Protubvita

General characteristics. Structure:

Active ingredients: 100,0 mg of an isoniazid, 400,0 mg of Pyrazinamidum, 150,0 mg of rifampicin, 15,0 mg of a pyridoxine.

The combined antitubercular drug having bactericidal effect on actively sharing Mycobacterium tuberculosis cells.

Pharmacological properties:

Pharmacodynamics. Protubvita contains a combination of three antitubercular drugs and B6 vitamin (pyridoxine). Bikyuizoniazid – has bactericidal effect on actively sharing Mycobacterium tuberculosis cells. The mechanism of its action consists in oppression of synthesis of the mikoliyevy acids which are a component of a cell wall of mycobacteria. For tuberculosis mycobacteria the minimum overwhelming concentration of drug makes 0,025-0,05 mg/l. The isoniazid possesses moderate action on slow and fast-growing atypical mycobacteria.

Pyrazinamidum - has bactericidal effect at acid values рН. Well gets into tuberculous focuses. Its activity is high at caseous and necrotic processes, caseous lymphadenites, tuberculomas. Is exposed to enzymatic transformation into an active form - pirazinoyevy acid. At acid values рН MPK of Pyrazinamidum in vitro makes 20 mg/l. On not tubercular pathogenic microorganisms does not work.

Rifampicin – an antibiotic of a broad spectrum of activity, inhibits synthesis of a DNA-dependent RNA polymerase. Has high activity concerning mycobacteria, including Mycobacterium tuberculosis, and some gram-positive activators. Activity concerning gram-negative microorganisms is lower. Cross resistance in relation to other antibiotics and chemotherapeutic means is not characteristic of it.

The pyridoxine (B6 vitamin) - participates in a metabolism. It is necessary for normal functioning of the central and peripheral nervous system. At a tuberculosis infection there comes deficit of a pyridoxine. In this regard the daily dose of vitamin raises to 60 mg. At a concomitant use of a pyridoxine inside with an isoniazid and Pyrazinamidum interaction of these drugs at the pharmacokinetic and microbiological levels is not observed. Reduces a neurotoxicity of antitubercular medicines.

Pharmacokinetics. Reception of an isoniazid inside together with the drugs which are a part of Protub-2 does not influence the speed of its absorption from digestive tract. The isoniazid is quickly and fully absorbed at intake, food reduces absorption and bioavailability. On a bioavailability indicator the great influence has effect of "the first passing" through a liver.

Time of achievement of the maximum concentration of drug in blood (TCmax) - 1-2 h, the maximum concentration of drug in blood (Cmax) after intake of a single dose of 300 mg - 3-7 mkg/ml. Communication with proteins insignificant - to 10%. Distribution volume - 0.57-0.76 l/kg. It is well distributed on all organism, getting into all fabrics and liquids, including cerebrospinal, pleural, ascitic; high concentration are created in pulmonary fabric, kidneys, a liver, muscles, saliva and a phlegm. Gets through a placental barrier and into breast milk. Is exposed to metabolism in a liver by acetylation with formation of inactive products. In a liver it is acetylated by N-acetyltransferase with formation of N-atsetilizoniazida which then turns into isonicotinic acid and моноацетилгидразин, having a hepatotoxic action by education by the mixed oksidazny system of P450 cytochrome at a N-hydroxylation of an active intermediate metabolite.

Speed of acetylation is genetically determined; people with "slow" acetylation have not enough N-acetyltransferase. Is inhibitor of isoenzymes of CYP2C9 and CYP2E1 in a liver. An elimination half-life from blood (T1/2) for "bystry acetylizers" - 0.5-1.6 h; for "slow" - 2-5 h. At a renal failure of T1/2 about 6.7 p. T1/2 for children aged from 1.5 up to 15 years - 2.3-4.9 h can increase, and newborns have 7.8-19.8 h (that is explained by imperfection of processes of acetylation at newborns). In spite of the fact that the indicator of T1/2 considerably varies depending on individual intensity of processes of acetylation, average T1/2 value makes 3 h (intake of 600 mg) and 5.1 h (900 mg).

