Protubwitis (Protubvita)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIsoniazid + Pyrazinamide + Rifampicin + [Pyridoxine]Isoniazid + Pyrazinamide + Rifampicin + [Pyridoxine]
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  • Protubwitis
    pills inwards 
    FARMASINTEZ, JSC (Irkutsk)     Russia
    • Dosage form: & nbspfilm-coated tablets
    Composition:
    Composition per one tablet.
    Active substances:
    Isoniazid - 100 mg
    Pyrazinamide 400 mg
    Rifampicin 150 mg
    Pyridoxine hydrochloride 15 mg
    Excipients:
    Core: microcrystalline cellulose-16.00 mg; Tween 80 (polysorbate 80) 0.32 mg; povidone medium-molecular (kollidon 25) - 11.18 mg; silicon dioxide colloid - 4.50 mg; sodium carboxymethyl starch - 18.00 mg; magnesium stearate - 2.50 mg; talc - 2.50 mg.
    Sheath: hypromelose E15 - 11.80 mg: propylene glycol - 1.70 mg; castor oil 0.30 mg; titanium dioxide - 2.40 mg; talc - 0.20 mg; dye iron oxide red - 3.60 mg.
    Description:Tablets covered with a film membrane of red-brown color, capsular with a risk on one side. On the cross section, the mass with red - white impregnations.
    Pharmacotherapeutic group:Anti-tuberculosis drug combined
    ATX: & nbsp

    J.04.A.M   Combinations of antituberculous drugs

    Pharmacodynamics:
    Isoniazid - has a bactericidal effect on the actively dividing cells of Mycobacterium tuberculosis. The mechanism of its action is the inhibition of the synthesis of mycolic acids, which are a component of the cell wall of mycobacteria.For mycobacteria tuberculosis, the minimum inhibitory concentration of the drug is 0.025-0.05 mg / l. Isoniazid has a moderate effect on slowly and rapidly growing atypical mycobacteria.
    Pyrazinamide. Pyrazinamide has bactericidal action at acidic pH values. Well penetrates into the tuberculosis foci. Its activity is high in caseous-necrotic processes, caseous lymphadenitis, tuberculomas. It is subjected to enzymatic conversion into the active form - pyrazinic acid. At acidic pH values, the MPA of pyrazinamide in vitro is 20 mg / l. On non-tuberculosis pathogens does not work.
    Rifampicin - broad-spectrum antibiotic, inhibits the synthesis of DNA-dependent RNA polymerase. Has a high activity against mycobacteria, including Mycobacterium tuberculosis, and some gram-positive pathogens. Activity against gram-negative microorganisms is lower. It is not characterized by cross-resistance to other antibiotics and chemotherapeutic agents.
    Pyridoxine (vitamin B6). Participates in the metabolism.It is necessary for the normal functioning of the central and peripheral nervous system. With tuberculosis infection, there is a deficiency of pyridoxine. In this regard, the daily dose of vitamin increases to 60 mg. With the simultaneous administration of pyridoxine inwards with isoniazid and pyrazinamide, no interaction of these drugs with pharmacokinetic and microbiological levels. Reduces neurotoxicity of anti-tuberculosis drugs.

    Pharmacokinetics:
    Isoniazid. Isoniazid quickly and completely absorbed when ingested, food reduces absorption and bioavailability. The effect of "first passage" through the liver has a great influence on the bioavailability index. The time to reach the maximum concentration of the drug in the blood (TCam) is 1-2 hours, the maximum concentration of the drug in the blood (Cmax) after ingestion of a single dose of 300 mg is 3-7 μg / ml. The connection with 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 all tissues and fluids, including cerebrospinal, pleural, ascites; high concentrations are created in the 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 with the formation of inactive products. In the liver N-acetyltransferase is acetylated to form N-atsetilizoniazida which is then converted to isonicotinic acid and monoacetyl hydrazine, providing hepatotoxic effects by forming mixed cytochrome P450 oxidase system with N-hydroxylation active intermediate metabolite. The rate of acetylation is genetically determined; in people with "slow" acetylation, there is little N-acetyltransferase. It is an inhibitor of the CYP2C9 and CYP2EI isoenzymes in the liver. The half-life of blood (T1 / 2) for "fast acetylators" is 0.5-1.6 h; to "slow." - 2-5 hours in renal insufficiency T1 / 2 can be increased up to 6.7 hours, T1 / 2 for children aged 1.5 to 15 years -. 2.3-4.9 hours, and in newborns - 7.8-19.8 hours (that due to the imperfection of acetylation processes in newborns). Despite the fact that the rate of T1 / 2 greatly varies depending on the individual intensity acetylation processes, the average value T of 3 h (ingestion of 600 mg) and 5.1 h (900 mg).With repeated appointments, T1 / 2 is shortened to 2-3 hours.
