Proteb-4 plus (Protub-4 plus)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceIsoniazid + Pyrazinamide + Rifampicin + Etambutol + PyridoxineIsoniazid + Pyrazinamide + Rifampicin + Etambutol + Pyridoxine
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    • Dosage form: & nbspTablets, film-coated
    Composition:

    Each tablet contains:

    Active substance:

    Isoniazid 75 mg 75 mg

    Pyrazinamide 400 mg 400 mg

    Rifampicin 150 mg 150 mg

    Ethambutol hydrochloride 275 mg 275 mg

    Pyridoxine hydrochloride 10 mg 15 mg

    Excipients.

    Icore: lactose monohydrate (milk sugar), microcrystalline cellulose, polysorbate 80 (Tween 80), povidone 25 (polyvinylpyrrolidone medium molecular weight, collidon 25), silicon colloidal dioxide (aerosil grade A -300), sodium carboxymethyl starch (primogel), magnesium stearate.

    Sheath: Hypromellose E15 (hydroxypropylmethylcellulose 15), hypromellose E5 (hydroxypropylmethylcellulose 5), macrogol 6000 (polyethylene glycol 6000), propylene glycol, titanium dioxide, magnesium hydrosilicate (talc), iron oxide yellow oxide (at a dosage of 75 mg + 400 mg + 150 mg + 275 mg + 15 mg), iron oxide red (at a dosage of 75 mg + 400 mg + 150 mg + 275 mg + 10 mg).

    Description:
    For the dosage of 75mg + 400mg + 150mg + 275mg + 10mg: pills covered with a film membrane, red-brown color, biconvex, oval. A thin shell of red-brown color and a nucleus of pinkish color with dark and light impregnations are visible on the cross-section.

    For dosage of 75mg + 400mg + 150mg + 275mg + 15mg: pills, film-coated, yellow, biconvex, oval. On the cross-section, a thin shell of yellow color and a nucleus of a pinkish color with dark and light impregnations are visible.


    Pharmacotherapeutic group:Anti-tuberculosis drug combined
    ATX: & nbsp

    J.04.A.M.06   Isoniazid in combination with pyrazinamide, rifampicin and ethambutol

    Pharmacodynamics:

    The pharmacological properties of Proteba-4® plus are due to the active ingredients that are included in its composition.

    Isoniazid acts bacteriostatically. Is a prodrug mycobacterial catalase peroxidase metabolizes isoniazid to the active metabolite, which, when bound to the enoyl (acyl transfer 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, when combined with arabinogalactan (polysaccharide), is involved in the formation of cell wall components Mycobacterium tuberculosis. 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 strains Mycobacterium kansasii (for infections caused by this pathogen, it is necessary to determine the sensitivity to isoniazid before starting treatment). For mycobacteria tuberculosis, the minimum inhibitory concentration (MIC) is 0.025-0.05 mg / l. Isoniazid has a moderate effect on slowly and rapidly growing atypical mycobacteria. The antimicrobial activity of isoniazid in combination with rifampicin is increased by 1.5 times.

    Rifampicin.

    The mechanism of action of rifampicin is the inhibition of the DNA-dependent RNA polymerase. With tuberculosis infection rifampicin has a bactericidal effect on intracellular and extracellularly located microorganisms. For mycobacteria tuberculosis, the minimum inhibitory concentration (MIC) for rifampicin is 2 mg / L.The anti-tuberculosis activity of pyrazinamide in The combination with rifampicin and isoniazid increases more than 2-fold.

    Pyrazinamide.

    Pyrazinamide has a bactericidal action at acidic pH values. To manifest the bactericidal activity of pyrazinamide, the preparation is subjected to enzymatic conversion into the active form - pyrazinic acid. At acid pH values, MIC (minimum inhibitory concentration) of pyrazinamide in vitro, is 20 mg / l.

    Ethambutol.

    Ethambutol acts bacteriostatically; penetrates into actively growing mycobacterial cells, inhibiting the synthesis of RNA, disrupts cellular metabolism, causes the cessation of reproduction and death of bacteria. It is active only for intensively dividing cells. Suppresses the growth and reproduction of mycobacteria tuberculosis, resistant to streptomycin, isoniazid, PASC, ethionamide, kanamycin, MIC (minimal inhibitory concentration) ethambutol is - 0,78-2,0 mg / l.

