Ломекомб®

General characteristics. Structure:

Active ingredients: 135 mg of an isoniazid, 200 mg of a lomefloksatsin of a hydrochloride, 370 mg of Pyrazinamidum, 325 mg of Ethambutolum of a hydrochloride, 10 mg of a pyridoxine of a hydrochloride.

Excipients: povidone, polyethyleneglycol, croscarmellose sodium, silicon dioxide colloid, magnesium stearate, a gipromelloz, глицерол, talc, titanium dioxide, dye — ferrous oxide red, sugar milk.

Pharmacological properties:

Pharmacodynamics. ^{Ломекомб®} represents the combined five-component drug containing the fixed quantity of an isoniazid, lomefloksatsin of a hydrochloride, Pyrazinamidum, Ethambutolum of a hydrochloride 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 overwhelming concentration of drug (MPK) makes 0,025-0,05 mg/l. The isoniazid possesses moderate action on slow and fast-growing atypical mycobacteria.

Lomefloksatsin. An antimicrobic microbicide of a broad spectrum of activity from group of ftorkhinolon. Influences bacterial DNK-girazu enzyme, the providing sverkhpiralization, forms a complex with its tetramer (A2B2 giraza subunit) and breaks a traskription 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 in the relation of 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 moderate are sensitive to the drug Staphylococcus aureus, Sraphylococcus epidermidis, Serratia liguifaciens 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.

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 carrying out 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 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, lomefloksatsiny, Pyrazinamidum and Ethambutolum do not observe interaction of these drugs at the pharmacokinetic and microbiological levels.

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

Lomefloksatsin. Reception of a lomefloksatsin inside together with the drugs which are a part ^{of Lomekomba®} does not influence the speed of its absorption from a GIT.

Bioavailability of a lomefloksatsin — more than 90%. Drug after intake is quickly soaked up from digestive tract. Cmax makes 5,1 mg/l, time of achievement of Cmax — in 1-1,5 h. It is long circulates in an organism: an elimination half-life in blood — 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. T1/2 - 8-9 h; 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).

Pyrazinamidum. After reception ^{of Lomekomba®} 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 Lomekomba®} 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). Get through a placenta, cosecretes with breast milk. T1/2 — 15-20 days. It is removed by kidneys.

Indications to use:

• 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, irrespective of meal of 1 times a day, it is more preferable in the first half of day. ^{Ломекомб®} no more than 5 tablets are dosed on a lomefloksatsina of 13,2 mg/kg of body weight, but.

Treatment duration — 3 months. At big body weight> 80 kg the isoniazid is in addition appointed in the evening (the general daily dose of an isoniazid to 10 mg/kg).

According to indications ^Lomekomb® it is combined with streptomycin (intramusculary in a dose of 16 mg/kg of 1 times a day within 3 months).

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.

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 CCC: decrease in the ABP, 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.

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 Lomekomba®} 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 Lomekomba®} together with rifampicin leads to decrease in antimicrobic activity of this combination concerning MBT because of existing between lomefloksatsiny and antagonism rifampicin.

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. PASK (p-aminosalicylic acid) worsens rifampicin absorption. Antacids, opioid analgetics reduce bioavailability of rifampicin.

Isoniazid. MAO inhibitors increase risk of development of side effects from TsNS, CCC. The pyridoxine (B6 vitamin), 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:

• hypersensitivity to a lomefloksatsin, an isoniazid, 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 in a cardboard pack; on 500 or 1000 tablets together with the application instruction in a plastic bag in a polymeric container.