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  • CLASSES

    Other Agents for Tuberculosis

    DEA CLASS

    Rx

    DESCRIPTION

    Antituberculosis agent; useful when resistance to isoniazid or rifampin has been confirmed; used in combination with other agents.

    HOW SUPPLIED

    Pyrazinamide Oral Tab: 500mg

    DOSAGE & INDICATIONS

    For the treatment of drug-susceptible tuberculosis infection as part of combination therapy.
    For the treatment of drug-susceptible tuberculosis infection in persons without HIV as part of combination therapy.
    Oral dosage
    Adults weighing more than 90 kg (lean body weight)

    15 to 30 mg/kg/dose PO once daily (Max: 3 g/day), or alternatively, 50 to 75 mg/kg/dose PO twice weekly.[30005] Daily dosing is preferred. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase as first-line therapy.[61094]

    Adults weighing 76 to 90 kg (lean body weight)

    2 g PO once daily or 5 days/week, or alternatively, 3 g PO 3 days/week or 4 g PO twice weekly.[61094] The FDA-approved dose is 15 to 30 mg/kg/dose PO once daily or 50 to 75 mg/kg/dose PO twice weekly.[30005] Daily dosing is preferred and is defined as 5- or 7 days/week. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase as first-line therapy.[61094] [65619]

    Adults weighing 56 to 75 kg (lean body weight)

    1.5 g PO once daily or 5 days/week, or alternatively, 2.5 g PO 3 days/week or 3 g PO twice weekly. The FDA-approved dose is 15 to 30 mg/kg/dose PO once daily or 50 to 75 mg/kg/dose PO twice weekly. Daily dosing is preferred and is defined as 5- or 7 days/week. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase of treatment as first-line therapy.[61094]

    Adults weighing 40 to 55 kg (lean body weight)

    1 g PO once daily or 5 days/week, or alternatively, 1.5 g PO 3 days/week or 2 g PO twice weekly. The FDA-approved dose is 15 to 30 mg/kg/dose PO once daily or 50 to 75 mg/kg/dose PO twice weekly. Daily dosing is preferred and is defined as 5- or 7 days/week. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase as first-line therapy.[61094]

    Infants, Children, and Adolescents

    30 to 40 mg/kg/dose (lean body weight) (Max: 2 g/dose) PO once daily or 5 days/week, or alternatively, 50 mg/kg/dose (lean body weight) PO 3 days/week (Max: 3 g/dose) or twice weekly (Max: 4 g/dose).[61094] [63245] The FDA-approved dose is 15 to 30 mg/kg/dose (lean body weight) PO once daily (Max: 3 g/day) or 50 to 75 mg/kg/dose (lean body weight) PO twice weekly.[30005] Daily dosing is preferred and is defined as 5- or 7 days/week. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase as first-line therapy.[61094] [63245]

    Neonates†


    20 to 40 mg/kg/dose PO once daily. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase as first-line therapy.[53484]

    For the treatment of drug-susceptible tuberculosis infection in persons with HIV as part of combination therapy.
    Oral dosage
    Adults weighing more than 90 kg (lean body weight)

    2 g PO once daily. Monitor for response and consider therapeutic drug monitoring to assure dosing adequacy.[34362] The FDA-approved dose is 15 to 30 mg/kg/dose PO once daily (Max: 3 g/day) or 50 to 75 mg/kg/dose PO twice weekly.[30005] Pyrazinamide is generally recommended as part of the initial 2-month intensive phase as first-line therapy.[34362] [61094]

    Adults weighing 76 to 90 kg (lean body weight)

    2 g PO once daily or 5 days/week.[34362] [61094] The FDA-approved dose is 15 to 30 mg/kg/dose PO once daily or 50 to 75 mg/kg/dose PO twice weekly.[30005] Daily dosing is defined as 5- or 7 days/week. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase of treatment as first-line therapy.[34362] [61094]

