Composition, form of production and packaging
Tablets, film-coated 1 tab.
Lomefloxacin (in the form of hydrochloride) 200 mg
pyrazinamide 400 mg
protionamide 188 mg
ethambutol 360 mg
pyridoxine hydrochloride 20 mg
10 pieces. - packings cellular planimetric (10) - packs cardboard.
Tablets, film-coated 1 tab.
Lomefloxacin (in the form of hydrochloride) 200 mg
pyrazinamide 370 mg
protionamide 150 mg
ethambutol 325 mg
pyridoxine hydrochloride 20 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.
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 epidermidis, Serratia liguifaciens imarcescens, 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 preparation Streptococcus spp ,, Pseudomonas cepacia, Ureaplasma urealyticum, Treponema pallidum, Mycoplasma hominis and anaerobic bacteria. It acts both on the extracellular and intracellular 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 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.
Prothionamide
It blocks the synthesis of mycolic acids, which are an important structural component of the Mycobacterium tuberculosis cell wall, a nicotinic acid antagonist. In high concentrations acts bactericidal, disrupting the synthesis of the protein of the microbial cell. It is also effective against mycobacteria, resistant to anti-tuberculosis drugs of the first series. Affects both extracellular and intracellularly located mycobacteria. It is not very active against mycobacteria of bovine tuberculosis, atypical mycobacteria and acid-resistant saprophytes (the minimum suppressing concentration is 20-30 Ојg / 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 resistance of mycobacterium tuberculosis to protionamide with monotherapy develops rapidly (after 2 months in 32%, 4 months - in 82%). With combined therapy, resistance can develop by 6 months (up to 15% ) .
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 does not act on nontuberculous pathogenic microorganisms.
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. With the simultaneous administration of pyridoxine inwards with 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
Lomefloxacin
Active components that are part of Proteb-5, do not affect the rate of absorption of Lomefloxacin from the gastrointestinal 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
Quickly and completely absorbed in the gastrointestinal tract. The connection with plasma proteins is 10-20%. TC max - 1-2 h. 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. T 1/2- 8-9 hours.
It is excreted by the kidneys: in unmodified form - 3%, in the form of pyrazinic acid - 33%, in the form of other metabolites - Z6%. Removed during hemodialysis.
Prothionamide
Absorption in the gastrointestinal tract is rapid. TC max - 2-3 hours. Easily penetrates into healthy and pathologically altered tissues (tubercular 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% unchanged).
Ethambutol
Absorption is high; bioavailability is 75-80%. After oral administration of a dose of 25 mg of TC max - 2-4 hours, C max of the drug 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 ; when renal dysfunction is 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 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 central nervous system. Penetrates through the placenta, is secreted with breast milk. The half-life is 15-20 days. It is excreted by the kidneys.
INDICATIONS
- drug-resistant tuberculosis with moderate resistance
Mycobacterium tuberculosis (isoniazid - up to 10, rifampicin - up to 40,
ethambutol - up to 2 Ојg / ml);
- acutely progressive course of tuberculosis;
- tuberculosis with concomitant inflammatory diseases,
caused by nonspecific pathogenic flora, sensitive to lomefloxacin.
DOSING MODE
Inside. The drug is taken 1 time per day after meals with a full glass of water, preferably in the morning. Dosage 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 in / m - 16 mg / mg 1 time per day for 3 months.
SIDE EFFECT
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 (AST) , alkaline phosphatase).
From the nervous system: fatigue, malaise, asthenia, headache, dizziness, fainting, insomnia, hallucinations, convulsions, hyperkinesia, tremor, paresthesia, nervousness, anxiety, depression, agitation.
On the part of the genitourinary system: glomerulonephritis, dysuria, polyuria, anuria, albuminuria, urethral bleeding, 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 side of 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 nervous system: dizziness, headache, sleep disorders, 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.
Prothionamide
On the part of the digestive system: nausea, vomiting, diarrhea, hypersalivation, "metallic" taste in the mouth, impaired liver function.
