Composition, form of production and packaging
Tablets, film-coated 1 tab.
Rifampicin 150 mg
isoniazid 75 mg
pyrazinamide 400 mg
ethambutol 275 mg
10 pieces. - packings cellular planimetric (10) - packs cardboard.
100 pieces. - polymer cans.
500 pcs. - polymer cans.
1000 pcs. - polymer cans.
10 pieces. - packings cellular planimetric (5) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
Proteb-4 is a combined preparation containing fixed amounts of rifampicin, isoniazid, pyrazinamide, and ethambutol.
The combined use of the active substances included in the preparation reduces the risk of developing resistance, which develops with monotherapy.
The mechanism of action of rifampicin is the inhibition of DNA-dependent RNA polymerase. Rifampicin has a bactericidal effect on both intracellular and extracellular microorganisms.
Isoniazid has a bactericidal effect mainly on the actively dividing cells of Mycobacterium tuberculosis. The mechanism of its action is to inhibit the synthesis of mycolic acids, which are a component of the cell wall of mycobacteria. For Mycobacterium tuberculosis, the minimum inhibitory concentration (MIC) of isoniazid is 0.05-0.025 mg / L. Resistance to isoniazid appears slowly.
Pyrazinamide has a bactericidal action at acidic pH values. It is supposed that for the manifestation of the bactericidal activity of this preparation, the enzymatic conversion of pyrazinamide to the active form, pyrazinic acid, is necessary.
The sensitivity of various strains of Mycobacterium tuberculosis to pyrazinamide depends on the activity of this enzyme, which can be measured in vitro, thereby assessing the sensitivity of a particular strain. At acidic pH values, the pyrazinamide MIC in vitro is 20 mg / L. Pyrazinamide does not act on atypical mycobacteria.
Etambutol is a bacteriostatic drug that is effective against Mycobacterium tuberculosis resistant to other antituberculosis drugs.
Etambutol suppresses the synthesis of the cell wall, blocking the inclusion of mycolic acids in it. Etambutol is active against virtually all strains of Mycobacterium tuberculosis and M.bovis, as well as against nontuberculous mycobacteria. (M. kansasii)
After taking Protub-4 in healthy adults, the peak concentration of rifampicin in plasma reaches 7.84% Ојg / ml. In the case of taking with food, the absorption of rifampicin, which is part of Proteb-4, is reduced by 30%.
C max rifampicin in plasma is achieved after 2 hours. Rifampicin is widely distributed in the body, quickly distributed to organs and tissues (the highest concentration in the liver and kidneys), penetrates into the bone tissue, the concentration in the saliva is 20% of the plasma. Through the blood-brain barrier (BBB) вЂ‹вЂ‹penetrates only in case of inflammation of the meninges. Penetrates through the placenta (concentration in fetal plasma - 33% of the concentration in the plasma of the mother) and in breast milk (breast-fed children receive no more than 1% of the therapeutic dose of the drug). Approximately 80% of the dose is associated with plasma proteins. The half-life of rifampicin averages 3.35 В± 0.66 h. Rifampicin is metabolized in the liver to deacetyltrifampicin, this metabolite is active. Rifampicin is excreted from the body with urine (up to 30% of the dose taken).
After receiving Protub-4 in healthy adults, the peak concentration of isoniazid in plasma reaches 4.75 Ојg / ml after 2 hours. The half-life of isoniazid from plasma is 2-6 hours. Isoniazid undergoes severe pre-systemic metabolism in the wall of the small intestine and liver, resulting in its concentration in the plasma of patients with a fast acetylation process is half the concentration in patients with a slow acetylation process and excreted in the urine in the first 24 hours. Less than 10% of the dose taken is excreted with feces. The main products of excretion in urine are N-acetylisoiniazide, monoacetylhydrazine and isonicotinic acid.
After receiving Protub-4 in healthy adults, the peak concentration of pyrazinamide in plasma reaches 24.13 Ојg / ml after 3 hours. The half-life of this drug is 10-24 hours, and it is widely distributed in the body, it penetrates well into tissues and biological fluids, including cerebrospinal fluid . Its concentrations in the cerebrospinal fluid are almost identical to those in the blood. In the liver, pyrazinamide is converted into the main active metabolite, pyrazinic acid. Approximately 30-40% of the dose taken is excreted in urine in the form of pyrazinic acid and 3.4% in the form of unchanged pyrazinamide.
