Composition, form of production and packaging
Tablets, film-coated 1 tab.
isoniazid 135 mg
Lomefloxacin (in the form of hydrochloride) 200 mg
pyrazinamide 370 mg
ethambutol hydrochloride 325 mg
pyridoxine hydrochloride 10 mg
10 pieces. - packings cellular planimetric (10) - packs cardboard.
100 pieces. - polypropylene cans.
500 pcs. - polypropylene cans.
1000 pcs. - polypropylene cans.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Combined anti-tuberculosis drug.
Isoniazid
It has a bactericidal effect on the actively dividing cells of Mycobacterium tuberculosis. The mechanism of its action is the inhibition of the synthesis of mycolic acids, which are a component of the cell wall of mycobacteria. For mycobacteria tuberculosis, the minimum inhibitory concentration of the drug is 0.025-0.05 mg / l. Isoniazid has a moderate effect on slow and fast-growing atypical mycobacteria.
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. Highly active against 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 and parainfluenzae, Legionella pneumophila, Pseudomonas aeruginosa. Moderately sensitive to the drug Staphylococcus aureus. Staphylococcus epidemidis, 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. Resistant to the drug Streptococcus spp., Pseudomonas cepacia, Ureaplasma urealyticum, Treponema pallidum, Mycoplasma hominis and anaerobic bacteria. It acts on both extracellular and intracellularly located Mycobacterium tuberculosis, shortens 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 Ојg / ml). Resistance is rare.
Pyrazinamide
Pyrazinamide has a bactericidal action at acidic pH values. Well penetrates into the tuberculosis foci. Its activity is high in caseous-necrotic processes, caseous lymphadenitis, tuberculomas. It is subjected to enzymatic conversion into the active form - pyrazinic acid. At acidic pH values, the minimum inhibitory concentration of pyrazinamide in vitro is 20 mg / l. On non-tuberculosis pathogens does not work.
Ethambutol
Bacteriostatic drug, 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. Etambutol is active against rapidly and slowly growing atypical mycobacteria. The minimum inhibitory concentration of ethambutol is - 0.78-2.0 mg / l. Ethambutol is not effective for non-tuberculosis pathogens.
Pyridoxine
Vitamin product. Participates in the metabolism. It is necessary for the normal functioning of the central and peripheral nervous system. With tuberculosis infection, there is a deficiency of pyridoxine. In this regard, the daily dose of vitamin increases to 60 mg. With the simultaneous administration of pyridoxine inwards with isoniazid, lomefloxacin, pyrazinamide and ethambutol, no interaction of these drugs is observed at the pharmacokinetic and microbiological levels. Reduces the neurotoxicity of anti-tuberculosis drugs.
PHARMACOKINETICS
Isoniazid
Isoniazid quickly and completely absorbed when ingested, food reduces absorption and bioavailability. The effect of "first passage" through the liver has a large effect on the bioavailability index.The time to reach C max in the blood is 1-2 h, C max in the blood after ingestion of a single dose of 300 mg is 3-7 Ојg / ml. - up to 10% V d - 0.57-0.76 l / kg It is well distributed throughout the body, penetrating all tissues and fluids, including cerebrospinal, pleural, ascitic, high concentrations are created in lung tissue, kidneys, liver, muscles, saliva and sponges through the placental barrier and into breast milk.
It is metabolized in the liver by acetylation with the formation of inactive products. The liver is acetylated with N-acetyltransferase to form N-acetylisoiniazide, which is then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect by forming a mixed oxidase system of cytochrome P450 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. It is an inhibitor of CYP2C9 and CYP2E1 isoenzymes in the liver. The half-life of blood (T 1/2 ) for "fast acetylators" is 0.5-1.6 h; for "slow" - 2-5 hours. In case of kidney failure, T 1/2 may increase to 6.7 hours. T 1/2 for children aged 1.5 to 15 years - 2.3-4.9 hours, and in newborns - 7.8-19.8 hours (which is due to the imperfection of acetylation processes in newborns). Despite the fact that the T 1/2 index varies considerably depending on the individual intensity of the acetylation processes, the average T 1/2 value is 3 hours (ingestion (600 mg) and 5.1 h (900 mg) .For repeated 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-acetylisonic acid and isonicotinic acid. At the same time, "fast acetylators" contain N-acetylisiniazide content of 93%, while "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. Active components that make up Proteb-Loma, do not affect the rate of absorption of Lomefloxacin from the digestive tract. Bioavailability of Lomefloxacin is more than 90%. The drug after intake is rapidly absorbed from the gastrointestinal tract. Cmax is 5.1 mg / l, the time to reach is 1-1.5 hours. It circulates for a long time in the body: the half-life is 8-9 hours. The connection with blood proteins is insignificant - 10%. Well penetrates into various organs and tissues, where concentrations are created, 9-13 times higher than serum. In small amounts, biotransformation is carried out in the liver with the formation of 5 metabolites, which have little antimicrobial activity. In 80% is excreted by the kidneys, in 20% with feces, then with saliva. Hepatic failure does not affect the biotransformation of lomefloxacin.
