Expiration date: 11/2026
Dosage form
Tablets from white to white with a creamy or yellowish tinge of color, flat-cylindrical, with a chamfer and a risk. The presence of "marbling" is allowed.
Composition
One tablet contains:
active ingredients: isoniazid - 150 mg, pyrazinamide - 500 mg, pyridoxine hydrochloride - 15 mg;
excipients: potato starch, sodium carboxymethyl starch, colloidal silicon dioxide, talc, stearic acid.
Pharmacotherapeutic group
antituberculous agent combined
Pharmacodynamics
A combined anti-tuberculosis drug.
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 delta 2-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 (in infections caused by this pathogen, sensitivity to isoniazid must be determined before starting treatment).
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.
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
It is quickly and completely absorbed when ingested, food reduces absorption and bioavailability.
The effect of the "first pass" through the liver has a great influence on the bioavailability index. The time to reach the maximum concentration of isoniazid in blood plasma is 1-2 hours, the maximum concentration in blood plasma after ingestion of a single dose of 300 mg is 3-7 mcg / ml. The association with plasma proteins is insignificant - up to 10%.
The volume of distribution is 0.57-0.76 l/kg. It is well distributed throughout the body, penetrating into all tissues and fluids, including cerebrospinal, pleural, ascitic; high concentrations are created in lung tissue, kidneys, liver, muscles, saliva and sputum. Penetrates through the placental barrier and into breast milk.
It is metabolized in the liver by acetylation to form inactive products.
In the liver, N-acetyltransferase is acetylated to form N-acetylisoniazide, which is then converted into isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect by the formation of cytochrome P450 by the system during N-hydroxylation of the active intermediate metabolite. The rate of acetylation is genetically determined; people with "slow" acetylation have little N-acetyltransferase. It is an inducer of the isoenzyme CYP2E1. The half-life (T1/2) for "fast acetylators" is 0.5-1.6 hours; for "slow" - 2-5 hours. In renal insufficiency, the half-life may increase to 6.7 hours. Limited evidence suggests that the pharmacokinetics of isoniazid may vary in patients with hepatic insufficiency.
The half-life for children aged 1.5 to 15 years is 2.3-4.9 hours, and for newborns - 7.8-9.8 hours (which is explained by the imperfection of acetylation processes in newborns). Despite the fact that the T1/2 index varies significantly depending on the individual intensity of the acetylation processes, the average T1/2 value is 3 hours (oral intake of 600 mg) and 5.1 hours (900 mg). With repeated prescriptions, the half-life is shortened to 2-3 hours.
It is mainly excreted by the kidneys: 75-95% of isoniazid is excreted within 24 hours, mainly in the form of inactive metabolites - N-acetylisoniazid and isonicotinic acid. At the same time, the content of N-acetylisoniazide in "fast acetylators" is 93%, and in "slow" ones - no more than 63%. Small amounts are excreted by the intestines.
Isoniazid is removed from the blood during hemodialysis; 5-hour hemodialysis allows up to 73% of isoniazid to be removed from the blood.
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.
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 and prevention of all forms of tuberculosis caused by M.tuberculosis sensitive to isoniazid and pyrazinamide 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, pyridoxine or any other component of the drug; drug hepatitis and/or other severe adverse reactions that developed against the background of previous treatment with isoniazid; acute liver disease; severe liver failure; cirrhosis of the liver; epilepsy, epileptic syndrome, bronchial asthma, psoriasis, chronic renal failure, gout, hyperuricemia, peptic ulcer of the stomach and duodenum; pregnancy, breastfeeding, children under 3 years of age.
With caution
Alcoholism, liver failure of mild to moderate severity, liver dysfunction in the anamnesis or chronic liver dysfunction, seizures, age over 35 years, 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, a history of mental illness, "slow acetylators", female gender.
Use during pregnancy and breastfeeding
The use of the drug during pregnancy is contraindicated. It is recommended to stop breastfeeding during treatment.
Method of administration and dosage
Treatment
The drug is taken orally, after meals, with plenty of water, once a day.
The calculation of the dose of the drug is performed according to isoniazid.
Adults: the daily dose of isoniazid (with daily intake) for patients with a body weight of 33-50 kg is 300 mg, for patients with a body weight of 51-70 kg is 300-600 mg, for patients with a body weight of more than 70 kg is 600 mg. The maximum daily dose is 600 mg.