    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-acetylisonic acid and isonicotinic acid. In this case, the "fast acetylagorov" content of N-acetylisiniazide is 93%, while "slow" - not more than 63%. Small amounts are excreted with feces. The drug is removed from the blood during hemodialysis; 5 h hemodialysis allows you to remove from the blood to 73% of the drug.
    Pyrazinamide. After oral administration, it is quickly and completely absorbed in the gastrointestinal tract. The connection with plasma proteins is 10-20%. The time to reach the maximum concentration of the drug in the blood TSam - 1-2 hours Well penetrates into tissues and organs.
    Metabolised in the liver, where an active metabolite, pyrazinic acid, is first formed, which is then converted into an inactive metabolite, 5-hydroxypyrazinic acid. The half-life of T1 / 2 is 8-9 hours.
    It is excreted by the kidneys: in unmodified form - 3%, in the form of pyrazinic acid - 33%, in the form of other metabolites - 36%. Removed during hemodialysis.
    Rifampicin. Absorption - fast, taking the medicine reduces the absorption of the drug.When administered on an empty stomach 600 mg, the maximum concentration of Q drug in the blood of Cmax is 10 μg / ml, and Tmax - 2-3 hours. The connection with plasma proteins is 84-91%.
    Quickly distributed to organs and tissues (the highest concentration in the liver and kidneys), penetrates into the bone tissue, the concentration in the saliva - 20% of the plasma. The apparent volume of distribution is 1.6 l / kg in adults and 1.1 l / kg in children.
    Through the blood-brain barrier (BBB) ​​penetrates only in case of inflammation of the meninges. Penetrates through the placenta (concentration in fetal plasma - 33% of the concentration in the mother's plasma) and excreted in breast milk (breastfed babies receive no more than 1% of the therapeutic dose of the drug).
    Metabolised in the liver with the formation of pharmacologically active metabolite - 25-O-deacetyltrifampicin. It is an autoinducer - it accelerates its metabolism in the liver, resulting in a systemic clearance of 6 l / h after the first dose, increases to 9 l / h after repeated administration. When ingestion is also possible, induction and enzymes of the intestinal wall.
    T1 / 2 after ingestion of 300 mg - 2.5 h, 600 mg - 3-4 hours, 900 mg - 5 hours. After several days of repeated intake, bioavailability decreases, and after repeated administration 600 mg is shortened to 1-2 hours.
    It is excreted mainly with bile, 80% - in the form of a metabolite; kidneys - 20%. After taking 150-900 mg of the drug, the amount of rifampicin excreted by the kidneys in unchanged form depends on the value of the dose taken and is 4-20%.
    In patients with impaired renal excretory function, T1 / 2 lengthens only in those cases where doses of rifampicin exceed 600 mg. It is excreted in peritoneal dialysis and hemodialysis. In patients with impaired hepatic function, an increase in rifampicin concentration in the plasma and lengthening
    Pyridoxine is absorbed rapidly throughout the small intestine, more is absorbed in the jejunum. Metabolised in the liver with the formation of pharmacologically active metabolites (pyridoxal phosphate and pyridoxamine phosphate). Pyridoxal phosphate with plasma proteins binds to 90%. It penetrates well into all tissues; accumulates mainly in the liver, less - in the muscles and central nervous system. Penetrates through the placenta, is secreted with breast milk. The half-life is 15-20 days. It is excreted by the kidneys.
    Indications:
    Tuberculosis of lung and extrapulmonary tuberculosis is an intensive phase of therapy (limited focal and infiltrative tuberculosis without decay) and the phase of healing.
    - Leprosy.
