Prothiocomb® (Protiocomb® )

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceLomefloxacin + Pyrazinamide + Prothionamide + Etambutol + PyridoxineLomefloxacin + Pyrazinamide + Prothionamide + Etambutol + Pyridoxine
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  • Prothiocomb®
    pills inwards 
    AKRIKHIN HFK, JSC     Russia
  • Protub-5
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    FARMASINTEZ, JSC (Irkutsk)     Russia
    • Dosage form: & nbspTfilm-covered abeys.
    Composition:

    One tablet contains:

    active substances: protionamid in terms of 100% substance - 150 mg, of lomefloxacin hydrochloride, calculated as 100% lomefloxacin - 200 mg, pyrazinamide calculated as 100% substance - 370 mg, ethambutol hydrochloride, calculated as 100% substance - 325 mg, pyridoxine hydrochloride, calculated 100% of the substance - 10 mg;

    Excipients: pregelatinized starch - 50.9 mg macrogol 6000 - 3.6 mg Povidone (Kollidon 90 F) - 11 mg sodium croscarmellose - 40.5 mg, colloidal silicon dioxide - 6 mg of magnesium stearate - 12 mg;

    composition of the shell: Hypromellose - 40.2 mg macrogol 6000 - 4.8 mg Glycerol - 4.2 mg talc - 6 mg, titanium dioxide - 1.8 mg, sunset yellow dye (yellow-orange Sikovit) - 3 mg.

    Description:

    Tablets, film-coated, from light orange to dark orange color, oval, biconcave. At the break, the tablet is yellow.

    Pharmacotherapeutic group:antituberculous agent combined
    ATX: & nbsp

    J.04.A.M   Combinations of antituberculous drugs

    Pharmacodynamics:

    Lomesfloxacin - a broad-spectrum antimicrobial bactericide from the group of fluoroquinolones. Affects the bacterial enzyme DNA-gyrase, which provides supercoiling, forms a complex with its tetramer (subunit of gyrase A2B2) and disrupts transcription and replication of DNA, leads to the death of the microbial cell.

    Beta-lactamases, produced by pathogens, do not affect the activity of lomefloxacin.

    Active for gram-negative aerobic microorganisms: Citrobacter diversus, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, Pseudomonas aeruginosa; Gram-positive aerobic microorganisms: Staphylococcus saprophyticus.

    With a minimum inhibitory concentration (MIC) of 2 μg / ml, is active against the following microorganisms: Gram-positive aerobic microorganisms: Staphylococcus aureus (including methicillin-resistant strains), Staphylococcus epidermidis (including methicillin-resistant strains); Gram-negative aerobic microorganisms: Aeromonas hydrophila, Citrobacter freundii, Enterobacter aerogenes, Enterobacter agglomerans, Haemophilus parainfluenzae, Hafnia alvei, Klebsiella oxytoca, Klebsiella ozaenae, Morganella morganii, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Serratia liquefaciens, Serratia marcescens; other microorganisms: Legionella pneumophila.

    To the preparation are stable: A, B, D and G groups of streptococcus, Streptococcus pneumoniae, Pseudomonas cepacia, Ureaplasma urealyticum, Mycoplasma hominis and anaerobic bacteria.

    It acts both on the outside and on the intracellularly located Mycobacterium tuberculosis, reduces the time of their isolation from the body, provides a faster resolution of infiltrates. Most microorganisms act at low concentrations (the concentration necessary to control the growth of 90% of strains, usually not more than 1 μg / ml). Resistance is rare.

    Prothionamide - an analog of ethionamide, is used more widely due to lower toxicity and somewhat greater antimicrobial activity. The minimum inhibitory concentration (MIC) is 0.6-3.2 μg / ml. It blocks the synthesis of mycolic acids, which are an important structural component of the cell wall of Mycobacterium tuberculosis (MBT), a nicotinic acid antagonist. In high concentrations acts bactericidal, disrupting the synthesis of the protein of the microbial cell.

    Effective in relation to MBT, resistant to anti-tuberculosis drugs I series. Affects both extracellular and intracellularly located mycobacteria.

