Composition, form of production and packaging
Tablets, film-coated 1 tab.
isoniazid 150 mg
pyrazinamide 750 mg
rifampicin 225 mg
100 pieces. - polypropylene cans.
500 pcs. - polypropylene cans.
1000 pcs. - polypropylene cans.
Tablets, film-coated 1 tab.
isoniazid 300 mg
pyrazinamide 1000 mg
rifampicin 450 mg
100 pieces. - polypropylene cans.
500 pcs. - polypropylene cans.
1000 pcs. - polypropylene cans.
Tablets, film-coated 1 tab.
isoniazid 75 mg
pyrazinamide 400 mg
Rifampicin 150 mg
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
Proteb-3 contains a combination of three antituberculous drugs.
Isoniazid
Isoniazid 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 Mycobacterium tuberculosis, the minimum inhibitory concentration (MIC) of the drug is 0.025-0.05 mg / L. Isoniazid has a moderate effect on slow and fast-growing atypical mycobacteria.
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 MPC of pyrazinamide in vitro is 20 mg / L. On non-tuberculosis pathogens does not work.
Rifampicin
Rifampicin is a broad-spectrum antibiotic that inhibits the synthesis of DNA-dependent RNA polymerase. Has a high activity against mycobacteria, including Mycobacterium tuberculosis, and some gram-positive pathogens. Activity against gram-negative microorganisms is lower. It is not characterized by cross-resistance to other antibiotics and chemotherapeutic agents.
PHARMACOKINETICS
Isoniazid
Taking isoniazid in together with the preparations that make up Proteb-3, does not affect the rate of its absorption from the gastrointestinal tract. Isoniazid quickly and completely absorbed when ingested, food reduces absorption and bioavailability. The effect of "first passage" through the liver has a great influence on the bioavailability index. The time to reach the C max drug in the blood is 1-2 h, the C max of the drug in the blood after ingestion of a single dose of 300 mg is 3-7 Ојg / ml.Binding to proteins is insignificant - up to 10%. V d - 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. 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. T 1/2 of blood for "fast acetylators" -0.5-1.6 h; for "slow" - 2-5 hours. In case of renal insufficiency, T 1/2 may increase to 6.7 hours for children aged 1.5 to 15 years - 2.3-4.9 hours, and in newborns - 7.8-19.8 hours (which is explained by imperfection processes of acetylation in newborns). Despite the fact that the T 1/2 index varies considerably depending on the individual intensity of the acetylation processes, the mean T 1/2 is 3 hours (ingestion 600 mg) and 5.1 h (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-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.
Pyrazinamide
After oral administration, it is quickly and completely absorbed into the digestive tract. Binding to plasma proteins - 10-20%. The time to reach the C max drug in the blood is 1-2 hours. It penetrates well into tissues and organs.
Metabolised in the liver, where the active metabolite is first formed -pyrazinic acid, which later becomes an inactive metabolite-5-hydroxypyrazinic acid. T 1/2 of blood - 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.
Rifampicin
Absorption - fast, eating reduces the absorption of the drug. When administered on an empty stomach 600 mg C max drug in the blood - 10 Ојg / ml, and the time to reach C max - 2-3 hours. Binding to plasma proteins - 84-91%.
Quickly distributed to organs and tissues (the highest concentration in the liver and kidneys), penetrates into the bone tissue, the concentration in the saliva - 20% of the plasma. Apparent V d is 1.6 l / kg in adults and 1.1 l / kg in children.
Through the blood-brain barrier (BBB) ​​penetrates only in case of inflammation of the meninges. Penetrates through the placenta (concentration in fetal plasma - 33% of the concentration in the mother's plasma) and excreted in breast milk (breastfed babies receive no more than 1% of the therapeutic dose of the drug).
Metabolised in the liver with the formation of pharmacologically active metabolite - 25-O-deacetyltrifampicin. It is an autoinducer - it accelerates its metabolism in the liver, resulting in a systemic clearance of 6 l / h after the first dose, increases to 9 l / h after repeated administration. When ingestion is also possible, induction and enzymes of the intestinal wall. T 1/2 after ingestion 300 mg - 2.5 h, 600 mg - 3-4 h, 900 mg - 5 h. After several days of repeated intake, bioavailability decreases, and T | d after repeated intake of 600 mg shortens to 1-2 h .
It is excreted mainly with bile, 80% - in the form of a metabolite; kidneys -20%. After taking 150-900 mg of the drug, the amount of rifampicin excreted by the kidneys in unchanged form depends on the value of the dose taken and is 4-20%.
In patients with impaired renal excretory function, T 1/2 is prolonged only when rifampicin doses exceed 600 mg. It is excreted in peritoneal dialysis and hemodialysis.In patients with impaired liver function, an increase in rifampicin plasma concentration and an elongation of T 1/2 are noted.
INDICATIONS
- pulmonary tuberculosis and extrapulmonary tuberculosis - an intensive phase of therapy (limited focal and infiltrative tuberculosis without decay) and the phase of aftercare;
- leprosy;
- prevention of tuberculosis in persons in close contact with patients with tuberculosis;
- with a bend of tuberculin sensitivity;
- with increasing sensitivity to tuberculin;
- with hyperergic sensitivity to tuberculin.
DOSING MODE
Inside, for 1-2 hours before a meal in 1 reception.
At a body weight of the patient less than 40 kg on 1 tab. with a dose of active components 150 mg + 750 mg + 225 mg.
