Combinet-Neo® (Combitub-Neo®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceLomefloxacin + Pyrazinamide + Prothionamide + EthambutolLomefloxacin + Pyrazinamide + Prothionamide + Ethambutol
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  • Combinet-Neo®
    pills inwards 
    Simpex Pharma Pvt Ltd.     India
    • Dosage form: & nbspfilm coated tablets
    Composition:

    Active substances:

    Lomefloxacin hydrochloride in recalculation on lomefloksatsin 200 mg.

    Pyrazinamide 400 mg.

    Prothionamide 188 mg.

    Etambutol hydrochloride 360 ​​mg.

    Excipients:

    Lactose monohydrate 35.00 mg, microcrystalline cellulose 76.50 mg, hypromellose 9.25 mg, corn starch 3.50 mg, gelatin 7,0 mg, sodium carboxymethyl starch 40.00 mg, crospovidone 20.00 mg, silicon dioxide colloid 8.00 mg, magnesium stearate 8.00 mg, talc 4.00 mg.

    Tablet casing: Hypromellose E5 2,0 mg, hypromellose E15 19.5 mg, macrogol 4000 5.2 mg, propylene glycol 3.0 mg, titanium dioxide 3.5 mg, talc 5.65 mg, iron dye oxide red 1.15 mg.
    Description:Tablets of the red-brown color are elongated biconvex, covered with a film membrane. On the fracture - yellow with impregnations of white color.
    Pharmacotherapeutic group:Anti-tuberculosis combination drug
    ATX: & nbsp

    J.04.A.M   Combinations of antituberculous drugs

    Pharmacodynamics:

    COMBITUB-Neo® is a combined preparation containing fixed amounts of lomefloxacin, protionamide, pyrazinamide and ethambutol.The combined use of the active substances included in the preparation reduces the risk of developing resistance, which develops with monotherapy.

    Pharmacodynamics:

    Lomefloxacin

    Antimicrobial bactericide of broad spectrum of action 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 against gram-negative aerobes: Citrobacter diversus, Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, Pseudomonas aeruginosa (only for urinary tract infections); Gram-positive aerobes: Staphylococcus saprophyticus. In vitro with a minimum inhibitory concentration of 2 μg / ml is active against the following microorganisms (however, clinical efficacy in infections caused by these microorganisms is not proven): gram-positive aerobes: Staphylococcus aureus (including methicillin-resistant strains), Staphylococcus epidermidis (including methicillin-resistant strains); gram-negative aerobes: 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. The drug is stable: Streptococcus spp. groups A, AT, D and G, Streptococcus pneumoniae, Pseudomonas cepacia, Ureaplasma urealyticum, Mycoplasma hominis and anaerobic bacteria.

    It acts both on the outside and on the intracellularly located Mycobacterium tuberculosis (MBT), 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

    The anti-tuberculosis drug of the II series, in chemical structure, is close to ethionamide. The minimum inhibitory concentration (MIC) of the protionamide is in the range of 0.6-3.2 μg / ml. The mechanism of its action is the blockade of the synthesis of mycolic acids, which are an important structural component of the cell wall Mycobacterium tuberculosis, antagonist of nicotinic acid. In high concentrations acts bactericidal, disrupting the synthesis of the protein of the microbial cell. Effective against MBT, resistant to anti-TB drugs I series. Affects both extracellular and intracellularly located mycobacteria.Maloactive in relation to MBT bovine type, atypical mycobacteria and acid-resistant saprophytes (MIC - 20-30 μg / ml). The pathogenic nonspecific flora does not work. Prothionamide it penetrates well into cells, particularly macrophages. The activity of the drug is higher in an acidic medium. The use in combination with other anti-tuberculosis drugs reduces the likelihood of development of MBT resistance.

    Pyrazinamide

    The pyrazinamide target is the synthase I gene of mycobacterial fatty acid, which is involved in the biosynthesis of mycolic acid. Pyrazinamide has bactericidal action at acidic pH values. It penetrates well into the tuberculosis foci. Its activity is high in caseous-necrotic processes, caseous lymphadenitis, tuberculosis. To manifest the bactericidal activity of pyrazinamide, the preparation is subjected to enzymatic conversion into the active form - pyrazinic acid. At acidic pH values, the MPC of pyrazinamide in vitro is 20 mg / l. Non-tuberculosis pathogens are not effective.

