Изокомб®

General characteristics. Structure:

Active ingredients: 60 mg of an isoniazid, 120 mg of rifampicin, 300 mg of Pyrazinamidum, 225 mg of Ethambutolum of a hydrochloride, 20 mg of a pyridoxine of a hydrochloride.

Excipients: starch corn, cellulose microcrystallic, croscarmellose sodium, silicon dioxide colloid, starch sodium glycollate, talc, magnesium stearate, опадрай brown 04B56936.

Pharmacological properties:

Pharmacodynamics. ^{Изокомб®} represents the five-component drug containing the fixed quantity of an isoniazid, rifampicin, Pyrazinamidum, Ethambutolum and pyridoxine of a hydrochloride.

The isoniazid 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 inhibiting concentration (MIC) makes 0,025-0,05 mg/l. The isoniazid possesses moderate action on slow and fast-growing atypical mycobacteria.

Rifampicin. The mechanism of effect of rifampicin consists in oppression of RNK-polimirazy DNA-dependent. At a tuberculosis infection rifampicin has bactericidal effect on intracellularly and vnekletochno the located microorganisms. For MIK tuberculosis mycobacteria for rifampicin makes 2 mg/l.

Pyrazinamidum. A target of Pyrazinamidum is the gene of synthase of 1 mikobakterialny fatty acid participating in biosynthesis of mikoliyevy acid. Affects intracellularly located mycobacteria, well gets into the centers of tubercular defeat. Is more effective in acid medium. For manifestation of bactericidal activity of Pyrazinamidum drug is exposed in an organism to enzymatic transformation into an active form - pirazinovy acid. At acid values рН MIK of Pyrazinamidum in vitro makes 20 mg/l.

Ethambutolum. Ethambutolum — bacteriostatic drug, is effective concerning mycobacteria of tuberculosis, resistant to other antitubercular drugs. MIK of Ethambutolum makes — 0,78-2,0 mg/l.

Ethambutolum suppresses synthesis of a cell wall, blocking inclusion in it of mikoliyevy acids. Ethambutolum is active against quickly - and slow-growing atypical mycobacteria.

Pyridoxine hydrochloride. Vitamin means. Participates in a metabolism. It is necessary for normal functioning of the central and peripheral nervous system. At treatment by antitubercular drugs there can come 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, rifampicin, Pyrazinamidum and Ethambutolum interaction of these drugs at the pharmacokinetic and microbiological levels is not observed.

Pharmacokinetics. Isoniazid. Reception of an isoniazid inside together with the drugs which are a part ^{of Izokomba®} does not influence the speed of its absorption from the digestive tract (DT). The isoniazid gets into many fabrics and liquids, including cerebrospinal fluid (SMZh). Time of achievement of the maximum concentration of drug in blood (Cmax) — 2 hours, the size of the maximum concentration — 6,6 mg/l, an elimination half-life — 5,8 hours. High Cmax the level of the maximum concentration and an elimination half-life (T1/2) is explained by delay of excretion of an isoniazid under the influence of Pyrazinamidum. The isoniazid practically does not contact proteins of plasma.

The isoniazid to 80-90% is excreted with urine and 10% with a stake within a day. Key products of metabolism of an isoniazid — N-atsetilizoniazid and isonicotinic acid.

Rifampicin. After reception ^{of Izokomba®} by healthy adults the maximum concentration of rifampicin in plasma reaches 16,3 mg/l. At administration of drug together with food absorption of rifampicin decreases by 30%. The maximum concentration of rifampicin is reached in 1,5-2 hours, the elimination half-life makes about 6 hours. 3 times less the rifampicin which is a part ^{of Izokomba®} contacts proteins of plasma. About 30% of drug are removed with urine.

Rifampicin is metabolized in a liver. The main metabolite - дезацетилрифампицин. All metabolites of rifampicin have antimicrobic activity concerning mycobacteria of tuberculosis (MBT).

Pyrazinamidum. After reception ^{of Izokomba®} of Cmax of Pyrazinamidum in plasma reaches 24,1 mg/l in 3 hours. T1/2 of drug averages 17 hours. The main active metabolite of Pyrazinamidum — pirazinovy acid. To 70% metabolites of Pyrazinamidum and about 4% — not changed drug are excreted with urine.

Ethambutolum. After reception ^{of Izokomba®} of Cmax of Ethambutolum makes 6,4-7,6 mg/l. High Cmax of Ethambutolum is explained by delay of its excretion under the influence of an isoniazid. Drug Cmax in plasma (60%) is reached in 2 h.

Ethambutolum is excreted with urine of 70% in not changed look in 30% in the form of aldehydic and carboxyl inactive metabolites. On average 25% of drug contact proteins of plasma.

Pyridoxine hydrochloride. It 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 get into all fabrics; collect preferential in a liver, it is less — in muscles and the central nervous system (CNS). Gets through a placenta, cosecretes with breast milk. T1/2 — 15-20 days. It is removed by kidneys.

Indications to use:

For the first time the diagnosed various forms and localizations of tuberculosis, with existence or lack of a bakteriovydeleniye (MBT sensitive to the main antitubercular drugs).

