Pyrazinamide Tablets, USP 8413801/0618 Rx only

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:

PYRAZINAMIDE Structural Formula

C ₅H ₅N ₃O       M.W. 123.11

Each Pyrazinamide tablet for oral administration contains 500 mg of pyrazinamide and the following inactive ingredients: Corn Starch, Magnesium Stearate, Pregelatinized Starch and Stearic Acid.

Pyrazinamide is well absorbed from the GI tract and attains peak plasma concentrations within 2 hours. Plasma concentrations generally range from 30 to 50 mcg/mL with doses of 20 to 25 mg/kg. It is widely distributed in body tissues and fluids including the liver, lungs and cerebrospinal fluid (CSF). The CSF concentration is approximately equal to concurrent steady-state plasma concentrations in patients with inflamed meninges. ¹ Pyrazinamide is approximately 10% bound to plasma proteins. ²

The half-life (t _½) of pyrazinamide is 9 to 10 hours in patients with normal renal and hepatic function. The plasma half-life may be prolonged in patients with impaired renal or hepatic function. Pyrazinamide is hydrolyzed in the liver to its major active metabolite, pyrazinoic acid. Pyrazinoic acid is hydroxylated to the main excretory product, 5-hydroxypyrazinoic acid. ³

Approximately 70% of an oral dose is excreted in urine, mainly by glomerular filtration within 24 hours. ³

Pyrazinamide may be bacteriostatic or bactericidal against Mycobacterium tuberculosis depending on the concentration of the drug attained at the site of infection. The mechanism of action is unknown. In vitro and in vivo the drug is active only at a slightly acidic pH.

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 recommendations 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 is contraindicated in persons:

• with severe hepatic damage.
• who have shown hypersensitivity to it.
• with acute gout.

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.

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

Overdosage experience is limited. In one case report of overdose, abnormal liver function tests developed. These spontaneously reverted to normal when the drug was stopped. Clinical monitoring and supportive therapy should be employed. Pyrazinamide is dialyzable. ¹³

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 to 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 70 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.

Pyrazinamide Tablets, USP 500 mg are round, white, scored tablets, debossed S above the score, 660 below the score.
Unit dose packages of 100 (10 x 10) NDC 60687-138-01

Store at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature].

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

1. Drug Information, American Hospital Formulary Service. American Society of Hospital Pharmacists. Bethesda, MD. 1991.
2. USPDI, Drug Information for the Health Care Professional. United States Pharmacopeial Convention, Inc. Rockville, MD. 1991:1B:2226-2227.
3. Goodman-Gilman A, Rall TW, Nies AS, Taylor P. The Pharmacological Basis of Therapeutics, ed 8. New York, Pergamon Press. 1990;1154.
4. Treatment of tuberculosis and tuberculosis infection in adults and children. Am Rev Respir Dis. 1986;134:363-368.
5. Reynolds JEF, Parfitt K, Parsons AV, Sweetman-SC. Martindale The Extra Pharmacopoeia, ed 29. London, The Pharmaceutical Press. 1989;569-570.
6. Bioassay of pyrazinamide for possible carcinogenicity. National Cancer Institute Carcinogenesis Technical Report Series No. 48, 1978.
7. Zerger E, Anderson B, Haworth S, Lawlor T, Mortelmans K, Speck W. Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ Mutagen. 1987;9 (Suppl 9):1-109.
8. Roman IC, Georgian L. Cytogenetic effects of some antituberculosis drugs in vitro. Mutation Research. 1977;48:215-224.
9. Holdiness M. Antituberculosis drugs and breast-feeding. Arch Intern Med. 1984;144:1888.
10. Turcios N, Evans H. Preventing and managing tuberculosis in children. J Resp Dis. 1989;10(6)(Jun):23.
11. Starke JR. Multidrug therapy for tuberculosis in children. Pediatr Infec Dis J. 1990;9:785-793.
12. Specific requirements on content and format of labeling for human prescription drugs; proposed addition of “geriatric use” subsection in the labeling. Federal Register. 1990;55(212)(Nov 1):46134-46137.
13. Stamathakis G, Montes C, Trouvin JH, et al. Pyrazinamide and pyrazinoic acid pharmacokinetics in patients with chronic renal failure. Clinical Nephrology. 1988;30:230-234.

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Par Pharmaceutical as follows:
(500 mg / 100 UD) NDC 60687-138-01 packaged from NDC 67253-660

Distributed by:
American Health Packaging
Columbus, OH 43217

8413801/0618

500 mg Pyrazinamide Tablets Carton

NDC 60687- 138-01

Pyrazinamide
Tablets, USP

500 mg

100 Tablets (10 x 10)              Rx Only

Usual Adult Dosage: 15-30 mg/kg once daily, not to
exceed 2 g. See package insert for full prescribing
information.

Store at 20° to 25°C (68° to 77°F); excursions permitted
between 15° to 30°C (59° to 86°F) [see USP Controlled
Room Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or
broken.

The drug product contained in this package is from
NDC # 67253-660, Par Pharmaceutical.

Packaged and Distributed by:
American Health Packaging
Columbus, Ohio 43217

713801
0413801/0419

500 mg Pyrazinamide Tablet Blister

Pyrazinamide
Tablet, USP

500 mg