    Ethambutol

    Etambutol is an anti-tuberculosis drug that acts bacteriostatically, is effective against typical and atypical mycobacteria tuberculosis.The mechanism of action of the drug is associated with a violation of the synthesis of RNA in bacterial cells, it suppresses the synthesis of the cell wall, blocking the inclusion of mycolic acids in it. Ethambutol Active against rapidly and slowly growing atypical mycobacteria. The MIC of ethambutol is - 0,78-2,0 mg / l. On non-tubercular pathogens ethambutol It does not work.

    Pharmacokinetics:

    Lomefloxacin

    Lomefloxacin intake in conjunction with the drugs that are part of COMBITUB-Neo®, does not affect the rate of its absorption from the gastrointestinal tract (GIT).

    Bioavailability of Lomefloxacin is more than 90%. The drug is rapidly absorbed from the digestive tract after ingestion. The maximum concentration in the blood plasma (CmOh) after ingestion of 400 mg is 5.1 mg / l, the time to reach CmOh - 1-1.5 hours Continuously circulates in the body: half-life (T1/2) - 8-9 hours. The connection with blood proteins is insignificant - 10%. It penetrates well into various organs and tissues, where concentrations are created, 2-7 times higher than plasma ones. Minor part drug is metabolized with the formation of metabolites. The average renal clearance is 145 ml / min.In elderly patients, plasma clearance is reduced by 25%. With a decrease in the clearance of creatinine (CC) to 10-40 ml / min / 1.73 square. m T1 / 2 increases. The kidneys produce 70-80% of the tubular secretion (mostly unchanged, 9% - in the form of glucuronides, 0.5% - in the form of other metabolites), the intestine - 20-30%.

    Prothionamide

    The protionamide is rapidly absorbed into the digestive tract. FROMmOh drug is achieved in 2-3 hours after its administration. The value of CmOh in blood plasma corresponds to 4.5 μg / ml, which exceeds the bacteriostatic concentration of protionamide. Well absorbed in an acidic environment. Penetrates into all tissues and body fluids, including spinal fluid (with inflammation of the meninges), tubercular foci, cavities and encapsulated formations. Biotransformiruetsya in the liver, partially turning into an active metabolite - sulfoxide. It is excreted partially by the kidneys - up to 18.5%. The rest of the medicinal part is excreted with bile.

    Pyrazinamide

    After taking COMBITUB-Neo® CmOh pyrazinamide in blood plasma reaches 12.0-14.0 μg / ml after 2 hours. T1/2 the drug is an average of 10-12 hours. Pyrazinamide well penetrates into the organs, tissues and body fluids, including the lymph nodes and cerebrospinal fluid.Metabolised in the liver. The main metabolite of pyrazinamide - pyrazinic acid has antituberculous activity. About 10-20% of the drug binds to plasma proteins. It is excreted by the kidneys (in unchanged form - about 10%, in the form of metabolites - about 70%).

    Ethambutol

    FROMmOh of the drug in plasma (60%) is achieved after 2 hours. T1/2 - 5-6 hours. On average, 25% of the drug binds to plasma proteins.

    Etambutol well penetrates into various organs and biological fluids with the exception of ascitic, pleural and cerebrospinal fluid. Partially metabolized in the liver (15%) with the formation of inactive metabolites. It is excreted by the kidneys - 80-90% (50% - unchanged, 15% - in the form of inactive metabolites) and the intestines - 10-20% (unchanged). Penetrates into breast milk.

    Indications:

    - Common forms of pulmonary tuberculosis and extrapulmonary tuberculosis (all forms) with bacterial excretion in patients with drug resistance;

    - tuberculosis with concomitant inflammatory diseases caused by nonspecific pathogenic flora, sensitive to lomefloxacin.

