Lomecombe - instructions for use, dose, side effects, contraindications

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Dosage form: & nbspcoated tablets

Composition:

One tablet contains:

active substances: isoniazid in terms of 100% substance - 135 mg, Lomefloxacin hydrochloride 100% Lomefloxacin 200 mg, pyrazinamide 100% substance 370 mg, ethambutol hydrochloride 100% substance 325 mg, pyridoxine hydrochloride in terms of 100% of the substance - 10 mg;

Excipients: povidone 10 mg, macrogol 6000 4.8 mg, croscarmellose sodium 58.1 mg, silicon dioxide colloid 4.8 mg, magnesium stearate 11.3 mg.

Shell composition: hypromellose 25.875 mg, giprolose 8.625 mg, macrogol 6000 4.6 mg, glycerol 4.6 mg, talc 6.9 mg, titanium dioxide 5.175 mg, iron oxide dye red 1,725 mg.

Description:The tablets covered with a film membrane, light brown or pinkish brown in color, oval in shape, biconvex. On the fracture, the tablet is white to white with a creamy or yellowish hue of color.

Pharmacotherapeutic group:Anti-tuberculosis drug combined

Pharmacodynamics:

Combined anti-tuberculosis drug.

Isoniazid - antituberculous agent; acts bacteriostatically. Is a prodrug - mycobacterial catalase peroxidase metabolizes isoniazid to the active metabolite,which, by binding to enoyl (acyl-transferring protein) reductase of fatty acid synthase II, disrupts the conversion of delta2-non-essential fatty acids into mikelic acid. The latter is a branched chain fatty acid that, when combined with arabinogalactan (polysaccharide), participates in the formation of the components of the cell wall of Mycobacterium tuberculosis. Isoniazid is also an inhibitor of mycobacterial catalase peroxidase, which reduces the protection of the microorganism against reactive oxygen species and hydrogen peroxide.

Isoniazid is also active against a small number of strains of Mycobacterium kansasii (for infections caused by this pathogen, it is necessary to determine the sensitivity to isoniazid before starting treatment).

Lomefloxacin - 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.It is active against 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.

The drug is resistant to: A, B, D, h G group 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, shortens the time of their isolation from the body, provides a faster resorption 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.

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 the active form - pyrazinic acid. In an acidic medium, the MPC of pyrazinamide iri 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. It is active only for intensively dividing cells. Suppresses the growth and reproduction of Mycobacterium tuberculosis, resistant to streptomycin, isoniazid, PASKaminosalicylic acid), 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 the enzymatic conversion of sulfur-containing and hydroxylated amino acids.

Participates in the exchange of tryptophan (participation in the reaction of biosynthesis of serotonin).

Pharmacokinetics:

Isoniazid. Quickly and fully absorbed when ingested, food reduces absorption and bioavailability. The effect of "first passage" through the liver has a great influence on the bioavailability index. Time to reach the maximum concentration of isoniazid in blood plasma - 1-2 hours, the maximum concentration in the blood plasma after ingestion of a single dose of 300 mg - 3-7 μg / ml. The connection with plasma proteins is insignificant - up to 10%.

The volume of distribution is 0.57-0.76 l / kg. Well distributed throughout the body, penetrating all tissues and fluids, including cerebrospinal, pleural, ascites; high concentrations are created in the lung tissue, kidneys, liver, muscles, saliva and sputum. Penetrates through the placental barrier and into breast milk.

It is metabolized in the liver by acetylation with the formation of inactive products. In the liver, acetylated with N-acetyltransferase to form N-acetyl-isoniazid,which is then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect by forming a cytochrome P450 system upon N-hydroxylation of the active intermediate metabolite. The rate of acetylation is genetically determined; in people with "slow" acetylation, there is little N-acetyltransferase. Is the inducer of the isoenzyme CYP2E1. Half-life (T_1/2) for "fast acetylators", 0.5-1.6 hours; for "slow" - 2-5 hours. In case of renal insufficiency, the half-life may increase to 6.7 hours. The half-life period for children aged 1.5 to 15 years is 2.3-4.9 hours, and in newborns - 7,8-19,8 h (which is explained by the imperfection of the processes of acetylation in newborns). Despite the fact that the indicator T_1/2 varies considerably depending on the individual intensity of the acetylation processes, the average value T_1/2 is 3 hours (intake of 600 mg) and 5.1 hours (900 mg). With repeated appointments T_1/2 is shortened to 2-3 hours. It is excreted mainly by the kidneys: 75-95% of the drug is excreted within 24 hours, mainly in the form of inactive metabolites - N-acetylisiniazide and isonicotinic acid. At the same time, "fast acetylators" contain 93% N-acetyl isoniazide, and "slow" - not more than 63%: Small amounts are excreted with feces.The drug is removed from the blood during hemodialysis; 5 h hemodialysis allows you to remove from the blood to 73% of the drug.