Children over 3 years of age: the daily dose of isoniazid (with daily intake) is 7-15 mg / kg of body weight. The maximum daily dose is 600 mg.
The doses and duration of treatment with the drug are set individually depending on the nature and severity of the disease, the effectiveness of treatment and tolerability.
The dose and duration of the drug should be determined in accordance with the official current federal guidelines on tuberculosis.
Prevention
Inside, 5-10 mg / kg / day, the maximum daily dose is 600 mg.
Doses and duration of administration should be determined according to the official current federal guidelines on tuberculosis.
Patients with liver failure
The drug Phthisopyram® B6 has a hepatotoxic effect, therefore, patients with moderate and mild liver dysfunction are prescribed with strict monitoring of "liver" enzymes and the use of hepatoprotectors (also see the section "Special instructions"). The use of the drug Phtizopyramum® B6 is contraindicated in patients with severe hepatic insufficiency.
In severe pulmonary heart failure, severe atherosclerosis, coronary heart disease and hypertension, doses of more than 10 mg / kg should not be prescribed.
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 (nicotinic acid deficiency). Nicotinic acid deficiency may be associated with pyridoxine deficiency caused by isoniazid, which affects the conversion of tryptophan to nicotinic acid.
Mental disorders: the frequency is unknown - mental disorders (irritability, anxiety), decreased concentration, depression, psychoses (manifest, catatonic 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, increased or decreased 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). Pyridoxine:
Hypersecretion of hydrochloric acid, numbness and the appearance of a feeling of compression in the extremities (a symptom of "stockings" and "gloves"), decreased lactation.
Overdose
Symptoms: nausea, vomiting, abdominal pain, jaundice, increased activity of "liver" transaminases, acute pulmonary edema, impaired consciousness, coma, convulsions, respiratory disorders, hyperglycemia, metabolic ketoacidosis.
Treatment: induction of vomiting or gastric lavage, intake of activated charcoal, forced diuresis, maintenance of vital functions, hemodialysis.
Drug interaction
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 of the liver cytochrome P450 system, 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 shown in the table 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
Disulfiram 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 surgical intervention
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
Pyrazinamide Increased hepatotoxicity of isoniazid and pyrazinamide Monitoring of liver function
Rifampicin Enhancement of 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
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 adjusted 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-HTZ 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 iso-niazide 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 every month 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 / teriflunomide. 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 cancellation 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 tranylcipromine 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 (inhibition of the incorporation of nicotinic acid into nicotinamide adenine dinucleotide)
Cytostatics
Bendamustine Isoniazid increases the concentration-
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 can 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) A decrease in the absorption and concentration of isoniazid in the blood Should be avoided by concomitant use, 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.
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 Phtizopyramum® B6 should be prescribed with caution to patients with convulsive disorders, exhaustion, diabetes mellitus, alcoholism and psychosis in the anamnesis, impaired liver and kidney function and patients taking other potentially hepatotoxic drugs.
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. With an increase in the activity of "liver" transaminases (ALT, AST) by 4 or more times or an increase in the concentration of bilirubin in the blood, treatment with the drug should be discontinued.
In addition to the use of ethanol, additional risk factors are chronic liver diseases and the postpartum period, female gender, "slow acetylators", exhaustion, HIV infection, parenteral use of any medications; 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, it is advisable to determine the rate of inactivation of isoniazid before using it (according to the dynamics of its content in blood and urine). In "fast acetylators" isoniazid is used in higher doses.
It should be borne in mind that isoniazid can cause hyperglycemia with secondary glucosuria; copper reduction tests may be false positive; the drug does not affect enzyme glucose tests.
It is necessary to monitor kidney function, peripheral blood picture, ALT activity and uric acid concentration in the blood on a monthly basis.
In patients with diabetes mellitus, the risk of hypoglycemia increases.
When prescribing to patients with hypoplastic anemia, it is necessary to take into account the effect of the drug on blood clotting time.
To slow down the development of microbial resistance, it is prescribed together with other anti-tuberculosis drugs.
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.
Influence on the ability to drive vehicles, mechanisms
During the treatment period, care must be taken when driving vehicles and engaging in other potentially dangerous activities that require increased concentration and speed of psychomotor reactions.
Storage temperature
from 2? to 25?
