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Pyrazinamide

Pronunciation

(peer a ZIN a mide)

Index Terms

  • Pyrazinoic Acid Amide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 500 mg

Pharmacologic Category

  • Antitubercular Agent

Pharmacology

Converted to pyrazinoic acid in susceptible strains of Mycobacterium which lowers the pH of the environment; exact mechanism of action has not been elucidated

Absorption

Well absorbed

Distribution

Widely into body tissues and fluids including liver, lung, and CSF

Relative diffusion from blood into CSF: Adequate with or without inflammation (exceeds usual MICs)

CSF:blood level ratio: Inflamed meninges: 100%

Metabolism

Hepatic

Excretion

Urine (4% as unchanged drug)

Time to Peak

Serum: Within 2 hours

Half-Life Elimination

9 to 10 hours, prolonged with reduced renal or hepatic function

Protein Binding

50%

Use: Labeled Indications

Tuberculosis: Adjunctive treatment of tuberculosis (TB) in combination with other antituberculosis agents

Contraindications

Hypersensitivity to pyrazinamide or any component of the formulation; acute gout; severe hepatic damage

Dosing: Adult

Tuberculosis, treatment (drug-susceptible): Oral: Note: Always administer in combination with other antitubercular drugs (Nahid 2016).

ATS/CDC/IDSA drug-sensitive tuberculosis guideline recommendations (Nahid 2016):

Dosing: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established) (Nahid 2016):

Once-daily therapy:

40 to 55 kg: 1,000 mg once daily Note: The preferred frequency of administration is once daily; however, 5-days per week administration by directly-observed therapy (DOT) is an acceptable alternative (Nahid 2016).

56 to 75 kg: 1,500 mg once daily

76 to 90 kg: 2,000 mg once daily

Three-times-weekly DOT:

40 to 55 kg: 1,500 mg 3 times weekly

56 to75 kg: 2,500 mg 3 times weekly

76 to 90 kg: 3,000 mg 3 times weekly

Twice-weekly DOT:

40 to 55 kg: 2,000 mg twice weekly

56 to 75 kg: 3,000 mg twice weekly

76 to 90 kg: 4,000 mg twice weekly

Regimens: Treatment regimens for pulmonary tuberculosis and tuberculous meningitis consist of an initial 2-month phase of a 4-drug regimen that includes pyrazinamide, followed by a continuation phase of a 2-drug regimen (does not include pyrazinamide) of an additional 4 to 7 months for pulmonary tuberculosis and a continuation phase of an additional 7 to 10 months of a 2-drug regimen (does not include pyrazinamide) for tuberculous meningitis (optimal duration is not defined although continuation phase must continue for a minimum of 7 additional months). Adjunctive corticosteroid therapy (eg, dexamethasone, prednisolone) tapered over 6 to 8 weeks is also recommended for tuberculous meningitis; pyrazinamide frequency and dosing differs depending on treatment regimen selected; consult current drug-sensitive TB guidelines (Nahid 2016).

Dosing: Pediatric

Tuberculosis, active (drug-susceptible) (excludes meningitis): Oral: Note: Always administer in combination with other antitubercular drugs (Nahid 2016).

ATS/CDC/IDSA drug-susceptible tuberculosis guideline recommendations (Nahid 2016):

Dosing:

Once-daily therapy: Note: The preferred frequency of administration is once daily; however, 5-days-per-week administration by directly observed therapy (DOT) is an acceptable alternative.

Infants, Children and Adolescents <15 years and ≤40 kg: 30 to 40 mg/kg/dose once daily

Children and Adolescents <15 years and >40 kg and Adolescents ≥15 years: Refer to adult dosing

Three-times-weekly DOT: Note: Although suggested dosing based on experience with twice-weekly regimen; experts suggest three-times-weekly regimens are more effective than twice-weekly DOT regimens; consult guidelines for specific information.

Infants, Children, and Adolescents <15 years, weighing ≤40 kg: 50 mg/kg/dose administered 3 times weekly.

Children and Adolescents <15 years weighing >40 kg or Adolescents ≥15 years: Refer to adult dosing.