Lomefloxacin. Absorption - 95-98%; food intake reduces absorption by 12%. 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-7 1.4 μg / ml, 400 mg 3-5 , 2 μg / ml. The intake of food reduces the maximum concentration of lomefloxacin in 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. Half-life (T_1/2) - 8-9 hours; the average renal clearance is 145 ml / min. In elderly patients, plasma clearance is reduced by 25%. With a decrease in creatinine clearance to 10-40 ml / min / 1.73 m2, the elimination half-life 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%.

Pyrazinamide. Quickly and completely absorbed in the gastrointestinal tract. The connection with plasma proteins is 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 an active metabolite, pyrazinic acid, is first formed, which is then converted 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 from plasma is 3-4 hours, with renal dysfunction -8 hours.It is excreted by the kidneys 80-90% (50% - unchanged, 15% - in the form of inactive metabolites) and with the feces - 10-20% (unchanged). It is excreted in hemodialysis and peritoneal dialysis.

Pyridoxine. Absorbed rapidly throughout the small intestine, more 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, 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:

Rapidly progressive tuberculosis.

Contraindications:

Hypersensitivity, peptic ulcer and duodenal ulcer, ulcerative colitis, acute hepatitis, drug hepatitis, hepatic insufficiency (against the background of the previous treatment with isoniazid), liver cirrhosis, thrombophlebitis, pregnancy, lactation period, children's age (under 18 years).

Carefully:Cerebral atherosclerosis, epilepsy and other diseases of the central nervous system with epileptic syndrome, prolongation of the QT interval, hypokalemia, simultaneous administration of antiarrhythmic drugs of the IA class (quinidine, procainamide) and III class (amiodarone, sotalol); diseases of the eye (inflammation of the optic nerve, cataracts, diabetic retinopathy, inflammatory diseases, eyes); Hyperuricemia, gout, liver failure, chronic renal failure; chronic heart failure, stenocardia, hypertension; alcoholism.

Dosing and Administration:Inside, regardless of food intake 1 time per day, preferably in the first half of the day. Dosing by Lomefloxacin - 13.2 mg / kg body weight, but not more than 5 tablets. Duration of treatment - 3 months. With a body weight of more than 80 kg is additionally assigned isoniazid in the evening (total daily dose of isoniazid up to 10 mg / kg). If necessary, it can be combined with intramuscular injection of streptomycin in a dose of 16 mg / kg 1 time per day for 3 months.

Side effects:

From the nervous system and sense organs: headache, dizziness, fatigue, malaise, asthenia, tremor, paresthesia, syncope, numbness of limbs, peripheral neuropathy; rare - excessive fatigue or weakness, irritability, euphoria, insomnia, optic neuritis (decreased visual acuity, color perception, color blindness, scotoma), toxic psychosis, confusion, emotional lability, hallucinations, depression, convulsions, hyperkinesia, toxic neuropathy , memory impairment, peripheral neuritis (paresthesia in the extremities, numbness, paresis, itching), pain and noise in the ears, pain in the eyes.

From the side of the cardiovascular system: tachycardia or bradycardia, extrasystole, arrhythmia, angina, progression of heart failure, increase or decrease in blood pressure, pulmonary embolism, myocardiopathy, phlebitis.

From the digestive system: nausea, vomiting, dryness of the oral mucosa, diarrhea or constipation, metallic taste in the mouth, flatulence, pseudomembranous colitis, dysphagia, discoloration of the tongue, decreased appetite or bulimia, gastralgia,exacerbation of peptic ulcer; hypersecretion of hydrochloric acid, increased activity of alanine aminotransferase (ALT), aspartic aminotransferase (ACT), hyperbilirubinemia, bilirubinuria, jaundice, hepatomegaly, tenderness in the liver, yellow atrophy of the liver; rarely - toxic hepatitis, incl. with a lethal outcome.

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

On the part of the organs of hematopoiesis and the system of hemostasis: bleeding from the organs of the gastrointestinal tract, purpura, increased fibrinolysis, epistaxis, agranulocytosis, hemolytic, sideroblastic or aplastic anemia, thrombocytopenia, eosinophilia, lymphadenopathy, erythrocyte vacuolization, porphyria, hypercoagulation, splenomegaly.

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

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

From the side of metabolism: hyperglycemia or hypoglycemia, gout, metabolic acidosis, gynecomastia.

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

Other: increased sweating, chills, thirst, superinfection, very rarely - menorrhagia, a tendency to bleeding and hemorrhages, hyperthermia, acne, increased serum iron concentration, 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, intake of activated charcoal, symptomatic therapy.