    Low-active in a relationship Mycobacterium bovis, atypical mycobacteria and acid-resistant saprophytes (MIC - 20-30 μg / ml). The pathogenic nonspecific flora does not work. Penetrates into cells, in particular macrophages. Has a bactericidal effect in an acidic environment.The development of MBT resistance to protionamide with monotherapy is rapid (in 2 months 32%, 4 months - 82%). With combined therapy, resistance can develop by 6 months, (up to 15%).

    Pyrazinamide acts on the gene of synthetase I of the mycobacterial fatty acid, involved in the biosynthesis of mycolic acid. Has a bactericidal effect in an acidic environment. Penetrates into tubercular foci. Its activity is high in caseous-necrotic processes, caseous lymphadenitis, tuberculomas. It is subjected to enzymatic conversion into an active form of pyrazinic acid. In an acidic environment, the IPC pyrazinamide in vitro is 20 mg / l. On non-tuberculosis pathogens does not work.

    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.

    Active only with respect to intensively dividing cells. Suppresses the growth and reproduction of mycobacterium tuberculosis, resistant to streptomycin, isoniazid, PASK, ethionamide, kanamycin. MPC - 0,78-2 mg / l. On non-tuberculosis pathogens does not work.

    Pyridoxine - vitamin B6, is involved in the metabolism; is necessary for the normal functioning of the central and peripheral nervous system. Entering the body, phosphorylated, converted to pyridoxal-5-phosphate and is part of the enzymes that carry 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).

    Pharmacokinetics:

    Lomefloxacin. Absorption - 95-98%; food intake reduces absorption by 12%. Time to reach the maximum concentration is 0.8-1.5 hours. The maximum concentration of lomefloxacin in the blood plasma after ingestion of 100 mg is 0.8 μg / ml, 200 mg - 1.4 μg / ml, 400 mg - 3-5 , 2 μg / ml. The intake of food reduces the maximum concentration of lomefloxacin in the blood plasma by 18% and increases the time to reach a maximum concentration of up to 2 hours. The equilibrium concentration of lomefloxacin in plasma is determined after 48 hours. The connection with plasma proteins is 10%. It penetrates well into organs and tissues, where the concentration of lomefloxacin is 2-7 times higher than in plasma.A small part undergoes metabolism with the formation of metabolites. The half-life (T1/2) - 8-9 hours; average renal clearance - 145 ml / min. In elderly patients plasma clearance is reduced by 25%. With a decrease in creatinine clearance up to 10-40 ml / min / 1.73 m2 the half-life period increases. By the kidneys, 70-80% of the tubular secretion is excreted (mostly unchanged, 9% - in the form of glucuronides, 0.5% - in the form of other metabolites); through the intestine - 20-30%.

    Prothionamide. Absorption in the gastrointestinal tract is rapid. The time to reach the maximum concentration in blood plasma is 2-3 hours. It easily penetrates into healthy and pathologically altered tissues (tuberculous foci, caverns in the lungs, serous and purulent pleural effusion, cerebrospinal fluid with meningitis). Metabolised in the liver (one of the metabolites - sulfoxide, has tuberculostatic activity). It is excreted by the kidneys and with bile (15-20% in unmodified form).

    Pyrazinamide. Quickly and completely absorbed in the gastrointestinal tract. Connection with proteins plasma - 10-20%. The time to reach the maximum concentration is 1-2 hours. It penetrates well into tissues and organs. Metabolised in the liver, where the first active metabolite - pyrazinic acid,which later turns into an inactive metabolite - 5-hydroxypyrazinic acid. The half-life is 8-9 hours. It is excreted by the kidneys: in unchanged form - 3%, in the form of pyrazinic acid - 33%, in the form of other metabolites - 36%. Removed during hemodialysis.

    Ethambutol. Absorption is high; bioavailability is 75-80%. After oral administration of a dose of 25 mg, the maximum concentration is reached in 2-4 hours, the maximum concentration of ethambutol in plasma is 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. The half-life period from plasma is 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% (unchanged). It is excreted in hemodialysis and peritoneal dialysis.