After taking Protub-4 in healthy adults, the peak concentration of ethambutol in plasma reaches 3.45 Ојg / ml after 2 hours. The concentration then decreases in a two-phase manner: at the beginning, the elimination half-life is 4 hours and then 10 hours. Approximately 50-70% of the dose taken is excreted in the urine in the unchanged form, and the rest - in the form of aldehyde and carboxyl metabolites. The average volume of distribution is 3.89 l / kg. About 10-40% of the drug binds to plasma proteins. An insignificant part of the dose is metabolized in the liver. Metabolite is excreted in the urine. In patients with impaired renal function, the elimination of ethambutol is slowed.
- Protub-4 is indicated for the treatment of the initial stage of pulmonary tuberculosis;
- it is also shown in the initial stages of extrapulmonary tuberculosis.
Adults and children from 13 years. The drug is dosed according to rifampicin 10 mg / kg body weight, but not more than 5 tablets. The drug is taken on an empty stomach for 30-40 minutes before breakfast. The total course dose is from 2 to 4 months, depending on the nature of the tuberculosis process. With a body weight> 80 kg, isoniazid is additionally prescribed in the evening (the total daily dose of isoniazid is 10 mg / kg). According to the indications Proteb-4 is combined with streptomycin (IM / dose 15 mg / kg 1 time per day).
Apply the drug in combination with other anti-tuberculosis drugs, such as streptomycin or kanamycin. Apply the drug with vitamin B6 at least 30 mg per day. The general course of treatment by Proteb-4om is 2-3 months.
Side effects in the treatment with Proteb-4 are determined by the active ingredients included in its composition.
Rifampicin can cause side effects from the gastrointestinal tract, such as heartburn, epigastric discomfort, anorexia, vomiting, intestinal colic and diarrhea. Some patients experience headache, drowsiness, weakness, ataxia, dizziness, confusion, visual disorders, muscle weakness, fever, pain in the limbs, itching, urticaria, skin rashes and eosinophilia, sore throat and soreness of the tongue. Men occasionally experience toxic liver damage, which usually develops in the first two weeks after the start of treatment.
From the digestive system: erosive gastritis, pseudomembranous enterocolitis.
Allergic reactions: Quincke's edema, bronchospasm, arthralgia, fever.
From the nervous system: disorientation.
From the urinary system: nephronecrosis, interstitial nephritis.
Other: leukopenia, dysmenorrhea, induction of Porphyria, muscle weakness. With irregular therapy or with the resumption of treatment after a break, flu-like syndrome is possible (fever, chills, headache, dizziness, myalgia), skin reactions, hemolytic anemia, thrombocytopenic purpura, acute renal failure.
Long-term use of isoniazid causes peripheral neuropathy in 3.5-17% of patients. There is a feeling of tingling and numbness in the fingers and toes, in some patients there is muscle weakness, headache, dizziness, nausea, vomiting, drug-induced hepatitis, gynecomastia in men and menorrhagia in women. Prophylactic and therapeutic use of isoniazid in the form of monotherapy or in combination with anti-tuberculosis drugs is associated with a significant risk of toxic damage to the liver.
Pyrazinamide can cause liver damage and fulminant hepatitis. The likelihood of toxic damage to the liver increases with increasing dose and duration of treatment. At a dose of 3 grams per day, signs of liver damage are observed in about 15% of patients. The abolition of pyrazinamide leads to a rapid normalization of liver enzyme levels.
The most serious side effects of ethambutol are retrobulbar neuritis, which is manifested by decreased visual acuity, narrowing of the field of vision, central or peripheral scotoma, and impaired color perception, especially the ability to distinguish between green and red.
Other side effects include confusion, disorientation, hallucinations, headache, dizziness, general malaise, jaundice or transient liver dysfunction, peripheral neuropathy, as well as gastrointestinal disturbances such as metallic taste in the mouth, nausea, vomiting, anorexia and pain in a stomach.
Proteb-4 is contraindicated:
- with increased sensitivity to any ingredient of this drug;
- patients with visual impairment (diabetic retinopathy, optic nerve damage, inflammatory eye diseases);
- Epilepsy and propensity to convulsive seizures, in the case of a previous history of poliomyelitis;
- with violations of the liver and kidneys;
- with jaundice, acute hepatitis;
- Thrombophlebitis, severe atherosclerosis.
With caution: with pregnancy and lactation, children under 13 years old, with psychosis, in old age.
PREGNANCY AND LACTATION
With caution take the drug during pregnancy and during lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
It is forbidden to take the drug for violations of kidney function.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
It is forbidden to take the drug for violations of the liver, with jaundice, acute hepatitis.