Pyrazinamide. After oral administration, it is quickly and completely absorbed in the gastrointestinal tract. The connection with plasma proteins is 10-20%. The time to reach C max in the blood 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 of blood T 1/2 - 8-9 h.
It is excreted by the kidneys: in unmodified 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 ingestion of 25 mg dose, the time to reach C max in the blood is 2-4 hours, C max in the blood - 1-5 Ојg / 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. T 1/2 - 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) through the gastrointestinal tract - 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 phosphate and pyridoxamine phosphate). Pyridoxal phosphate with plasma proteins binds to 90%. It penetrates well into all tissues; accumulates mainly in the liver, less - in the muscles and the central nervous system. Penetrates through the placenta, is secreted with breast milk. Half-life is 5-20 days. It is excreted by the kidneys.
INDICATIONS
- acutely progressive course of tuberculosis;
- tuberculosis with concomitant inflammatory diseases caused by nonspecific pathogenic flora, sensitive to lomefloxacin.
DOSING MODE
Dosing regimen: inside, regardless of food intake 1 time per day, preferably in the first half of the day. Proteb-lome is dosed according to lomemfloxacin 13.2 mg / kg body weight, but not more than 5 tablets. Duration of treatment - 3 months. With a large body weight of 80 kg, isoniazid is additionally prescribed in the evening (total daily dose of isoniazid up to 10 mg / kg). According to the indications Proteb-lome is combined with streptomycin (IM / dose 16 mg / kg 1 time per day for 3 months).
SIDE EFFECT
Isoniazid
From the side of the central nervous system (CNS): headache, dizziness, rarely excessive fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of limbs, peripheral neuropathy, optic neuritis, polyneuritis, psychosis, mood change, depression. Seizures can occur in patients with epilepsy.
From the cardiovascular system: palpitation, angina pectoris, increased blood pressure.
On the part of the digestive system: nausea, vomiting, gastralgia, toxic hepatitis.
Allergic reactions: skin rash, itching, hyperthermia, arthralgia.
Other: very rarely - gynecomastia, menorrhagia, tendency to bleeding and hemorrhage.
Lomefloxacin
From the digestive system: nausea, vomiting, dry mouth, gastralgia, abdominal pain, diarrhea or constipation, flatulence, pseudomembranous enterocolitis, dysphagia, discoloration of the tongue, decreased appetite or bulimia, taste distortion, dysbiosis, increased activity of "liver" transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase).
From the nervous system: 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; 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 musculoskeletal system: arthralgia, vasculitis, calf muscle cramps, pain in the back and chest.
On the part of the organs of hematopoiesis and hemostasis system: bleeding from the digestive tract, thrombocytopenia, purpura, fibrinolysis, nosebleeds, lymphadenopathy.
On the part of the respiratory system: dyspnoea, respiratory infections, bronchospasm, cough, hypersecretion of phlegm, influenza-like symptoms.
From the senses: visual impairment, pain and noise in the ears, pain in the eyes.
From the cardiovascular system: lowering blood pressure, tachycardia, bradycardia, extrasystole, arrhythmias, progression of heart failure and angina pectoris, pulmonary embolism, myocardiopathy, phlebitis.
Allergic reactions: pruritus, hives, photosensitivity, malignant exudative erythema (Stevens-Johnson syndrome).
Influence on the fetus: the experiment described fetotoxic action (arthropathy),
Other: candidiasis, increased sweating, chills, thirst, superinfection.
Pyrazinamide
On the part of the digestive system: nausea, vomiting, diarrhea, "metallic" taste in the mouth, impaired liver function (decreased appetite, liver tenderness, hepatomegaly, jaundice, yellow atrophy of the liver); exacerbation of peptic ulcer.
From the side of the central nervous system: headache, sleep disturbances, increased excitability, depression; in some cases - hallucinations, convulsions, confusion.
On the part of the hematopoiesis and hemostasis system: thrombocytopenia, sideroblastic anemia, erythrocyte vacuolization, porphyria, hypercoagulation, splenomegaly.
From the musculoskeletal system: arthralgia, myalgia.
From the side of the urinary system: dysuria, interstitial nephritis.
Allergic reactions: skin rash, hives.
Other: hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitivity, increased serum iron concentration.
Ethambutol
From the side of the nervous system and sensory organs: weakness, headache, dizziness, impaired consciousness, disorientation, hallucinations, depression, peripheral neuritis (paresthesia in the extremities, numbness, paresis, itching), optic neuritis (decreased visual acuity, mostly green and red flowers, color blindness, scotoma).
On the part of the digestive system: decreased appetite, nausea, vomiting, gastralgia, impaired liver function - increased activity of "liver" transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase).
Allergic reactions: dermatitis, skin rash, itching, arthralgia, fever, anaphylaxis.
Other: hyperuricemia, exacerbation of gout.
Pyridoxine
Allergic reactions, hypersecretion of hydrochloric acid, numbness, the appearance of a feeling of compression in the limbs - a symptom of "stocking" and "gloves", rarely - a skin rash, itching of the skin.