    - Prophylaxis of tuberculosis in persons in close contact with patients with tuberculosis
    - With a bend of tuberculin sensitivity; with increasing sensitivity to tuberculin; with hyperergic sensitivity to tuberculin.

    Contraindications:Children's age (up to 12 years), pregnancy and lactation period, jaundice, kidney disease with a decrease in excretory function, acute liver disease, hypersensitivity to the components of the drug.
    Carefully:Diseases of the liver, diabetes, elderly, emaciated patients.
    Pregnancy and lactation:During pregnancy and during lactation it is not applied.
    Dosing and Administration:The dose is set individually, depending on the nature and form of the disease. The route of administration is inside. The drug is recommended to appoint 30 minutes before meals 1 time per day. Drink with water (0.5 to 1 cup). Dosed according to rifampicin 10 mg / kg body weight, not more than 0.6 g. It is recommended to take the entire daily dose in 1 reception on an empty stomach. Dosage regimen for children. For children over 12 years of age 10-15 mg / kg / day in terms of rifampicin, but not more than 600 mg / day.
    Side effects:
    Isoniazid. From the central nervous system (CNS): headache, dizziness, rarely excessive fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of limbs, peripheral neuropathy, optic neuritis, polyneuritis, psychosis, mood change, depression. Seizures can occur in patients with epilepsy.
    From the side of the cardiovascular system: palpitation, angina, increased blood pressure.
    From the digestive system: nausea, vomiting, gastralgia, toxic hepatitis.
    Allergic reactions: skin rash, itching, hyperthermia, arthralgia.
    Other: very rarely - gynecomastia, menorrhagia, a tendency to bleeding and hemorrhage.
    Pyrazinamide. From the digestive system: nausea, vomiting, diarrhea, "metallic" taste in the mouth, impaired liver function (decreased appetite, liver soreness, hepatomegaly, jaundice, yellow atrophy of the liver); exacerbation of peptic ulcer.
    From the side of the central nervous system: headache, sleep disturbances, increased excitability, depression; in some cases - hallucinations, convulsions, confusion.
    On the part of the organs of hematopoiesis and the system of hemostasis: thrombocytopenia, sideroblastic anemia, erythrocyte vacuolization, porphyria, hypercoagulation, splenomegaly.
    From the musculoskeletal system: arthritis, myalgia.
    From the urinary system: dysuria, interstitial nephritis.
    Allergic reactions: skin rash, hives.
    Other: hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitivity, increased serum iron concentration. Rifampicin. From the digestive system: nausea, vomiting, diarrhea, increased levels of "liver" transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphogase), hyperbilirubinemia, decreased appetite, erosive gastritis, pseudomembranous enterocolitis, hepatitis.
    From the side of the central nervous system: headache, impaired coordination of movements, visual impairment, disorientation.
    From the urinary system: interstitial nephritis.
    Allergic reactions: skin rash, itching, Quincke's edema, bronchospasm, fever, urticaria, eosinophilia.
    Other: arthralgia; rarely - leukopenia, menstrual irregularity, dysmenorrhea, induction of porphyria, muscle weakness, hyperuricemia, exacerbation of gout.
    Pyridoxine. Allergic reactions, hypersecretion of hydrochloric acid, numbness, the appearance of a feeling stifled and I in the limbs - a symptom of "stocking" and "gloves," rarely skin rash, itching of the skin.
    Overdose:
    Isoniazid. Symptoms: dizziness, dysarthria, lethargy, disorientation, hyperreflexia, peripheral polyneuropathy, abnormal liver function, metabolic acidosis, hyperglycemia, glucosuria, koeurouria, convulsions (1-3 hours after drug administration), coma. Treatment: peripheral polyneuropathy (vitamins: pyridoxine, thiamine, gluten new acid, nicotinamide; massage, physiotherapy procedures); seizures (in / m pyridoxine hydrochloride - 200-250 mg, in / m 25% solution of magnesium sulfate - 10 ml, diazepam); abnormal liver function (methionine, thioctic acid, cyanocobalamin).
    Pyrazinamide. Symptoms: a violation of the liver, increased severity of side effects from the central nervous system. Treatment: symptomatic.
    Rifampicin. Symptoms: pulmonary edema, lethargy, confusion, convulsions.