    Contraindications:

    - Hypersensitivity to Lomefloxacin (incl.to other fluoroquinolones), protionamide, pyrazinamide, ethambutol and other components of the drug;

    - lactose intolerance, lactase deficiency, glucose-galactose malabsorption (since the formulation contains lactose);

    - peptic ulcer of stomach and duodenum;

    - ulcerative colitis;

    - acute gastritis;

    - acute hepatitis, cirrhosis;

    - diseases of the central nervous system (epilepsy and other diseases with a tendency to convulsive seizures);

    - diseases of the eye (optic neuritis, cataracts, diabetic retinopathy, inflammatory eye diseases);

    - gout;

    - thrombophlebitis;

    - pregnancy, lactation;

    - children's age to 18 years (the period of formation and growth of the skeleton).

    Carefully:

    It is necessary to limit the stay in the sun of patients. Caution should be used when using in elderly patients, due to the increased risk of developing toxic effects. Cerebral atherosclerosis, lengthening interval Q-T, simultaneous reception of antiarrhythmic drugs IA class (quinidine, procainamide) and III class (amiodarone, sotalol), renal failure (CK less than 50 ml / min), congenital lengthening syndrome Q-T, heart disease (heart failure, myocardial infarction, bradycardia), electrolyte imbalance (eg, hypokalemia, hypomagnesemia), simultaneous reception of drugs that extend the interval Q-T (tetracyclic antidepressants, antipsychotics, antifungal drugs, imidazole derivatives, some antihistamines, incl. astemizole, terfenadine, ebastine), diabetes mellitus, severe hepatic impairment, hyperuricemia.

    Dosing and Administration:

    Inside, the daily dose of the drug is divided into two methods. Tablets should be taken after a meal with 1 glass of water. Dosage is carried out by lomefloxacin, patients with a body weight of up to 40 kg are prescribed 10 mg / kg or 2 tablets of the drug, with a body weight of more than 40 kg - 13.2 mg / kg. Daily dose at a body weight of more than 60 kg should not exceed 5 tablets. Duration of therapy - 3 months (intensive phase of treatment). To treat common forms of pulmonary tuberculosis and extrapulmonary tuberculosis (all forms) with bacterial excretion in patients with drug resistance, 10 mg / kg of body weight are prescribed, for the treatment of tuberculosis with concomitant inflammatory diseases caused by nonspecific pathogenic flora,sensitive to lomefloxacin - 13.2 mg / kg body weight, but not more than 5 tablets.

    Simultaneously with COMBITUB-Neo®, the appointment of pyridoxine to 60 mg per day for 2 doses is indicated.

    Side effects:

    Side effects in the treatment of COMBITUB-Neo® are determined by the active ingredients in the formulation.

    Lomefloxacin

    From the digestive system: nausea, vomiting, dryness of the oral mucosa, gastralgia, abdominal pain, diarrhea or constipation, flatulence, pseudomembranous colitis, dysphagia, discoloration of the tongue, decreased appetite or bulimia, taste distortion, dysbiosis, increased activity of "liver" transaminases, hyperbilirubinemia , hepatitis.

    From the nervous system: fear, dyskinesia, nightmarish dreams, anxiety, drowsiness, peripheral sensory and sensory-motor neuropathy, fatigue, malaise, asthenia, headache, dizziness, fainting, insomnia, hallucinations, convulsions, hyperkinesia, tremor, paresthesia, nervousness , anxiety, depression, agitation.

    From the genitourinary system: glomerulonephritis, dysuria, polyuria, anuria, albuminuria,urethral hemorrhages, crystalluria, hematuria, urinary retention, edema, interstitial nephritis, hypercreatininaemia, hyperuricemia, renal failure; in women - vaginitis, leukorrhea, intermenstrual bleeding, pain in the perineum, vaginal candidiasis; in men - orchitis, epididymitis.

    From the side of metabolism: hypoglycemia, gout.

    From the side of the musculoskeletal system: muscle weakness, tendonitis, myasthenia exacerbation, arthralgia, vasculitis, gastrocnemius cramps, back and chest pain.

