Pyrazinamide

Class: Antituberculosis Agents
VA Class: AM500
CAS Number: 98-96-4
Brands: Rifater

Introduction

Antituberculosis agent; synthetic niacinamide derivative.124

Uses for Pyrazinamide

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

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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.)

Pyrazinamide 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

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

Cautions for Pyrazinamide

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 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 for Pyrazinamide

Specific Drugs and Laboratory Tests

Drug

Interaction

Comments

Rifampin

Severe liver injuries, including some fatalities, reported in patients receiving a 2-month daily regimen of rifampin and pyrazinamide for treatment of LTBI101 125 127

Use of rifampin and pyrazinamide for treatment of LTBI should be considered only in carefully selected patients with close monitoring and only if potential benefits outweigh the risk of hepatotoxicity and death127

Tests for ketones in urine (Acetest, Ketostix)

Pyrazinamide produces a pink-brown color that may interfere with interpretation of test124

 

Pyrazinamide 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

  • 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.

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

Pyrazinamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

500 mg*

Pyrazinamide Tablets (scored)

Dava, VersaPharm

Pyrazinamide Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

300 mg with Isoniazid 50 mg and Rifampin 120 mg

Rifater (with povidone and propylene glycol)

Sanofi-Aventis

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. American Academy of Pediatrics. 2006 Red Book: Report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2006.

101. Centers for Disease Control and Prevention. Update: fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations—United States, 2001. MMWR Morb Mortal Wkly Rep. 2001; 50:733-5. [IDIS 469163] [PubMed 11787580]

102. US Public Health Service (USPHS) and Infectious Diseases Society of America (IDSA) Prevention of 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 Health and Human Services HIV/AIDS Information Services (AIDSinfo) website ()

107. Ellard GA, Humphries MJ, Gabriel M et al. Penetration of pyrazinamide into the cerebrospinal fluid in tuberculous meningitis. 1987; 294:284-5.

108. Steele MA, Des Prez RM. The role of pyrazinamide in tuberculosis chemotherapy. Chest. 1988; 94:845-50. [IDIS 246642] [PubMed 3048929]

109. Salfinger M, Heifets LB. Determination of pyrazinamide MICs for Mycobacterium tuberculosis at different pHs by the radiometric method. Antimicrob Agents Chemother. 1988; 32:1002-4. [PubMed 3142340]

110. Heifets LB, Flory MA, Lindholm-Levy PJ. Does pyrazinoic acid as an active moiety of pyrazinamide have specific activity against Mycobacterium tuberculosis? Antimicrob Agents Chemother. 1989; 33:1252-4.

111. US Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Recomm Rep. 1993; 42(RR-7):1-8.

113. Anon. Drugs for tuberculosis. Med Lett Drugs Ther. 1993; 35:99-101. [PubMed 8412982]

114. US Centers for Disease Control and Prevention. Tuberculosis among pregnant women—New York City, 1985–1992. MMWR Morb Mortal Wkly Rep. 1993; 42:605,611,612. [PubMed 8336692]

116. Centers for Disease Control. Prevention and control of tuberculosis in migrant farm workers. Recommendations of the Advisory Council for the Elimination of Tuberculosis. MMWR Recomm Rep. 1992; 41(RR-10):1-15.

117. Anon. Drugs for AIDS and associated infections. Med Lett Drugs Ther. 1993; 35:79-86. [PubMed 8394503]

118. Sanofi-aventis. Rifater (rifampin, isoniazid, and pyrazinamide) tablets prescribing information. Bridgewater, NJ; 2007 Mar.

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

121. American Thoracic Society (ATS) and Centers for Disease Control Prevention (CDC). Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000; 161:S221-S247.

122. Centers for Disease Control and Prevention. Prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. MMWR Recomm Rep. 1998; 47(RR-20):1-58.

123. Centers for Disease Control and Prevention. Use of short-course tuberculosis preventive therapy regimens in HIV-seronegative patients. MMWR Morb Mortal Wkly Rep. 1998; 47:911-2.

124. VersaPharm Incorporated. Pyrazinamide tablets USP 500 mg prescribing information. Marietta, GA; 2001 Apr.

125. Centers for Disease Control and Prevention. Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection— New York and Georgia, 2000. MMWR Morb Mortal Wkly Rep. 2001; 50:289-90. [IDIS 463131] [PubMed 11330495]

126. Centers for Disease Control and Prevention. Treatment of tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Recomm Rep. 2003; 52(RR-11):1-77.

127. Centers for Disease Control and Prevention. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection—United States, 2003. MMWR Morb Mortal Wkly Rep. 2003; 52:735-9. [PubMed 12904741]

a. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414), to June 28, 1996. Rockville, MD: 1996 Jul.

c. AHFS drug information 2007. McEvoy GK. Pyrazinamide. Bethesda, MD. American Society of Health-System Pharmacists;2007:559-62.

d. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(RR-15):1-112.

e. Centers for Disease Control and Prevention. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep. 2004; 53(RR-14):1-92.

f. Griffith DE, Aksamit T, Brown-Elliott BA et al. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007; 175:367-416. [PubMed 17277290]

g. Zhang Y, Wade MM, Scorpio A et al. Mode of action of pyrazinamide: disruption of Mycobacterium tuberculosis membrane transport and energetics by pyrazinoic acid. J Antimicrob Chemother. 2003; 52:790-5. [PubMed 14563891]

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