Regimens: Treatment regimens for pulmonary tuberculosis consist of an initial 2-month phase of a 4-drug regimen that includes pyrazinamide, followed by a continuation phase of a 2-drug regimen (does not include pyrazinamide) of an additional 4 to 7 months. Pyrazinamide frequency and dosing differs depending on treatment regimen selected; consult current drug-sensitive TB guidelines (Nahid 2016).

Dosing: Renal Impairment

CrCl <30 mL/minute or receiving intermittent hemodialysis: Treatment of drug-susceptible TB: Adults: 25 to 35 mg/kg/dose 3 times per week administered after dialysis (do not administer daily) (Nahid 2016).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling. Use is contraindicated in cases of severe hepatic impairment.

Extemporaneously Prepared

A 100 mg/mL oral suspension may be made with tablets. Crush two-hundred pyrazinamide 500 mg tablets and mix with a suspension containing 500 mL methylcellulose 1% and 500 mL simple syrup. Add to this a suspension containing one-hundred forty crushed pyrazinamide tablets in 350 mL methylcellulose 1% and 350 mL simple syrup to make 1.7 L suspension. Label "shake well" and "refrigerate". Stable for 60 days refrigerated (preferred) and 45 days at room temperature.

Nahata MC, Morosco RS, and Peritre SP, “Stability of Pyrazinamide in Two Suspensions,” Am J Health Syst Pharm, 1995, 52(14):1558-60.7552903

Storage

Store at controlled room temperature of 15°C to 30°C (59°F to 86°F).

Drug Interactions

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Benzbromarone: Pyrazinamide may diminish the therapeutic effect of Benzbromarone. Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

CycloSPORINE (Systemic): Pyrazinamide may decrease the serum concentration of CycloSPORINE (Systemic). Monitor therapy

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

RifAMPin: Pyrazinamide may enhance the hepatotoxic effect of RifAMPin. Severe (even fatal) liver injury has been reported in patients receiving these 2 drugs as a 2-month treatment regimen for latent TB infection. Consider therapy modification

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Test Interactions

Reacts with Acetest® and Ketostix® to produce pinkish-brown color

Adverse Reactions

1% to 10%:

Central nervous system: Malaise

Gastrointestinal: Anorexia, nausea, vomiting

Neuromuscular & skeletal: Arthralgia, myalgia

<1% (Limited to important or life-threatening): Acne vulgaris, acquired blood coagulation disorder (anticoagulant effect), angioedema (rare), dysuria, fever, gout, hepatotoxicity, interstitial nephritis, porphyria, pruritus, sideroblastic anemia, skin photosensitivity, skin rash, thrombocytopenia, urticaria

Warnings/Precautions

Concerns related to adverse effects:

• Hepatotoxicity: Dose-related hepatotoxicity ranging from transient ALT/AST elevations to jaundice, hepatitis and/or liver atrophy (rare) has occurred.

Disease-related concerns:

• Alcoholism: Due to concerns for preexisting hepatic dysfunction, use with caution in patients with a history of alcoholism (even if ethanol consumption is discontinued during therapy).

• Diabetes: Use with caution in patients with diabetes mellitus.

• Gout: May inhibit uric acid excretion; acute gouty attacks have been reported. Use with caution in patients with chronic gout; contraindicated with acute gout.

• Porphyria: Use with caution in patients with porphyria.

• Renal impairment: Use with caution in patients with renal failure.

Concurrent drug therapy issues:

• Hepatotoxic agents: Use with caution in patients receiving concurrent medications associated with hepatotoxicity (particularly with rifampin). The 2-month rifampin-pyrazinamide regimen for the treatment of latent tuberculosis infection (LTBI) has been associated with severe and fatal liver injuries; incidence increased with pyrazinamide doses >30 mg/kg/day. The Infectious Diseases Society of America and Centers for Disease Control and Prevention recommend that the 2-month rifampin-pyrazinamide regimen should not generally be used in patients with LTBI.

Monitoring Parameters

Periodic liver function tests, serum uric acid, sputum culture, chest x-ray 2-3 months into treatment and at completion

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Due to the risk of tuberculosis to the fetus, treatment is recommended when the probability of maternal disease is moderate to high. Drug-susceptible TB guidelines recommend pyrazinamide as part of the initial treatment regimen; however, risks and benefits of use during pregnancy should be considered for each individual patient (Nahid 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience muscle pain. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), joint pain, or joint edema (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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