At repeated purposes of T1/2 it is shortened to 2-3 h. It is removed generally by kidneys: during 24 h 75-95% of drug, generally in the form of inactive metabolites - N-atsetilizoniazida and isonicotinic acid are removed. At the same time at "bystry acetylizers" the maintenance of N-atsetilizoniazida makes 93%, and at "slow" - no more than 63%. Small amounts are removed with excrements. Drug is removed from blood during a hemodialysis; 5 h allow to remove a hemodialysis from blood to 73% of drug.

Pyrazinamidum. After intake the maximum concentration of Pyrazinamidum in plasma reaches 24,1 mg/l in 3 hours. The elimination half-life of drug averages 17 hours. The main active metabolite of Pyrazinamidum - pirazinoyevy acid. Also about 4% - in not changed look are allocated with kidneys with urine in the form of metabolites (to 70%).

Rifampicin. Absorption - bystry, meal reduces drug absorption. At intake on an empty stomach 600 mg the maximum concentration of drug in Cmax blood - 10 mkg/ml, and TCmax - 2-3 h. Communication with proteins of plasma – 84-91%. It is quickly distributed on bodies and fabrics (the greatest concentration in a liver and kidneys), concentration in saliva - 20% from plasma gets into a bone tissue. The seeming distribution volume - 1.6 l/kg is at adults and 1.1 l/kg - at children. Through a blood-brain barrier (GEB) gets only in case of an inflammation of a meninx. Gets through a placenta (concentration in fruit plasma - 33% of concentration in mother's plasma) and it is allocated with breast milk (the children raised by breast milk receive no more than 1% of a therapeutic dose of drug). It is metabolized in a liver with formation pharmacological of an active metabolite - 25-O-deatsetilrifampitsina.

Is an autoinduktor - accelerates the metabolism in a liver therefore system clearance - 6 l/h after reception of the first dose, increase up to 9 l/h after repeated reception. At intake also induction and intestines wall enzymes is probable. T1/2 after intake of 300 mg is 2.5 h, 600 mg - 3-4 h, 900 mg - 5 h. In several days of repeated reception bioavailability decreases, and T1/2 after multiple dose of 600 mg is shortened to 1-2 h. 80% - in the form of a metabolite are removed preferential with bile; kidneys - 20%. After reception of 150-900 mg of drug the amount of the rifampicin which is removed kidneys in not changed look depends on the size of the accepted dose and makes 4-20%.

At patients with disturbances of secretory function of kidneys of T1/2 it is extended only when doses of rifampicin exceed 600 mg. It is removed at peritoneal dialysis and at a hemodialysis. At patients with abnormal liver functions increase in concentration of rifampicin in plasma and lengthening of T1/2 is noted.

The pyridoxine is soaked up quickly throughout a small intestine, the bigger quantity is absorbed in a jejunum. It is metabolized in a liver with formation pharmacological of active metabolites (пиридоксаль phosphate and пиридоксаминофосфат). Piridoksal phosphate contacts proteins of plasma for 90%. Well gets into all fabrics; collects preferential in a liver, it is less - in muscles and the central nervous system. Gets through a placenta, cosecretes with breast milk. An elimination half-life - 15-20 days. It is removed by kidneys.

Indications to use:

Pulmonary tuberculosis and extra pulmonary tuberculosis – an intensive phase of therapy (limited focal and infiltrative tuberculosis without disintegration) and an aftercare phase. Leprosy. Prevention of tuberculosis at the persons which are in close contact with TB patients. At a bend of tuberkulinovy sensitivity; at increase of sensitivity to tuberculine; at giperergichesky sensitivity to tuberculine.

