Protubpira (Tablets) Instructions for Use

Marketing Authorization Holder

Pharmasintez, JSC (Russia)

ATC Code

J04AC51 (Isoniazid in combination with other drugs)

Active Substances

Pyrazinamide (Rec.INN)

Isoniazid (Rec.INN)

Dosage Forms

	Protubpira	Tablets 150 mg+500 mg: 100, 500 or 1000 pcs.
		Tablets 300 mg+750 mg: 100, 500 or 1000 pcs.

Dosage Form, Packaging, and Composition

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

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

Clinical-Pharmacological Group

Antituberculosis drug

Pharmacotherapeutic Group

Combined antitubercular agent

Pharmacological Action

Isoniazid

It exerts a bactericidal effect on actively dividing *Mycobacterium tuberculosis* cells. 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 exerts 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 into an active form – pyrazinoic acid. At acidic pH values, the minimum inhibitory concentration of pyrazinamide in vitro is 20 mg/L. It does not act on non-tuberculous pathogenic microorganisms.

Pharmacokinetics

Isoniazid

Oral administration of isoniazid together with the drugs included in Protubpira does not affect its absorption rate from the gastrointestinal tract. 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. The time to reach C_max in the blood (T_max) is 1-2 hours, C_max 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, penetrates into all tissues and fluids, including cerebrospinal, pleural, and ascitic fluids; high concentrations are created in lung tissue, kidneys, liver, muscles, saliva, and sputum. It crosses 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 by the cytochrome P450 mixed oxidase system 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 5.1 hours (900 mg). With repeated administration, 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 the 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

It is rapidly and completely absorbed from the gastrointestinal tract. Binding to plasma proteins is 10-20%. The time to reach C_max in the blood T_max is 1-2 hours. It penetrates well into tissues and organs.

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

It is excreted by the kidneys: unchanged – 3%, in the form of pyrazinoic acid – 33%, in the form of other metabolites – 36%. It is removed by hemodialysis.

Indications

• Tuberculosis (any location, in adults and children, treatment and prevention as part of combination therapy).

ICD codes

Dosage Regimen

It is taken orally, after meals, 1-3 tablets once a day (based on 5-15 mg/kg/day of isoniazid – (maximum dose 900 mg/day). The duration of the treatment course during the intensive therapy phase is 3-4 months daily, then 2 months – every other day. The drug can be used in combination with other antituberculosis drugs, such as streptomycin, etc.

Prescription of the drug to children over 3 years of age is based on the maximum daily dosages of isoniazid (5-10 mg/kg/day).

Adverse Reactions

The side effects during treatment with Protubpira are determined by its active ingredients.

Isoniazid

From the central nervous system (CNS): headache, dizziness, rarely – excessive fatigue or weakness, irritability, euphoria, insomnia, paresthesia, numbness of extremities, peripheral neuropathy, optic neuritis, polyneuritis, psychoses, 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: rarely – gynecomastia, menorrhagia, tendency to bleeding and hemorrhages.

Pyrazinamide

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

From the central nervous system: 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, photosensitization, increased serum iron concentration.

Contraindications

• Hypersensitivity;
• Epilepsy;
• Epileptic syndrome;
• Bronchial asthma;
• Psoriasis;
• Chronic renal failure;
• Hepatitis;
• Liver cirrhosis;
• Hyperuricemia;
• Acute gout;
• Gastric and duodenal ulcer;
• Myxedema;
• Pregnancy;
• Lactation;
• Children under 3 years of age.

Use in Pregnancy and Lactation

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

Use in Hepatic Impairment

Contraindicated in hepatitis, liver cirrhosis.

During long-term therapy in patients with impaired liver function, it is necessary to regularly monitor the complete blood count and liver function indicators.

Use in Renal Impairment

Contraindicated in chronic renal failure.

Pediatric Use

Forbidden for children under 3 years of age.

Special Precautions

During treatment, it is necessary to refrain from taking ethanol.

During long-term therapy in patients with impaired liver function, it is necessary to regularly monitor the complete blood count and liver function indicators.

For the prevention and treatment of peripheral polyneuropathy, which may develop during therapy, pyridoxine (vitamin B6) is additionally prescribed.

In patients with a history of gout attacks, serum uric acid concentration is periodically monitored.

When prescribing to patients with hypoplastic anemia, the effect of the drug on blood clotting time is taken into account.

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 – 200-250 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 central nervous system.

Treatment: symptomatic.

Drug Interactions

Isoniazid

When combined with paracetamol, hepatotoxicity and nephrotoxicity increase; 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. It reduces metabolic transformations and increases the concentration of alfentanil 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 inhibits 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

It is 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).

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.

Storage Conditions

List B.

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

Shelf Life

Shelf life 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.