    The antimicrobial activity of ethambutol in combination with isoniazid increases in 2 times.

    Pyridoxine

    Entering the body, pyridoxine phosphorylated, converted to pyridoxal-5-phosphate and is part of the enzymes,carrying out decarboxylation, transamination and racemization of amino acids, as well as enzymatic conversion of sulfur-containing and hydroxylated amino acids. Participates in the exchange of tryptophan (participation in the reaction of biosynthesis of serotonin). It is necessary for the normal functioning of the central and peripheral nervous systems. With tuberculosis infection, there is a deficiency of pyridoxine. In this regard, the daily dose of vitamin increases to 60-80 mg. With the simultaneous administration of pyridoxine inwards with isoniazid, rifampicin, pyrazinamide and ethambutol, no interaction of these drugs is observed at the pharmacokinetic and microbiological levels.

    Pharmacokinetics:

    Isoniazid

    Taking isoniazid in together with the preparations that make up Proteb®-4 plus, does not affect the rate of its absorption from the gastrointestinal tract. Penetrates isoniazid in many tissues and fluids, including cerebrospinal fluid. Time to reach the maximum concentration (TCmax) -2 hours, the maximum concentration (Cmah) - 6.6 mg / l, half-life (T1 / 2) - 5.8 hours. A high level of maximum concentration and half-life is due to slowing downexcision of isoniazid under the influence of pyrazinamide. Isoniazid practically does not bind to plasma proteins. Isoniazid up to 80-90% is excreted in the urine and 10% with feces during the day. The main products of isoniazid excretion - N-acetyl isosine and isonicotinic acid.

    Rifampicin

    After taking Proteb-4® plus a healthy adult, the peak concentration of rifampicin in plasma reaches 16.3 mg / l. When taking the drug with food, the absorption of rifampicin is reduced by 30%. The maximum concentration of rifampicin is reached after 1.5-2 hours, the half-life is 6.1 hours. 3 times less is associated with plasma proteins rifampicin, which is part of the Protub-4® Plus. About 30% of the drug is excreted in the urine. Rifampicin is metabolized in the liver. The main metabolite is deacetyltrifampicin. All metabolites of rifampicin have antimicrobial activity against mycobacterium tuberculosis. Pyrazinamide

    After taking Protub-4 plus the maximum concentration of pyrazinamide in the plasma reaches 24.13 mg / L after 3 hours. The half-life of the drug is an average of 17 hours. The main active metabolite of pyrazinamide is pyrazinic acid.Up to 70% excreted urine metabolites of pyrazinamide and in 3,4 % - unchanged drug.

    Ethambutol hydrochloride

    Absorption is high; bioavailability is 75-80%. After oral administration of a dose of 25 mg TCmah - 2-4 hours, Cmah - 1-5 μg / ml. Connection with plasma proteins - 20-30%. It penetrates well into tissues and organs, as well as into biological fluids, with the exception of ascitic and pleural (in cerebrospinal fluid only with meningitis).

    The greatest concentrations are created in the kidneys, lungs, saliva, urine. Penetrates into breast milk. Do not pass through the intact blood-brain barrier.

    Partially metabolized in the liver (15%) with the formation of inactive metabolites. T1 / 2 3-4 hours, with renal dysfunction -8 hours. It is excreted by the kidneys - 80-90% (50% in unchanged form, 15% in the form of inactive metabolites) and with fecal masses - 10-20% ( in unmodified form). It is excreted in hemodialysis and peritoneal dialysis.

    Pyridoxine hydrochloride

    After taking Proteb®-4 plus is absorbed rapidly throughout the small intestine, more is absorbed in the jejunum. Metabolized in the liver with the formation of pharmacologically active metabolites (pyridoxalphosphate and pyridoxamino phosphate). Pyridoxalphosphate 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. T1 / 2 - 15-20 days. It is excreted by the kidneys (with intravenous injection - with bile 2%), as well as during hemodialysis.

