/kg).

Use in Hepatic Impairment

Contraindicated: chronic renal failure.

Use in Renal Impairment

Contraindicated: liver cirrhosis, hepatitis.

Pediatric Use

Dosage for children

Isoniazid is taken at a rate of 20 mg per m² of body surface area, or approximately 10 mg per kg of body weight.

Special Precautions

To slow the development of microbial resistance, it is prescribed in combination with other anti-tuberculosis drugs.

Due to different rates of metabolism, before using isoniazid, it is advisable to determine the rate of its inactivation by the content of the active substance in the blood and urine.

In case of rapid inactivation, Isoniazid is used in higher doses.

During treatment, consumption of cheese (especially Swiss or Cheshire) and fish (especially tuna, sardine, skipjack) should be avoided, since when consumed simultaneously with isoniazid, reactions such as skin hyperemia, itching, sensation of heat or cold, palpitations, increased sweating, chills, headache, dizziness may occur, associated with suppression of MAO and diamine oxidase activity and leading to impaired metabolism of tyramine and histamine contained in fish and cheese.

It should be borne in mind that Isoniazid can cause hyperglycemia with secondary glucosuria; tests with Cu²⁺ reduction may be false positive, but the drug does not affect enzymatic glucose tests.

Laboratory parameters — ALT, AST, serum bilirubin concentration may transiently increase without clinical manifestations.

If signs of toxic hepatitis appear, the drug should be discontinued.

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.

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

It reduces metabolic transformations and increases the concentration of alfentanil in the blood.

Cycloserine and disulfiram enhance the adverse central effects of isoniazid.

It increases the hepatotoxicity of rifampicin.

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.

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

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

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

Pyridoxine. It enhances the effect of diuretics; weakens the activity of levodopa. Isonicotinic acid hydrazide, penicillamine, cycloserine and estrogen-containing oral contraceptives weaken the effect of pyridoxine.

Storage Conditions

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

Shelf Life

Shelf life — 4 years. Do not use after the expiration date indicated on the packaging.

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.