Interaction:

When combined with paracetamol, hepato- and nephrotoxicity increases; isoniazid induces a system of cytochrome P450, which increases the metabolism of paracetamol to toxic products.

Ethanol increases the hepatotoxicity of isoniazid and speeds up its metabolism.

Isoniazid reduces the metabolism of theophylline, which can lead to an increase in its concentration in the blood.

Isoniazid reduces metabolic transformations and increases the concentration in the blood of alfentanil.

Cycloserine and disulfiram enhance the adverse central effects of isoniazid.

Isoniazid increases the hepatotoxicity of rifampicin.

Isoniazid enhances the action of coumarin and indanedione derivatives, benzodiazepines, carbamazepine, theophylline, as it reduces their metabolism by activating the cytochrome P450 system.

Glucocorticosteroids accelerate the metabolism of isoniazid in the liver and reduce active concentrations in the blood.

Antacid medicines (especially aluminum containing) slow down absorption and reduce the concentration of isoniazid in the blood (antacids should be taken no earlier than 1 hour after taking isoniazid).

When used simultaneously with enflurane isoniazid can increase the formation of inorganic fluoride metabolite, which has a nephrotoxic effect. Inhibitors of monoamine oxidase (MAO) increase the risk of side effects from the central nervous system and the cardiovascular system.

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 excretion of lomefloxacin; with rifampicin leads to a decrease in the antimicrobial activity of this combination against mycobacterium tuberculosis (MBT) due to the antagonism existing between lomefloxacin and rifampicin at the microbial level.

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. Ethambutol enhances the effects of anti-tuberculosis drugs, 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:

In some cases, fatal drug hepatitis develops during treatment. The risk rises with age (the highest frequency in the age group is 35-64 years), especially with daily consumption of ethanol. Therefore, every month it is necessary to monitor the function of the liver, people over 35 years of age, the function of the liver is further examined before treatment.

In addition to the use of ethanol, additional risk factors are chronic liver disease and the postpartum period; under these circumstances, monitoring of liver function (laboratory and clinical) should be conducted more often.

If liver side effects (unexplained anorexia, nausea, vomiting, darkening of the urine, jaundice, rash, paresthesia of the hands and feet, weakness, fatigue or fever lasting more than 3 days, abdominal pain, especially in the right upper quadrant), the drug is immediately withdrawn.

Patients who have previously undergone isoniazid hepatitis are prescribed alternative antituberculous drugs. If it is necessary to resume therapy, it begins after a complete resolution of clinical and laboratory signs of hepatitis with subsequent monitoring of liver function.

In connection with the different metabolic rate before the use of isoniazid, it is expedient to determine the rate of its inactivation (by the dynamics of the content in the blood and urine). The "fast acetylators" isoniazid used in higher doses.

During the treatment, cheese (especially Swiss or Cheshire), fish (especially tuna, sardinella, skipjack) should be avoided, since, with simultaneous use with isoniazid, reactions (skin flushing, itching, heat or cold sensation, palpitation, increased sweating , chills, headache, dizziness),associated with the suppression of MAO activity and diaminoksidazy and leading to a disruption of the metabolism of tyramine and histamine contained in fish and cheese.

It should be borne in mind that isoniazid can cause hyperglycemia with secondary glucosuria; tests with copper reduction can be false positive; the drug does not affect the enzymatic glucose tests.

During the treatment period, prolonged exposure to sunlight and the use of artificial ultraviolet (UV) lighting should be avoided (evening reception reduces the risk of reaction to UV radiation). At the first sign of photosensitization (increased skin sensitivity, burn, hyperemia, swelling, the appearance of blisters, rashes, itching, dermatitis) or allergic reactions, neurotoxicity (excitation, convulsions, tremor, photophobia, confusion, toxic psychosis, hallucinations), therapy to cease.

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

It is necessary to monitor the kidney function monthly, the function of the eyes, the peripheral blood picture, the activity of AJIT 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 period of treatment, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.

Form release / dosage:

Tablets coated with a film coat, 135 mg + 200 mg + 370 mg + 325 mg + 10 mg.

Packaging:

For 100 tablets in a can 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 inpatient) -

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:3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:P N003651 / 01

Date of registration:14.07.2009 / 11.01.2017

Expiration Date:Unlimited

The owner of the registration certificate:AKRIKHIN HFK, JSC AKRIKHIN HFK, JSC Russia

Manufacturer: & nbsp

AKRIKHIN HFK, JSC Russia

Information update date: & nbsp03.04.2018

Illustrated instructions

Instructions

Lomecomb® (Lomecomb)