At a body weight of the patient from 40 to 50 kg on 1 tab. with a dose of active components 300 mg + 1000 mg + 450 mg.
At a body weight of the patient from 50 kg to 64 kg on 4 tab. with a dose of active components 75 mg + 400 mg + 150 mg.
At a body weight of the patient more than 65 kg on 2 tab. with a dose of active components 150 mg + 750 mg + 225 mg.
Children 10-15 mg / kg / day in terms of rifampicin, but not more than 600 mg / day. The course of treatment is 2 months, with the further administration of combinations of isoniazid and rifampicin or isoniazid and ethambutol.
SIDE EFFECT
Isoniazid
From the side of the central nervous system: 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, 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.
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 disturbance, 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.
Rifampicin
On the part of the digestive system: nausea, vomiting, diarrhea, increased levels of hepatic transaminases (ALT, ACT, alkaline phosphatase), hyperbilirubinemia, decreased appetite, erosive gastritis, pseudomembranous enterocolitis, hepatitis.
From the side of the central nervous system: headache, impaired coordination of movements, visual impairment, disorientation.
From the side of the urinary system: interstitial nephritis.
Allergic reactions: skin rash, itching, Quincke's edema, bronchospasm, fever, urticaria, eosinophilia.
Other: arthralgia; rarely - leukopenia, menstrual irregularity, dysmenorrhea, induction of porphyria, muscle weakness, hyperuricemia, exacerbation of gout.
CONTRAINDICATIONS
- jaundice;
- kidney disease with a decrease in excretory function;
- liver disease (of various genesis) in the acute stage;
- pulmonary heart failure of II-III st .;
- Hyperuricemia;
- gout;
- purple;
- Children's age (up to 3 years);
- Pregnancy;
- lactation period;
- Hypersensitivity to any component of the drug.
With caution, liver disease, kidney disease, diabetes mellitus, chronic alcoholism, in elderly and weakened patients.
PREGNANCY AND LACTATION
Contraindicated in pregnancy and lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
Carefully.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Carefully.
APPLICATION FOR CHILDREN
Children 10-15 mg / kg / day in terms of rifampicin, but not more than 600 mg / day. The course of treatment is 2 months, with the further administration of combinations of isoniazid and rifampicin or isoniazid and ethambutol.
Contraindicated in children under 3 years.
APPLICATION IN ELDERLY PATIENTS
Carefully.
SPECIAL INSTRUCTIONS
Before the start of treatment and every 2-4 weeks, the activity of the enzymes ACT and ALT is determined. With an increase in their activity, the drug is canceled.Renewal treatment after the normalization of indicators.
Pyrazinamide worsens the course of gout and diabetes, requires monitoring of kidney function, uric acid. In the case of persistent hyperuricemia and exacerbation of gouty arthritis, treatment is withdrawn.
During the treatment period, microbiological methods are used to determine the concentration of folic acid and cyanocobalamin in the blood serum.
During the treatment should not be used bromsulfaleinovy ​​test (false positive results).
With prolonged admission, liver function, kidney function, peripheral blood picture and ophthalmologist examination are performed.
Do not use ethanol.
In the course of treatment, an additional reception of ergocalciferol is recommended to prevent metabolic disorders of calcium and phosphorus.
With the appointment in the last weeks of pregnancy, postpartum bleeding in the mother and bleeding in the newborn are possible (treatment: phylloquinone).
Women during the treatment period are recommended to use non-hormonal methods of contraception.
Rifampicin stains skin, phlegm, sweat, faeces, teardrop, urine, soft contact lenses in orange-red color.
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, thiamin, 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).
Pyrazinamide
Symptoms: a violation of the liver, increased severity of adverse reactions from the central nervous system.
Treatment: symptomatic.
Rifampicin
Symptoms: pulmonary edema, lethargy, confusion, convulsions.
Treatment: symptomatic; gastric lavage, the appointment of activated charcoal; forced diuresis.
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 in the 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 nephroxic medicines because of the risk of side effects.
Enhances the effect of derivatives of coumarin and indanedione, benzodiazepines, carbamazepine, since it reduces their metabolism due to the activation of the system of cytochrome P450.
SCS accelerates metabolism in the liver and reduces 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).
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.
With simultaneous use 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.
Rifampicin .
Reduces the activity of oral anticoagulants, oral hypoglycemic drugs, hormonal contraceptives, digitalis preparations, antiarrhythmic drugs (disopyramide, pirmenol, quinidine, mexiletine, tokaine), GCS, dapsone, phenytoin, hexobarbital, nortriptyline, benzodiazepines, sex hormones, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporine A, azathioprine, beta adrenoblockers, slow calcium channel blockers, enalapril, cimetidine (rifampicin induces ind ktsiyu certain liver enzyme system, speeds up the metabolism).
Antacids, opiates, anticholinergic drugs and ketoconazole reduce (in the case of simultaneous ingestion) the bioavailability of rifampicin.
Isoniazid and / or pyrazinamide increases the frequency and severity of liver function disorders more than with the administration of a single rifampicin in patients with a previous liver disease.
Paraaminosalicylic acid preparations containing bentonite (aluminum hydrosilicate) should be administered no earlier than 4 hours after taking the drug; absorption impairment is possible.
TERMS OF RELEASE FROM PHARMACY
For hospitals.
TERMS AND CONDITIONS OF STORAGE
List B. Store the drug in a dry, dark place at a temperature of no higher than 25 В° C. Keep away from children.
Shelf life - 2 years. Do not use after the expiration date printed on the package.
