PYRAZINAMIDE

Pyrazinamide, the pyrazine analogue of nicotinamide, is an antituberculous agent. It is a white crystalline powder, stable at room temperature, and sparingly soluble in water. Pyrazinamide has the following structural formula: C 5 H 5 N 3 O M.W. 123.11 Each pyrazinamide tablet for oral administration contains 500 mg of pyrazinamide and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate (dihydrate), microcrystalline cellulose, and stearic acid. structural formula image

Pyrazinamide is indicated for the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents. (The current recommendation of the CDC for drug-susceptible disease is to use a six-month regimen for initial treatment of active tuberculosis, consisting of isoniazid, rifampin and pyrazinamide given for 2 months, followed by isoniazid and rifampin for 4 months.* 4 ) (Patients with drug-resistant disease should be treated with regimens individualized to their situation. Pyrazinamide frequently will be an important component of such therapy.) (In patients with concomitant HIV infection, the physician should be aware of current recommendation of CDC. It is possible these patients may require a longer course of treatment). It is also indicated after treatment failure with other primary drugs in any form of active tuberculosis. Pyrazinamide should only be used in conjunction with other effective antituberculous agents. *See recommendations of Center for Disease Control (CDC) and American Thoracic Society for complete regimen and dosage recommendations. 4

Pyrazinamide should always be administered with other effective antituberculous drugs. It is administered for the initial 2 months of a 6-month or longer treatment regimen for drug-susceptible patients. Patients who are known or suspected to have drug-resistant disease should be treated with regimens individualized to their situation. Pyrazinamide frequently will be an important component of such therapy. Patients with concomitant HIV infection may require longer courses of therapy. Physicians treating such patients should be alert to any revised recommendations from CDC for this group of patients. Usual dose: Pyrazinamide is administered orally, 15 to 30 mg/kg once daily. Older regimens employed 3 or 4 divided doses daily, but most current recommendations are for once a day. Three grams per day should not be exceeded. The CDC recommendations do not exceed 2 g per day when given as a daily regimen (see table). Alternatively, a twice weekly dosing regimen (50 to 75 mg/kg twice weekly based on lean body weight) has been developed to promote patient compliance with a regimen on an outpatient basis. In studies evaluating the twice weekly regimen, doses of pyrazinamide in excess of 3 g twice weekly have been administered. This exceeds the recommended maximum 3 g/daily dose. However, an increased incidence of adverse reactions has not been reported. This table is taken from the CDC-American Thoracic Society joint recommendations. 4 Recommended Drugs for the Initial Treatment of Tuberculosis in Children and Adults Drug Daily Dose* Children Adults Isoniazid 10 to 20 mg/kg PO or IM 5 mg/kg PO or IM Rifampin 10 to 20 mg/kg PO 10 mg/kg PO Pyrazinamide 15 to 30 mg/kg PO 15 to 30 mg/kg PO Streptomycin 20 to 40 mg/kg IM 15 mg/kg IM Ethambutol 15 to 25 mg/kg PO 15 to 25 mg/kg PO Drug Maximal Daily Dose in Children and Adults Isoniazid 300 mg Rifampin 600 mg Pyrazinamide 2 g Streptomycin 1 g** Ethambutol 2.5 g Drug Twice Weekly Dose Children Adults Isoniazid 20 to 40 mg/kg Max. 900 mg 15 mg/kg Max. 900 mg Rifampin 10 to 20 mg/kg Max. 600 mg 10 mg/kg Max. 600 mg Pyrazinamide 50 to 70 mg/kg 50 to 70 mg/kg Streptomycin 25 to 30 mg/kg IM 25 to 30 mg/kg IM Ethambutol 50 mg/kg 50 mg/kg Definition of abbreviations: PO = perorally; IM = intramuscularly.

Pyrazinamide is contraindicated in persons: • with severe hepatic damage. • who have shown hypersensitivity to it. • with acute gout.

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