pyrazinamide 500 mg Tablet, 500-count — NDC 0054-0812-29 (Billing 00054-0812-29)

WARNINGS Patients started on pyrazinamide should have baseline serum uric acid and liver function determinations. Those patients with preexisting liver disease or those at increased risk for drug related hepatitis (e.g., alcohol abusers) should be followed closely. Pyrazinamide should be discontinued and not be resumed if signs of hepatocellular damage or hyperuricemia accompanied by an acute gouty arthritis appear.

ADVERSE REACTIONS General Fever, porphyria and dysuria have rarely been reported. Gout (see PRECAUTIONS ). Gastrointestinal The principal adverse effect is a hepatic reaction (see WARNINGS ).

Hepatotoxicity appears to be dose related, and may appear at any time during therapy. GI disturbances including nausea, vomiting and anorexia have also been reported. Hematologic and Lymphatic Thrombocytopenia and sideroblastic anemia with erythroid hyperplasia, vacuolation of erythrocytes and increased serum iron concentration have occurred rarely with this drug.

Adverse effects on blood clotting mechanisms have also been rarely reported. Other Mild arthralgia and myalgia have been reported frequently. Hypersensitivity reactions including rashes, urticaria, and pruritis have been reported.

Fever, acne, photosensitivity, porphyria, dysuria and interstitial nephritis have been reported rarely.

Interactions Drug/Laboratory Test Interactions Pyrazinamide has been reported to interfere with ACETEST ® and KETOSTIX ® urine tests to produce a pink-brown color. 5

Drug/Laboratory Test Interactions Pyrazinamide has been reported to interfere with ACETEST ® and KETOSTIX ® urine tests to produce a pink-brown color. 5

PRECAUTIONS General Pyrazinamide inhibits renal excretion of urates, frequently resulting in hyperuricemia which is usually asymptomatic. If hyperuricemia is accompanied by acute gouty arthritis, pyrazinamide should be discontinued. Pyrazinamide should be used with caution in patients with a history of diabetes mellitus, as management may be more difficult.

Primary resistance of M. tuberculosis to pyrazinamide is uncommon. In cases with known or suspected drug resistance, in vitro susceptibility tests with recent cultures of M. tuberculosis against pyrazinamide and the usual primary drugs should be performed. There are few reliable in vitro tests for pyrazinamide resistance.

A reference laboratory capable of performing these studies must be employed. Information for Patients Patients should be instructed to notify their physicians promptly if they experience any of the following: fever, loss of appetite, malaise, nausea and vomiting, darkened urine, yellowish discoloration of the skin and eyes, pain or swelling of the joints. Compliance with the full course of therapy must be emphasized, and the importance of not missing any doses must be stressed.

Laboratory Tests Baseline liver function studies [especially ALT (SGPT), AST (SGOT) determinations] and uric acid levels should be determined prior to therapy. Appropriate laboratory testing should be performed at periodic intervals and if any clinical signs of symptoms occur during therapy. Interactions Drug/Laboratory Test Interactions Pyrazinamide has been reported to interfere with ACETEST ® and KETOSTIX ® urine tests to produce a pink-brown color.

5 Carcinogenesis, Mutagenesis, Impairment of Fertility 6,7,8 In lifetime bioassays in rats and mice, pyrazinamide was administered in the diet at concentrations of up to 10,000 ppm. This resulted in estimated daily doses for the mouse of 2 g/kg, or 40 times the maximum human dose, and for the rat of 0.5 g/kg, or 10 times the maximum human dose. Pyrazinamide was not carcinogenic in rats or male mice and no conclusion was possible for female mice due to insufficient numbers of surviving control mice.

Pyrazinamide was not mutagenic in the Ames bacterial test, but induced chromosomal aberrations in human lymphocyte cell cultures. Pregnancy Teratogenic Effects Animal reproduction studies have not been conducted with pyrazinamide. It is also not known whether pyrazinamide can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Pyrazinamide should be given to a pregnant woman only if clearly needed. Nursing Mothers Pyrazinamide has been found in small amounts in breast milk. Therefore, it is advised that pyrazinamide be used with caution in nursing mothers taking into account the risk-benefit of this therapy.

9 Pediatric Use Pyrazinamide regimens employed in adults are probably equally effective in pediatric patients. 4,10,11 Pyrazinamide appears to be well tolerated in pediatric patients. Geriatric Use 12 Clinical studies of pyrazinamide did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic or renal function, and of concomitant disease or other drug therapy. It does not appear that patients with impaired renal function require a reduction in dose.

It may be prudent to select doses at the low end of the dosing range, however. 13