    Pyridoxine. Absorbed rapidly throughout the small intestine, a larger amount is absorbed in the jejunum.Metabolised in the liver with the formation of pharmacologically active metabolites (pyridoxal-5-phosphate and pyridoxamine phosphate). Pyridoxal-5-phosphate 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. The half-life of plasma is 15-20 days. It is excreted by the kidneys, as well as during hemodialysis.

    Indications:Multiple-resistant tuberculosis with moderate resistance to MBT (isoniazid - to 10, rifampicin - up to 40, ethambutol - up to 2 mcg / ml), rapidly progressing tuberculosis.
    Contraindications:

    Hypersensitivity, peptic ulcer of stomach and duodenum; ulcerative colitis, acute hepatitis, cirrhosis, childhood (under 18 years), pregnancy, lactation.

    Carefully:

    Cerebral atherosclerosis, epilepsy other diseases of the central nervous system with epileptic syndrome, lengthening of the interval QT, hypokalemia, simultaneous reception of antiarrhythmic drugs IA class (quinidine, procainamide) and III class (amiodarone, sotalol); diseases of the organs of vision (inflammation of the optic nerve, cataracts, diabetic retinopathy, inflammatory diseases of the eyes); gouty arthritis, chronic renal failure, thrombophlebitis, hyperuricemia, hepatic insufficiency; diabetes; cardiac ischemia.

    Dosing and Administration:

    Inside, 1 time per day after meals with a full glass of water, preferably in the morning.

    Dosing is carried out by lomefloxacin - 13.2 mg / kg, but not more than 5 tablets.

    The course of treatment - 3 months.

    If necessary, can be combined with streptomycin or kanamycin intramuscularly - 16 mg / kg once a day for 3 months.

    Side effects:

    From the digestive system: nausea, vomiting, dryness of the oral mucosa or hypersalivation, abdominal pain, hypersecretion of hydrochloric acid, diarrhea or constipation, flatulence, pseudomembranous colitis, dysphagia, discoloration of the tongue, "metallic" taste in the mouth, loss of appetite or bulimia, taste perversion , dysbiosis, increased activity of "liver" transaminases, impaired liver function (tenderness in the liver, hepatomegaly, jaundice, "yellow" liver atrophy); exacerbation of peptic ulcer.

    From the nervous system and sense organs: fatigue, malaise, asthenia, headache, dizziness, fainting, insomnia, hallucinations, confusion, convulsions, hyperkinesia, tremor, paresthesia, nervousness, anxiety, depression, agitation, peripheral neuritis (paresthesia in the extremities, numbness, paresis, itching ), optic neuritis (decreased visual acuity, color perception, mostly green and red, color blindness, scotoma), pain and noise in the ears, pain in the eyes.

    From the genitourinary system: glomerulonephritis, interstitial nephritis, dysuria, polyuria, anuria, albuminuria, urethral bleeding, crystalluria, hematuria, urinary retention, edema; in women - vaginitis, leukorrhea, intermenstrual bleeding, pain in the perineum, dysmenorrhea, vaginal candidiasis; in men - orchitis, epididymitis, gynecomastia, decreased potency.

    From the endocrine system: hypoglycemia, gout, hypothyroidism.

    From the side of the musculoskeletal system: arthralgia, gastrocnemius muscle cramps, back and chest pain, myalgia.

    On the part of the organs of hematopoiesis and the system of hemostasis: bleeding from the organs of the gastrointestinal tract, thrombocytopenia, sideroblastic anemia, erythrocyte vacuolization, porphyria, hypercoagulation, splenomegaly, purpura, fibrinolysis, nosebleeds, lymphadenopathy.

    From the respiratory system: dyspnea, bronchospasm, cough, hypersecretion of sputum, flu-like syndrome, respiratory infections.

    From the side of the cardiovascular system: lowering of arterial pressure, tachycardia, bradycardia, extrasystole, arrhythmias, progression of heart failure and angina, pulmonary embolism, myocardiopathy, phlebitis, orthostatic hypotension, vasculitis.

    Allergic reactions: skin rash, itching, urticaria, dermatitis, photosensitivity, malignant exudative erythema (Stevens-Johnson syndrome), anaphylaxis.

    Other: increased sweating, chills, thirst, superinfection, hyperthermia, acne, hyperuricemia, increased concentration of serum iron, the appearance of a feeling of compression in the extremities - a symptom of "stocking" and "gloves."

