Pyrazinamide (Monograph)

Drug class: Antituberculosis Agents
VA class: AM500
CAS number: 98-96-4

Introduction

Antituberculosis agent; synthetic niacinamide derivative.

Uses for Pyrazinamide

Tuberculosis

Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents.

First-line agent for treatment of all forms of TB caused by Mycobacterium tuberculosis known or presumed to be susceptible to the drug.

Usually used in the initial intensive phase of treatment in a 4-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol. Also used in multiple-drug regimens for the management of patients with treatment failure or drug-resistant pulmonary TB.

Fixed combination preparation containing rifampin, isoniazid, and pyrazinamide (Rifater) used for treatment of pulmonary TB; designated an orphan drug by US FDA for short-term treatment of TB. Used only in the initial intensive treatment phase since pyrazinamide is not usually indicated for the continuation phase.

For initial treatment of active TB caused by drug-susceptible M. tuberculosis, recommended multiple-drug regimens consist of an initial intensive phase (2 months) and a continuation phase (4 or 7 months). Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except disseminated infections and TB meningitis) is 6–9 months, ATS, CDC, and IDSA state that completion of treatment is determined more accurately by the total number of doses and should not be based solely on the duration of therapy. A longer duration of treatment (e.g., 12–24 months) usually is necessary for infections caused by drug-resistant M. tuberculosis.

Patients with treatment failure or drug-resistant M. tuberculosis, including multidrug-resistant (MDR) TB (resistant to both isoniazid and rifampin) or extensively drug-resistant (XDR) TB (resistant to both isoniazid and rifampin and also resistant to a fluoroquinolone and at least one parenteral second-line antimycobacterial such as capreomycin, kanamycin, or amikacin), should be referred to or managed in consultation with experts in the treatment of TB as identified by local or state health departments or CDC.

Latent Tuberculosis Infection

Although a 2-drug regimen of rifampin and pyrazinamide was previously used for treatment of latent tuberculosis infection^{† [off-label]} (LTBI), these regimens have been associated with an increased risk of hepatotoxicity and are no longer recommended by the ATS, CDC, and IDSA. (See Hepatic Effects under Cautions.)

Related/similar drugs

ciprofloxacin, levofloxacin, rifampin, Levaquin, isoniazid, rifapentine, Rifadin

Pyrazinamide Dosage and Administration

Administration

Oral Administration

Administer orally.

Rifater: Administer orally with a full glass of water 1 hour before or 2 hours after a meal.

Dosage

Should not be used alone for treatment of TB; must be given in conjunction with other antituberculosis agents.

Can be used in daily or intermittent (2 or 3 times weekly) multiple-drug TB regimens.

Dosage of Rifater expressed as number of tablets.

Pediatric Patients

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

15–30 mg/kg (up to 3 g) once daily or 50–75 mg/kg twice weekly recommended by manufacturer.

Children <15 years of age or weighing ≤40 kg: 15–30 mg/kg (up to 2 g) once daily recommended by ATS, CDC, and IDSA; 20–40 mg/kg (up to 2 g) once daily recommended by AAP and others. If an intermittent regimen is used, 50–70 mg/kg (up to 2 g) twice weekly recommended by ATS, CDC, IDSA, and AAP.

Adolescents ≥15 years of age weighing 40–55 kg: 1 g once daily, 2 g twice weekly, or 1.5 g 3 times weekly recommended by ATS, CDC, IDSA.

Adolescents ≥15 years of age weighing 56–75 kg: 1.5 g once daily, 3 g twice weekly, or 2.5 g 3 times weekly recommended by ATS, CDC, IDSA.

Adolescents ≥15 years of age weighing 76–90 kg: 2 g once daily, 4 g twice weekly, or 3 g 3 times weekly recommended by ATS, CDC, IDSA.

Rifater in adolescents ≥15 years of age: 4 tablets once daily in those weighing ≤44 kg, 5 tablets once daily in those weighing 45–54 kg, or 6 tablets once daily in those weighing ≥55 kg.