APPLICATION FOR CHILDREN
Take care with children under 13 years of age.
APPLICATION IN ELDERLY PATIENTS
Take with caution in old age.
Given that the drug has a side effect on eyesight, it is recommended that a complete ophthalmological examination of the patient is performed before the start of treatment, which includes the definition of visual acuity, color vision, visual fields and ophthalmoscopy.
It should be borne in mind that the side effect on the part of the eye is basically reversible after discontinuation of the drug. In rare cases, recovery may be delayed for 1 year or more and may be irreversible. Therefore, patients should be advised to immediately inform the doctor of any change in visual acuity.
During treatment with Proteb-4, control of the kidney, liver and blood function is necessary.
When prescribing Protub-4a, it should be borne in mind that urine, feces, saliva and tears can be painted in orange.
Do not interrupt (accidentally or intentionally) taking the drug without consulting a doctor.
Women during the treatment period are recommended to use non-hormonal methods of contraception.
During the treatment period, microbiological methods for determining contraception of folic acid and cyanocobalamin in the blood serum are not used. Progressive deterioration of visual acuity during therapy should be considered a side effect. If corrective glasses were used before the treatment, they should be worn during the assessment of visual acuity. During 1-2 years of therapy, a refractive error may develop, which must be corrected to obtain accurate results of the study. The study of visual acuity through the stenopathic opening eliminates the error of refraction. Caution should be used when using in elderly patients, due to the increased risk of developing toxic effects.
To avoid the development of a hepatotoxic effect during treatment, ethanol should be avoided.
The use of certain types of cheese (Swiss, Cheshire) or fish (tuna, sardines) during eating can lead to pruritus of the skin, palpitation, chills and headache (inhibition of MAO and diamino oxidase of plasma by isoniazid, which affects the metabolism of tyramine and histamine , found in fish and cheese).
Pyrazinamide worsens the course of gout and diabetes, requires monitoring of kidney function, uric acid. In the case of a persistent increase in the level of acid and exacerbation of gouty arthritis, treatment is canceled.
Symptoms : pulmonary edema, confusion, convulsions, peripheral neuropathy, impaired liver function, nausea, vomiting, impaired vision and hearing, slurred speech, respiratory depression, stupor, coma.
Treatment: gastric lavage, the appointment of activated charcoal; symptomatic therapy, forced diuresis, artificial lung ventilation, short-acting barbiturates, pyridoxine, osmotic diuretics, sodium bicarbonate in the development of metabolic acidosis.
Rifampicin accelerates the metabolism of phenytoin, quinidine, oral anticoagulants and antifungal drugs. Antacids, opiates reduce the bioavailability of rifampicin.Reduces the activity of oral hypoglycemic drugs, oral hormonal contraceptives, digitalis preparations, antiarrhythmics (disopyramide, mexiletine), glucocorticosteroids, dapsone, hydantoins (phenytoin), hexobarbital, nortriptyline, benzodiazepines, sex hormones, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporine A, beta adrenoblockers, enalapril and cimetidine. It is known that rifampicin induces certain enzymes of the cytochrome P-450 system.Rifampicin reduces the antimicrobial activity of lomefloxacin (maxachvin) and ofloxacin.
Isoniazid enhances the effects of phenytoin, such as drowsiness and ataxia. Prednisolone can significantly reduce the concentration of isoniazid in blood plasma in slow and fast acetylates, but this effect is more pronounced in slow acetylars. Isoniazid increases the frequency and severity of liver function disorders in combination with rifampicin in patients with previous liver disease. PASC preparations containing bentonite (aluminum hydrosilicate) reduce the absorption of rifampicin. Antacids reduce the absorption of isoniazid. Isoniazid reduces the effectiveness of oral hypoglycemic drugs, theophylline, tolazomide, vitamin B1 (enhance its secretion);reduces the content of zinc in the blood (increase its excretion).
Pyrazinamide somewhat reduces the concentration of isoniazid in the blood serum, especially in slow acetyls.
Aluminum hydroxide disrupts the absorption of ethambutol, and therefore it is necessary to use alternative antacids.
When combined with neurotoxic agents, the neurotoxic effect of ethambutol may be enhanced.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug should be stored in a dry, dark place at a temperature of no higher than 25 В° C. In a place inaccessible to children.
Shelf life - 2 years.
Do not use after the expiration date indicated on the package.