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Pyrazinamide (Systemic)
Introductory Information
Antituberculosis agent; synthetic niacinamide derivative.124
Class: 8:16.04 Antituberculosis Agents; am500 (VA primary)
Brands*: Rifater® (combination) *also available generically
Generic Name: Pyrazinamide
CAS Number: 98-96-4
Synonym: Pyrazinoic Acid Amide
Generic Name Abbreviation: PZA

Uses
Tuberculosis
- Treatment of active (clinical) tuberculosis (TB) in conjunction with other antituberculosis agents. 100, 124,
126, d, e

- First-line agent for treatment of all forms of TB caused by Mycobacterium tuberculosis known or presumed
to be susceptible to the drug.126
- Usually used in the initial intensive phase of treatment in a 4-drug regimen of isoniazid, rifampin,
pyrazinamide, and ethambutol.100, 124, 126, d, e Also used in multiple-drug regimens for the management of
patients with treatment failure or drug-resistant pulmonary TB.100, 124, 126, d, e
- Fixed combination preparation containing rifampin, isoniazid, and pyrazinamide (Rifater®) used for
treatment of pulmonary TB;118 designated an orphan drug by US FDA for short-term treatment of TB.a
Used only in the initial intensive treatment phase since pyrazinamide is not usually indicated for the
continuation phase.118
- 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).100, 126
Although the usual duration of treatment for drug-susceptible pulmonary and extrapulmonary TB (except
disseminated infections and TB meningitis) is 6-9 months,100, 126 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.126 A longer duration of treatment (e.g., 12-24 months) usually is
necessary for infections caused by drug-resistant M. tuberculosis.100, 126
- 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.126

Latent Tuberculosis Infection

Although a 2-drug regimen of rifampin and pyrazinamide was previously used for treatment of latent
tuberculosis infection (LTBI), these regimens have been associated with an increased risk of hepatotoxicity
and are no longer recommended by the ATS, CDC, and IDSA.101, 125, 127 (See Hepatic Effects under Cautions.)

Dosage and Administration

Administration
Oral Administration
- Administer orally.124
- Rifater®: Administer orally with a full glass of water 1 hour before or 2 hours after a meal.118

Dosage
- Should not be used alone for treatment of TB; must be given in conjunction with other antituberculosis
agents.100, 124, 126
- Can be used in daily or intermittent (2 or 3 times weekly) multiple-drug TB regimens.100, 124, 126
- Dosage of Rifater® expressed as number of tablets.118

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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.124
- 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;122, 126 20-40 mg/kg (up to 2 g) once daily recommended by AAP and others.100, e If an
intermittent regimen is used, 50-70 mg/kg (up to 2 g) twice weekly recommended by ATS, CDC, IDSA,
and AAP.100, 126, e
- 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.126, d
- 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.126, d
- 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.126, d
- 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.118

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.124
- 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.126, d
- 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.126, d
- Adults weighing 76-90 kg: 2 g once daily, 4 g twice weekly, or 3 g 3 times weekly recommended by ATS,
CDC, IDSA .126, d
- 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.118

Prescribing Limits
Pediatric Patients
Treatment of Active (Clinical) Tuberculosis
Oral: Maximum 3 g per dose in once-daily regimens recommended by manufacturer.124
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.100, 126, e

Adults
Treatment of Active (Clinical) Tuberculosis
Oral: Maximum 3 g per dose in once-daily regimens recommended by the manufacturer.124
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.126

Special Populations
Renal Impairment
Treatment of Active (Clinical) Tuberculosis
Oral: End-stage renal disease (i.e., Clcr <30 mL/minute, on hemodialysis): 25-35 mg/kg 3 times weekly after
dialysis.126

Geriatric Patients
Select dosage with caution; start at the low end of the dosage range.124

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Cautions
Contraindications
• Known hypersensitivity to pyrazinamide or any ingredient in the formulation.124
• Severe hepatic damage.124
• Acute gout.124

Warnings/Precautions
Warnings
Hyperuricemia
- Asymptomatic hyperuricemia is an expected effect.124, 126 Pyrazinamide inhibits renal excretion of urates,
which frequently results in hyperuricemia.124
- Measure baseline uric acid concentrations; monitor uric acid concentrations periodically and if signs or
symptoms of hyperuricemia occur.124 Discontinue if hyperuricemia accompanied by an acute gouty arthritis
occurs.124 (See Contraindications under Cautions.)

Hepatic Effects
- Hepatotoxicity can occur at any time; appears to be dose related.124
- Obtain baseline measurements of liver function (AST, ALT); monitor liver function periodically and if
signs or symptoms of hepatotoxicity occur.124 Closely follow patients at risk for drug-related hepatitis (e.g.,
alcohol abusers).124 Permanently discontinue if signs of hepatocellular damage occur.124
- 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.101, 125, 127 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.127 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.127 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).127

Sensitivity Reactions
Rash, urticaria, and pruritus reported.124 May cause photosensitivity dermatitis.124, 126

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. 118 Use the
fixed-combination preparation only when all 3 drugs are indicated.126

