Pyrazinamide + Prothionamide + Rifabutin + [Pyridoxine] - instructions for use, dose, side effects, contraindications

Clinical and pharmacological group: & nbsp

Other synthetic antibacterial agents

Included in the formulation

Protubutin®

pills inwards

FARMASINTEZ, JSC (Irkutsk) Russia

АТХ:

J.04.A.M Combinations of antituberculous drugs

Pharmacodynamics:

Anti-tuberculosis combined remedy, well penetrating into the centers of tuberculosis lesion.

Pyrazinamide. Anti-tuberculosis, antibacterial drug. It acts on intracellularly located mycobacteria, it penetrates well into the centers of tubercular lesion. Its activity does not decrease in the acidic environment of caseous masses, and in this connection it is prescribed for caseo-necrotic processes, caseous lymphadenitis, tuberculomas. Depending on the dose, it has a bactericidal or bacteriostatic effect.

Prothionamide. Anti-tuberculosis means, by chemical structure, is close to ethionamide. It has a bacteriostatic effect mainly on multiplying mycobacteria (including atypical ones), on outside and intracellularly located microorganisms. It blocks the synthesis of mycolic acids, which are the most important structural component of the cell wall of mycobacterium tuberculosis, has the properties of a nicotinic acid antagonist. In high concentrations, the synthesis of the protein of the microbial cell is disrupted. Secondary resistance develops rapidly.

Rifabutin. Semisynthetic antibiotic of broad spectrum of action, a group of rifamycins. Effective against intracellular and extracellularly distributed microorganisms. Selectively inhibits the DNA-dependent RNA polymerase of bacteria. Has a bactericidal effect. 5 to 15% of strains Mycobacterium tuberculosis, resistant to rifampicin, are sensitive to rifabutin.

Pyridoxine. It plays an important role in the metabolism, it is necessary for the normal functioning of the nervous system. In the phosphorylated form pyridoxine is a coenzyme of a large number of enzymes acting on a non-oxidative exchange of amino acids. Participates in the exchange of tryptophan, methionine, cysteine, glutamic and other amino acids. It plays an important role in the exchange of histamine. Promotes the normalization of lipid metabolism.

The use of rifabutin and protionamide in combination is due to the pronounced synergistic effect.

Pharmacokinetics:

Pyrazinamide. Quickly and completely absorbed in the gastrointestinal tract. In plasma, it binds to proteins by 10-20%. Maximum concentrationis achieved in 1-2 hours. It penetrates well into tissues and organs, including through the blood-brain barrier.Metabolized in the liver, with the formation of an intermediate active metabolite, which has mycobacteriostatic activity. The half-life of the organism 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%.

Prothionamide. In the gastrointestinal tract absorbed quickly. Maximum concentrationin the plasma is noted 2-3 hours after ingestion. Easily penetrates into organs and 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).

Rifabutin. Quickly absorbed from the gastrointestinal tract. Maximum concentrationis achieved approximately 2-4 hours after ingestion. The concentration of rifabutin in the plasma is maintained above the minimum inhibitory concentration for M. tuberculosis up to 30 hours from the moment of admission. Rifabutin penetrates into the cells of various organs and tissues, penetrates the blood-brain barrier (concentration in the cerebrospinal fluid is about 50% of the concentration in the plasma).Metabolized in the liver with the formation of inactive metabolites. It is excreted by the kidneys in the form of metabolites (53%) and with bile (30%). The half-life is 35-40 hours.

Pyridoxine. Absorbed rapidly throughout the small intestine. Metabolised in the liver with the formation of pharmacologically active metabolites. 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, as well as during hemodialysis.

Indications:

Tuberculosis (various forms and localizations), as part of complex therapy; in patients with multidrug-resistant mycobacterium tuberculosis (with established sensitivity to the components of the drug); chronic multidrug-resistant tuberculosis; in the empirical regimens of treatment of acute progressive tuberculosis in newly diagnosed patients, with a high risk of drug resistance in the intensive phase of treatment; tuberculosis associated with HIV infection.

ICD-10

I.A15-A19.A18 Tuberculosis of other organs

I.A15-A19.A17 Tuberculosis of the nervous system

I.A15-A19.A15.8 Tuberculosis of other respiratory organs, confirmed bacteriologically and histologically

I.B20-B24.B20 Disease caused by the human immunodeficiency virus [HIV], manifested as infectious and parasitic diseases

Contraindications:

Hypersensitivity to the components of the drug and to rifampicin. Acute gastritis, gastric and duodenal ulcer disease, erosive and ulcerative colitis, acute hepatitis, liver cirrhosis, hyperuricemia, gout, coronary artery disease, lactase deficiency, lactose intolerance, glucose-galactose malabsorption, pregnancy, lactation, infancy.

Carefully:

Diabetes mellitus, severe hepatic or renal failure, hyperuricemia, gout.

