Protub®-2 (Protub®-2)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIsoniazid + Rifampicin + [Pyridoxine]Isoniazid + Rifampicin + [Pyridoxine]
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  • Protub®-2
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    FARMASINTEZ, JSC (Irkutsk)     Russia
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    Ipka Laboratories Ltd.     India
  • Tubavit
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    VALENTA PHARM, PAO     Russia
    • Dosage form: & nbspfilm-coated tablets
    Composition:
    Composition:
    Active substances:
    Isoniazid - 100 mg 100 mg 300 mg
    Rifampicin 150 mg 150 mg 450 mg
    Pyridoxine-10 mg 20 mg 20 mg
    hydrochloride

    Excipients:
    Core: cellulose microcrystalline - 48.40 mg / 48.60 mg / 143.60 mg; polysorbate 80 (Tween 80) - 1.30 mg / 1.30 mg / 3.70 mg; povidone K90 (high molecular weight polyvinylpyrrolidone) 6.10 mg / 6.30 mg / 18.30 mg; silicon dioxide colloid (aerosil grade A-300) - 6.60 mg / 6.60 mg / 20.00 mg; carboxymethyl starch sodium (sodium starch glycolate, primogel) 18.00 mg / 18.00 mg / 57.40 mg; magnesium stearate 18.00 mg / 18.00 mg / 57.40 mg; magnesium stearate - 2.30 mg / 2.60 mg / 8.50 mg; talc - 2.30 mg / 2.60 mg / 8.50 mg.
    Film Sheath: hypromellose E 5 (hydroxypropylmethylcellulose E 5) 0.34 mg / 0.34 mg / 1.02 mg; hypromellose E 15 (hydroxypropylmethylcellulose E 15) -5.74 mg / 5.74 mg / 17.26 mg;
    propylene glycol 0.50 mg / 0.50 mg / 1.49 mg; macrogol 6000 (polyethylene glycol 6000) -1.09 mg / 1.09 mg / 3.26 mg; polysorbate 80 (Tween 80) 0.29 mg / 0.29 mg / 0.87 mg; titanium dioxide - 0.44 mg / 0.44 mg / 1.31 mg; talc - 1.02 mg / 1.02 mg / 3.05 mg; ferric oxide red oxide - 0.58 mg / 0.58 mg / 1.74 mg.
    Description:
    For the dosage of 100 mg + 150 mg + 10 mg; 100 mg + 150 mg + 20 mg: round biconvex tablets, covered with a film coating of red-brown color.
    For dosing 300 mg + 450 mg + 20 mg capsular tablets coated with a film coating of red-brown color, with a risk on one side.
    On the cross section, the core is red with light and dark impregnations.
    Pharmacotherapeutic group:Antituberculous combined agent.
    ATX: & nbsp

    J.04.A.M.02   Isoniazid in combination with rifampicin

    Pharmacodynamics:

    PROTUB-2 contains a combination of two antituberculous drugs and pyridoxine.

    Isoniazid - has a bactericidal effect on actively dividing cells 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.

    Rifampicin - a semisynthetic broad-spectrum antibiotic, a series I antituberculous drug. At low concentrations, it has a bactericidal effect on Mycobacterium tuberculosis, Brucella spp., Chlamydia trachomatis, Legionella pneumophila, Rickettsia typhi, Mycobacterium leprae; in high concentrations - on some gram-negative microorganisms.Characterized by high activity in relation to Staphylococcus spp. (including penicillinase-forming and many strains of methicillin-resistant), Streptococcus spp., Clostridium spp., Bacillus anthracis; gram-negative coca: meningococci, gonococci. Gram-positive bacteria acts in high concentrations. It is active with respect to intracellular and extracellularly located microorganisms. Suppresses the DNA-dependent RNA polymerase of microorganisms. When the drug is monotherapy, the selection of rifampicin-resistant bacteria is observed relatively quickly. Cross-resistance with other antibiotics (with the exception of the other rifamycins) does not develop.