    Adults weighing 56 to 75 kg (lean body weight)

    1.5 g PO once daily or 5 days/week. The FDA-approved dose is 15 to 30 mg/kg/dose PO once daily or 50 to 75 mg/kg/dose PO twice weekly. Daily dosing is defined as 5- or 7 days/week. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase as first-line therapy. [61094]

    Adults weighing 40 to 55 kg (lean body weight)

    1 g PO once daily or 5 days/week.[34362] [61094] The FDA-approved dose is 15 to 30 mg/kg/dose PO once daily or 50 to 75 mg/kg/dose PO twice weekly.[30005] Daily dosing is defined as 5- or 7 days/week. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase of treatment as first-line therapy.[34362] [61094]

    Infants, Children, and Adolescents

    30 to 40 mg/kg/dose (lean body weight) (Max: 2 g/dose) PO once daily or 5 days/week.  [61094] [63245]  The FDA-approved dose is 15 to 30 mg/kg/dose (lean body weight) PO once daily (Max: 3 g/day) or 50 to 75 mg/kg/dose (lean body weight) PO twice weekly. Daily dosing is defined as 5- or 7 days/week. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase as first-line therapy.  [61094] [63245]

    Neonates†

    20 to 40 mg/kg/dose PO once daily. Although tuberculosis is rare in neonates, congenital and postnatal cases have been successfully treated with antitubercular agents. Pyrazinamide is generally recommended as part of the initial 2-month intensive phase as first-line therapy.[53484]

    For the treatment of drug-resistant tuberculosis infection as part of combination therapy.
    Oral dosage
    Adults

    25 to 40 mg/kg/dose (lean body weight) PO once daily.   The FDA-approved dose is 15 to 30 mg/kg/dose (lean body weight) PO once daily (Max: 3 g/day) or 50 to 75 mg/kg/dose (lean body weight) PO twice weekly.[30005]

    Infants, Children, and Adolescents

    30 to 40 mg/kg/dose (lean body weight) PO once daily.   The FDA-approved dose is 15 to 30 mg/kg/dose (lean body weight) PO once daily (Max: 3 g/day) or 50 to 75 mg/kg/dose (lean body weight) PO twice weekly.[30005]

    MAXIMUM DOSAGE

    Dosing is based on lean body weight.

    Adults

    30 mg/kg/dose (Max: 3 g/dose) PO once daily or 75 mg/kg/dose PO twice weekly are the FDA-approved maximum dosages. Other regimens and maximum dosages have been used off-label.
    Weighing more than 90 kg: 30 mg/kg/dose (Max: 3 g/dose) PO once daily or 75 mg/kg/dose PO twice weekly.
    Weighing 76 to 90 kg: 2 g PO once daily or 5 days/week, 3 g PO 3 days/week, or 4 g PO twice weekly.
    Weighing 56 to 75 kg: 1.5 g PO once daily or 5 days/week, 2.5 g PO 3 days/week, or 3 g PO twice weekly.
    Weighing 40 to 55 kg: 1 g PO once daily or 5 days/week, 1.5 g PO 3 days/week, or 2 g PO twice weekly.

    Geriatric

    30 mg/kg/dose (Max: 3 g/dose) PO once daily or 75 mg/kg/dose PO twice weekly are the FDA-approved maximum dosages. Other regimens and maximum dosages have been used off-label.
    Weighing more than 90 kg: 30 mg/kg/dose (Max: 3 g/dose) PO once daily or 75 mg/kg/dose PO twice weekly.
    Weighing 76 to 90 kg: 2 g PO once daily or 5 days/week, 3 g PO 3 days/week, or 4 g PO twice weekly.
    Weighing 56 to 75 kg: 1.5 g PO once daily or 5 days/week, 2.5 g PO 3 days/week, or 3 g PO twice weekly.
    Weighing 40 to 55 kg: 1 g PO once daily or 5 days/week, 1.5 g PO 3 days/week, or 2 g PO twice weekly.

