Протиокомб®

General characteristics. Structure:

Active ingredients: 200 mg of a lomefloksatsin of a hydrochloride, 150 mg of Prothionamidum, 370 mg of Pyrazinamidum, 325 mg of Ethambutolum of a hydrochloride, 10 mg of a pyridoxine of a hydrochloride.

Excipients: starch prezhelatinizirovanny, povidone, polyethyleneglycol, croscarmellose sodium, silicon dioxide colloid, magnesium stearate, gipromelloz, глицерол, talc, titanium dioxide, dye yellow-orange.

Pharmacological properties:

Pharmacodynamics. ^{Протиокомб®} represents the combined five-component drug containing the fixed quantity of Prothionamidum, lomefloksatsin of a hydrochloride, Pyrazinamidum, Ethambutolum of a hydrochloride and pyridoxine of a hydrochloride.

Lomefloksatsin. An antimicrobic microbicide of a broad spectrum of activity from group of ftorkhinolon. Influences bacterial DNK-girazu enzyme, the providing superspiralling, forms a complex with its tetramer (A2B2 giraza subunit) and breaks a transcription and DNA replication, leads to death of a microbic cell.

Beta лактамазы, produced by activators, do not exert impact on activity of a lomefloksatsin. It is highly active concerning gram-negative aerobic microorganisms: Neisseria gonorrhoeae, Neisseria meningitidis, Escherichia coli, Citrobacter diversus, Klebsiella pneumoniae, Enterobacter cloacae, Proteus vulgaris, Salmonella spp., Shigella spp, Moraxella catarrhalis, Morganella morganii, Haemophilus influenzae edparainfluenzae, Legionella pneumophila, Pseudomonas aeruginosa.

Are moderately sensitive to the drug Staphylococcus aureus, Sraphylococcus epidermidis, Serratia liquifaciens and marcescens, Pseudomonas aeruginosa, Mycobacterium tuberculosis, Chlamydia trachomatis, Hafnia alvei, Citrobacter freundii, Aeromonas hydrophila, Proteus mirabilis and Proteus stuartii, Providencia rettgeri and Providencia alcalifaciens, Klebsiella oxytoca, Klebsiella ozaenae, Enterobacter aerogenes, Enterobacter agglomerans.

Are steady against the drug Streptococcus spp., Pseudomonas cepacia, Ureaplasma urealyticum, Treponema pallidum, Mycoplasma hominis and anaerobic bacteria.

Affects both on out of - and intracellularly located Mycobacterium tuberculosis, reduces terms of their allocation from an organism, provides more bystry rassasyvaniye of infiltrates. Affects the majority of microorganisms in low concentration (the concentration necessary for suppression of height of 90% of strains, usually no more than 1 mkg/ml). Resistance develops seldom.

Prothionamidum. Prothionamidum — Etioniamidum analog, is applied more widely in connection with smaller toxicity and a little bigger antimicrobic activity. The Minimum Overwhelming Concentration (MOC) of Prothionamidum is in limits of 0,6-3,2 mkg/ml. The mechanism of its action in blockade of synthesis of the mikoliyevy acids which are an important structural component of a cell wall Mycobacterium tuberculosis (MBT), the antagonist of niacin. In high concentration works bakteritsidno, breaking synthesis of protein of a microbic cell. It is effective concerning MBT steady against antitubercular drugs of 1 row. Influences both on out of - and intracellularly located mycobacteria. It is a little active concerning MBT of bull type, atypical mycobacteria and acid resisting saprophytes (MPK — 20-30 mkg/ml). Does not affect pathogenic nonspecific flora. Prothionamidum well gets into cells, in particular in macrophages. Activity of drug is higher in acid medium. Development of resistance of MBT to Prothionamidum at monotherapy happens quickly (in 2 months in 32%, in 4 months in 82%). At a combination therapy stability can develop by 6th month (to 15%). Cross stability of Prothionamidum is noted only with tiatsetazony.

Pyrazinamidum. A target of Pyrazinamidum is the gene of synthase of 1 mikobakterialny fatty acid participating in biosynthesis of mikoliyevy acid. 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. 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 MPK of Pyrazinamidum in vitro makes 20 mg/l. On not tubercular pathogenic microorganisms does not work.

