Expiration date: 03/2026

Dosage form

film-coated tablets, dark brown in color, oval in shape, biconvex. The tablet is reddish-brown in color with white inclusions on the cross section.

Composition

1 tablet contains:

Active ingredients: isoniazid - 60 mg, pyrazinamide - 300 mg, rifampicin - 120 mg, ethambutol hydrochloride - 225 mg, pyridoxine hydrochloride - 20 mg;

excipients: corn starch, microcrystalline cellulose, sodium croscarmellose, colloidal silicon dioxide, starch sodium glycolate, talc, magnesium stearate, brown powder 04B56936.

Pharmacotherapeutic group

antituberculous agent combined

Pharmacodynamics

Isocomb® is a five-component preparation containing a fixed amount of isoniazid, rifampicin, pyrazinamide, ethambutol and pyridoxine hydrochloride.

Isoniazid

Isoniazid is an anti-tuberculosis agent; it acts bacteriostatically. It is a prodrug - mycobacterial catalase peroxidase metabolizes isoniazid to an active metabolite, which, by binding to enoyl-(acyl-transferring protein)-reductase of fatty acid synthase II, disrupts the conversion of delta2-unsaturated fatty acids into mycolic acid. The latter is a branched chain fatty acid, which, combining with arabinogalactan (polysaccharide), participates in the formation of components of the Mycobacterium tuberculosis cell wall. Isoniazid is also an inhibitor of mycobacterial catalase peroxidase, which reduces the protection of the microorganism against reactive oxygen species and hydrogen peroxide. Isoniazid is also active against a small number of Mycobacterium kansasii strains.

Pyrazinamide

Pyrazinamide is an anti-tuberculosis drug. It acts on intracellularly located Mycobacterium tuberculosis. Depending on the concentration and sensitivity, it may have a bacteriostatic or bactericidal effect. In terms of tuberculostatic activity, it is more active than aminosalicylic acid, although it is inferior to isoniazid, streptomycin, rifampicin. It acts on Mycobacterium tuberculosis, resistant to other anti-tuberculosis drugs of the II series. Pyrazinamide penetrates well into the foci of tuberculous lesions. Its antibacterial activity does not decrease in the acidic environment of caseous masses, and therefore it is often prescribed for caseous lymphadenitis, tuberculosis and caseous-pneumonic processes. During treatment, resistance may develop, the likelihood of which is reduced by combination with other anti-tuberculosis drugs.

Rifampicin

A semi-synthetic broad-spectrum antibiotic, an antituberculous agent of the I series. In low concentrations, it has a bactericidal effect on Mycobacterium tuberculosis and Mycobacterium leprae. It is active against intracellularly and extracellularly located microorganisms. Suppresses DNA-dependent RNA polymerase of microorganisms. With rifampicin monotherapy, the selection of rifampicin-resistant bacteria is relatively rapid. Cross-resistance with other antibiotics (with the exception of other rifamycins) does not develop.

Ethambutol

Ethambutol is a chemotherapeutic agent with bacteriostatic action against Mycobacterium tuberculosis. The mechanism of action of the drug is associated with a violation of RNA synthesis in bacterial cells. It affects intracellular and extracellular bacterial species. About 1% of patients have primary resistance to ethambutol.

Pyridoxine

Pyridoxine acts as a coenzyme, participating in biochemical reactions, including the metabolism of amino acids and glycogen, in the synthesis of nucleic acids, hemoglobin, sphingomyelin and other sphingolipids, in the synthesis of the mediator serotonin, dopamine, norephedrine and gamma-aminobutyric acid. Pyridoxine has an anti-neurotoxic effect. The use of pyridoxine reduces side effects from the central nervous system (CNS).

Pharmacokinetics

Isoniazid

Isoniazid is rapidly absorbed after oral administration, however, when taking the drug with food, its absorption and bioavailability decrease. After a single oral administration of 300 mg of isoniazid, maximum plasma concentrations are observed after 1-2 hours. The maximum concentration after ingestion of a single dose is 300 mg -

3-7 mcg/ml.

The bond with plasma proteins is up to 10%. Isoniazid penetrates well into various tissues and body fluids, including bones and cerebrospinal fluid. Isoniazid is acetylated and hydrolyzed in the liver. Acetylation is the main pathway of isoniazide metabolism. The rate of acetylation depends on the individual characteristics of the patient. People with "slow" acetylation have little N-acetyltransferase. The half-life (T1/2) is 0.5-1.6 hours ("fast acetylators") or 2-5 hours ("slow acetylators"). Limited evidence suggests that the pharmacokinetics of iso-niazide may vary in patients with hepatic insufficiency. In case of impaired liver function, T1/2 of isoniazid is prolonged. Isoniazid metabolites do not have antimicrobial activity.

Within 24 hours, 75-95% of the administered dose is excreted in the urine in the form of metabolites (N-acetylisoniazid, etc.). Part of isoniazid is excreted unchanged by the kidneys: up to 12% with rapid acetylation and up to 27% with slow acetylation. Isoniazid is removed from the blood during hemodialysis; 5-hour hemodialysis allows up to 73% of isoniazid to be removed from the blood. With severe renal insufficiency, accumulation of the drug is possible in patients with slow acetylation.

