PYRAZINAMIDE

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PYRAZINAMIDE (PYRAZINAMIDE)

Composition:

Active substance: pyrazinamide;

1 tablet contains 500 mg of pyrazinamide calculated as 100% anhydrous substance;

Excipients: povidone, crospovidone, microcrystalline cellulose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or white with a yellowish tint tablets, round-shaped, flat-faced, bevelled edges and a score line.

Pharmacotherapeutic group. Antibacterials for systemic use. Antituberculosis agents. Pyrazinamide. ATC Code J04AK01.

Pharmacological properties.

Pharmacodynamics.

Pyrazinamide belongs to the pharmacotherapeutic group of first-line antituberculosis agents. The drug penetrates well into the foci of tuberculosis lesions. Its activity is not reduced in the acidic environment of caseous masses; therefore, it is often prescribed for caseous lymphadenitis, tuberculomas, and caseous-pneumonic processes.

When used as monotherapy, pyrazinamide may lead to rapid development of resistance in Mycobacterium tuberculosis; therefore, it is generally administered in combination with other antituberculosis drugs.

Pharmacokinetics.

Pyrazinamide is almost completely absorbed in the gastrointestinal tract. After oral administration of 1 g of the drug, plasma concentration reaches 45 mcg/mL within 2 hours and 10 mcg/mL within 15 hours. Pyrazinamide is hydrolyzed into its active metabolite—pyrazinoic acid—and then into an inactive metabolite. The elimination half-life of the drug is 9–10 hours under normal renal function. Approximately 70 % of pyrazinamide is excreted by the kidneys. The drug is eliminated within 24 hours, primarily in the form of metabolites.

Clinical characteristics.

Indications.

Treatment of all forms of tuberculosis (in combination with other antituberculosis agents).

Contraindications.

• Hypersensitivity to pyrazinamide, to other components of the drug, or to other medicinal agents closely related in chemical structure (ethionamide, isoniazid, niacin).
• Severe hepatic insufficiency.
• Acute gout.
• Asymptomatic hyperuricemia.

Interaction with other medicinal products and other forms of interaction.

Alcohol: possible enhancement of alcohol toxicity.

Isoniazid: possible reduction of isoniazid serum concentration, especially in patients with slow isoniazid metabolism.

In chronic destructive forms, pyrazinamide is recommended to be combined with rifampicin (pronounced effect) or ethambutol (better tolerability).

Drugs blocking tubular secretion: possible reduction of their excretion and enhancement of toxic reactions.

Ofloxacin, lomefloxacin: enhanced anti-tuberculosis activity.

Ethionamide: concomitant use increases the risk of hepatotoxicity, especially in diabetic patients. During treatment with this combination, regular liver function tests should be performed. If any signs of impaired liver function occur, treatment with this drug combination should be discontinued.

Cyclosporine: possible reduction of its metabolism, decreased serum levels, and diminished immunosuppressive effect. Patients receiving cyclosporine should have serum cyclosporine levels monitored from the start of pyrazinamide therapy and after its discontinuation.

Phenytoin: possible increase in phenytoin serum concentration and, consequently, phenytoin toxicity. If central nervous system adverse effects (e.g., ataxia, hyperreflexia, nystagmus, tremor) occur during concomitant administration of pyrazinamide and phenytoin, the drugs should be discontinued, serum phenytoin concentrations determined, and the phenytoin dose adjusted accordingly.

Drugs promoting urinary excretion of uric acid (allopurinol, colchicine, probenecid, sulfinpyrazone): possible reduction in their effectiveness. This may elevate serum uric acid levels in patients treated with pyrazinamide; therefore, doses of uricosuric agents should be increased accordingly.

Allopurinol: possible slowing of further metabolism of pyrazinamide metabolites. However, the metabolism of pyrazinamide itself is not significantly altered.

Zidovudine: possible significant reduction in pyrazinamide serum levels and increased risk of anemia.

Hypoglycemic agents: possible enhancement of their effect.

Pyrazinamide reduces the reliability of ketone testing in urine using test strips (Acetest® and Ketostix®) because it turns the test sample reddish-brown.

Pyrazinamide may interfere with the determination of serum iron concentration using the Ferrochem® II instrument, as serum iron levels may appear falsely low.

Usage characteristics.

Pyrazinamide should be used with caution in patients with impaired liver function and in patients who have an increased risk of drug-induced liver injury (e.g., patients with alcoholism). During treatment with the drug, regular liver function tests should be performed every 2-4 weeks (thymol test, bilirubin determination, serum glutamic-oxaloacetic transaminase, alanine aminotransferase, and aspartate aminotransferase), as well as determination of serum uric acid. If liver function abnormalities occur, the drug should be discontinued immediately.