    Adolescents

    30 mg/kg/dose (Max: 3 g/dose) PO once daily or 75 mg/kg/dose PO twice weekly are the FDA-approved maximum dosages. 40 mg/kg/dose (Max: 2 g/dose) PO once daily or 5 days/week or 50 mg/kg/dose PO 3 days/week (Max: 3 g/dose) or twice weekly (Max: 4 g/dose) have been used off-label.

    Children

    30 mg/kg/dose (Max: 3 g/dose) PO once daily or 75 mg/kg/dose PO twice weekly are the FDA-approved maximum dosages. 40 mg/kg/dose (Max: 2 g/dose) PO once daily or 5 days/week or 50 mg/kg/dose PO 3 days/week (Max: 3 g/dose) or twice weekly (Max: 4 g/dose) have been used off-label.

    Infants

    30 mg/kg/dose (Max: 3 g/dose) PO once daily or 75 mg/kg/dose PO twice weekly are the FDA-approved maximum dosages. 40 mg/kg/dose (Max: 2 g/dose) PO once daily or 5 days/week or 50 mg/kg/dose PO 3 days/week (Max: 3 g/dose) or twice weekly (Max: 4 g/dose) have been used off-label.

    Neonates

    Safety and efficacy have not been established. 40 mg/kg/dose PO once daily has been used off-label.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Pyrazinamide is contraindicated in patients with severe hepatic disease.

    Renal Impairment

    It may be prudent to select doses at the low end of the dosing range. Dosing is based on lean body weight.[30005]
     
    Adult patients† [34362] [61094] [65465]
    CrCl 30 mL/minute or more: No dosage adjustment needed.
    CrCl less than 30 mL/minute: 25 to 40 mg/kg/dose PO 3 days/week.
     
    Pediatric patients† [32569] [65465]
    GFR 30 mL/minute/1.73 m2 or more: No dosage adjustment needed.
    GFR less than 30 mL/minute/1.73 m2: 30 to 40 mg/kg/dose PO 3 days/week.
     
    Intermittent hemodialysis†
    Adult patients [34362] [61094]
    25 to 35 mg/kg/dose PO 3 days/week administered after hemodialysis on dialysis days.
     
    Pediatric patients [32569]
    40 mg/kg/dose PO 3 days/week.
     
    Peritoneal dialysis†
    Adult patients [32569]
    No dosage adjustment is needed.
     
    Pediatric patients [32569]
    40 mg/kg/dose PO 3 days/week.
     
    Continuous renal replacement therapy (CRRT)†
    NOTE: Various CRRT modalities include continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous high-flux hemodialysis (CVVHFD), continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), and continuous arteriovenous hemodiafiltration (CAVHDF). Dosing should take into consideration patient-specific factors (e.g., intrinsic renal function), type of infection, the duration of renal replacement therapy, the effluent flow rate, and the replacement solution administered.[42303]
     
    Adult patients [32569]
    No dosage adjustment is needed.
     
    Pediatric patients [32569]
    Avoid in patients with a GFR less than 30 mL/minute/1.73m3.

    ADMINISTRATION

     
    Directly observed therapy (DOT) is recommended for all children, adolescents, and adults living with HIV and any regimen consisting of intermittent therapy.[34361] [34362] [61094]

    Oral Administration
    Extemporaneous Compounding-Oral

    NOTE: Extemporaneously compounded oral pyrazinamide solution is not FDA-approved.
     