Pyrazinamide

Pyrazinamide is well absorbed from the gastrointestinal tract (GI tract). After oral administration of a dose of 500 mg, the maximum concentration of pyrazinamide in blood plasma is 9-12 mcg/ml and is reached within 2 hours, after 8 hours and 24 hours, the concentration is 7 mcg/ml and 2 mcg/ml, respectively. Pyrazinamide penetrates into tissues and body fluids, including liver, lungs, kidneys, cerebrospinal fluid. The bond with plasma proteins is 10-20%. It is metabolized in the liver to form an active metabolite - pyrazinoic acid, which later turns into an inactive metabolite - 5-hydroxypyrazinoic acid. The half-life (T1/2) of pyrazinamide is 9-10 hours in patients whose liver and kidney function are not impaired. It is excreted mainly by the kidneys (3% - unchanged, 33% - in the form of pyrazinoic acid and 36% - in the form of other metabolites). Within 24 hours, about 70% of the oral dose is excreted by the kidneys. It is excreted during hemodialysis.

Rifampicin

Absorption is fast, food intake reduces the absorption of the drug. When ingested on an empty stomach, 600 mg, the maximum concentration (Cmax) is 10 mcg / ml, the time to reach the maximum concentration (TCmax) is 2-3 hours. The bond with plasma proteins is 84-91%. It is rapidly distributed to organs and tissues (the highest concentration is in the liver and kidneys), penetrates into bone tissue, the concentration in saliva is 20% of plasma. The apparent volume of distribution is 1.6 l/kg in adults and 1.1 l/kg in children. It penetrates through the blood-brain barrier (BBB) only in case of inflammation of the meninges. It penetrates through the placenta (the concentration in fetal plasma is 33% of the concentration in maternal plasma) and is excreted in breast milk (breastfed children receive no more than 1% of the therapeutic dose of the drug). It is metabolized in the liver to form a pharmacologically active metabolite - 25-O-deacetylrifampicin. It is an auto-inducer - accelerates its metabolism in the liver, as a result of which the systemic clearance is 6 l / h after the first dose, increases to 9 l / h after repeated administration. When ingested, induction of intestinal wall enzymes is also likely. The half-life (T1 / 2) after oral administration of 300 g is 2.5 hours, 600 mg is 3-4 hours, 900 mg is 5 hours. After a few days of repeated administration, bioavailability decreases, and T1 / 2 after repeated administration of 600 mg is shortened to 1-2 hours. It is excreted mainly with bile, 80% - as a metabolite; kidneys - 20%. After taking 150-900 mg of the drug, the amount of rifampicin excreted unchanged by the kidneys depends on the amount of the dose taken and is 4-20%. In patients with impaired renal excretory function, T1/2 is prolonged only in cases when its doses exceed 600 mg. It is excreted during peritoneal dialysis and hemodialysis. In patients with impaired liver function, there is an increase in the concentration of rifampicin in plasma and an elongation of T1/2.

Ethambutol

Absorption is high; bioavailability is 75-80%. After oral administration at a dose of 25 mg / kg, the maximum plasma concentration is reached in 2-4 hours and is 1-5 mcg / ml, after 24 hours the concentration is less than 1 mcg / ml.

It binds to plasma proteins by 20-30%.

It penetrates well into tissues and organs, as well as into biological fluids, with the exception of ascitic and pleural (into cerebrospinal fluid − only in meningitis). The highest concentrations are created in the kidneys, lungs, saliva, and urine. Penetrates into breast milk. It does not pass through the intact blood-brain barrier. Ethambutol penetrates through the placenta. In the fetal blood, the concentration of ethambutol is approximately 30% of the concentration in the mother's blood.

Ethambutol is partially metabolized in the liver to dicarboxylic acid derivatives (inactive metabolites). The half-life is 3-4 hours, and in case of renal insufficiency it is prolonged to 8 hours. It is excreted by the kidneys - 80-90% (50% − unchanged, 15% − as inactive metabolites) and by the intestine - 10-20% (unchanged). It is excreted during hemodialysis and peritoneal dialysis.

Pyridoxine

It is absorbed rapidly throughout the small intestine, a larger amount is absorbed in the jejunum. It is metabolized in the liver to form pharmacologically active metabolites (pyridoxal-5-phosphate and pyridoxaminophosphate). Pyridoxal-5-phosphate binds to plasma proteins by 90%. It penetrates well into all tissues; accumulates mainly in the liver, less in the muscles and central nervous system. It penetrates through the placenta and is secreted with breast milk. The plasma half-life is 15-20 days. It is excreted by the kidneys, as well as during hemodialysis.

Indications

Treatment of all forms of tuberculosis caused by isoniazid, ethambutol, pyrazinamide, rifampicin-sensitive M.tuberculosis as part of combination therapy.

It is necessary to take into account the current official guidelines on the rules for the use of antibacterial drugs.

Contraindications

• hypersensitivity to isoniazid, pyrazinamide, rifampicin, ethambutol, pyridoxine or any other component of the drug;
• pregnancy and breastfeeding;
• children under the age of 13;
• diseases of the visual organs (diabetic retinopathy, optic neuritis, inflammatory eye diseases, cataracts);
• epilepsy, epileptic syndrome;
• pulmonary heart failure of II-III degree;
• severe liver failure;
• liver diseases in the acute stage;
• cirrhosis of the liver;
• recently transmitted (less than 1 year) infectious hepatitis;
• medicinal hepatitis and / or other severe adverse reactions that have developed against the background of previous treatment with isoniazid;
• bronchial asthma;
• psoriasis;
• gout;
• hyperuricemia;
• thrombophlebitis;
• uncontrolled arterial hypertension;
• severe coronary insufficiency;
• mixedema;
• peptic ulcer of the stomach and duodenum;
• chronic renal failure;
• concomitant administration with ritonavir, saquinavir, atazanavir, darunavir, fosamprenavir, tipranavir, amprenavir, indinavir, lopinavir, nelfinavir is contraindicated.