To reduce the toxic effects of pyrazinamide, methionine, lipocaine, glucose, and vitamin B12 are prescribed. Pyrazinamide may enhance the toxic effects of alcohol; therefore, alcohol consumption should be avoided during treatment with this drug.

In patients with porphyria, pyrazinamide may provoke acute attacks of porphyria.

If any clinical signs or symptoms of hepatic insufficiency occur, administration of the drug should be discontinued.

Pyrazinamide inhibits renal excretion of urates, which may lead to hyperuricemia, which can be asymptomatic. If hyperuricemia is accompanied by acute gouty arthritis, treatment with pyrazinamide should be discontinued.

In patients with renal insufficiency, pyrazinamide may accumulate in the body.

Pyrazinamide should be administered with caution in patients with diabetes mellitus due to difficulties in maintaining desired blood glucose concentrations.

Dosage selection for elderly patients requires caution and should start at the lowest dose range (see "Method of administration and dosage").

Use during pregnancy or breastfeeding.

The drug is contraindicated during pregnancy or breastfeeding.

Ability to affect reaction rate when driving or operating machinery.

Adverse reactions involving the nervous system may occur during treatment with this drug; therefore, patients should refrain from driving or operating machinery during this period.

Dosage and Administration

Take tablets as a single dose after meals, whole, with water. For calculating the daily dose, always use ideal body weight.

The daily dose for adults and children aged 15 years and older is 20–30 mg/kg body weight per dose. Take 1–3 times daily depending on tolerance. The maximum daily dose should not exceed 1.5 g.

Due to possible reduced kidney and liver function, elderly patients should be administered doses close to the lower limit of the usual adult dose – 15 mg/kg body weight per day.

The dose for patients with moderate renal impairment is 12–20 mg/kg body weight per day. Pyrazinamide should be avoided in patients with creatinine clearance below 50 mL/min.

For patients undergoing hemodialysis or peritoneal dialysis, administer the usual adult dose. It is recommended to administer the drug within 24 hours before the start of dialysis.

In patients with impaired liver function, administration of usual doses leads to accumulation of pyrazinamide in the body; therefore, lower doses are required – 15 mg/kg body weight per day. Liver function tests should be performed before initiating pyrazinamide therapy and every 2–4 weeks during treatment.

The duration of treatment depends on the course of the disease, patient tolerance, and is determined by the physician (usually 6–8 months).

Children.

Pyrazinamide in this dosage form is indicated for children aged 15 years and older.

Overdose.

In individual cases – liver function disturbances and increased transaminase levels. These abnormalities returned to normal after discontinuation of the drug.

Excitation, dyspeptic symptoms, liver function disturbances, hyperuricemia, and exacerbation of adverse reactions have also been observed.

Treatment. Gastric lavage, activated charcoal, monitoring of liver function, and serum urate level determination are required. Treatment is symptomatic. It is important for the patient to maintain high fluid intake. Hemodialysis is effective.

Side effects.

Skin and subcutaneous tissue: hyperemia, skin rashes, urticaria, itching, photosensitization, acne, toxic-allergic dermatitis.

Immune system: anaphylactoid reactions, angioneurotic edema, fever; in isolated cases – anaphylactic shock.

Gastrointestinal tract: dyspeptic symptoms, epigastric and stomach pain, loss of appetite, nausea, vomiting, diarrhea, peptic ulcer, metallic taste in the mouth.

Hepatobiliary system: liver function disturbances, increased levels of liver transaminases, bilirubin, thymol test; acute dose-dependent liver atrophy, jaundice.

Urinary system: interstitial nephritis; myoglobinuric renal failure due to rhabdomyolysis, dysuria, pain during urination.

Nervous system: dizziness, headache, sleep disturbances, increased excitability, depression; hallucinations, seizures, confusion, peripheral neuropathy, paresthesia.

Cardiovascular system: hypotension, discomfort in the cardiac area, sensation of warmth, facial hyperemia.

Blood and lymphatic system: thrombocytopenia, eosinophilia, anemia, sideroblastic anemia, erythrocyte vacuolization, porphyria, increased serum iron concentration, hypercoagulation, tendency to thrombus formation, splenomegaly.

Musculoskeletal and connective tissue: arthralgia, myalgia, rhabdomyolysis, gout attacks, joint swelling, joint stiffness.

Respiratory system: dyspnea, shortness of breath, dry cough.

Other: general weakness, malaise, hyperuricemia, pellagra.

Shelf life. 3 years.

Storage conditions. In the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging. 10 tablets in a blister, 5 blisters per pack.

Prescription status. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchagov Chemical and Pharmaceutical Plant".

Limited Liability Company "Agrofarm".

Manufacturer's address and location of business activity.

17 Miru Street, Kyiv, 03134, Ukraine.

113-A Tsentralna Street, Irpin, Kyiv Oblast, 08200, Ukraine.