    Overdose:

    Symptoms: nausea, vomiting, impaired liver function, hallucinations, polyneuritis, increased severity of side effects from the central nervous system.

    Treatment: induction of vomiting or gastric lavage, adequate hydration, symptomatic therapy.

    Interaction:

    Lomefloxacin does not interact with theophylline, caffeine.

    Lomefloxacin increases the activity of indirect anticoagulants and increases the toxicity of non-steroidal anti-inflammatory drugs.

    Do not take antacid medicines and sucralfate for 4 hours before and 2 hours after taking Lomefloxacin (forms with them chelate compounds, which reduces its bioavailability).

    Drugs that block tubular secretion, slow the excretion of lomefloxacin.

    Lomefloxacin is compatible with isoniazid, ethambutol and pyrazinamide.

    The combined use of the drug with probenecid slows the withdrawal of lomefloxacin, with rifampicin leads to a decrease in antimicrobial activity of this combination against MBT due to the antagonism existing at the microbial level between lomefloxacin and rifampicin.

    Pyrazinamide increases the concentration of isoniazid in the serum, slowing its excretion.

    The likelihood of developing a hepatotoxic effect of pyrazinamide is increased when combined with rifampicin.

    With the simultaneous use of pyrazinamide with drugs that block tubular secretion, it is possible to reduce their excretion and enhance toxic reactions.

    Pyrazinamide strengthens the anti-tuberculosis effect of ofloxacin and lomefloxacin.

    Prothionamide is compatible with isoniazid, pyrazinamide, cycloserine and other antituberculous drugs.

    Isoniazid increases the concentration of protionamide in plasma.

    Antacids reduce the absorption of protionamide.

    Prothionamide reduces the effectiveness of antihypertensive drugs.

    Etambutol enhances the effects of antituberculous drugs, the neurotoxicity of ciprofloxacin, aminoglycosides, asparaginase, carbamazepine, lithium salts, imipenem, methotrexate, quinine.

    Pyridoxine enhances the action of diuretics; weakens the activity of levodopa.

    Reduces the risk of toxic effects of antituberculosis drugs on the central and peripheral nervous system.

    Pyridoxine does not affect the antimicrobial activity of the drugs that make up the drug.

    Special instructions:

    During the treatment period, prolonged exposure to sunlight and the use of artificial UV light should be avoided (evening reception reduces the risk of reaction to UV radiation). At the first signs of photosensitivity (the increase in skin sensitivity, burn, hyperemia, swelling, the appearance of blisters, rash, itching, dermatitis) or allergic reactions, manifestations of neurotoxicity (agitation, convulsions, tremors, photophobia, confusion, toxic psychoses, hallucinations) .

    At the beginning of treatment, it is possible to increase cough, increase the amount of sputum.

    It is necessary to monitor the function of the liver and kidneys every month, the function of the eyes, the picture of peripheral blood, the activity of alanine aminotransferase and the concentration of uric acid in the blood.

    In patients with diabetes, the risk of hypoglycemia increases.

    When determining urobilinogen using Ehrlich's reagent, the results may be distorted.

    Effect on the ability to drive transp. cf. and fur:

    During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions.

    Form release / dosage:

    Tablets coated with a film coat, 200 mg + 370 mg + 150 mg + 325 mg + 10 mg.

    Packaging:

    For 50 or 100 tablets in a jar of polypropylene (polyethylene).

    Each bank along with instructions for use in a pack of cardboard.

    For 500 tablets in a bag of polyethylene film.

    A polyethylene bag together with instructions for use in a container made of polypropylene (polyethylene) (for hospital).

    Storage conditions:

    In a dry, the dark 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.

    Terms of leave from pharmacies:On prescription
    Registration number:P N003650 / 01
    Date of registration:15.07.2009 / 07.08.2015
    Expiration Date:Unlimited
    The owner of the registration certificate:AKRIKHIN HFK, JSC AKRIKHIN HFK, JSC Russia
    Manufacturer: & nbsp
    Representation: & nbspAKRIKHIN OJSC AKRIKHIN OJSC Russia
    Information update date: & nbsp04.10.2016
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