Adults

Tuberculosis

Treatment of Active (Clinical) Tuberculosis

Oral

15–30 mg/kg (up to 3 g) once daily or 50–75 mg/kg twice weekly recommended by manufacturer.

Adults weighing 40–55 kg: 1 g once daily, 2 g twice weekly, or 1.5 g 3 times weekly recommended by ATS, CDC, IDSA.

Adults weighing 56–75 kg: 1.5 g once daily, 3 g twice weekly, or 2.5 g 3 times weekly recommended by ATS, CDC, IDSA.

Adults weighing 76–90 kg: 2 g once daily, 4 g twice weekly, or 3 g 3 times weekly recommended by ATS, CDC, IDSA .

Rifater: 4 tablets once daily in adults weighing ≤44 kg, 5 tablets once daily in adults weighing 45–54 kg, or 6 tablets once daily in adults weighing ≥55 kg.

Prescribing Limits

Pediatric Patients

Treatment of Active (Clinical) Tuberculosis

Oral

Maximum 3 g per dose in once-daily regimens recommended by manufacturer.

Children <15 years of age or weighing ≤40 kg: ATS, CDC, IDSA, and AAP recommend maximum 2 g per dose in once-daily or twice-weekly regimens.

Adults

Treatment of Active (Clinical) Tuberculosis

Oral

Maximum 3 g per dose in once-daily regimens recommended by the manufacturer.

ATS, CDC, and IDSA recommend maximum 2 g per dose when used in once-daily regimens, maximum 3 g per dose when used in 3-times weekly regimens, and maximum 4 g per dose when used in twice-weekly regimens.

Special Populations

Renal Impairment

Treatment of Active (Clinical) Tuberculosis

Oral

End-stage renal disease (i.e., Cl_cr <30 mL/minute, on hemodialysis): 25–35 mg/kg 3 times weekly after dialysis.

Geriatric Patients

Select dosage with caution; start at the low end of the dosage range.

Cautions for Pyrazinamide

Contraindications

• Known hypersensitivity to pyrazinamide or any ingredient in the formulation.

• Severe hepatic damage.

• Acute gout.

Warnings/Precautions

Warnings

Hyperuricemia

Asymptomatic hyperuricemia is an expected effect. Pyrazinamide inhibits renal excretion of urates, which frequently results in hyperuricemia.

Measure baseline uric acid concentrations; monitor uric acid concentrations periodically and if signs or symptoms of hyperuricemia occur. Discontinue if hyperuricemia accompanied by an acute gouty arthritis occurs. (See Contraindications under Cautions.)

Hepatic Effects

Hepatotoxicity can occur at any time; appears to be dose related.

Obtain baseline measurements of liver function (AST, ALT); monitor liver function periodically and if signs or symptoms of hepatotoxicity occur. Closely follow patients at risk for drug-related hepatitis (e.g., alcohol abusers). Permanently discontinue if signs of hepatocellular damage occur.

Severe liver injuries, including some fatalities, have been reported in patients receiving a 2-drug regimen of pyrazinamide and rifampin (once daily for 2 months) for the treatment of LTBI. A 2-drug regimen of rifampin and pyrazinamide should be considered for treatment of LTBI only in carefully selected patients with close monitoring and only if potential benefits outweigh the risk of hepatotoxicity and death. If a rifampin and pyrazinamide regimen is used, monitor serum aminotransferases and bilirubin at baseline and at 2, 4, 6, and 8 weeks; assess patient at 2, 4, 6, and 8 weeks for adherence, tolerance, and adverse effects. Permanently discontinue in asymptomatic patients with an aminotransferases concentration >5 times the ULN, in patients with symptoms of hepatitis who have an aminotransferases concentration above ULN, and in patients who have serum bilirubin concentrations above ULN (regardless of the presence or absence of symptoms).

Sensitivity Reactions

Rash, urticaria, and pruritus reported. May cause photosensitivity dermatitis.

General Precautions

Use of Fixed Combinations

When the fixed-combination preparation containing isoniazid, rifampin, and pyrazinamide (Rifater) is used, observe the usual precautions and contraindications associated with all drugs in the preparation. Use the fixed-combination preparation only when all 3 drugs are indicated.