Route of administration and doses:

Inside. To adults and children since 13 years. Drug is dosed on rifampicin of 10 mg/kg of body weight, but no more than 5 tablets. Drug is accepted on an empty stomach in 30-40 minutes prior to a breakfast. The general course dose from 2 to 4 months depending on the nature of tubercular process.

At body weight> 80 kg the isoniazid is in addition appointed in the evening (the general daily dose of an isoniazid — 10 mg/kg). According to indications ^Izokomb® it is combined with streptomycin (intramusculary in a dose of 15 mg/kg of 1 times a day).

Side effects:

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 (CCC): heartbeat, stenocardia, increase in the arterial pressure (AP).

From the alimentary system: nausea, vomiting, gastralgia, toxic hepatitis.

Allergic reactions: skin rash, itch, hyperthermia, arthralgia.

Others: very seldom - a gynecomastia, a menorrhagia, tendency to bleedings and hemorrhages.

Rifampicin. From the alimentary system: nausea, vomiting, diarrhea, loss of appetite, erosive gastritis, pseudomembranous coloenteritis; increase in activity of "hepatic" transaminases in blood serum, a hyperbilirubinemia, hepatitis.

Allergic reactions: urticaria, eosinophilia, Quincke's disease, bronchospasm, arthralgia, fever.

From a nervous system: headache, decrease in visual acuity, ataxy, disorientation.

From an urinary system: невронекроз, intersticial nephrite.

Others: leukopenia, dysmenorrhea, induction of a porphyria, myasthenia, hyperuricemia, exacerbation of gout.

At irregular reception or when resuming treatment after a break the grippopodobny syndrome (fever, a fever, a headache, dizziness, a mialgiya), skin reactions, hemolitic anemia, a Werlhof's disease, an acute renal failure are possible.

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); round ulcer aggravation.

From TsNS: dizziness, headache, sleep disorders, 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.

Others: hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitization, increase in concentration of serumal iron.

Ethambutolum. From a nervous system and sense bodys: weakness, a headache, dizziness, consciousness disturbance, a disorientation, hallucinations, a depression, peripheral neuritis (paresthesias in extremities, numbness, paresis, an itch), an optic neuritis (decrease in visual acuity, disturbance of color perception, generally green and red colors, color-blindness, scotoma).

From the alimentary system: a loss of appetite, nausea, vomiting, a gastralgia, an abnormal liver function — increase in activity of "hepatic" transaminases.

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

Others: hyperuricemia, exacerbation of gout.

Pyridoxine hydrochloride. 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.

Treatment of patients with multicomponent drug reduces a pill burden on the patient by 3 times that promotes improvement of portability of drugs.

Interaction with other medicines:

Reception of an isoniazid, rifampicin, Ethambutolum and, especially, Pyrazinamidum in the combined dosage form considerably increases antimicrobic activity concerning MBT.

Rifampicin induces some enzymes of system R-450 cytochrome, accelerating metabolism of Prednisolonum, Phenytoinum, quinidine, peroral anticoagulants, hormonal contraceptives, antifungal drugs, Cimetidinum, cyclosporine A. The isoniazid reduces communication of rifampicin with proteins of plasma, Pyrazinamidum slows down rifampicin excretion. P-aminosalicylic acid (PASK) worsens rifampicin absorption. Reception of rifampicin with lomefloksatsiny and ofloksatsiny leads to decrease in antimicrobic activity of these combinations concerning MBT.

Antacids, opiodny analgetics reduce bioavailability of rifampicin.

Isoniazid. MAO inhibitors increase risk of development of side effects from TsNS, CCC.

The pyridoxine, glutaminic acid reduce risk of development of side effects of an isoniazid. Joint reception of an isoniazid and Cycloserinum increases risk of development of neurotoxic side effects.

Pyrazinamidum. Pyrazinamidum increases concentration of an isoniazid and rifampicin in blood serum, slowing down their excretion. At reception of rifampicin together with Pyrazinamidum the risk of development of hepatotoxic reactions increases.

Ethambutolum. Aluminum hydroxide reduces absorption of Ethambutolum. Reception of Ethambutolum with aminoglycosides, ciprofloxacin, imipenemy, carbamazepine, lithium salts, quinine strengthens risk of neurotoxic effect of drug. Ethambutolum increases antimicrobic activity of other antitubercular drugs.

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

Contraindications:

• at hypersensitivity to an isoniazid, rifampicin, Pyrazinamidum, Ethambutolum, a pyridoxine;
• pregnancy and breastfeeding;
• children's age up to 13 years;
• diseases of a liver and digestive tract in an acute phase;
• diseases of the central nervous system (epilepsy and other diseases with tendency to convulsive attacks);
• diseases of organs of sight (inflammation of an optic nerve, cataract, diabetic retinopathy, inflammatory diseases of eyes);
• gout;
• thrombophlebitis.

Storage conditions:

List B. In the dry, protected from light place unavailable to children, at a temperature not above 25 °C. Not to use after the term specified on packaging. A period of validity - 2 years.

Issue conditions:

According to the recipe

Packaging:

Tablets, coated. On 50 or 100 tablets in a polymeric can in a cardboard pack together with the instruction on a medical use. On 500 or 1000 tablets in a plastic bag in a polymeric container together with the instruction on a medical use.