CONTRAINDICATIONS
- hypersensitivity to lomefloxacin, isoniazid, pyrazinamide, ethambutol, pyridoxine;
- pregnancy, lactation period;
- Children's age to 18 years (the period of formation and growth of the skeleton);
- Stomach ulcer and duodenal ulcer;
- ulcerative colitis;
- Acute hepatitis, cirrhosis of the liver;
- diseases of the central nervous system (epilepsy and other diseases with a tendency to convulsive seizures);
- Diseases of the organs of vision (inflammation of the optic nerve, cataracts, diabetic retinopathy, inflammatory diseases of the eyes);
- gout;
- Thrombophlebitis.
PREGNANCY AND LACTATION
It is forbidden to take the drug during pregnancy and lactation.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindicated in acute hepatitis, cirrhosis.
APPLICATION FOR CHILDREN
Contraindicated in children under 18 years (the period of formation and growth of the skeleton).
SPECIAL INSTRUCTIONS
Treatment of patients with a multicomponent drug reduces the medical burden on the patient by 3 times, which contributes to the improvement of drug tolerance.
OVERDOSE
Isoniazid
Symptoms: dizziness, dysarthria, lethargy, disorientation, hyperreflexia, peripheral polyneuropathy, abnormal liver function, metabolic acidosis, hyperglycemia, glucosuria, ketonuria, seizures (1-3 hours after drug administration), coma.
Treatment: peripheral polyneuropathy (vitamins: pyridoxine, thiamine, glutamic acid, nicotinamide, massage, physiotherapeutic procedures); seizures (in / m pyridoxine hydrochloride - 200-250 mg, in / m 25% solution of magnesium sulfate - 10 ml, diazepam); a violation of liver function (methionine, thioctic acid, cyanocobalamin).
Lomefloxacin
Treatment: induction of vomiting or gastric lavage, adequate hydration, symptomatic therapy. Hemo- and peritoneal dialysis with an overdose are ineffective (less than 3% is output).
Pyrazinamide
Symptoms: a violation of liver function, an increase in the severity of side effects from the central nervous system.
Treatment: symptomatic.
Ethambutol
Symptoms: nausea, vomiting, hallucinations, polyneuritis.
Treatment: symptomatic.
DRUG INTERACTION
Isoniazid
When combined with paracetamol, hepato- and nephrotoxicity increases; isoniazid induces a cytochrome P450 system, which increases the metabolism of paracetamol to toxic products.
Ethanol increases the hepatotoxicity of isoniazid and speeds up its metabolism.
Reduces the metabolism of theophylline, which can lead to an increase in its concentration and blood. Reduces metabolic transformations and increases the concentration in the blood of alfentanil. Cycloserine and disulfiram increases the adverse central effects of isoniazid. Combination with pyridoxine reduces the risk of peripheral neuritis.
Caution should be combined with potentially neuro-, hepato- and nephrotoxic drugs because of the risk of side effects.
Strengthens the action of coumarin and indanedione derivatives, benzodiazepines, carbamazepine, as it reduces their metabolism by activating the cytochrome P450 system.
Glucocorticosteroids accelerate metabolism in the liver and reduce active concentrations in the blood.
It suppresses the metabolism of phenytoin, which leads to an increase in its concentration in the blood and an increase in the toxic effect (correction of the dosing regimen of phenytoin may be necessary, especially in patients with slow acetylation of isoniazid).
Lomefloxacin
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. Forms chelated compounds with antacid medicines and sucralfate, which reduces its bioavailability. In the treatment of patients with tuberculosis, lomefloxacin is used in conjunction with isoniazid, pyrazinamide, streptomycin and ethambutol. Drugs that block tubular secretion, slow down its excretion. There is no cross-resistance with penicillins, cephalosporins, aminoglycosides, co-trimoxazole, metronidazole.
Vitamins with mineral supplements should be taken 2 hours before or 2 hours after the application of Lomefloxacin.
Pyrazinamide
Compatible with other antituberculous drugs: in chronic destructive forms, pyrazinamide is recommended to be combined with rifampicin or ethambutol (better tolerability than when combined with rifampicin, but weaker effect).
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 anti-tuberculosis effect of ofloxacin and lomefloxacin.
Ethambutol
Aluminum hydroxide reduces the absorption of ethambutol. The use of ethambutol with aminoglycosides, ciprofloxacin, imipenem, carbamazepine, lithium salts, quinine increases the risk of neurotoxic action of the drug. Etambutol enhances the antimicrobial activity of other antituberculosis drugs.
Pyridoxine
It reduces the effect of levodopa when combined. Pyridoxine reduces the risk of toxic effects of antituberculosis drugs on the central and peripheral nervous system.
TERMS OF RELEASE FROM PHARMACY
For hospitals.
TERMS AND CONDITIONS OF STORAGE
List B.
The drug should be stored in a dry, dark place at a temperature of no higher than 25 0 C. Keep away from children.
Shelf life - 2 years. Do not use after the expiration date indicated on the package.
