Protub-3 (Protub-3)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIsoniazid + Pyrazinamide + RifampicinIsoniazid + Pyrazinamide + Rifampicin
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  • Protub-3
    pills inwards 
    FARMASINTEZ, JSC (Irkutsk)     Russia
  • Ftizamax
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    McLeodz Pharmaceuticals Co., Ltd.     India
    • Dosage form: & nbspfilm-coated tablets
    Composition:Active substances:
    Isoniazid 75 mg 150 mg 300 mg
    Pyrazinamide 400 mg 750 mg 1000 mg
    Rifampicin 150 mg 225 mg 450 mg

    Excipients:
    Kernel: microcrystalline cellulose 14 mg / 33 mg / 51 mg, polysorbate 80 (Tween 80) 1 mg / 1.8 mg / 9 mg, povidone-K25 (medium-molecular weight polyvinylpyrrolidone, callidone 25) 9 mg / 17.2 mg / 50 mg , silicon dioxide colloid (aerosil) 4 mg / 10 mg / 11.5 mg, carboxymethyl starch sodium (sodium glycolate starch, primogel) 24 mg / 47 mg / 66 mg, magnesium stearate 1.5 mg / 6 mg / 1.25 mg , talc (magnesium hydrosilicate) 1.5
    mg / 5 mg / 1.25 mg.
    Composition of the film membrane: hypromellose (hydroxypropylmethylcellulose 15) 11.5 mg / 20 mg / 34.5 mg, macrogol 6000 (polyethylene glycol 6000) 1.6 mg / 2.8 mg / 4.8 mg castor oil 0.3 mg / 0.5 mg / 0.9 mg, titanium dioxide 2.3 mg / 4.0 mg / 6.9 mg, talc (magnesium hydrosilicate) 0.2 mg / 0.4 mg / 0.6 mg, iron oxide yellow 1.6 mg / 2.8 mg / 4.8 mg, iron oxide red 2.5 mg / 4.5 mg / 7.5 mg.
    Description:Tablets from light brown to brown, capsular with a risk on one side. On a cross - section of a tablet with red - white impregnations.
    Pharmacotherapeutic group:anti-tuberculosis drug
    ATX: & nbsp

    J.04.A.M   Combinations of antituberculous drugs

    J.04.A.M.05   Isoniazid in combination with pyrazinamide and rifampicin

    Pharmacodynamics:
    PROTUB-3 contains a combination of three antituberculous drugs.
    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 a 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. For acidic pH, the minimum inhibitory concentration 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.
    Pharmacokinetics:
    Isoniazid. Taking isoniazid in together with the preparations that make up Protub-3, does not affect the rate of its absorption from the gastrointestinal tract. 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. 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. The liver is acetylated with N-acetyltransferase to form N-acetylisoiniazide, which is then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect by forming a mixed oxidase system of cytochrome P450 upon N-hydroxylation of the 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 CYP2C9 and CYP2E1 isoenzymes in the liver. The half-life of blood (T1 / 2) for "fast acetylators" is 0.5-1.6 h; for "slow" - 2-5 hours. With renal insufficiency, T1 / 2 can increase 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 T1 / 2 index varies considerably depending on the individual intensity of the acetylation processes, the average T1 / 2 value is 3 hours (ingestion 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. At the same time, "fast acetylators" contain N-acetylisiniazide 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%. Time
    reaching the maximum concentration of the drug in the blood TSam - 1-2 hours. It penetrates well 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, eating reduces the absorption of the drug.When administered on an empty stomach 600 mg, the maximum concentration of the drug in the blood of Cmax is 10 μg / ml, and TCmax is 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 T1 / 2 after repeated administration of 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 is prolonged only when doses of rifampicin exceed 600 mg. It is excreted in peritoneal dialysis and hemodialysis. In patients with impaired hepatic function, an increase in rifampicin plasma concentration and an elongation of T1 / 2 were noted.
    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.
    - Prevention of tuberculosis in persons in close contact with patients with tuberculosis; with a twist of tuberculin sensitivity; with increasing sensitivity to tuberculin; with hyperergic sensitivity to tuberculin.

