Pyrazinamide

Pyrazinamide
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]

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Overview

Pyrazinamide is an antitubercular, anti- infective agent that is FDA approved for the treatment of the initial treatment of active tuberculosis in adults and children when combined with other antituberculous agents. Common adverse reactions include hyperuricemia, nausea, vomiting, arthralgia.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

HIV infection - Tuberculosis

• Dosing Information

• HIV infection - Tuberculosis: (40 to 55 kg) 1000 mg ORALLY once daily OR 1500 mg ORALLY 3 times a week OR 2000 mg ORALLY 2 times a week in combination with other antitubercular agents; twice-weekly dosing not recommended in HIV-patients with CD4 lymphocyte counts less than 100 cells/millimeter(3)
• HIV infection - Tuberculosis: (56 to 75 kg) 1500 mg ORALLY once daily OR 2500 mg ORALLY 3 times a week OR 3000 mg ORALLY 2 times a week in combination with other antitubercular agents; twice-weekly dosing not recommended in HIV-patients with CD4 lymphocyte counts less than 100 cells/millimeter(3)
• HIV infection - Tuberculosis: (76 to 90 kg) 2000 mg ORALLY once daily OR 3000 mg ORALLY 3 times a week OR 4000 mg ORALLY 2 times a week in combination with other antitubercular agents; twice-weekly dosing not recommended in HIV-patients with CD4 lymphocyte counts less than 100 cells/millimeter(3)

Tuberculosis

• Dosing Information

• Tuberculosis: (40 to 55 kg) 1000 mg ORALLY once daily OR 1500 mg ORALLY 3 times a week OR 2000 mg ORALLY 2 times a week in combination with other antitubercular agents
• Tuberculosis: (56 to 75 kg) 1500 mg ORALLY once daily OR 2500 mg ORALLY 3 times a week OR 3000 mg ORALLY 2 times a week in combination with other antitubercular agents
• Tuberculosis: (76 to 90 kg) 2000 mg ORALLY once daily OR 3000 mg ORALLY 3 times a week OR 4000 mg ORALLY 2 times a week in combination with other antitubercular agents

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

• There is limited information regarding Off-Label Guideline-Supported Use of Pyrazinamide in adult patients.

Non–Guideline-Supported Use

• There is limited information regarding Off-Label Non–Guideline-Supported Use of Pyrazinamide in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

HIV infection - Tuberculosis

• Dosing Information

• HIV infection - Tuberculosis: 15 to 30 mg/kg ORALLY once daily (MAX, 2000 mg/day) OR 50 mg/kg ORALLY 2 times a week (MAX, 4000 mg/day) in combination with other antitubercular agents

Tuberculosis

• Dosing Information

• Tuberculosis: 15 to 30 mg/kg ORALLY once daily (MAX, 2000 mg/day) OR 50 mg/kg ORALLY 2 times a week (MAX, 4000 mg/day) in combination with other antitubercular agents

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

• There is limited information regarding Off-Label Guideline-Supported Use of Pyrazinamide in pediatric patients.

Non–Guideline-Supported Use

• There is limited information regarding Off-Label Non–Guideline-Supported Use of Pyrazinamide in pediatric patients.

Contraindications

• Pyrazinamide is contraindicated in persons:

• with severe hepatic damage.

• who have shown hypersensitivity to it.

• with acute gout.

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.

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 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.

• 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.

• 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 or symptoms occur during therapy.

• Pyrazinamide has been reported to interfere with ACETEST® and KETOSTIX® urine tests to produce a pink-brown color.

• 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.

• 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.

• Pyrazinamide has been found in small amounts in breast milk. Therefore, it is advised the pyrazinamide be used with caution in nursing mothers taking into account the risk-benefit of this therapy.

• Pyrazinamide regimens employed in adults are probably equally effective in children. Pyrazinamide appears to be well tolerated in children.

• 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.

Adverse Reactions

Clinical Trials Experience

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.

Postmarketing Experience

There is limited information regarding Pyrazinamide Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Pyrazinamide Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Pyrazinamide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Pyrazinamide during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Pyrazinamide with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Pyrazinamide with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Pyrazinamide with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Pyrazinamide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Pyrazinamide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Pyrazinamide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Pyrazinamide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Pyrazinamide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Pyrazinamide in patients who are immunocompromised.

Administration and Monitoring

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 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.

• The table is taken from the CDC-American Thoracic Society joint recommendations

Monitoring

• There is limited information regarding Monitoring of Pyrazinamide in the drug label.

IV Compatibility

• There is limited information regarding IV Compatibility of Pyrazinamide in the drug label.

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.

Pharmacology

Mechanism of Action

Structure

• 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:

• C5H5N3O- 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.

Pharmacodynamics

• There is limited information regarding Pharmacodynamics of Pyrazinamide in the drug label.

Pharmacokinetics

• 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 (t1/2) 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. 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.

Nonclinical Toxicology

• There is limited information regarding Nonclinical Toxicology of Pyrazinamide in the drug label.

Clinical Studies

• There is limited information regarding Clinical Studies of Pyrazinamide in the drug label.

How Supplied

Storage

There is limited information regarding Pyrazinamide Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

• There is limited information regarding Patient Counseling Information of Pyrazinamide in the drug label.

Precautions with Alcohol

• Alcohol-Pyrazinamide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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