With caution

Alcoholism, liver failure of mild and moderate severity, liver dysfunction in the anamnesis or chronic liver dysfunction, age over 35 years, old age, prolonged use of other potentially hepatotoxic drugs, withdrawal of therapy with isoniazid in the anamnesis, peripheral neuropathy, HIV infection, decompensated diseases of the cardiovascular system (chronic heart failure, angina pectoris, hypertension), hypothyroidism, diabetes mellitus, exhaustion, porphyria, a history of mental illness, "slow acetylators", female gender.

Use during pregnancy and breastfeeding

The use of the drug is contraindicated during pregnancy and during breastfeeding.

Women of reproductive age should use reliable methods of contraception during treatment (oral hormonal contraceptives and additional non-hormonal methods of contraception).

Method of administration and dosage

Inside. Adults and children from the age of 13. The drug is dosed with rifampicin 10 mg / kg of body weight, but no more than 5 tablets.

The drug is taken on an empty stomach 1 time a day 30-40 minutes before breakfast. The total duration of treatment is from 2 to 4 months, depending on the nature of the tuberculosis process. If the body weight is > 80 kg, isoniazid is additionally prescribed in the evening (the total daily dose of isoniazid is 10 mg / kg). According to indications, Isocomb® is combined with streptomycin (intramuscularly at a dose of 15 mg / kg 1 time per day).

The calculation of the dose of other components of combined drug therapy for tuberculosis (isoniazid, pyrazinamide, ethambutol) should be carried out by the attending physician, taking into account the intake of the drug Isocomb® individually for each patient on the basis of current guidelines for the treatment of tuberculosis. If necessary, other components of combined drug therapy for tuberculosis can be prescribed in the form of mono-drugs in addition to the drug Isocomb®.

Patients with renal insufficiency

The drug is contraindicated in patients with renal insufficiency.

Patients with liver failure

Isocomb® has a hepatotoxic effect, therefore, in patients with moderate and mild liver dysfunction, it is prescribed with strict monitoring of "liver" enzymes and the use of hepatoprotectors (also see the section "Special instructions"). The use of Isocomb® is contraindicated in patients with severe hepatic insufficiency.

Side effects

Isoniazid

Isoniazid-related adverse events mainly depend on age and dose and are more pronounced in "slow acetylators".

The following adverse events noted with the use of isoniazid are distributed by frequency according to the following gradation: very common (≥ 1/10), common (≥ 1/100 to 1/10), infrequent (≥ 1/1000 to 1/100), rare (≥ 1/10000 to 1/1000), very rare (1/10000), frequency unknown (it is impossible to estimate based on the available data).

Disorders of the blood and lymphatic system: the frequency is unknown − eosinophilia, bone marrow depression, granulocytopenia, thrombocytopenia, agranulocytosis, sideroblastic anemia, hemolytic or megaloblastic anemia, pyridoxine deficiency anemia, coagulopathy, aplastic anemia.

Disorders of the immune system: the frequency is unknown - exanthema (including acne, especially in young patients), exfoliative dermatitis, Stevens-Johnson syndrome, photosensitization, fever, asthma, myalgia and arthralgia, anaphylactic reactions, anaphylactic shock, systemic lupus erythematosus, lupus-like syndrome, lymphadenopathy.

Endocrine disorders: the frequency is unknown - mainly reversible hyperfunction of the adrenal cortex (Itsenko-Cushing syndrome) and the anterior pituitary gland (with menstrual disorders in women or gonadotropic disorders/gynecomastia in men).

Metabolic and nutritional disorders: very rarely - hypoglycemia; frequency unknown - hyperglycemia, metabolic acidosis, pellagra (nicotine deficiency

acids). Nicotinic acid deficiency may be associated with pyridoxine deficiency caused by isoniazid, which affects the conversion of tryptophan into nicotinic acid

Mental disorders: the frequency is unknown - mental disorders (irritability, anxiety), decreased concentration, depression, psychoses (manifest, catotonic or paranoid), euphoria.

Disorders of the nervous system: often - peripheral polyneuropathy with paresthesia, sensory disturbances, headache, dizziness; frequency unknown - convulsions, drowsiness, lethargy. Hyperreflexia occurs more often at doses of 10 mg/ kg of body weight.

Visual organ disorders: rarely - optic nerve atrophy; frequency unknown - optic neuritis, diplopia, strabismus.

Hearing disorders and labyrinthine disorders: the frequency is unknown - deafness, tinnitus, vertigo. These effects have been reported in patients with end-stage renal failure. Vertigo occurs more often at doses of 10 mg/ kg of body weight.

Cardiac disorders: the frequency is unknown arrhythmia, increase or decrease in blood pressure.

Disorders of the respiratory system, chest and mediastinal organs: the frequency is unknown - acute respiratory distress syndrome, interstitial lung disease.

Disorders of the gastrointestinal tract: often - gastrointestinal disorders (diarrhea, constipation, regurgitation, bloating, vomiting); frequency unknown - pancreatitis (see section "Special instructions"), dry mouth.

Disorders of the liver and biliary tract: very often - increased activity of "hepatic" transaminases; infrequently - hepatitis; frequency unknown - acute liver failure, liver damage, jaundice, acute hepatitis (including fatal).

Disorders of musculoskeletal and connective tissue: often - muscle tremor; frequency unknown - rheumatic syndrome, rhabdomyolysis.

Disorders of the kidneys and urinary tract: the frequency is unknown - glomerulonephritis (mostly reversible), dysuria.

Disorders of the skin and subcutaneous tissues: rarely - toxic epidermal necrolysis, drug rash with eosinophilia and systemic manifestations (DRESS syndrome).

Vascular disorders: the frequency is unknown - vasculitis.

