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}

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., Cl_cr <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 SpectrumActions

• 
  

  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

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions January 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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