Ethambutolum. Ethambutolum — bacteriostatic drug, is effective concerning typical and atypical mycobacteria of tuberculosis. The mechanism of effect of drug is connected with disturbance of synthesis of RNA in bacterial cells, it suppresses synthesis of a cell wall, blocking inclusion in it of mikoliyevy acids. Ethambutolum is active in the relation quickly - and slow-growing atypical mycobacteria. MPK of Ethambutolum makes — 0,78-2,0 mg/l. On not tubercular pathogenic microorganisms Ethambutolum does not work.

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. Lomefloksatsin. Reception of a lomefloksatsin inside together with the drugs which are a part ^{of Protiokomba®} does not influence the speed of its absorption from the digestive tract (DT).

Bioavailability of a lomefloksatsin - more than 90%. Drug after intake is quickly soaked up from a GIT. The maximum concentration (Cmax) makes 5,1 mg/l, achievement time — in 1-1,5 h. It is long circulates in an organism: an elimination half-life (T1/2) — 8-9 hours. Communication with blood proteins insignificant — 10%. Well gets into various bodies and fabrics where concentration, at 9-13 times the exceeding serumal are created. In small amounts is exposed to biotransformation in a liver with formation of 5 metabolites having insignificant antimicrobic activity. In 80% it is removed by kidneys, in 20% with excrements, then and saliva. The liver failure does not exert impact on biotransformation of a lomefloksatsin. An insignificant part of drug is exposed to metabolism with formation of metabolites. Average renal clearance — 145 ml/min. At elderly patients the plasma clearance decreases by 25%. At decrease in the clearance of creatinine (CC) to 10-40 ml/min. / 1,73 the sq.m of T1/2 increases.

Kidneys by canalicular secretion remove 70-80% (preferential in not changed look, 9% — in the form of glucuronides, 0,5% — in the form of other metabolites).

Prothionamidum. Prothionamidum is quickly soaked up in a GIT. Cmax of drug is reached in 2-3 hours after its reception. The size of the maximum concentration in a blood plasma corresponds to 4,5 mkg/ml that exceeds bacteriostatic concentration of Prothionamidum. It is well soaked up in acid medium. Gets into all fabrics and liquids of an organism, including into cerebrospinal fluid (at an inflammation of a meninx), into tuberculous focuses, into cavities and the encapsulated educations. Biotransformirutsya in a liver, partially turning into an active metabolite — sulphoxide. It is removed partially by kidneys — to 18,5%. Other part of medicine is removed with bile.

Pyrazinamidum. After reception ^{of Protiokomba®} of Cmax of Pyrazinamidum in a blood plasma reaches 12,0-14 mkg/ml in 2 hours. T1/2 of drug averages 10-12 hours. Pyrazinamidum well gets into bodies, fabrics and fluid mediums of an organism, including into lymph nodes and cerebrospinal liquid. It is metabolized in a liver. The main metabolite of Pyrazinamidum — pirazinovy acid — has antitubercular activity. About 10-20% of drug contact proteins of plasma. To 70% metabolites of Pyrazinamidum and in 10% — not changed drug are excreted with urine.

Ethambutolum. After reception ^{of Protiokomba®} 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. The maximum concentration of drug in plasma (60%) is reached through the 2nd p. T1/2 — 5-6 hours. On average 25% of drug contact proteins of plasma. Ethambutolum well gets into various bodies and biological liquids except for ascitic, pleural and liquor. Is exposed to biotransformation in a liver with formation of inactive metabolites. Ethambutolum is excreted with urine in 70% in not changed look and in 30% in the form of aldehydic and carboxyl inactive metabolites.

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

Indications to use:

• drug resistant tuberculosis with moderate stability of MBT (an isoniazid — to 10, rifampicin — to 40, Ethambutolum — to 2 mkg/ml);
• sharply progressing course of tuberculosis;
• tuberculosis with the accompanying inflammatory diseases caused by the nonspecific pathogenic flora sensitive to a lomefloksatsin.

Route of administration and doses:

Inside. Drug is accepted 1 time a day after food, preferably in the morning. ^{Протиокомб®} no more than 5 tablets are dosed on a lomefloksatsina of 13,2 mg/kg of body weight, but. Treatment duration — 3 months.

At indications ^Protiokomb® it is combined with streptomycin or Kanamycinum (intramusculary, in a dose of 16 mg/kg of 1 times a day within 3 months).

Side effects:

Lomefloksatsin. From the alimentary system: nausea, vomiting, dryness in a mouth, a gastralgia, an abdominal pain, diarrhea or locks, a meteorism, a pseudomembranous coloenteritis, a dysphagy, language discoloration, a loss of appetite or bulimia, a food faddism, dysbacteriosis, increase in activity of "hepatic" transaminases.