Pyrazinamide

Disorders of the central nervous system: dizziness, headache, sleep disorders, weakness, increased excitability, depression, in some cases hallucinations, convulsions, confusion.

Disorders of the gastrointestinal tract: nausea, vomiting, diarrhea, a "metallic" taste in the mouth, epigastric pain, exacerbation of peptic ulcer.

Disorders of the liver and biliary tract: impaired liver function (lack of appetite, soreness in the right hypochondrium, hepatomegaly, jaundice, yellow liver atrophy).

Disorders of the blood and lymphatic system: thrombocytopenia, sideroblastic anemia, vacuolation of erythrocytes, porphyria, hypercoagulation, splenomegaly.

Disorders of the musculoskeletal system: arthralgia, myalgia.

Disorders of the immune system: skin rash, urticaria.

Metabolic and nutritional disorders: hyperuricemia, exacerbation of gout. Disorders of the kidneys and urinary tract: dysuria, interstitial nephritis.

Common disorders and disorders at the injection site: hyperthermia, acne, photosensitization, fever.

Effect on the results of laboratory and instrumental studies: increased serum iron concentration, hypoglycemia (in patients with diabetes mellitus).

Rifampicin

Infectious and parasitic diseases: pseudomembranous colitis.

Disorders of the blood and lymphatic system: thrombocytopenic purpura (with intermittent therapy), thrombocytopenia and leukopenia, eosinophilia, agranulocytosis, acute hemolytic anemia, disseminated intravascular coagulation syndrome, porphyria induction.

Disorders of the immune system: angioedema, bronchospasm, arthralgia, fever, lupus-like syndrome.

Disorders of the endocrine system: adrenal insufficiency.

Metabolic and nutritional disorders: decreased appetite, hyperuricemia, exacerbation of gout.

Mental disorders: disorientation, psychosis.

Disorders of the nervous system: headache, dizziness, ataxia, paresthesia.

Visual organ disorders: decreased visual acuity, optic neuritis.

Vascular disorders: decreased blood pressure, shock.

Disorders of the gastrointestinal tract: abdominal discomfort, flatulence, nausea, vomiting, diarrhea, erosive gastritis, acute pancreatitis.

Disorders of the liver and biliary tract: increased activity of "hepatic" transaminases, alkaline phosphatase in blood serum, hyperbilirubinemia, jaundice, hepatomegaly, hepatitis.

Skin and subcutaneous tissue disorders: erythema, rash, urticaria, exfoliative dermatitis, erythema multiforme (including Stevens-Johnson syndrome, Layel syndrome and vasculitis).

Disorders of musculoskeletal and connective tissue: myopathy, muscle weakness.

Disorders of the kidneys and urinary tract: nephronecrosis, interstitial nephritis.

Effects on the course of pregnancy, postpartum and perinatal conditions: when used in the last weeks of pregnancy, postpartum bleeding in the mother and bleeding in the newborn may occur.

Disorders of the genital organs and breast: dysmenorrhea.

General disorders and disorders at the injection site: against the background of treatment, skin, sputum, sweat, feces, lacrimal fluid, urine turn orange-red; may persistently stain soft contact lenses.

Influence on the results of laboratory and instrumental studies: rifampicin affects the results of microbiological methods for determining the concentration of folic acid and vitamin B12 in blood serum.

With irregular administration 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.

Ethambutol

Disorders of the immune system: hypersensitivity, anaphylactic/anaphylactoid reactions, including shock, eosinophilia.

Disorders of the skin and subcutaneous tissues: bullous dermatitis, skin rash, itching, urticaria, Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitization reaction.

Disorders of the gastrointestinal tract: decreased appetite, nausea, vomiting, diarrhea, a "metallic" taste in the mouth, impaired liver function (up to death), increased activity of "hepatic" transaminases, jaundice.

Disorders of the nervous system and sensory organs: weakness, headache, dizziness, confusion, disorientation, hallucinations, depression, convulsions, peripheral neuritis (paresthesia in the extremities, numbness, paresis, itching), optic neuritis (decreased visual acuity, limited field of vision, impaired color perception (mainly green and red), color blindness, central or peripheral scotoma), retinal hemorrhage.

Disorders of the blood and lymphatic system: leukopenia, thrombocytopenia, neutropenia.

Disorders of the respiratory system, chest and mediastinal organs: pneumonitis, infiltrates in the lungs with/without eosinophilia.

Other: increased concentration of uric acid in the blood serum, exacerbation of gout, interstitial nephritis, joint pain, increased body temperature.

Pyridoxine

Hypersecretion of hydrochloric acid, numbness, the appearance of a feeling of compression in the extremities (a symptom of "stockings" and "gloves"), decreased lactation.

Overdose

Symptoms: lethargy, blurred speech, ataxia, nausea, vomiting, abdominal pain, enlarged liver, jaundice, periorbital edema or swelling of the face, "red man syndrome" (red-orange staining of the skin, mucous membranes and sclera), pulmonary edema, lethargy, confusion, decompensated acidosis, convulsions.

Treatment: symptomatic, probe gastric lavage and enterosorption, forced diuresis, anticonvulsant therapy (diazepam), correction of acidosis.

Drug interaction

Isoniazid

Simultaneous administration of isoniazid with certain medications may lead to an increase or decrease in the effect.

Isoniazid inhibits the isoenzymes CYP2C19, CYP1A2, CYP2A6, CYP2E1 and CYP3A

the cytochrome P450 system of the liver, which can lead to a slowdown in the excretion of drugs metabolized by these enzymes.

The administration of other drugs may affect the metabolism of isoniazid.