    On the part of the organs of hematopoiesis and the system of hemostasis: bleeding from the digestive tract, thrombocytopenia, leukopenia, leukocytosis, eosinophilia, prolonged prothrombin time, hemolytic anemia, decreased hemoglobin, purpura, increased fibrinolysis, epistaxis, lymphadenopathy.

    From the respiratory system: dyspnoea, respiratory infections, bronchospasm, cough, hypersecretion of phlegm, influenza-like symptoms.

    From the sense organs: visual impairment, pain and noise in the ears, pain in the eyes.

    From the side of the cardiovascular system: lowering blood pressure, tachycardia, bradycardia, extrasystole,arrhythmias, progression of heart failure and angina, myocardial infarction, vascular collapse, pulmonary embolism, myocardiopathy, phlebitis, lengthening of the Q-T interval.

    Allergic reactions: anaphylaxis, skin itching, swelling of the skin and mucous membranes, urticaria, photosensitivity, malignant exudative erythema (Stevens-Johnson syndrome).

    Influence on the fetus: fetotoxic action (arthropathy).

    Other: Candidiasis, increased sweating, chills, thirst, toxic epidermal necrolysis, exfoliative dermatitis, superinfection.

    Prothionamide

    From the digestive system: nausea, vomiting, diarrhea, hypersalivation, "metallic" taste in the mouth, impaired liver function.

    From the nervous system: insomnia, agitation, depression, anxiety, dizziness, drowsiness, headache, asthenia, paresthesia, peripheral neuropathy, optic neuritis.

    From the side of the cardiovascular system: tachycardia, weakness, orthostatic hypotension.

    From the endocrine system: hypoglycemia in patients with diabetes mellitus, gynecomastia, dysmenorrhea, hypothyroidism, decreased potency.

    Allergic reactions: skin rash.

    Pyrazinamide

    From the digestive system: nausea, vomiting, diarrhea, "metallic" taste in the mouth, impaired liver function (decreased appetite, liver pain, hepatomegaly, jaundice, yellow atrophy of the liver); exacerbation of peptic ulcer.

    From the central nervous system: dizziness, headache, sleep disturbances, increased excitability, depression; in some cases - hallucinations, convulsions, confusion.

    On the part of the organs of hematopoiesis and the system of hemostasis: thrombocytopenia, sideroblastic anemia, erythrocyte vacuolization, porphyria, hypercoagulation, splenomegaly.

    From the side of the musculoskeletal system: arthralgia, myalgia.

    From the urinary system: dysuria, interstitial nephritis. Allergic reactions: skin rash, hives.

    Other: hyperthermia, acne, hyperuricemia, gout, photosensitivity, increased serum iron concentration.

    Ethambutol

    From the nervous system and sense organs: weakness, headache, dizziness, impaired consciousness, disorientation, hallucinations, depression,peripheral neuritis (paresthesia in the extremities, numbness, paresis, pruritus), optic neuritis (decreased visual acuity, violation of color perception, mainly green and red colors, color blindness, scotoma).

    From the digestive system: decreased appetite, nausea, vomiting, gastralgia, impaired liver function - increased activity of "liver" transaminases.

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

    Other: photosensitivity, hyperuricemia, gout.

    Overdose:

    Symptoms: nausea, vomiting, impaired liver function, peripheral neuropathy, slurred speech, confusion, visual and hearing impairment, convulsions, respiratory depression, pulmonary edema, stupor, coma.

    Treatment: symptomatic - gastric lavage, the appointment of activated charcoal, forced diuresis, artificial ventilation of the lungs, intravenous short-acting barbiturates, pyridoxine, osmotic diuretics, sodium hydrogen carbonate with the development of metabolic acidosis.

    Interaction:

    Lomefloxacin

    The use of lomefloxacin together with isoniazid, ethambutol and especially pyrazinamide significantly increases antimicrobial activity against sensitive and particularly resistant MW.

    Joint use with probenecid slows the excretion of lomefloxacin. Sucralfate and antacid agents containing magnesium or aluminum form chelate-forming complexes with lomefloxacin. The use of these drugs should be performed 4 hours before or 2 hours after taking Lomefloxacin.

    The use of rifampicin is contraindicated.