Route of administration and doses:

The dose is established individually, depending on character and a form of a disease. A way of introduction – inside. It is recommended to appoint drug in 30 minutes prior to food of 1 times a day. To wash down with water (from 0,5 to 1 glasses). No more than 0,6 g are dosed on rifampicin of 10 mg/kg of body weight. It is recommended to accept all daily dose in 1 reception on an empty stomach. The dosing mode for children. For children over 12 years 10-15 mg/kg/days in terms of rifampicin, but no more than 600 mg/days.

Features of use:

Appoint as a part of complex therapy, as a rule, at an initial stage of tubercular process. In the course of treatment control of activity of "hepatic" transaminases, uric acid in plasma is necessary. At emergence of signs of an abnormal liver function, it is necessary to stop administration of drug. After interruption of a course of treatment it is necessary to resume administration of drug with care, because of risk of development gepato-and nephrotoxicity. At use of drug coloring of saliva, a phlegm, urine and the lacrimal liquid in orange-red color is possible. During treatment it is necessary to appoint in addition ergocalciferol (vitamin D) for prevention of disturbances of exchange of calcium and phosphorus.

Side effects:

Connected with an isoniazid. From a nervous system: a headache, dizziness, it is rare - extraordinary fatigue or weakness, irritability, euphoria, sleeplessness, paresthesias, numbness of extremities, a peripheral neuropathy, an optic neuritis, a polyneuritis, psychoses, change of mood, a depression. At patients with epilepsy attacks can become frequent. From cardiovascular system: heartbeat, stenocardia, increase in arterial pressure. From the alimentary system: nausea, vomiting, gastralgia, toxic hepatitis. Allergic reactions: skin rash, itch, hyperthermia, arthralgia. Other: very seldom - a gynecomastia, a menorrhagia.

Connected with Pyrazinamidum. From the alimentary system: nausea, vomiting, diarrhea, "metal" smack in a mouth, an abnormal liver function (a loss of appetite, morbidity of a liver, a hepatomegalia, jaundice, a yellow hepatatrophia); aggravation of a round ulcer. From a nervous system: headache, sleep disorder, hyperexcitability, depressions; in some cases - hallucinations, spasms, confusion of consciousness. From bodies of a hemopoiesis and system of a hemostasis: thrombocytopenia, sideroblastny anemia, vacuolation of erythrocytes, porphyria, hypercoagulation, splenomegaly. From a musculoskeletal system: arthralgia, mialgiya. From an urinary system: dysuria, intersticial nephrite. Allergic reactions: skin rash, small tortoiseshell. Other: hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitization, increase in concentration of serumal iron.

Connected with rifampicin. From the alimentary system: nausea, vomiting, diarrhea, increase in level of "hepatic" transaminases (alaninaminotranspherase (ALT), aspartate aminotransferase (nuclear heating plant), alkaline phosphatase), hyperbilirubinemia, loss of appetite, erosive gastritis, pseudomembranous coloenteritis, hepatitis. From a nervous system: headache, incoordination of movements, vision disorder, disorientation. From an urinary system: intersticial nephrite. Allergic reactions: skin rash, itch, Quincke's edema, bronchospasm, fever, small tortoiseshell, eosinophilia. Other: arthralgia; seldom – a leukopenia, disturbance of a menstrual cycle, a dysmenorrhea, induction of a porphyria, muscular weakness, a hyperuricemia, an exacerbation of gout.

Connected with a pyridoxine. Allergic reactions, hypersecretion of hydrochloric acid, numbness, emergence of feeling of a prelum in extremities - a symptom of "stockings" and "gloves", it is rare - skin rash, a skin itch.

Interaction with other medicines:

Isoniazid. At a combination with paracetamol also nephrotoxicity increases gepato-; the isoniazid induces system of P450 cytochrome therefore metabolism of paracetamol increases up to toxic products. Ethanol raises a hepatotoxic of an isoniazid and accelerates his metabolism. Reduces theophylline metabolism that can lead to increase in its concentration in blood. Cycloserinum and Disulfiramum strengthens adverse central effects of an isoniazid. The combination to a pyridoxine reduces danger of development of peripheral neuritis.