    Oral suspension using simple syrup†
    Crush 140 pyrazinamide 500 mg tablets and mix with a small amount of simple syrup.
    Transfer contents to a graduate and add simple syrup to prepare 700 mL of suspension.
    Repeat to yield 1.4 L of pyrazinamide 100 mg/mL in simple syrup.
    Storage: The suspension was stable for 60 days in glass or plastic bottles at 4 or 25 degrees C.[25499]
     
    Oral suspension using methylcellulose and simple syrup†
    Crush 200 pyrazinamide 500 mg tablets and mix with a suspension containing 500 mL of 1% methylcellulose (25.5 g Citrucel powder mixed with 500 mL of purified water) and 500 mL simple syrup.
    Crush 140 pyrazinamide 500 mg tablets and mix with a suspension containing 350 mL of 1% methylcellulose and 350 mL of simple syrup.
    Add the suspensions together to yield 1.7 L of pyrazinamide 100 mg/mL in 0.5% methylcellulose and simple syrup.
    Storage: The suspension was stable for 60 days in glass or plastic bottles at 4 or 25 degrees C.[25499]
     
    Oral suspension using Ora-Sweet and Ora-Plus†
    Prepare pyrazinamide in a 1:1 mixture of Ora-Sweet and Ora-Plus to a concentration of 10 mg/mL.
    Storage: The suspension was stable for 60 days in plastic bottles at 5 or 25 degrees C.[30315]
     
    Oral suspension using Ora-Sweet SF and Ora-Plus†
    Prepare pyrazinamide in a 1:1 mixture of Ora-Sweet SF and Ora-Plus to a concentration of 10 mg/mL.
    Storage: The suspension was stable for 60 days in plastic bottles at 5 or 25 degrees C.[30315]
     
    Oral suspension using cherry syrup†
    Prepare pyrazinamide in cherry syrup (cherry syrup concentrate diluted 1:4 with simple syrup) to a concentration of 10 mg/mL.
    Storage: The suspension was stable for 60 days in plastic bottles at 5 or 25 degrees C.[30315]

    STORAGE

    Generic:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Pyrazinamide is contraindicated in persons with known pyrazinamide hypersensitivity.

    Alcoholism, hepatic disease, hepatitis

    Pyrazinamide is contraindicated in persons with severe hepatic disease. Assess hepatic function at baseline and periodically. Follow patients with preexisting liver disease or those at increased risk for drug-related hepatitis (e.g., alcoholism) closely. Discontinue pyrazinamide if signs of hepatocellular damage occur. Most combination therapy for active TB disease includes more than 1 agent that may contribute to hepatotoxicity.[61094]

    Gout, hyperuricemia

    Pyrazinamide is contraindicated in persons with acute gout. Obtain baseline serum uric acid concentration before starting pyrazinamide therapy. Discontinue pyrazinamide if hyperuricemia accompanied by acute gouty arthritis occurs. Pyrazinamide inhibits renal excretion of urates, frequently resulting in hyperuricemia, which is usually asymptomatic.[30005]

    Diabetes mellitus, laboratory test interference

    Use pyrazinamide with caution in patients with diabetes mellitus as management may be more difficult. Also, pyrazinamide may cause laboratory test interference. Pyrazinamide has been reported to interfere with Acetest and Ketostix, which are urine ketone tests, to produce a pink-brown color.[30005]

    Obesity

    Optimal pyrazinamide dosing for obesity is not established. Pyrazinamide dosing is based on lean body weight, in general.[30005] 

    Acquired immunodeficiency syndrome (AIDS), human immunodeficiency virus (HIV) infection

    Do not treat persons with tuberculosis (TB) and human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS) with intermittent (i.e., twice weekly or 3 days/week) TB treatment regimens to avoid recurrent disease and the emergence of drug resistance.[34361] [34362] [61094]

    Pregnancy

    Use pyrazinamide during pregnancy only if clearly needed. It is not known whether pyrazinamide can cause fetal harm when administered to pregnant women or if it can affect reproduction capacity. Animal reproduction studies have not been conducted with pyrazinamide. Pyrazinamide has been used extensively in high-burden countries for many years. Tuberculosis guidelines suggest evaluating pyrazinamide use on a case-by-case basis. In pregnant women with tuberculosis and HIV or extrapulmonary or severe tuberculosis, it is more beneficial to include pyrazinamide in the treatment regimen than to not include pyrazinamide.