From the nervous system: insomnia, agitation, depression, anxiety, rarely - dizziness, drowsiness, headache, asthenia, in single cases - paresthesia, peripheral neuropathy, optic neuritis.
From the cardiovascular system: tachycardia, weakness, orthostatic hypotension.
On the part of the endocrine system: hypoglycemia in patients with diabetes mellitus, gynecomastia, dysmenorrhea, hypothyroidism, decreased potency.
Allergic reactions: skin rash.
Ethambutol
From the nervous system and sensory 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).
On the part of the digestive system: decreased appetite, nausea, vomiting, gastralgia, impaired liver function - increased activity of "liver" transaminases (ALT, 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, protionamide pyrazinamide, ethambutol, pyridoxine;
- pregnancy, lactation period;
- Children's age under 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);
- kidney failure;
- gouty arthritis;
- Thrombophlebitis.
PREGNANCY AND LACTATION
It is forbidden to take this drug during pregnancy and lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
It is forbidden to take this medication with renal failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
It is forbidden to take this drug for acute hepatitis and cirrhosis of the liver.
APPLICATION FOR CHILDREN
It is forbidden to take in childhood to 18 years (the period of formation and growth of the skeleton).
SPECIAL INSTRUCTIONS
During the treatment period, prolonged exposure to sunlight and the use of artificial ultraviolet light should be avoided (evening reception reduces the risk of reaction to ultraviolet radiation). At the first signs of photosensitivity arising from the lomefloxacin (increased skin sensitivity, burn, hyperemia, edema, blisters, rash, itching, dermatitis) or allergic reactions, neurotoxicity (excitation, convulsions, tremor, photophobia, confusion, toxic psychosis, hallucinations), therapy must be stopped,
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 organ of vision, the picture of peripheral blood, the activity of alanine aminotransferase (ALT) 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.
During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities requiring increased attention and speed of psychomotor reactions.
OVERDOSE
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 the liver, increased severity of side effects from the central nervous.
Treatment: symptomatic.
Prothiopamide
Symptoms: nausea, vomiting. Metallic taste in the mouth; rinse the stomach. There are no specific antidotes.
Ethambutol
Symptoms: nausea, vomiting, hallucinations, polyneuritis.
Treatment: symptomatic.
DRUG INTERACTION
Lomefloxacin together with isoniazid, ethambutol and, especially, pyrazinamide, significantly increases antimicrobial activity against sensitive and especially resistant mycobacteria tuberculosis. The combined use of the drug with probenecid slows the management of lomefloxacin; with rifampicin leads to a decrease in antimicrobial activity of this combination against mycobacterium tuberculosis due to the antagonism existing between lomefloxacin and rifampicin at the microbial level. Sucralfate and antacid agents containing magnesium or aluminum ions form chelate-forming complexes with lomefloxacin. The interval between admission should be at least 2 hours before or after taking Lomefloxacin.
Prothionamide in combination with lomefloxacin significantly increases antimicrobial activity against mycobacteria tuberculosis. Antacids reduce the absorption of protionamide. Reduces the effectiveness of antihypertensive drugs.
Pyrazinamide increases the concentration of isoniazid in the serum, slowing its excretion. When taking rifampicin together with pyrazinamide, the risk of developing hepatotoxic reactions increases.
Aluminum hydroxide reduces the absorption of ethambutol. The administration of ethambutol with aminoglycosides, imipenem, carbamazepine, lithium salts, quinine increases the risk of neurotoxic action of the drug, and also enhances the antimicrobial activity of other antituberculous drugs.
Pyridoxine weakens the action of levodopa when combined.
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 preparations that make up Protub-5.
TERMS OF RELEASE FROM PHARMACY
For hospitals.
TERMS AND CONDITIONS OF STORAGE
Shelf life - 2 years.
Do not use after the expiration date indicated on the package.
List B.
The drug should be stored in a dry, dark place at a temperature of no higher than 25 В° C. Keep away from children.