With care it is necessary to combine with potentially neuro, gepato-and nefrotoksichny medicines because of danger of strengthening of side effect. Strengthens action of derivatives of coumarin and an indandion, benzodiazepines, carbamazepine as reduces their metabolism due to activation of system of P450 cytochrome. Glucocorticosteroids accelerate metabolism in a liver and reduce active concentration in blood. Suppresses metabolism of Phenytoinum that leads to increase in its concentration in blood and to strengthening of toxic effect (correction of the mode of dosing of Phenytoinum, especially at patients with slow acetylation of an isoniazid can be required).

Pyrazinamidum. Let's combine with other antitubercular medicines: at chronic destructive forms Pyrazinamidum is recommended to be combined with rifampicin or Ethambutolum (portability is better, than at a combination to rifampicin, but the effect is weaker). The probability of development of a hepatotoxic action increases at combined use with rifampicin. At simultaneous use with the medicines blocking canalicular secretion decrease in their removal and strengthening of toxic reactions is possible. Strengthens antitubercular action of an ofloksatsin and lomefloksatsin.

Rifampicin. Reduces activity of peroral anticoagulants, peroral hypoglycemic medicines, hormonal contraceptives, drugs of a foxglove, antiarrhytmic medicines (Disopyramidum, пирменол, quinidine, мексилетин, токаинид), glucocorticosteroids, dapsone, Phenytoinum, hexobarbital, a nortriptilin, benzodiazepines, sex hormones, theophylline, chloramphenicol, a ketokonazol, an itrakonazol, cyclosporine A, Azathioprinum, beta adrenoblockers, blockers of slow calcium channels, enalapril, Cimetidinum (rifampicin causes induction of some fermental systems of a liver, accelerates metabolism). Antacids, opiates, anticholinergic medicines and кетоконазол reduce (in case of a concomitant use inside) bioavailability of rifampicin. The isoniazid and/or Pyrazinamidum increase the frequency and weight of abnormal liver functions more than at purpose of one rifampicin, at patients with the previous liver disease. The drugs of p-aminosalicylic acid containing bentonite (aluminum hydrosilicate), it is necessary to appoint not earlier than in 4 hours after administration of drug since absorption disturbance is possible.

Pyridoxine. Weakens action of a levodopa at their combined use. The pyridoxine reduces risk of development of toxic effect of antitubercular drugs on the central and peripheral nervous system.

Contraindications:

Children's age (up to 12 years), pregnancy and the period of a lactation, jaundice, diseases of kidneys with decrease in secretory function, acute diseases of a liver, hypersensitivity to the components which are a part of drug.

With care. Liver diseases, a diabetes mellitus, advanced age, the exhausted patients.

Overdose:

Isoniazid. Symptoms: dizziness, a dysarthtia, slackness, a disorientation, a hyperreflexia, a peripheral polyneuropathy, an abnormal liver function, a metabolic acidosis, a hyperglycemia, a glucosuria, a ketonuria, spasms (in 1-3 h after drug use), a coma. Treatment: peripheral polyneuropathy (vitamins: pyridoxine, thiamin, glutaminic acid, niacinamide; massage, physiotherapeutic procedures); spasms (a pyridoxine in oil a hydrochloride - 200-250 mg, 25% in oil sulfate magnesium solution - 10 ml, diazepam); abnormal liver function (methionine, thioctic acid, cyanocobalamine).

Pyrazinamidum. Symptoms: an abnormal liver function, strengthening of expressiveness of side effects from TsNS. Treatment: symptomatic.

Rifampicin. Symptoms: fluid lungs, lethargy, confusion of consciousness, spasm. Treatment: symptomatic; gastric lavage, purpose of absorbent carbon; artificial diuresis.

Storage conditions:

List B. Drug should be stored in the dry, protected from light place, at a temperature not above 25 °C. To protect from children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, on 100, 500 or 1000 tablets (for hospitals) in a polymeric can.