In patients with diabetes, the risk of hypoglycemia increases. The risk of uveitis increases with combination with clarithromycin or in high doses. With the development of uveitis, consultation of an ophthalmologist, temporary withdrawal of the drug is indicated.

Pregnancy and lactation:

It is forbidden to use during pregnancy and lactation.

Dosing and Administration:

Active ingredients in a single tablet: 600 mg of pyrazinamide, 25 mg of protionamide, 75 mg of rifabutin, 15 mg of pyridoxine.

Adults inside after eating 3-4 tablets per day once. In case of poor tolerance, daily intake of 2-3 doses is acceptable.

Side effects:

Side effects are determined by the active ingredients in the combination:

Pyrazinamide

From the side digestive system: nausea, vomiting, diarrhea, "metallic" taste in the mouth, impaired liver function (decreased appetite, pain in the right hypochondrium, hepatomegaly, jaundice, yellow atrophy of the liver), exacerbation of peptic ulcer.

From the side nervous system: dizziness, headache, sleep disturbances, increased excitability, depression, in some cases - hallucinations, convulsions, confusion.

From the side hemopoiesis: thrombocytopenia, sideroblastic anemia, erythrocyte vacuolization, porphyria, hypercoagulation, splenomegaly.

From the side musculoskeletal system: arthralgia, myalgia.

From the side urinary system: dysuria, interstitial nephritis.

Allergic reactions: skin rash, hives.

Other: hyperthermia, acne, hyperuricemia, exacerbation of gout, photosensitivity, increased serum iron concentration.

Prothionamide

From the side digestive system: nausea, vomiting, diarrhea, hypersalivation, "metallic" taste in the mouth, impaired liver function.

From the side nervous system: insomnia, agitation, depression, anxiety, rarely - dizziness, drowsiness, headache, asthenia, in single cases - paresthesia, peripheral neuropathy, optic neuritis.

From the side of cardio-vascular system: tachycardia, weakness, orthostatic hypotension.

From the side endocrine system: hypoglycemia in patients with diabetes mellitus, gynecomastia, dysmenorrhea, hypothyroidism, decreased potency.

Allergic reactions: skin rash.

Rifabutin

From the side gastrointestinal tract, liver: nausea, vomiting, taste change (dysgeusia), diarrhea, abdominal pain, increased activity of "liver" transaminases, jaundice.

From the side hemopoiesis: leukopenia, thrombocytopenia, anemia.

From the side musculoskeletal system: arthralgia, myalgia.

Allergic reactions: fever, rash, rarely - eosinophilia, bronchospasm, anaphylactic shock, uveitis.

Pyridoxine

Allergic reactions, hypersecretion of hydrochloric acid, numbness, the appearance of a feeling of compression of the limbs - the symptoms of "stocking" and "gloves", rarely - rash, itching of the skin.

Overdose:

Symptoms: pulmonary edema, confusion, convulsions, peripheral neuropathy, impaired liver function, nausea, vomiting, diarrhea, slurred speech, respiratory depression, stupor, coma.

Treatment: gastric lavage, the appointment of activated charcoal; symptomatic therapy, forced diuresis, artificial ventilation, intravenous - barbiturates of short action, pyridoxine, osmotic diuretics, sodium bicarbonate in the development of metabolic acidosis.

Interaction:

Pyrazinamide increases the concentration of isoniazid and rifampicin in the serum, slowing their excretion. When taking rifampicin together with pyrazinamide, hepatotoxicity increases. 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.

Prothionamide. Compatible with isoniazid, pyrazinamide, cycloserine and other anti-tuberculosis drugs. Isoniazid increases the concentration of protionamide in the plasma.

Rifabutin. Accelerates the metabolism of drugs (induces isoenzymes CYP3A and thus can affect the pharmacokinetics) in the liver, which may require an increase in the dose of medicines. Reduces the concentration of zidovudine in plasma. It is unlikely to develop clinically significant interactions with ethambutol, theophylline, sulfonamides, pyrazinamide, fluconazole, zalcitabine. Fluconazole and clarithromycin increase the concentration of rifabutin in plasma. Between rifabutin and fluoroquinolones there is antagonism at the microbial level.

Pyridoxine weakens the action of levodopa when combined. Enhances the diuretic effect of diuretics. Pharmaceutically incompatible with vitamins thiamine and cyanocobalamin. 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 antituberculous drugs that make up the drug.

Special instructions:

With long-term treatment, it is necessary to monitor the number of leukocytes, platelets in peripheral blood, the activity of alanine aminotransferase, aspartate aminotransferase and the concentration of uric acid in the blood once a month.

Can give a reddish-orange color of urine, skin and secreted fluids, contact lenses. It is necessary to consider the possibility of cross-resistance and not prescribe the drug with established resistance to ethionamide.

Oral contraceptives may be ineffective, other contraceptive methods should be used.

During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

Instructions

Pyrazinamide + Prothionamide + Rifabutin + [Pyridoxine] (Pyrazinamidum + Prothionamidum + Rifabutinum + [Pyridoxinum])