Tebrazid 500 mg

Absorption: Pyrazinamide is well absorbed from the gastrointestinal tract. Following a single 500 mg oral dose in healthy adults, peak plasma concentrations of pyrazinamide ranging from 9 to 12 µg/mL are attained within 2 hours; plasma concentrations of the drug average 7 µg/mL at 8 hours and 2 µg/mL at 24 hours. Plasma concentrations following doses of 20 to 25 mg/kg reportedly range from 30 to 50 µg/mL. Plasma concentrations of pyrazinoic acid, the major active metabolite of pyrazinamide, generally are greater than those of the parent drug and peak within 4 to 8 hours after an oral dose of the drug. In a single dose study in healthy fasting males, the extent of absorption (as measured by area under the plasma concentration-time curve) of isoniazid, rifampin, or pyrazinamide in dosages of 250, 600, or 1500 mg, respectively, was similar whether the drugs were administered individually as capsules (rifampin) and tablets (isoniazid and pyrazinamide) or as a fixed combination containing isoniazid 50 mg, rifampin 120 mg, and pyrazinamide 300 mg per tablet.

Distribution: Pyrazinamide is widely distributed into body tissues and fluids including the liver, lungs, kidneys, and CSF. In a limited number of adults with tuberculous meningitis, mean serum and CSF concentrations of pyrazinamide 2 hours after an oral dose of approximately 41 mg/kg were 52 and 39 µg/mL, respectively. Within 5 hours after an oral dose, CSF concentrations of pyrazinamide are reported to be approximately equal to concurrent plasma concentrations of the drug. Plasma protein binding of pyrazinamide (determined by ultrafiltration) in a limited number of healthy men averaged approximately 17% at a pyrazinamide concentration of 20 µg/mL. It is not known if pyrazinamide crosses the placenta or if it is distributed into milk.

Elimination: The plasma half-life of pyrazinamide is 9 to 10 hours in patients with normal renal and hepatic function. The plasma half-life of the drug may be prolonged in patients with impaired renal (approximately 26 hours) or hepatic function.

Pyrazinamide is hydrolyzed in the liver to pyrazinoic acid, the major active metabolite; some hydrolysis may also occur in the stomach and bladder. Pyrazoic acid is hyroxylated to 5-hydroxypyrazinoic acid, the major excretory product. Within 24 hours, approximately 70% of an oral dose of pyrazinamide is excreted as unchanged drug; the remainder is excreted as metabolites.

A single 3 to 4 hour hemodialysis session reduced serum pyrazinamide concentrations by approximately 55% and pyrazinoic acid concentrations by 50 to 60%.

Appropriate studies on the relationship of age to the effects of pyrazinamide have not been performed in the geriatric population. However, no geriatric-specific problems have been documented to date.

See Pregnancy.

Safe use of pyrazinamide in children has not been definitely established. Because of the drug's potential toxicity, the manufacturer recommends that its use in children be avoided unless essential to therapy.

Animal reproduction studies have not been conducted with pyrazinamide. Adequate and well-controlled studies in humans have not been done. The risk for teratogenicity has not been determined. If the organism is drug-susceptible, pregnant women can be safely treated with isoniazid, rifampin, and ethambutol for 9 months. If resistance to any of these medications is probable and susceptibility to pyrazinamide is likely, its use should be considered.

Pyrazinamide was not mutagenic in the Ames bacterial test (Salmonella), but it did induce chromosomal aberrations in human lymphocyte cell cultures.

Pyrazinamide was administered in the diet of rats and mice. The estimated daily dose was 2 g/kg, or 40 times the maximum human dose, for the mouse, and 0.5 g/kg, or 10 times the maximum human dose, for the rat. Pyrazinamide was not carcinogenic in rats or male mice. No conclusion was possible for female mice due to insufficient numbers of surviving control mice.

Interactions between pyrazinamide and the following medications (or combinations containing the following medications) have been reported: allopurinol; colchicine; probenecid; sulfinpyrazone (pyrazinamide may increase serum uric acid concentrations and decrease the efficacy of gout therapy; dosage adjustments of these medications may be necessary to control hyperuricemia and gout when antigout medications are used concurrently with pyrazinamide). Cyclosporine (concurrent use with pyrazinamide may decrease the serum concentrations of cyclosporine, possibly leading to inadequate immunosuppression; cyclosporine serum concentrations should be monitored).