    Breast-feeding

    Use pyrazinamide with caution in breast-feeding mothers, taking into account the risk-benefit of this therapy. Pyrazinamide has been found in small amounts in breast milk. Tuberculosis guidelines encourage breast-feeding for women who are noninfectious and being treated with first-line tuberculosis agents, such as pyrazinamide, as the small concentrations of these drugs measured in breast milk have not been reported to produce toxic effects in the nursing infant.

    ADVERSE REACTIONS

    Severe

    sideroblastic anemia / Delayed / 0-1.0
    porphyria / Delayed / 0-1.0
    angioedema / Rapid / 0-1.0
    interstitial nephritis / Delayed / 0-1.0

    Moderate

    thrombocytopenia / Delayed / 0-1.0
    dysuria / Early / 0-1.0
    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hyperbilirubinemia / Delayed / Incidence not known
    hyperuricemia / Delayed / Incidence not known
    gout / Delayed / Incidence not known

    Mild

    photosensitivity / Delayed / 0-1.0
    acneiform rash / Delayed / 0-1.0
    myalgia / Early / 10.0
    arthralgia / Delayed / 10.0
    rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    nausea / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    vomiting / Early / Incidence not known

    DRUG INTERACTIONS

    Allopurinol: (Minor) Because pyrazinamide, PZA can increase serum uric acid levels and precipitate gouty attacks, the dosages of antigout agents, including allopurinol, may need to be adjusted.
    Aminosalicylate sodium, Aminosalicylic acid: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of pyrazinamide, PZA and aminosalicylate sodium, aminosalicylic acid. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Colchicine: (Minor) Because pyrazinamide can increase serum uric acid levels and precipitate gouty attacks, the dosages of antigout agents, including colchicine, may need to be adjusted.
    Ethambutol: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of pyrazinamide, PZA and ethambutol. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.[.
    Ethanol: (Major) Pyrazinamide, PZA is associated with dose-related hepatoxicity. Daily use of alcohol while receiving pyrazinamide, PZA increases the risk of drug-induced hepatitis. Liver-function tests should be conducted prior to and every 2-4 weeks during treatment in patients who consume alcohol routinely while receiving pyrazinamide therapy. (Major) Pyrazinamide, PZA is associated with dose-related hepatoxicity. Daily use of ethanol while receiving pyrazinamide, PZA increases the risk of drug-induced hepatitis. Liver-function tests should be conducted prior to and every 2-4 weeks during treatment in patients who consume ethanol routinely while receiving pyrazinamide therapy.
    Ethionamide: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of ethionamide and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs may be used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Isoniazid, INH: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of pyrazinamide, PZA and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of pyrazinamide, PZA and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. The use of the 2-month rifampin plus pyrazinamide latent tuberculosis infection (LTBI) regimen should no longer be offered due to the known increased risk of severe liver injury and death. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Isoniazid, INH; Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of pyrazinamide, PZA and isoniazid, INH. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program. (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. The use of the 2-month rifampin plus pyrazinamide latent tuberculosis infection (LTBI) regimen should no longer be offered due to the known increased risk of severe liver injury and death. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Lesinurad; Allopurinol: (Minor) Because pyrazinamide, PZA can increase serum uric acid levels and precipitate gouty attacks, the dosages of antigout agents, including allopurinol, may need to be adjusted.
    Omeprazole; Amoxicillin; Rifabutin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with pyrazinamide. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
    Probenecid: (Minor) Because pyrazinamide can increase serum uric acid levels and precipitate gouty attacks, the dosages of antigout agents, including probenecid, may need to be adjusted.
    Probenecid; Colchicine: (Minor) Because pyrazinamide can increase serum uric acid levels and precipitate gouty attacks, the dosages of antigout agents, including colchicine, may need to be adjusted. (Minor) Because pyrazinamide can increase serum uric acid levels and precipitate gouty attacks, the dosages of antigout agents, including probenecid, may need to be adjusted.
    Rifabutin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifabutin and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Rifampin: (Moderate) Careful monitoring of hepatic function is recommended with the concurrent use of rifampin and pyrazinamide, PZA. Each drug has the potential to cause hepatotoxicity, and hepatotoxicity risk may be increased with concomitant use. These drugs are often used together for the treatment of active tuberculosis (TB) infection, and patients should also be assessed for additional risk factors for hepatotoxicity, such as other hepatotoxic drugs, alcohol use, and underlying hepatic disease. The use of the 2-month rifampin plus pyrazinamide latent tuberculosis infection (LTBI) regimen should no longer be offered due to the known increased risk of severe liver injury and death. Any adverse event leading to hospitalization or death should be reported to local or state health departments as well as the FDA MedWatch program.
    Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and pyrazinamide. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
    Sulfinpyrazone: (Minor) Because pyrazinamide can increase serum uric acid levels and precipitate gouty attacks, the dosages of antigout agents, including sulfinpyrazone, may need to be adjusted.

