Protubvita (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J04AM05 (Rifampicin, Pyrazinamide and Isoniazid)

Dosage Form

Protubvita

Film-coated tablets: 100, 500, or 1000 pcs.

Dosage Form, Packaging, and Composition

100 pcs. – polymer jars.
500 pcs. – polymer jars.
1000 pcs. – polymer jars.

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Agents active against mycobacteria; antituberculosis agents; combinations of antituberculosis agents

Pharmacological Action

Protubvita contains a combination of three antituberculosis drugs and vitamin B₆ (pyridoxine).

Isoniazid

It has a bactericidal effect on actively dividing cells of Mycobacterium tuberculosis. Its mechanism of action involves the inhibition of the synthesis of mycolic acids, which are a component of the mycobacterial cell wall. For Mycobacterium tuberculosis, the minimum inhibitory concentration of the drug is 0.025-0.05 mg/L. Isoniazid has a moderate effect on slowly and rapidly growing atypical mycobacteria.

Pyrazinamide

Pyrazinamide has a bactericidal effect at acidic pH values. It penetrates well into tuberculosis foci. Its activity is high in caseous-necrotic processes, caseous lymphadenitis, and tuberculomas. It undergoes enzymatic conversion to the active form, pyrazinoic acid. At acidic pH values, the MIC of pyrazinamide in vitro is 20 mg/L. It does not act on non-tuberculous pathogenic microorganisms.

Rifampicin

A broad-spectrum antibiotic, it inhibits the synthesis of DNA-dependent RNA polymerase. It has 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.

Pyridoxine (vitamin B₆)

It is involved in metabolism. It is necessary for the normal functioning of the central and peripheral nervous systems. In tuberculosis infection, a deficiency of pyridoxine occurs. In this regard, the daily dose of the vitamin is increased to 60 mg. When pyridoxine is taken orally simultaneously with isoniazid and pyrazinamide, no interaction of these drugs is observed at the pharmacokinetic and microbiological levels. It reduces the neurotoxicity of antituberculosis drugs.

Pharmacokinetics

Isoniazid

Isoniazid is rapidly and completely absorbed after oral administration; food reduces absorption and bioavailability. The bioavailability indicator is greatly influenced by the “first-pass” effect through the liver. T_max in blood is 1-2 hours, C_max in blood after a single oral dose of 300 mg is 3-7 µg/ml. Protein binding is insignificant – up to 10%. V_d is 0.57-0.76 L/kg. It is well distributed throughout the body, penetrating all tissues and fluids, including cerebrospinal, pleural, and ascitic fluids; high concentrations are created in lung tissue, kidneys, liver, muscles, saliva, and sputum. It penetrates the placental barrier and into breast milk.

It is metabolized in the liver by acetylation to form inactive products. In the liver, it is acetylated by N-acetyltransferase to form N-acetylisoniazid, which is then converted to isonicotinic acid and monoacetylhydrazine, which has a hepatotoxic effect through the formation of a mixed oxidase system of cytochrome P450 during 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 from blood (T_1/2) for “fast acetylators” is 0.5-1.6 hours; for “slow” ones – 2-5 hours. In renal failure, T_1/2 can increase to 6.7 hours. T_1/2 for children aged 1.5 to 15 years is 2.3-4.9 hours, and for newborns – 7.8-19.8 hours (which is explained by the imperfection of acetylation processes in newborns). Although the T_1/2 indicator varies significantly depending on the individual intensity of acetylation processes, the average T_1/2 is 3 hours (oral administration of 600 mg) and 1.5 hours (900 mg). With repeated prescriptions, T_1/2 shortens to 2-3 hours.

It is excreted mainly by the kidneys: within 24 hours, 75-95% of the drug is excreted, mainly in the form of inactive metabolites – N-acetylisoniazid and isonicotinic acid. In this case, in “fast acetylators” the content of N-acetylisoniazid is 93%, and in “slow” ones – no more than 63%. Small amounts are excreted in feces. The drug is removed from the blood during hemodialysis; 5 hours of hemodialysis can remove up to 73% of the drug from the blood.

Pyrazinamide

After oral administration, it is rapidly and completely absorbed in the gastrointestinal tract. Plasma protein binding is 10-20%. T_max of the drug in the blood is 1-2 hours. It penetrates well into tissues and organs.

It is metabolized in the liver, where an active metabolite, pyrazinoic acid, is first formed, which is then converted into an inactive metabolite, 5-hydroxynipyrazinoic acid. The half-life from blood T_1/2 is 8-9 hours.

It is excreted by the kidneys: unchanged – 2%, in the form of pyrazinoic acid – 33%, in the form of other metabolites – 36%. It is removed by hemodialysis.

Rifampicin

Absorption is rapid; food intake reduces the absorption of the drug. When taken orally on an empty stomach, 600 mg, C_max of the drug in the blood is 10 µg/ml, and T_max is 2-3 hours. Plasma protein binding is 84-91%.