In "slow acetylators" and in patients using aminosalicylic acid at the same time, tissue concentrations of isoniazid may be increased and the frequency of side effects increased.

Possible interactions are presented below:

Active substance Type of interaction Clinical consequence

Alpha-1-adrenoblockers

Alfuzosin Increased concentration of alfuzosin in the blood Hemodynamic monitoring at the beginning of therapy

Alcohol dehydrogenase inhibitors

Increased dopamine activity due to inhibition of dopamine metabolism by isoniazid and disulfiram, monitoring of neurological changes (such as dizziness, ataxia, mood swings or behavioral changes) is necessary, in which case therapy should be discontinued or the dose of disulfiram reduced.

Analgesics

Acetylsalicylic acid May weaken the effect of isoniazid, joint use is not recommended

Opioids (such as morphine, fentanyl, alfentanyl, buprenorphine, methadone, codeine) Isoniazid slows down the metabolism of opioids, monitoring of side effects is necessary, if necessary, correction of the dose of opioids

Paracetamol Isoniazid enhances the hepatotoxicity of paracetamol, co-administration is not recommended, monitoring of liver function is necessary

Anesthetics

Isoflurane

Enflurane Isoniazid may increase the formation of potentially nephrotoxic inorganic fluorine as a metabolite of isoflurane and enflurane (especially in "fast acetylators"), increased nephrotoxicity, control of renal function, especially in "fast acetylators" after surgery

General anesthetics Possible enhancement of hepatotoxicity of isoniazid Monitoring of liver function

Anti-asthmatic agents

Theophylline Isoniazid slows down metabolism

theophylline Control of theophylline concentration in blood serum, in particular after discontinuation of isoniazid, correction of theophylline dose

Antibiotics

Cycloserine /

Terizidone Increased toxicity to the central nervous system of cycloserine /terizidone, increased attention should be paid to side effects from the central nervous system, if necessary, dose adjustment of cycloserine / terizidone

Rifampicin Increased hepatotoxicity of isoniazid and rifampicin Monitoring of liver function

Ethionamide / Protionamide Increased toxicity to the central nervous system of isoniazid and ethionamide / protionamide, increased attention should be paid to side effects from the central nervous system

Antifungal agents

Itraconazole Decrease in the concentration of itraconazole in the blood Ineffectiveness of treatment, co-administration is not recommended

Ketoconazole Decrease in ketaconazole concentration in the blood It is necessary to monitor the effectiveness of ketoconazole, if necessary, adjust the dose of ketoconazole

Anticholinergic drugs

Atropine Increased toxicity of atropine Co-administration is not recommended

Darifenacin Isoniazid may slow down the elimination of darifenacin, it is possible to enhance the effect of darifenacin, if necessary, adjust the dose of darifenacin

Antidepressants

Citalopram Isoniazid may slow the elimination of citalopram, Increase cardiotoxicity, if necessary, adjust the dose of citalopram; hypokalemia and hypomagnesemia should be corrected before starting treatment and monitored regularly

Hypoglycemic agents

Insulin and derivatives/

Alpha-glucosidase inhibitors/ Sulfonylurea derivatives, biguanides, glinides, incretinomimetics, DPP4 inhibitors

Violation of the effect of hypoglycemic drugs Monitoring of blood glucose concentration, possible reduction or increase in the effectiveness of hypoglycemic drugs, if necessary, dose adjustment

Antiepileptic drugs

Carbamazepine Isoniazide slows down the metabolism of carbamazepine, it is possible to increase hepatotoxicity, clinical monitoring is necessary, control of carbamazepine concentration and liver function, if necessary, correction of the dose of carbamazepine

Phenytoin Isoniazid slows down the metabolism of phenytoin, monitoring of side effects is necessary, determination of the concentration of hydantoin in the blood, if necessary, correction of the dose of phenytoin, it is recommended to control the concentration of phenytoin after the withdrawal of isoniazid

Primidone Isoniazid slows down the metabolism of primidone, monitoring of side effects is necessary, if necessary, correction of the dose of primidone

Valproic acid The toxicity of isoniazid and valproic acid can be enhanced by mutual interaction, monitoring of side effects is necessary, especially at the beginning and end of therapy, if necessary, dose adjustment of valproic acid

Ethosuximide Isoniazide slows down the metabolism of ethosuximide, monitoring of side effects is necessary, if necessary, dose adjustment of ethosuximide

Anticoagulants

Warfarin and other coumarins/

Indanedione derivatives Isoniazid slows down the metabolism of anticoagulants, increases the tendency to bleeding While using blood clotting indicators, especially after discontinuation of therapy with isoniazid, if necessary, dose adjustment of anticoagulants

Antiparkinsonian drugs

Levodopa Decrease in the AUC (area under the pharmacokinetic curve) of levodopa, increased risk of peripheral neuropathy due to levodopa and isoniazid Loss of levodopa effectiveness, motor restlessness, tremor, general worsening of Parkinsonism symptoms; with signs of peripheral neuropathy, therapy should be discontinued

Antiprotozoal

Chloroquine Increased risk of peripheral neuropathy due to chloroquine and isoniazid, monitoring of side effects is necessary, with signs of peripheral neuropathy, therapy should be discontinued

Halofantrin Decreased metabolism of halofantrin, increased concentration of halofantrin in plasma, monitoring of side effects from the heart, ECG monitoring before, during and after therapy is necessary

Beta blockers

Propranolol Propranolol can reduce the plasma clearance of isoniazid, There may be a slight increase in the concentration of isoniazid in blood plasma, the clinical significance is probably low

Antagonists of CCR5 chemokine receptors

Maraviroc Isoniazid may increase plasma concentrations of maraviroc, if necessary, dose adjustment of maraviroc