    PREGNANCY AND LACTATION

    Pregnancy

    Use pyrazinamide during pregnancy only if clearly needed. It is not known whether pyrazinamide can cause fetal harm when administered to pregnant women or if it can affect reproduction capacity. Animal reproduction studies have not been conducted with pyrazinamide. Pyrazinamide has been used extensively in high-burden countries for many years. Tuberculosis guidelines suggest evaluating pyrazinamide use on a case-by-case basis. In pregnant women with tuberculosis and HIV or extrapulmonary or severe tuberculosis, it is more beneficial to include pyrazinamide in the treatment regimen than to not include pyrazinamide.

    Use pyrazinamide with caution in breast-feeding mothers, taking into account the risk-benefit of this therapy. Pyrazinamide has been found in small amounts in breast milk. Tuberculosis guidelines encourage breast-feeding for women who are noninfectious and being treated with first-line tuberculosis agents, such as pyrazinamide, as the small concentrations of these drugs measured in breast milk have not been reported to produce toxic effects in the nursing infant.

    MECHANISM OF ACTION

    Mechanism of Action: Pyrazinamide's exact mechanism of action is not known. Susceptible strains of M. tuberculosis release pyrazinamidase, which converts PZA to pyrazinoic acid (POA). Conversion of PZA to this active metabolite may be partially responsible for its activity. In vitro studies have demonstrated that POA decreases the pH below that which promotes the growth of M. tuberculosis. The mechanism of the parent compound has not been elucidated. Pyrazinamide exhibits bacteriocidal or bacteriostatic action, depending on the drug concentrations within the infected site and the susceptibility of the organism. Pyrazinamide exerts its most significant effect at intracelluar sites where M. tuberculosis replicates slowly, such as within macrophages. Studies indicate that PZA is most effective in the initial stages of treatment, which may be the result of diminished organism populations in macrophages early in therapy. Pyrazinamide also inhibits the tubular secretion of uric acid.M. tuberculosis is the only organism susceptible to pyrazinamide.

    PHARMACOKINETICS

    Pyrazinamide (PZA) is administered orally. PZA is widely distributed. It penetrates inflamed meninges to reach therapeutic levels in the CSF. It is unknown whether PZA crosses the placenta, but distribution into breast milk has been documented (see Contraindications). The plasma half-life is 9—10 hours. Pyrazinamide is hydrolyzed in the liver to pyrazinoic acid, its major active metabolite. Subsequently, pyrazinoic acid is hydroxylated to the main excretory compound. Pyrazinamide and its metabolites are excreted in the urine (70%), primarily via glomerular filtration.

    Oral Route

    Pyrazinamide is rapidly absorbed from the GI tract. Peak serum levels are attained within 2 hours. Plasma levels of the major active metabolite peak within 4—8 hours.