Precautions Related to Treatment of Tuberculosis

- Should not be used alone for treatment of TB; must be given in conjunction with other antituberculosis
agents.100, 124, 126
- 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.126 The antituberculosis regimen should be modified as needed.126 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).126
- Compliance with the full course of antituberculosis therapy and all drugs included in the multiple-drug
regimen is critical.126 Missed doses increase the risk of treatment failure and increase the risk that M.
tuberculosis will develop resistance to the antituberculosis regimen.126
- 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

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 regimens are used, when the patient is immunocompromised or infected with HIV, or when drug-resistant
M. tuberculosis is involved.100, 126, d, e

Diabetes Mellitus
Use with caution; management of diabetes may be more difficult.124

Specific Populations
Pregnancy
Category C.124
ATS, CDC, IDSA, and others state that routine use of pyrazinamide in pregnant women is not
recommended,102, 126 especially during the first trimester.102 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.114, 126

Lactation
Distributed into milk; use caution taking into account the benefits and risks.124

Pediatric Use
- Used in pediatric patients; generally well tolerated in children.100, 124
- 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.118

Geriatric Use
Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently
than younger adults.124 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.124

Hepatic Impairment
Carefully monitor patients with preexisting liver disease.124 (See Contraindications under Cautions.)

Renal Impairment
Dosage adjustment may be needed.126 (See Renal Impairment under Dosage and Administration.)
Risk of hyperuricemia may be increased in patients with renal impairment.126 (See Hyperuricemia under
Cautions.)

Common Adverse Effects

GI effects (nausea, vomiting, anorexia), mild arthralgia and myalgia, rash, hyperuricemia.124, 126

Interactions
Specific Drugs and Laboratory Tests
Drug Interaction Comments
Severe liver injuries, including some Use of rifampin and pyrazinamide for treatment
fatalities, reported in patients receiving of LTBI should be considered only in carefully
Rifampin a 2-month daily regimen of rifampin selected patients with close monitoring and only
and pyrazinamide for treatment of if potential benefits outweigh the risk of
LTBI101, 125, 127 hepatotoxicity and death127
Tests for ketones Pyrazinamide produces a pink-brown
in urine (Acetest®, color that may interfere with
Ketostix®) interpretation of test124

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Pharmacokinetics
Absorption
Bioavailability
Well absorbed from the GI tract; peak plasma concentrations attained within 2 hours.124

Distribution
Extent
- Distributed into body tissues and fluids, including liver and lung.124
- CSF concentrations are approximately equal to concurrent plasma concentrations in patients with inflamed
meninges.124
- Not known whether pyrazinamide crosses the placenta.c
- Distributed into milk.124

Plasma Protein Binding

10%.124

Elimination
Metabolism
Hydrolyzed in the liver to major active metabolite, pyrazinoic acid; pyrazinoic acid undergoes further
hydrolysis.124

Elimination Route
Excreted in urine (70%), mainly by glomerular filtration.124
Removed by dialysis.124

Half-life
9-10 hours.124

Special Populations
Half-life may be prolonged in patients with renal or hepatic impairment.124

Stability
Storage
Oral
Tablets
15-30°C in well-closed container.124
Rifater®: 15-30°C.118 Protect from excessive humidity.118

Actions and Spectrum

• Bacteriostatic or bactericidal in action.108, 110
• The exact mechanism of action has not been fully elucidated.109, 110, g Pyrazinoic acid, the active metabolite,
appears to disrupt membrane energetics and inhibit membrane transport function in susceptible M.
tuberculosis.g
• A highly specific agent; active only against M. tuberculosis.124 Other mycobacteria, including M. kansasii
and M. marinum, are resistant.f
• Natural and acquired resistance to pyrazinamide observed in vitro and in vivo in strains of M. tuberculosis.c

Advice to Patients
• 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.127
• Importance of completing full course of therapy; importance of not missing any doses.124
• Importance of informing clinicians if fever, loss of appetite, malaise, nausea, vomiting, dark urine, icterus,
or pain or swelling of the joints occurs.124

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• Importance of informing clinicians of existing or contemplated therapy, including prescription and OTC
drugs, as well as any concomitant illnesses.124
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.124
• Importance of informing patients of other important precautionary information.124 (See Cautions.)

Preparations
Excipients in commercially available drug preparations may have clinically important effects in some
individuals; consult specific product labeling for details.
Pyrazinamide
Routes Dosage Forms Strengths Brand Names Manufacturer
Oral Tablets 500 mg* Pyrazinamide Tablets (scored) Dava, VersaPharm
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Pyrazinamide Combinations
Dosage
Routes Strengths Brand Names Manufacturer
Forms
300 mg with Isoniazid 50 mg and Rifater® (combination) (with povidone Sanofi-
Oral Tablets
Rifampin 120 mg and propylene glycol) Aventis

References
Only references cited for selected revisions after 1984 are available electronically.
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rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic
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[IDIS 469163] [PubMed 11787580]
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Opportunistic Infections Working Group. 2001 USPHS/IDSA guidelines for the prevention of
opportunistic infections in persons with human immunodeficiency virus. From the US Department of
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107. Ellard GA, Humphries MJ, Gabriel M et al. Penetration of pyrazinamide into the cerebrospinal fluid in
tuberculous meningitis. 1987; 294:284-5.
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3142340] [Free Fulltext PMC]
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Bridgewater, NJ; 2007 Mar.

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119. Marion Merrell Dow Inc, Kansas City, MO: Personal communication.
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