    Indications:Proteb®-4 plus is used for chemotherapy for newly diagnosed patients with respiratory tuberculosis and extrapulmonary forms of tuberculosis, with or without bacterial release, without drug resistance to the drugs that make up the drug.
    Contraindications:
    - hypersensitivity to any ingredient in this drug;

    - visual impairment (diabetic retinopathy, optic nerve damage, inflammatory eye diseases);

    - epilepsy and a tendency to convulsive seizures in the case of previously transferred poliomyelitis;

    - kidney failure;

    - diseases of the liver and gastrointestinal tract in acute stage;

    - thrombophlebitis and severe atherosclerosis;

    - the presence of drug or alcohol dependence;

    - pregnancy and lactation;

    - children's age till 13 years.

    - lactose intolerance, lactase deficiency and glucosogalactose malabsorption syndrome.
    Carefully:decompensated diseases of the cardiovascular system (chronic heart failure, angina pectoris, arterial hypertension), hypothyroidism, hyperuricemia, gout.
    Dosing and Administration:When dosing Protub®-4 plus are guided by rifampicin (0.45 g per day for one dose, with a body weight of more than 70 kg, it is possible to administer 0.6 g for two doses), but not more than 4 tablets per day. Tablets (do not divide, do not grind, do not dissolve in water, do not dissolve and do not chew) take inside. Proteb®-4 plus and additional medications are taken once 1-2 hours after lunch for 2 months. The tablets are washed down with water. In case of side effects, the medication should be divided into 2 times. If necessary, the patient may be prescribed intramuscularly streptomycin or kanamycin (intramuscularly, at a dose of 15 mg / kg once a day).
    Side effects:

    Side effects in the treatment with Proteb®-4 plus are determined

    active ingredients included in its composition.

    Isoniazid.

    From the nervous system headache, dizziness, rarely fatigue, weakness, irritability, euphoria, insomnia, paresthesia, numbness of limbs, peripheral neuropathy, optic neuritis, polyneuritis, psychoses, emotional lability, depression, seizures in epilepsy patients.

    From the side of the cardiovascular system: heart palpitations, 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

    hemorrhages. The frequency and severity of adverse reactions to isoniazid closely

    are related to the dose and duration of administration.

    Rifampicin.

    From the digestive system - nausea, vomiting, diarrhea, decreased appetite, erosive gastritis, pseudomembranous colitis, increased activity of "hepatic" transaminases in the blood serum, hyperbilirubinemia, hepatitis.

    Allergic reactions: urticaria, eosinophilia, angioedema, bronchospasm, arthralgia, fever.

    From the nervous system: headache, decreased visual acuity, ataxia, disorientation.

    From the urinary system: nephronecrosis, interstitial nephritis, acute renal failure.

    Other: leukopenia, dysmenorrhea, induction of porphyria, myasthenia gravis, hyperuricemia, exacerbation of gout, influenza-like syndrome, skin reactions, hemolytic anemia, thrombocytopenic purpura.

    Pyrazinamide.

    From the digestive system - nausea, vomiting, diarrhea, "metallic" taste in the mouth, impaired liver function (decreased appetite, liver tenderness, hepatomegaly, jaundice, yellow atrophy of the liver), exacerbation of peptic ulcer.

    From the nervous system: dizziness, headache, sleep disturbances, increased excitability, depression, in some cases - hallucinations, convulsions, confusion.

    On the part of the organs of hematopoiesis: 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,

    photosensitization, increased serum iron concentration.

    Ethambutol.

    From the nervous system - weakness, headache, dizziness, impairment of consciousness, disorientation, hallucinations, depression, peripheral neuritis (paresthesias in extremities, numbness, paresis, itching).

    From the sense organs: optic neuritis (blurred vision, impaired color perception, mainly green and red colors, color blindness, scotoma).

    From the digestive system: decreased appetite, nausea, vomiting, gastralgia, increased activity of "liver" transaminases.

    Allergic reactions: dermatitis, skin rash, itching, arthralgia, fever, anaphylaxis.

    Other: hyperuricemia, exacerbation of gout.

    Pyridoxine: allergic reactions, hypersecretion of hydrochloric acid, numbness in the extremities, the emergence of a sense of compression of the limb - a symptom of "stocking" and "gloves", a rash, itchy skin.