    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. With the simultaneous administration of pyridoxine inwards with isoniazid, lomefloxacin, pyrazinamide and ethambutol, no interaction of these drugs is observed at the pharmacokinetic and microbiological levels. Reduces the 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. Time to reach the maximum concentration of the drug in the blood (TSmOh) - 1-2 hours, the maximum concentration of the drug in the blood (CmOh) after ingestion of a single dose of 300 mg - 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. In the liver acetylated N-acetyltransferase with formation of N-acetyl isosine, which. then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect by forming a mixed oxidase system of cytochrome P450 at Nhydroxylation of the active intermediate metabolite.The rate of acetylation is genetically determined; in people with "slow" acetylation, little N- acetyltransferase. Is an inhibitor of isoenzymes CYP2C9 and CYP2E1 in the liver. Half-life of blood (T1/2) for "fast acetylators" - 0.5-1.6 hours; for "slow" - 2-5 hours With renal failure T1/2 can increase to 6.7 hours. T1/2 for children aged 1.5 to 15 years - 2.3-4.9 h, and in newborns - 7.8-19.8 h (which is explained by the imperfection of the processes of acetylation in newborns). Despite the fact that the indicator Ti/2 varies considerably depending on the individual intensity of the acetylation processes, the average value Ti/2 is 3 hours (intake of 600 mg) and 5.1 hours (900 mg). With repeated appointments T1/2 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-acetylisoiniazide and isonicotinic acid. At the same time, "fast acetylators" contain N- acetylisiniazide is 93%, while in "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.

    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 CmOh - 10 μg / ml, and TCmOh - 2-3 hours. Communication with plasma proteins - 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 300 mg - 2.5 h, 600 mg - 3-4 h, 900 mg - 5 h. After several days of repeated intake, bioavailability decreases, and T1/2 after repeated administration, 600 mg is shortened to 1-2

    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 lengthened only in cases where doses of rifampicin exceed 600 mg. It is excreted in peritoneal dialysis and hemodialysis. In patients with impaired liver function, an increase in rifampicin plasma concentration and an increase in T1/2.

    Pyridoxine absorbed rapidly throughout the small intestine, a larger amount 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.
    - 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 in the acute stage.
    Carefully:Hepatic insufficiency, renal failure, diabetes mellitus, advanced age, emaciated patients, alcoholism, seizures, decompensated diseases of the cardiovascular system (chronic heart failure, angina pectoris, hypertension), hypothyroidism.
    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 10-20 mg / kg body weight, but not more than 0.6 grams per day. It is recommended to take the entire daily dose in 1 reception on an empty stomach.
    Side effects:

    Associated with isoniazid

    From the nervous system: 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.

    Associated with 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 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.

    Associated with pyridoxine

    Allergic reactions, hypersecretion of hydrochloric acid, numbness, the appearance of a feeling of compression in the limbs - a symptom of "stocking" and "gloves", rarely - a skin rash, itching of the skin.

    Overdose

    Isoniazid. Symptoms: dizziness, dysarthria, lethargy, disorientation, hyperreflexia, peripheral polyneuropathy, abnormal liver function, metabolic acidosis, hyperglycemia, glucosuria, ketonuria, convulsions (1-3 hours after drug administration), 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).

    Rifampicin. Symptoms: pulmonary edema, lethargy, confusion, convulsions.

    Treatment: symptomatic; gastric lavage, administration activated carbon; 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. 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).

    Rifampicin. Reduces the activity of oral anticoagulants, oral hypoglycemic drugs, hormone contraceptives, digitalis drugs, antiarrhythmic drugs (disopyramide, pirmenol, quinidine, mexiletine, Tocainide), corticosteroids, dapsone, phenytoin, gekeobarbitala, nortriptyline, benzodiazepines, hormones, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporine, azathioprine, beta adrenoblockers, slow calcium channel blockers, enalapril, cimetidine (rifampicin causes the induction of certain enzyme systems of the liver, accelerates metabolism). Antacids, opiates, anticholinergic medicines 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. Preparations of paraaminesalicylic acid, containing bentonite (aluminum hydrosilicate), should be prescribed not earlier than 4 hours after taking the drug, tk. absorption impairment is possible.

    Pyridoxine weakens the action 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 it is necessary to additionally ergocalciferol (vitamin D) for the prevention of metabolic disorders of calcium and phosphorus.
    Form release / dosage:Film coated tablets 100 mg + 150 mg + 10 mg, 100 mg + 150 mg + 20 mg, 300 mg + 450 mg + 20 mg.
    Packaging:
    Primary packaging of medicinal product.
    100, 500 or 1000 tablets (for hospitals) are placed in a polyethylene polymer jar with a lid of polyethylene stretched under control with the first opening. Free space is filled with cotton wool. Labels are applied to cans from paper label or writing or from polymeric materials, self-adhesive.
    Secondary packaging of medicinal product.
    From 1 to 150 cans, together with an equal number of instructions for use, are placed in a cardboard box.
    Storage conditions:
    In a dry, protected from light 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-003521/09
    Date of registration:13.05.2009
    The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia
    Manufacturer: & nbsp
    Information update date: & nbsp19.05.2016
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