From a nervous system: fatigue, indisposition, adynamy, headache, dizziness, unconscious states, sleeplessness, hallucinations, spasms, hyperkinesia, tremor, paresthesias, nervousness, uneasiness, depression, excitement.

From urinogenital system: glomerulonephritis, dysuria, polyuria, anury, albuminuria, urethral bleedings, crystalluria, hamaturia, ischuria, hypostases; women have a vaginitis, a leukorrhea, intermenstrual bleedings, crotch pains, vaginal candidiasis; men have an orchitis, an epididymite.

From a metabolism: hypoglycemia, gout.

From a musculoskeletal system: arthralgia, vasculitis, spasms of gastrocnemius muscles, dorsodynias and breasts.

From bodies of a hemopoiesis and system of a hemostasis: bleedings from bodies of a GIT, thrombocytopenia, a purpura, increase in a fibrinolysis, nasal bleeding, a limfoadenopatiya.

From respiratory system: диспноэ, respiratory infections, bronchospasm, cough, phlegm hypersecretion, grippopodobny symptoms.

From sense bodys: vision disorder, pain and sonitus, eye pain.

From cardiovascular system (CCC): lowering of arterial pressure, tachycardia, bradycardia, premature ventricular contraction, arrhythmias, progressing of SN and stenocardia, thrombembolia of a pulmonary artery, myocardiopathy, phlebitis.

Allergic reactions: skin itch, small tortoiseshell, photosensitization, malignant exudative erythema (Stephens-Johnson's syndrome).

Influence on a fruit: in an experiment fetotoksichny action (arthropathy) is described.

Others: candidiasis, sweating strengthening, fever, thirst, superinfection.

Prothionamidum. From the alimentary system: nausea, vomiting, diarrhea, hypersalivation, "metal" smack in a mouth, an abnormal liver function.

From a nervous system: sleeplessness, excitement, a depression, uneasiness, it is rare — dizziness, drowsiness, a headache, an adynamy, in isolated cases — paresthesias, a peripheral neuropathy, an optic neuritis.

From CCC: tachycardia, weakness, orthostatic hypotension.

From endocrine system: a hypoglycemia at patients with a diabetes mellitus, a gynecomastia, a dysmenorrhea, a hypothyroidism, decrease in a potentiality.

Allergic reactions: skin rash.

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 TsNS: dizziness, 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.

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 a lomefloksatsin together with an isoniazid, Ethambutolum and, especially, Pyrazinamidum considerably increases antimicrobic activity concerning sensitive and especially steady MBT.

Combined use ^{of Protiokomba®} with probenetsidy slows down removal of a lomefloksatsin. Sukralfat and the antiacid means containing magnesium or aluminum create chelating complexes with lomefloksatsiny. Use of these means has to be carried out in 2 hours prior to or in 2 hours after reception of a lomefloksatsin.

Reception ^{of Protiokomba®} together with rifampicin leads to decrease in antimicrobic activity of this combination concerning MBT because of existing between lomefloksatsiny and antagonism rifampicin at the microbic level.

Prothionamidum. Prothionamidum in combination with lomefloksatsiny considerably increases antimicrobic activity concerning MBT. Antacids reduce absorbability of Prothionamidum. Prothionamidum reduces efficiency of hypotensive medicines.

Pyrazinamidum. Pyrazinamidum increases concentration of an isoniazid in blood serum, slowing down its 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, imipenemy, carbamazepine, lithium salts, quinine strengthens risk of neurotoxic effect of drug. Ethambutolum increases antimicrobic activity of other antitubercular drugs.

Pyridoxine. The pyridoxine weakens action of a levodopa at their combined use. The pyridoxine reduces risk of emergence of toxic impact of antitubercular drugs on the central and peripheral nervous system. The pyridoxine in structure ^{of Protiokomba®} does not influence antimicrobic activity of the drugs which are its part.

Contraindications:

• hypersensitivity to a lomefloksatsin, Prothionamidum, Pyrazinamidum, Ethambutolum, a pyridoxine;
• pregnancy, lactation period;
• children's age up to 18 years (the period of formation and growth of a skeleton);
• peptic ulcer of a stomach and 12-perstny gut;
• ulcer colitis;
• acute hepatitis, cirrhosis;
• 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. A period of validity - 2 years.

Issue conditions:

According to the recipe

Packaging:

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