    Treatment: symptomatic; gastric lavage, the appointment of activated charcoal; forced diuresis.
    Interaction:
    Isoniazid. When combined with paracetamol, hepato- and nephrotoxicity increases; isoniazid induces a system of cytochrome P450, which increases the metabolism of paracetamol to toxic products. Ethanol increases the hepatotoxicity of isoniazid and accelerates its metabolism. Reduces the metabolism of theophylline, which can lead to an increase in its concentration in the blood. Cycloserine and disulfiram strengthens the adverse central effects of isoniazid. Combination with pyridoxine reduces the risk of peripheral neuritis. Caution should be combined with potentially neuro-, hepato- and nephrotoxic drugs because of the risk of side effects.
    Strengthens the action of coumarin and indanedione derivatives, benzodiazepines, carbamazepine, as it reduces their metabolism by activating the cytochrome P450 system.
    Glucocorticosteroids accelerate metabolism in the liver and reduce active concentrations in the blood.
    It suppresses the metabolism of phenytoin, which leads to an increase in its concentration in the blood and an increase in the toxic effect (correction of the dosing regimen of phenytoin may be necessary, especially in patients with slow acetylation of isoniazid).
    Pyrazinamide. Compatible with other antituberculous drugs: in chronic destructive forms pyrazinamide it is recommended to combine with rifampicin or ethambutol (better tolerability than when combined with rifampicin, but weaker effect).
    The likelihood of developing a hepatotoxic effect increases when combined with rifampicin.
    When used simultaneously with drugs that block tubular secretion, it is possible to reduce their excretion and enhance toxic reactions. Strengthens the anti-tuberculosis effect of ofloxacin and lomefloxacin.
    Rifamycin. Reduces the activity of oral anticoagulants, oral hypoglycemic drugs, hormone contraceptives, digitalis drugs, antiarrhythmic drugs (disopyramide, pirmenol, quinidine, mexiletine, tokainid), glucocorticosteroids, dapsone, phenytoin, hexobarbital, nortriptyline, benzodiazepines, sex hormones, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporine A, azathioprine, beta adrenoblockers, slow calcium channel blockers, enalapril, cnmethidinerifampicin causes the induction of certain enzyme systems of the liver, accelerates metabolism). Antacids, opiates, anticholinergic drugs and ketoconazole reduce (in the case of simultaneous ingestion) bioavailability of rifampicin. Isoniazid and / or pyrazinamide increase the frequency and severity of liver function disorders to a greater extent than with the appointment of a single rifampicin, in patients with a previous liver disease. Paraaminosalicylic acid preparations containing bentonite (aluminum hydrosilicate) should be administered no earlier than 4 hours after taking the drug; absorption impairment is possible.
    Pyridoxine. It reduces the effect of levodopa when combined. Pyridoxine reduces the risk of developing toxic effects of anti-tuberculosis drugs on the central and peripheral nervous system.
    Special instructions:
    Assign as part of complex therapy, usually at the initial stage of the tuberculosis process.
    In the process of treatment, it is necessary to control the activity of "hepatic" transaminases, uric acid in the plasma.
    When there are signs of impaired liver function, it is necessary to stop taking the drug.
    After discontinuing the course of treatment, it is necessary to resume taking the drug with caution, because of the risk of developing hepato- and nephrotoxicity. When applying the drug, it is possible to stain saliva, sputum, urine and tear fluid in an orange-red color.
    During the treatment period, it is necessary to additionally appoint ergocalciferol (vitamin D) for the prevention of metabolic disorders of calcium and phosphorus.

    Form release / dosage:Tablets, film-coated 100 mg + 400 mg + 150 mg + 15 mg.
    Packaging:
    Primary packaging of medicinal product.
    100, 500 or 1000 tablets (for hospitals) are placed in a polymer jar with a lid tightened with the control of the first opening. Free space is filled with cotton wool.
    Secondary packaging of medicinal product.
    Banks, together with an equal number of instructions for use, are placed in a group package.
    Storage conditions:Store in a dry, dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children.
    Shelf life:
    4 years. Do not use after the expiration date indicated on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-002412/10
    Date of registration:24.03.2010
    The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia
    Manufacturer: & nbsp
    Information update date: & nbsp07.02.2014
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