    Does not affect the pharmacokinetics of isoniazid. Does not interact with theophylline, caffeine. Increases the activity of oral anticoagulants and increases the toxicity of non-steroidal anti-inflammatory drugs. There is no cross-resistance with penicillins, cephalosporins, aminoglycosides, co-trimoxazole, metronidazole. Vitamins with mineral supplements should be used 2 hours before or 2 hours after the application of Lomefloxacin. Joint use with antiarrhythmic drugs IA class (quinidine, procainamide) and III class (amiodarone, sotalol), tetracyclic antidepressants, neuroleptics and other drugs that extend the interval Q-T, may cause lengthening of the interval Q-T.

    Prothionamide

    Prothionamide reduces the effectiveness of antihypertensive drugs.Compatible with isoniazid, pyrazinamide, cycloserine and other antituberculous drugs. Isoniazid increases the concentration of protionamide in the blood plasma.

    Pyrazinamide

    Pyrazinamide increases the concentration of isoniazid in the serum, slowing its excretion. The likelihood of developing a hepatotoxic effect increases when combined with rifampicin. When used simultaneously with drugs that block tubular secretion, it is possible to reduce their excretion and enhance toxic reactions. Strengthens the antituberculous action of lomefloxacin.

    Ethambutol

    The use of ethambutol with aminoglycosides, imipenem, carbamazepine, lithium salts, quinine increases the risk of neurotoxic action of the drug. Strengthens the effects of anti-tuberculosis drugs, neurotoxicity of ciprofloxacin, asparaginase, methotrexate.

    Special instructions:

    Lomefloxacin causes phototoxic effects.

    Fluoroquinolones can cause ligament ruptures. If there is tendonitis, the drug should be discarded. For the prevention of candidamycosis, antifungal agents are recommended.

    During the treatment period, prolonged exposure to sunlight and the use of artificial UV radiation should be avoided. At the first sign of photosensitization (increased skin sensitivity, burn, hyperemia, swelling, blisters, rash, itching, dermatitis) or hypersensitivity, neurotoxicity (excitation, convulsions, tremors, photophobia, confusion, toxic psychosis, hallucinations) the beginning of treatment is recommended to conduct an ophthalmological examination of the patient, which includes the definition of visual acuity, color vision, visual fields and ophthalmoscopy.

    During treatment, regular monitoring of the ophthalmologist (at least once a month) is necessary.

    Women during the treatment period are recommended to use non-hormonal methods of contraception. During the treatment period, microbiological methods are used to determine the concentration of folic acid and cyanocobalamin in the blood serum.

    To avoid the development of a hepatotoxic effect during treatment, ethanol should be avoided.

    Pyrazinamide worsens the course of gout and diabetes, it is necessary to monitor the liver function and the concentration of uric acid in the blood every month.

    It is necessary to monitor the activity of "hepatic" transaminases, gamma-glutamatransferase and alkaline phosphatase monthly. Patients with diabetes need to monitor the concentration of glucose in the blood at least once a month.

    When pellagro-like side effects occur, the drug should be discarded.

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

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

    Form release / dosage:

    Film-coated tablets, 200 mg + 400 mg + 188 mg + 360 mg.

    Packaging:

    Primary packaging:

    - 10 tablets are placed in strips Al.-polyethylene / al, - polyethylene; 10 tablets are placed in Al / PVC blisters.

    Secondary packaging:

    - 4, 6, 10 strips, together with instructions for medical use, are placed in a cardboard box;

    - 4, 6, 10 blisters together with instructions for medical use are placed in a cardboard box.

    Storage conditions:

    In a dry, the dark place at a temperature of no higher than 25 C. Keep out of reach of children.

    Shelf life:

    2 years.Do not use after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LS-002111
    Date of registration:29.12.2011 / 17.09.2013
    Expiration Date:Unlimited
    The owner of the registration certificate: Simpex Pharma Pvt Ltd. Simpex Pharma Pvt Ltd. India
    Manufacturer: & nbsp
    Representation: & nbspKORAL-MED, CJSCKORAL-MED, CJSC
    Information update date: & nbsp01.02.2018
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