Pyrazinamide Information
Pyrazinamide ()
Pyrazinamide () Description:
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:
Each Pyrazinamide () tablet for oral administration contains 500 mg of Pyrazinamide () and the following inactive ingredients: dibasic calcium phosphate (dihydrate), colloidal silicon dioxide, croscarmellose sodium, microcrystalline cellulose, and stearic acid.
Pyrazinamide () Clinical Pharmacology:
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. Pyrazinamide () is approximately 10% bound to plasma proteins. The half-life (t 1/2) 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.
Approximately 70% of an oral dose is excreted in the urine, mainly by glomerular filtration within 24 hours.
Pyrazinamide () may be bacteriostatic or bactericidal against depending on the concentration of the drug attained at the site of infection. The mechanism of action is unknown. and the drug is active only at a slightly acidic pH.
Pyrazinamide () Indications And Usage:
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 drugsusceptible 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.*)
(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.
Pyrazinamide () Contraindications:
Pyrazinamide () is contraindicated in persons:
Pyrazinamide () 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.
Pyrazinamide () Precautions:
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 to Pyrazinamide () is uncommon. In cases with known or suspected drug resistance, susceptibility tests with recent cultures of against Pyrazinamide () and the usual primary drugs should be performed. There are few reliable tests for Pyrazinamide () resistance. A reference laboratory capable of performing these studies must be employed.
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.
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.
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.
Pyrazinamide () Overdosage:
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.
Pyrazinamide () Dosage And Administration:
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 evaluation 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.
Pyrazinamide () How Supplied:
Pyrazinamide () Tablets USP contain Pyrazinamide () 500 mg. They are supplied as white, round, scored tablets, debossed "EFF/12" on one side, in containers of 60 tablets, NDC #55806-012-02, in containers of 90 tablets, NDC #55806-012-08, in containers of 100 tablets, NDC #55806-012-03, in containers of 500 tablets, NDC #55806-012-04, and in hospital unit-dose cartons of 100 tablets (10 strips of 10 tablets per strip), NDC #55806-012-21.
Pyrazinamide ()