It is rapidly distributed throughout organs and tissues (the highest concentration is in the liver and kidneys), penetrates into bone tissue, the concentration in saliva is 20% of the plasma concentration. Apparent V_d is 1.6 L/kg in adults and 1.1 L/kg in children.

It penetrates the blood-brain barrier (BBB) only in case of inflammation of the meninges. It penetrates the placenta (concentration in fetal plasma is 33% of the concentration in maternal plasma) and is excreted in breast milk (breastfed infants receive no more than 1% of the therapeutic dose of the drug).

It is metabolized in the liver with the formation of a pharmacologically active metabolite, 25-O-desacetylrifampicin. It is an autoinducer – it accelerates its metabolism in the liver, resulting in a systemic clearance of 6 L/h after the first dose, increasing to 9 L/h after repeated administration. When taken orally, induction of intestinal wall enzymes is also likely.

T_1/2 after oral administration of 300 mg is 2.5 hours, 600 mg – 3-4 hours, 900 mg – 5 hours. After several days of repeated administration, bioavailability decreases, and T_1/2 after multiple doses of 600 mg shortens to 1-2 hours.

It is excreted mainly with bile, 80% in the form of a metabolite; by the kidneys – 20%. After taking 150-900 mg of the drug, the amount of rifampicin excreted by the kidneys unchanged depends on the dose taken and is 4-20%.

In patients with impaired renal excretory function, T_1/2 is prolonged only in cases where rifampicin doses exceed 600 mg. It is excreted during peritoneal dialysis and hemodialysis. In patients with impaired liver function, an increase in the concentration of rifampicin in plasma and a prolongation of T_1/2 are noted.

Pyridoxine

It is rapidly absorbed throughout the entire small intestine, with a larger amount absorbed in the jejunum. It is metabolized in the liver to form pharmacologically active metabolites (pyridoxal phosphate and pyridoxamine phosphate). Pyridoxal phosphate is 90% bound to plasma proteins. It penetrates well into all tissues; it accumulates mainly in the liver, and less in muscles and the central nervous system. It penetrates the placenta and is secreted into breast milk. The half-life is 15-20 days. It is excreted by the kidneys.

Indications

• Pulmonary tuberculosis and extrapulmonary tuberculosis – intensive phase of therapy (limited focal and infiltrative tuberculosis without decay) and continuation phase;
• Leprosy;
• Prevention of tuberculosis in persons in close contact with tuberculosis patients;
• With a change in tuberculin sensitivity; with an increase in sensitivity to tuberculin; with hyperergic sensitivity to tuberculin.

ICD codes

Dosage Regimen

The dose is set individually, depending on the nature and form of the disease. The route of administration is oral. The drug is recommended to be prescribed 30 minutes before meals once a day. Drink with water (from 0.5 to 1 glass).

Dosed at 10 mg/kg of body weight based on rifampicin, but not more than 0.6 g.

It is recommended to take the entire daily dose in one dose on an empty stomach.

Dosage regimen for children

For children over 12 years old, 10-15 mg/kg/day based on Rifampicin, but not more than 600 mg/day.

Adverse Reactions

Isoniazid

From the central nervous system (CNS): headache, dizziness, rarely – excessive fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of the extremities, peripheral neuropathy, optic neuritis, polyneuritis, psychosis, mood changes, depression. In patients with epilepsy, seizures may become more frequent.

From the cardiovascular system: palpitations, angina pectoris, increased blood pressure.

From 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

From the digestive system: nausea, vomiting, diarrhea, “metallic” taste in the mouth, impaired liver function (decreased appetite, liver tenderness, hepatomegaly, jaundice, yellow liver atrophy); exacerbation of peptic ulcer.

From the CNS: headache, sleep disturbance, increased excitability, depression; in some cases – hallucinations, convulsions, confusion.

From the hematopoietic organs and hemostasis system: thrombocytopenia, sideroblastic anemia, erythrocyte vacuolization, porphyria, hypercoagulation, splenomegaly.

From the musculoskeletal system: arthralgia, myalgia.

From the urinary system: dysuria, interstitial nephritis. Allergic reactions: skin rash, urticaria.

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

Rifampicin

From the digestive system: nausea, vomiting, diarrhea, increased levels of “liver” transaminases (ALT, AST, alkaline phosphatase), hyperbilirubinemia, decreased appetite, erosive gastritis, pseudomembranous enterocolitis, hepatitis.

From the CNS: headache, impaired coordination of movements, visual impairment, disorientation.

From the urinary system: interstitial nephritis. Allergic reactions: skin rash, itching, angioedema, bronchospasm, fever, urticaria, eosinophilia.

Other: arthralgia; rarely – leukopenia, menstrual cycle disorders, dysmenorrhea, induction of porphyria, muscle weakness, hyperuricemia, exacerbation of gout.

Pyridoxine

Allergic reactions, hypersecretion of hydrochloric acid, numbness, the appearance of a feeling of tightness in the extremities – “stocking” and “glove” symptom, rarely – skin rash, skin itching.

Contraindications

• Children’s age (under 12 years);
• Pregnancy and lactation period;
• Jaundice;
• Kidney diseases with reduced excretory function;
• Acute liver diseases;
• Hypersensitivity to the components included in the drug.

