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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

9-10 hours

Protein Binding

50%

Special Populations: Renal Function Impairment

The t½ of pyrazinamide and metabolite is increased.

Special Populations: Hepatic Function Impairment

The t½ of pyrazinamide and metabolite is increased.

Use: Labeled Indications

Adjunctive treatment of tuberculosis in combination with other antituberculosis agents

Contraindications

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

Dosage

Oral: Treatment of tuberculosis:

Note: Used as part of a multidrug regimen. Treatment regimens consist of an initial 2-month phase, followed by a continuation phase of 4 or 7 additional months; pyrazinamide is administered in the initial phase of treatment.

Children:

HIV negative (CDC, 2003):

Daily therapy: 15-30 mg/kg/day (maximum: 2 g/day)

Twice weekly directly observed therapy (DOT): 50 mg/kg/dose (maximum: 2 g/dose)

HIV-exposed/-infected: Daily therapy: 20-40 mg/kg/dose once daily (maximum: 2 g/day) (CDC, 2009)

Adults: Suggested dosing based on lean body weight (Blumberg, 2003; CDC, 2003):

Daily therapy:

40-55 kg: 1000 mg

56-75 kg: 1500 mg

76-90 kg: 2000 mg (maximum dose regardless of weight)

Twice weekly directly observed therapy (DOT):

40-55 kg: 2000 mg

56-75 kg: 3000 mg

76-90 kg: 4000 mg (maximum dose regardless of weight)

Three times/week DOT:

40-55 kg: 1500 mg

56-75 kg: 2500 mg

76-90 kg: 3000 mg (maximum dose regardless of weight)

Dosage adjustment in renal impairment: Adults: CrCl <30 mL/minute or receiving hemodialysis: Treatment of TB: 25-35 mg/kg/dose 3 times per week administered after dialysis (Blumberg, 2003; CDC, 2003)

Dosage adjustment in hepatic impairment: No dosage adjustment provided in 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

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

CycloSPORINE (Systemic): Pyrazinamide may increase the serum concentration of CycloSPORINE (Systemic). 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

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, angioedema (rare), anticoagulant effect, dysuria, fever, gout, hepatotoxicity, interstitial nephritis, itching, photosensitivity, porphyria, rash, sideroblastic anemia, 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

Teratogenic effects 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. Although not recommended as the initial treatment regimen, the use of pyrazinamide during pregnancy is recommended by The World Health Organization (Blumberg, 2003).

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?)

• Have patient report immediately to prescriber signs of hepatic impairment, severe osteodynia, considerable arthralgia, significant myalgia, urinary retention, or oliguria (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 healthcare 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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