Glucocorticosteroids

Budesonide Isoniazid may increase plasma concentrations of budesonide, possibly enhancing the effect of budesonide with prolonged therapy

Prednisolone Prednisolone can reduce plasma concentrations of isoniazid, It is possible to reduce the effect of isoniazid, if necessary, correction of the dose of isoniazid is required

Antagonists of serotonin 5-HT3 receptors

Alosetron An increase in the concentration of alosetron in plasma is not recommended for combined use

Immunomodulators

BCG vaccine Loss of vaccine effect (including use in bladder cancer therapy) Co-administration is not recommended

Interferon beta-1a Increased hepatotoxicity of isoniazid and interferon beta-1a Liver function monitoring is necessary, if ALT is 5 times higher than normal, it is recommended to reduce the dose of interferon beta-1a, which can be increased again after normalization of ALT

Immunosuppressants

Cyclosporine Isoniazid can affect the concentration of cyclosporine in blood plasma Monitoring the concentration of cyclosporine in blood plasma, if necessary, dose adjustment of cyclosporine

Leflunomide /

Teriflunomide Increased risk of hepatotoxicity due to isoniazid and leflunomide / teriflunomide Increased risk of hepatotoxicity, activity of "liver" enzymes and bilirubin concentration should be measured before starting therapy with leflunomide /teriflunomide, then monthly during the first

6 months of therapy, and then every 6-8 months.

Patients with hepatic insufficiency or increased transaminase activity (ALT 2 times > normal) should not take leflunomide / teraflunomide. With ALT 3 times > normal, it is necessary to cancel therapy and remove the active metabolite of leflunomide with colestyramine or activated charcoal, weekly monitoring, if necessary, repeat the intake of adsorbents

Thalidomide Risk of peripheral neuropathy due to thalidomide and isoniazid Monthly monitoring of side effects in the first 3 months of treatment, electrophysiological tests before and after 6 months of treatment, possible discontinuation of therapy if signs of neuropathy appear

Hypolipidemic agents

Fluvastatin Simvastatin Pravastatin Atorvastatin Increased risk of peripheral neuropathy due to isoniazid and fluvastatin, simvastatin, pravastatin and atorvastatin With signs of peripheral neuropathy, therapy should be discontinued

MAO inhibitors

Tranylcypromine

Moclobemide Isoniazide reduces the metabolism of tranylcypromine and moclobemide (clinically significant only in "slow acetylators") It is possible to increase the effectiveness of tranylcypromine and moclobemide in "slow acetylators", monitoring of side effects

Muscle relaxants

Tizanidine Isoniazid can slow down the metabolism of tizanidine, an increase in the concentration of tizanidine in plasma is not recommended, increased cardiotoxicity and toxicity to the central nervous system, increased effect of tizanidine

Chlorzoxazone Decreased clearance, increased plasma concentration, and increased AUC (about 125%) of chlorzoxazone, monitoring of side effects is necessary, if necessary, correction of the dose of chlorzoxazone

Neuroleptics

Haloperidol Isoniazid can slow down the metabolism of haloperidol, monitoring of the neurological status is necessary, if necessary, correction of the dose of haloperidol

Pimozide Isoniazide may slow down the metabolism of pimozide, an increase in the concentration of pimozide in plasma is not recommended, severe side effects from the heart

Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Efavirenz Increased risk of hepatotoxicity due to efavirenz and isoniazid Liver function testing is necessary before and during treatment

Nucleoside Reverse transcriptase inhibitors (NRTIs)

Didanosine Stavudine Increased risk of peripheral neuropathy due to isoniazid, didanosine and stavudine, monitoring of side effects is necessary, with signs of peripheral neuropathy, therapy should be discontinued or doses of isoniazid, didanosine or stavudine should be reduced

Zalcitabine Increased clearance of isoniazid in

Monitoring of the effectiveness of isoniazid is necessary 2 times

Opioid receptor antagonists

Naltrexone Increased risk of hepatotoxicity due to naltrexone and isoniazid Should be avoided when used together, liver function testing is necessary

Phosphodiesterase inhibitors

Roflumilast Isoniazid can increase the bioavailability of roflumilast and roflumilast N-oxide, It is possible to increase the effectiveness of roflumilast

Selective Estrogen Receptor Modulators (SERM)

Toremifene Isoniazid can increase the concentration of toremifene in plasma Regular measurement of electrolytes, general blood test, liver function check

Antispasmodics

Tolterodine Isoniazid can increase plasma concentrations of tolterodine, if necessary, reduce the dose of tolterodine when used concomitantly with CYP3A4 inhibitors such as isoniazid (1 mg tolterodine 2 times a day), clinical monitoring is necessary

Sympathomimetics

Adrenaline, Norepinephrine Increased side effects

Inhibitors of platelet aggregation

Clopidogrel Isoniazid reduces bioactivation by inhibiting CYP2C19 and thereby reduces the effect of clopidogrel, co-administration is not recommended, monitoring of the effectiveness of clopidogrel is necessary

Tranquilizers

Benzodiazepines (such as diazepam, midazolam, triazolam) Isodiazide can slow down the metabolism of benzodiazepines, monitoring of side effects is necessary, if necessary, dose adjustment of benzodiazepines

Vitamins

Vitamin B6 Isoniazid enhances the elimination of pyridoxine Prophylactic administration of pyridoxine during isoniazid therapy is recommended

Vitamin D Isoniazid reduces the plasma concentration of vitamin D In the case of taking drugs containing vitamin D, it is necessary to monitor serum calcium concentration, serum phosphate concentration, as well as kidney function, if necessary, dose adjustment of vitamin D