    Contraindications:Hypersensitivity to any component of the drug. Children's age (up to 3 years), pregnancy and lactation period, jaundice, kidney disease with a decrease in excretory function, liver disease (various genesis) in the acute stage, pulmonary heart disease II-111, hyperuricemia, gout, purpura.
    Carefully:Diseases of the liver, kidneys, diabetes mellitus, chronic alcoholism, in elderly and weakened patients.
    Pregnancy and lactation:Contraindicated
    Dosing and Administration:
    Inside, for 1-2 hours before meals in one session. 0 At a body weight of the patient less than 40 kg for 1 tablet of the preparation "Proteb-3" with a dose of active components 150 mg + 750 mg + 225 mg.
    At a body weight of the patient from 40 to 50 kg for 1 tablet of the preparation "Protub -3" with a dose of active components 300 mg + 1000 mg + 450 mg.
    At a body weight of the patient from 50 kg to 64 kg, 4 tablets of the preparation "Protub-3" with a dose of active components of 75 mg + 400 mg + 150 mg.
    At a body weight of the patient over 65 kg, 2 tablets of the preparation "Proteb-3" with a dose of active components of 150 mg + 750 mg + 225 mg.
    Children 10-15 mg / kg / day in terms of rifampicin, but not more than 600 mg / day. The course of treatment is 2 months, with the further administration of combinations of isoniazid and rifampicin or isoniazid and ethambutol.

    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 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: arthralgia, 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 phosphatase), 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.
    Overdose:
    Isoniazid. Symptoms: dizziness, dysarthria, lethargy, disorientation, hyperreflexia, peripheral polyneuropathy, impaired liver function, metabolic acidosis, hyperglycemia, glucosuria, ketonuria,convulsions (1-3 h after the drug), coma.
    Treatment: peripheral polyneuropathy (vitamins: pyridoxine, thiamine, glutamic 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 liver function, an increase in the 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 speeds up its metabolism. Reduces the metabolism of theophylline, which can lead to an increase in its concentration in the blood.Reduces metabolic transformations and increases the concentration in the blood of alfentanil. 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 increase toxic reactions. Strengthens the anti-tuberculosis effect of ofloxacin and lomefloxacin.
    Rifampicin.
    Reduces the activity of oral anti-coagulants, oral hypoglycemic drugs, hormonal contraceptives, digitalis preparations, antiarrhythmic drugs (disopyramide, pirmenol, quinidine, mexiletine, tokainid), glycocorticosteroids, dapsone, phenytoin, hexobarbital, nortriptyline, benzodiazepines, sex hormones, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporine A, azathioprine, beta adrenoblockers, slow calcium channel blockers, enalapril, cimetidinerifampicin 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.
    Special instructions:
    Before the start of treatment and every 2-4 weeks, the activity of enzymes aspartate aminotransferase (ACT) and alanine aminogransferase (ALT) is determined. With an increase in their activity, the drug is canceled. Renewal treatment after the normalization of indicators.
    Pyrazinamide worsens the course of gout and diabetes, requires monitoring of kidney function, uric acid. In the case of persistent hyperuricemia and exacerbation of gouty arthritis, treatment is withdrawn. During the treatment period, microbiological methods are used to determine the concentration of folic acid and cyanocobalamin in the blood serum. During the treatment should not be used bromsulfaleinovy ​​test (false positive results). With prolonged admission, liver function, kidney function, peripheral blood picture and ophthalmologist examination are performed. Do not use ethanol.
    In the course of treatment, an additional reception of ergocalciferol is recommended to prevent metabolic disorders of calcium and phosphorus. With the appointment in the last weeks of pregnancy, postpartum bleeding in the mother and bleeding in the newborn are possible (treatment: phylloquinone). Women during the treatment period are recommended to use non-hormonal methods of contraception. Rifampicin stains skin, phlegm, sweat, feces, lacrimal fluid, urine, soft contact lenses in orange-red color.

    Form release / dosage:Tablets coated with a film membrane 75 mg + 400 mg + 150 mg; 150 mg + 750 mg + 225 mg; 300 mg + 1000 mg + 450 mg.
    Packaging:For 100, 500 or 1000 tablets (for hospitals) in a can of polypropylene or low-density polyethylene, sealed with a lid of polypropylene or high-pressure polyethylene or a can of polyethylene terephthalate for medicines, with a screw cap or with the control of the first opening. The space free from tablets is filled with cotton absorbent cotton.
    Banks, together with an equal number of instructions for use, are placed in a group package.
    Storage conditions:
    In a dry, the dark place at a temperature of no higher than 25 ° C.Keep out of the reach of children.

    Shelf life:
    2 years. Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:For hospitals
    Registration number:LSR-003520/09
    Date of registration:13.05.2009
    The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia
    Manufacturer: & nbsp
    Information update date: & nbsp04.07.2013
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