    Overdose:Symptoms occur within 0.5-3 hours after drug administration: nausea, vomiting, dizziness, slurred speech, impaired vision, visual hallucinations.In severe overdose: respiratory distress syndrome, central nervous system depression, rapidly shifting from stupor to coma, severe indigestible convulsions, severe metabolic acidosis, acetonuria, hyperglycemia, impaired liver function, pulmonary edema, lethargy, pluneuritis. Treatment: with severe overdose, insufficient therapy leads to neurotoxicity with a fatal outcome. With adequate therapy, the prognosis is favorable. In case of an overdose: apply Activated carbon, gastric lavage, intravenously injected - short-acting barbiturates, pyridoxine, osmotic diuretics, sodium bicarbonate in the development of metabolic acidosis. Adults inject intravenously 5 g of pyridoxine. If the convulsions do not stop, the dose can be repeated. It is rare to prescribe a dose of more than 10 g. If pyridoxine is ineffective, diazepam.
    At clinical displays: adequate ventilation, maintenance of activity of cardiovascular system, prevention of aspiration of gastric contents.
    It is necessary to control the content of electrolytes, urea, glucose and partial pressure of gases in the blood.With the development of metabolic acidosis sodium hydrogen carbonate can enhance hypercapnia (continuous monitoring is necessary). Dialysis is prescribed if seizures and acidosis are not stopped by pyridoxine, diazepam and sodium bicarbonate.
    Interaction:
    Rifampicin induces certain enzymes of the cytochrome P450 system, accelerating the metabolism of prednisolone, phenytoin, quinidine, indirect anticoagulants, hormonal contraceptives, antifungals, cimetidine, cyclosporine.

    Isoniazid reduces the association of rifampicin with plasma proteins, pyrazinamide slows the excretion of rifampicin. Aminosalicylic acid impairs the absorption of rifampicin. The use of rifampicin with lomefloxacin and ofloxacin leads to a decrease in the antimicrobial activity of these combinations against mycobacteria tuberculosis.

    Antacids, opioid analgesics reduce the bioavailability of rifampicin Isoniazid: monoamine oxidase inhibitors (MAO) increase the risk of side effects from the central nervous system, cardiovascular system. Pyridoxine, glutamic acid reduce the risk of developing side effects of isoniazid.The combined use of isoniazid and cycloserine increases the risk of developing neurotoxic side effects. Pyrazinamide increases the concentration of isoniazid and rifampicin in the serum, slowing their excretion. When taking rifampicin together with pyrazinamide, hepatotoxicity increases.

    Aluminum hydroxide reduces the absorption of ethambutol. The use of ethambutol with aminoglycosides, ciprofloxacin, imipenem, carbamazepine, lithium salts, quinine increases the risk of neurotoxic action of drugs. Ethambutol enhances the antimicrobial activity of other antituberculous drugs.

    Pyridoxine weakens the action of levodopa in joint use, reduces the risk of toxic effects of antituberculous drugs on the central nervous system and peripheral nervous system.
    Special instructions:
    During the treatment it is necessary to refrain from taking ethanol. With prolonged therapy, it is necessary to regularly monitor the general blood test and liver function parameters. Laboratory indices are the activity of alanine aminotransferase and aspartate aminotransferase,the concentration of bilirubin in the blood serum can transiently increase without clinical manifestations. When there are signs of toxic hepatitis the drug is canceled.

    At the beginning of treatment, it is possible to increase cough, increase the amount of sputum. Patients with gout attacks in history, periodically monitor the concentration of uric acid in the serum. During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
    Form release / dosage:Film-coated tablets 75 mg + 400 mt + 150 mg + 275 mg + 10 mg, 75 mg + 400 mg + 150 mg + 275 mg + 15 mg
    Packaging:For 100, 500 and 1000 tablets (for hospitals), put in a jar a polymer or a can of polypropylene with a lid or with a cover made of polypropylene or high-pressure polyethylene. Banks, together with an equal number of instructions for use, are placed in a group package - a box of corrugated cardboard.
    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:
    2 years.Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-006567/10
    Date of registration:09.07.2010
    The owner of the registration certificate:FARMASINTEZ, JSC (Irkutsk) FARMASINTEZ, JSC (Irkutsk) Russia
    Manufacturer: & nbsp
    Information update date: & nbsp15.05.2016
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