Nicotinic acid Isoniazid reduces the concentration of nicotinic acid (there is no inhibition of the inclusion of nicotinic acid in nicotinamide adenine dinucleotide)

Cytostatics

Bendamustine Isoniazid increases the concentration of bendamustine in plasma. The effect of bendamustine should be carefully monitored for signs of toxicity, such as leukopenia, infections, thrombocytopenia, bleeding, anemia and neutropenia, if necessary, dose adjustment of bendamustine

Clofarabine Increased hepatotoxicity of clofarabine and isoniazid Should be avoided when used together, liver function monitoring is necessary

Gefitinib Isoniazid may slow down the metabolism of gefitinib, monitoring of side effects is necessary, if necessary, dose adjustment of gefitinib

Methotrexate Increased hepatotoxicity of methotrexate and isoniazid Should be avoided when used together, liver function indicators should be monitored

Pazopanib Isoniazid may slow down the metabolism of pazopanib Side effects monitoring, electrolyte measurement, ECG, liver function tests, before and during treatment, if necessary, dose adjustment of pazopanib

Thioguanine Increased hepatotoxicity of thioguanine and isoniazid Liver function testing

Antacids

Antacids (especially aluminum-containing ones) Reducing the absorption and concentration of isoniazid in the blood Should be avoided, antacids should be taken no earlier than 1 hour after taking isoniazid

Other

Henodeoxycholic acid Metabolism (acetylation) and isoniazid excretion may be increased Co-administration is not recommended

Interaction with food and drinks.

Ethanol increases the hepatotoxicity of isoniazid and accelerates its metabolism.

The absorption of isoniazid worsens after eating, especially carbohydrates.

During treatment, cheese (especially Swiss or Cheshire), fish (especially tuna, sardinella, skipjack) should be avoided, since when used simultaneously with isoniazid, reactions may occur (skin hyperemia, itching, feeling hot or cold, palpitations, increased sweating, chills, headache, dizziness) associated with by suppressing the activity of monoamine oxidase (MAO) and diamine oxidase and leading to a violation of the metabolism of tyramine and histamine contained in fish and cheese.

Effect on laboratory parameters

Isoniazid can lead to false positive blood glucose determination results using a copper reagent; it does not affect enzymatic glucose determination tests.

Pyrazinamide

Increases the concentration of isoniazid in the blood serum, slowing its excretion. Enhances the hepatotoxicity of isoniazid.

The probability of developing the hepatotoxic effect of pyrazinamide increases when combined with rifampicin.

Liver function monitoring is necessary.

With the simultaneous use of pyrazinamide with drugs that block tubular secretion, it is possible to reduce their excretion and increase toxic reactions.

Pyrazinamide enhances the anti-tuberculosis effect of ofloxacin and lomefloxacin.

Pyrazinamide can increase serum uric acid concentrations and reduce the effectiveness of drugs for the treatment of gout, such as allopurinol, colchicine, probenecid, sulfinpyrazone.

When used concomitantly with pyrazinamide, blood concentrations and the effectiveness of cyclosporine may decrease.

Rifampicin

Rifampicin induces the induction of cytochrome P450 isoenzymes, accelerating the metabolism of drugs, and accordingly reduces the activity of indirect anticoagulants, oral hypoglycemic drugs, cardiac glycosides (digoxin, etc.), antiarrhythmic drugs (disopyramide, pyrmenol, quinidine, mexiletine, tocainide, propafenone), glucocorticosteroids, dapsone, hydaitoines ( phenytoin), carbamazepine, buspirone, barbiturates (phenobarbital, hexobarbital, etc.), some tricyclic antidepressants (nortriptyline), antiviral drugs (including nucleoside reverse transcriptase inhibitors (NIOT): zidovudine, stavudine, etc.); (including non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine, etc.), benzodiazepines (diazepam, etc.), theophylline, chloramphenicol, neuroleptics (haloperidol, etc.), antifungal drugs (itraconazole, terbinafine, etc.), cyclosporine, azathioprine, beta-blockers (propranolol, etc.) , "slow" blockers calcium channels (nifedipine, verapamil, diltiazem), lipid-lowering drugs (simvastatin, etc.), antimalarial drugs (mefloquine, etc.), cytostatics (tamoxifen, etc.), cyclooxygenase-2 inhibitors (celecoxib, etc.), losartan, enalapril, cimetidine, thyroxine, and sex hormones. Concomitant use with HIV protease inhibitors (indinavir, nelfinavir, atazanavir, darunavir, fosamprenavir, saquinavir and tipranavir, amprenavir, lopinavir) should be avoided. Rifampicin accelerates the metabolism of estrogens and progestogens (the effect of oral contraceptives decreases).

With the simultaneous use of rifampicin (600 mg / day), ritonavir (100 mg 2 times a day) and saquinavir (1000 mg), severe hepatotoxicity may develop. When used together, rifampicin significantly reduces the plasma concentrations of atazanavir, darunavir, fosamprenavir, saquinavir and tipranavir, amprenavir, indinavir, lopinavir, nelfinavir, which may lead to a decrease in antiviral activity.

Isoniazil and / or pyrazinamide increase the frequency and severity of liver dysfunction to a greater extent than with the use of rifampicin alone in patients with previous liver disease. Co-trimoxazole (sulfamethoxazole/trimethoprim) increases the concentration of rifampicin in the blood.

Ethambutol

Simultaneous administration of ethambutol and drugs with neurotoxic effects may increase the likelihood of developing optic neuritis and peripheral neuritis.