Precautions Related to Treatment of Tuberculosis

Should not be used alone for treatment of TB; must be given in conjunction with other antituberculosis agents.

Clinical specimens for microscopic examination and mycobacterial cultures and in vitro susceptibility testing should be obtained prior to initiation of antituberculosis therapy and periodically during treatment to monitor therapeutic response. The antituberculosis regimen should be modified as needed. Patients with positive cultures after 4 months of treatment should be considered to have failed treatment (usually as the result of noncompliance or drug-resistant TB).

Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug regimen is critical. Missed doses increase the risk of treatment failure and increase the risk that M. tuberculosis will develop resistance to the antituberculosis regimen.

To ensure compliance, ATS, CDC, IDSA, and AAP recommend that directly observed (supervised) therapy (DOT) be used for treatment of active (clinical) TB whenever possible, especially when intermittent regimens are used, when the patient is immunocompromised or infected with HIV, or when drug-resistant M. tuberculosis is involved.

Diabetes Mellitus

Use with caution; management of diabetes may be more difficult.

Specific Populations

Pregnancy

Category C.

ATS, CDC, IDSA, and others state that routine use of pyrazinamide in pregnant women is not recommended, especially during the first trimester. However, the benefits may outweigh the possible (but unquantified) risk for treatment of TB in some pregnant women, especially when M. tuberculosis is resistant to other antituberculosis agents but may be susceptible to pyrazinamide.

Lactation

Distributed into milk; use caution taking into account the benefits and risks.

Pediatric Use

Used in pediatric patients; generally well tolerated in children.

Rifater: Safety and efficacy not established in children <15 years of age; the ratio of drugs in this preparation may not be appropriate for this age group.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Select dose with caution starting at the low end of the dosing range because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.

Hepatic Impairment

Carefully monitor patients with preexisting liver disease. (See Contraindications under Cautions.)

Renal Impairment

Dosage adjustment may be needed. (See Renal Impairment under Dosage and Administration.)

Risk of hyperuricemia may be increased in patients with renal impairment. (See Hyperuricemia under Cautions.)

Common Adverse Effects

GI effects (nausea, vomiting, anorexia), mild arthralgia and myalgia, rash, hyperuricemia.

Drug Interactions

Specific Drugs and Laboratory Tests

Pyrazinamide Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract; peak plasma concentrations attained within 2 hours.

Distribution

Extent

Distributed into body tissues and fluids, including liver and lung.

CSF concentrations are approximately equal to concurrent plasma concentrations in patients with inflamed meninges.

Not known whether pyrazinamide crosses the placenta.

Distributed into milk.

Plasma Protein Binding

10%.

Elimination

Metabolism

Hydrolyzed in the liver to major active metabolite, pyrazinoic acid; pyrazinoic acid undergoes further hydrolysis.

Elimination Route

Excreted in urine (70%), mainly by glomerular filtration.

Removed by dialysis.

Half-life

9–10 hours.

Special Populations

Half-life may be prolonged in patients with renal or hepatic impairment.

Stability

Storage

Oral

Tablets

15–30°C in well-closed container.

Rifater: 15–30°C. Protect from excessive humidity.

Actions and Spectrum

• Bacteriostatic or bactericidal in action.

• The exact mechanism of action has not been fully elucidated. Pyrazinoic acid, the active metabolite, appears to disrupt membrane energetics and inhibit membrane transport function in susceptible M. tuberculosis.

• A highly specific agent; active only against M. tuberculosis. Other mycobacteria, including M. kansasii and M. marinum, are resistant.

• Natural and acquired resistance to pyrazinamide observed in vitro and in vivo in strains of M. tuberculosis.

• Advise patients that poor compliance with antituberculosis regimens can result in treatment failure and development of drug-resistant TB, which can be life-threatening and lead to other serious health risks.

• Importance of completing full course of therapy; importance of not missing any doses.

• Importance of informing clinicians if fever, loss of appetite, malaise, nausea, vomiting, dark urine, icterus, or pain or swelling of the joints occurs.

• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Reload page with references included

Medical Disclaimer