With caution: liver diseases, diabetes mellitus, elderly age, debilitated patients.

Use in Pregnancy and Lactation

It is forbidden to take the drug during pregnancy and lactation.

Use in Hepatic Impairment

Contraindicated in acute liver diseases, jaundice. Use with caution in liver diseases.

If signs of impaired liver function appear, it is necessary to stop taking the drug.

After interruptions in the course of treatment, resumption of the drug should be done with caution due to the risk of developing hepatotoxicity.

Use in Renal Impairment

Contraindicated in kidney diseases with reduced excretory function.

After interruptions in the course of treatment, resumption of the drug should be done with caution due to the risk of developing nephrotoxicity.

Pediatric Use

Contraindicated in children under 12 years of age.

Geriatric Use

The drug should be taken with caution in the elderly.

Special Precautions

It is prescribed as part of complex therapy, usually at the initial stage of the tuberculous process.

During treatment, monitoring of the activity of “liver” transaminases and uric acid in plasma is necessary.

If signs of impaired liver function appear, it is necessary to stop taking the drug.

After interruptions in the course of treatment, resumption of the drug should be done with caution due to the risk of developing hepato- and nephrotoxicity.

When using the drug, saliva, sputum, urine, and tear fluid may turn orange-red.

During treatment, it is necessary to additionally prescribe ergocalciferol (vitamin D) to prevent disorders of calcium and phosphorus metabolism.

Overdose

Isoniazid

Symptoms: dizziness, dysarthria, lethargy, disorientation, hyperreflexia, peripheral polyneuropathy, impaired liver function, metabolic acidosis, hyperglycemia, glucosuria, ketonuria, convulsions (1-3 hours after drug application), coma.

Treatment: peripheral polyneuropathy (vitamins: pyridoxine, thiamine, glutamic acid, nicotinamide; massage, physiotherapeutic procedures); convulsions (IM Pyridoxine hydrochloride – 200-350 mg, IM 25% magnesium sulfate solution – 10 ml, diazepam); impaired liver function (methionine, thioctic acid, cyanocobalamin).

Pyrazinamide

Symptoms: impaired liver function, increased severity of side effects from the CNS.

Treatment: symptomatic.

Rifampicin

Symptoms: pulmonary edema, lethargy, confusion, convulsions.

Treatment: symptomatic; gastric lavage, administration of activated charcoal; forced diuresis.

Drug Interactions

Isoniazid

When combined with paracetamol, hepato- and nephrotoxicity increases; Isoniazid induces the cytochrome P450 system, resulting in increased metabolism of paracetamol to toxic products.

Ethanol increases the hepatotoxicity of isoniazid and accelerates its metabolism.

It reduces the metabolism of theophylline, which can lead to an increase in its concentration in the blood.

Cycloserine and disulfiram enhance the adverse central effects of isoniazid.

Combination with pyridoxine reduces the risk of developing peripheral neuritis.

It should be combined with caution with potentially neuro-, hepato-, and nephrotoxic drugs due to the risk of increased side effects.

It enhances the effect of coumarin and indandione 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, leading to an increase in its concentration in the blood and an increase in the toxic effect (correction of the phenytoin dosage regimen may be required, especially in patients with slow acetylation of isoniazid).

Pyrazinamide

Compatible with other antituberculosis drugs: for 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 used together with rifampicin.

When used simultaneously with drugs that block tubular secretion, a decrease in their excretion and an increase in toxic reactions are possible.

It enhances the antituberculosis effect of ofloxacin and lomefloxacin.

Rifampicin

It reduces the activity of oral anticoagulants, oral hypoglycemic drugs, hormonal contraceptives, digitalis preparations, antiarrhythmic drugs (disopyramide, pirmenol, quinidine, mexiletine, tocainide), glucocorticosteroids, dapsone, phenytoin, hexobarbital, nortriptyline, benzodiazepines, sex hormones, theophylline, chloramphenicol, ketoconazole, itraconazole, cyclosporine A, azathioprine, beta-blockers, slow calcium channel blockers, enalapril, cimetidine (Rifampicin causes induction of some liver enzyme systems, accelerates metabolism).

Antacids, opiates, anticholinergic drugs, and ketoconazole reduce (in case of simultaneous oral administration) the bioavailability of rifampicin.

Isoniazid and/or Pyrazinamide increase the frequency and severity of liver function disorders to a greater extent than when prescribing rifampicin alone, in patients with pre-existing liver disease.

Para-aminosalicylic acid preparations containing bentonite (aluminum hydrosilicate) should be prescribed no earlier than 4 hours after taking the drug, because absorption may be impaired.

Pyridoxine

It weakens the effect of levodopa when used together.

Pyridoxine reduces the risk of developing the toxic effect of antituberculosis drugs on the central and peripheral nervous system.

Storage Conditions

List B.

The preparation should be stored in a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Do not use after the expiration date printed on the packaging.

Dispensing Status

For hospitals.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.