Aluminum hydroxide reduces the absorption of ethambutol from the digestive tract. The intake of aluminum hydroxide is recommended 4 hours after taking ethambutol. Ethambutol alters the metabolism of certain trace elements, mainly zinc.

Pyridoxine

Enhances the effect of diuretics; weakens the pharmacological effects of levodopa. Isoniazid, penicillamine, cycloserine and estrogen-containing oral contraceptives weaken the effect of pyridoxine. Pyridoxine is combined with cardiac glycosides (promotes an increase in contractile proteins in the myocardium), with glutamic acid, potassium and magnesium asparaginate.

Special instructions

The drug should be prescribed with caution to patients with exhaustion, impaired liver function and patients taking other potentially hepatotoxic drugs.

During treatment with the drug, patients should refrain from drinking alcohol.

Patients who are intolerant to ethionamide, pyrazinamide, nicotinic acid or other substances similar in chemical structure may have intolerance to isoniazid.

In some cases, fatal drug hepatitis develops during treatment, which can occur even after several months of termination of use. The risk increases with age (the highest frequency in the 35-64 age group), especially with daily ethanol consumption. Therefore, liver function must be monitored monthly in all patients, and liver function is additionally examined in persons over 35 years of age before starting treatment. In addition to the use of ethanol, additional risk factors are chronic liver diseases, female gender, "slow acetylators", exhaustion, HIV infection, parenteral use of any medications and the postpartum period. With an increase in the activity of "hepatic" transaminases (ALT, AST) by 4 or more times or an increase in the concentration of bilirubin in the blood, treatment with isoniazid should be discontinued.

In addition to the use of ethanol, additional risk factors are chronic liver diseases, female sex, "slow" acetylators, exhaustion, HIV infection, parenteral use of any medications and the postpartum period; under these circumstances, liver function monitoring (laboratory and clinical) should be carried out more often. Patients should be informed of the need to report any manifestations of liver damage (unexplained anorexia, nausea, vomiting, darkening of urine, jaundice, rash, paresthesia of the hands and feet, weakness, fatigue or fever lasting more than 3 days, abdominal pain, especially in the right hypochondrium). In these cases, the drug is immediately discontinued.

Patients who have previously suffered from isoniazid hepatitis are prescribed alternative anti-tuberculosis drugs. If it is necessary to resume therapy, it is started after complete resolution of clinical and laboratory signs of hepatitis, followed by constant monitoring of liver function. At any signs of relapse, the drug is immediately discontinued.

Due to the different metabolic rates of isoniazid before using the drug, it is advisable to determine the rate of its inactivation by the content of isoniazid in blood and urine. With rapid inactivation, isoniazid is used in higher doses. Risk factors for the development of peripheral neuritis when using the drug include: age over 65 years, diabetes mellitus, pregnancy, alcoholism, eating disorders, concomitant anticonvulsant therapy. During treatment, cheese (especially Swiss or Cheshire), fish (especially tuna, sardinella, skipjack) should be avoided, since when used simultaneously with isoniazid, reactions may occur (skin hyperemia, itching, feeling hot or cold, palpitations, increased sweating, chills, headache, dizziness) associated with by suppressing the activity of monoamine oxidase (MAO) and diamine oxidase and leading to a violation of the metabolism of tyramine and histamine contained in fish and cheese.

Women of childbearing age should use reliable methods of contraception during treatment (oral hormonal contraceptives and additional non-hormonal methods of contraception).

It should be borne in mind that rifampicin interacts with contrast agents used in cholecystography. Under its influence, the results of X-ray examinations may be distorted. It can permanently stain soft contact lenses. In the case of flu-like syndrome (caused by rifampicin), not complicated by thrombocytopenia, hemolytic anemia, bronchospasm, shortness of breath, shock and renal failure, in patients receiving the drug according to an intermittent regimen, the possibility of switching to daily intake should be considered. If the above serious complications are noted, the drug is canceled. It is necessary to monitor kidney function; additional administration of glucocorticosteroids is possible. Simultaneous alcohol consumption contributes to increased hepatotoxic reactions.

With prolonged use, systematic monitoring of the peripheral blood pattern and liver function is indicated. Microbiological methods for determining serum concentrations of folic acid and vitamin B12 should not be used during treatment. It should be borne in mind that isoniazid can cause hyperglycemia with secondary glucosuria; copper ion reduction tests may be false positive, and the drug does not affect enzyme glucose tests. Laboratory parameters of alanine aminotransferase and aspartate aminotransferase, the concentration of bilirubin in blood serum may increase transiently without clinical manifestations. In severe liver damage, pyridoxine in high doses can cause deterioration of its function. When determining urobilinogen using the Ehrlich reagent, pyridoxine may distort the results.

Before starting treatment, ophthalmological control should be performed: examination of the fundus, fields of vision, visual acuity and color perception. During treatment, it is necessary to periodically conduct ophthalmological examinations, taking into account the possibility of developing optic neuritis. The occurrence of visual impairment depends on the duration of treatment and existing diseases of the eyeball. In case of their occurrence, treatment with the drug should be discontinued. Changes in vision are usually reversible, after discontinuation of treatment they disappear after a few weeks, in some cases after several months. In exceptional cases, changes in the eyeball are irreversible due to optic nerve atrophy.

Against the background of treatment, the skin, sputum, sweat, feces, lacrimal fluid, urine acquire an orange-red color.

Influence on the ability to drive vehicles, mechanisms

The drug can cause headache and decreased visual acuity in some patients, confusion, hallucinations, seizures, therefore care must be taken when driving vehicles and working with mechanisms. If the described adverse events occur, you should refrain from performing these types of activities.

Storage temperature

from 2℃ to 25℃