Drug General Information (ID: DDI82URGIQ)
  Drug Name Pyrazinamide Drug Info Rifampicin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antitubercular Agents Antituberculosis Agents
  Structure

 Mechanism of Pyrazinamide-Rifampicin Interaction (Severity Level: Major)
     Increased risk of hepatotoxicity Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Pyrazinamide Rifampicin
      Mechanism Hepatotoxicity Hepatotoxicity
      Key Mechanism Factor 1
Factor Name Hepatotoxicity
Factor Description Combination of drugs that can induce hepatotoxicity may increase the risk of liver injury. Symptoms vary depending on the level of exposure and the total extent of liver damage, and may cause few symptoms if the damage is mild, and eventually lead to liver failure in patients with severe damage.
      Mechanism Description
  • Increased risk of hepatotoxicity by the combination of Pyrazinamide and Rifampicin 

Recommended Action
      Management The American Thoracic Society and the Centers for Disease Control and Prevention recommend that the two-month RIF-PZA regimen generally not be offered to patients with LTBI (Note: This recommendation does not apply to the appropriate use of RIF and PZA in multidrug regimens for the treatment of persons with active TB disease). A nine-month course of daily INH remains the preferred treatment for LTBI in both HIV-negative and HIV-positive patients. Other acceptable options include nine months of twice-weekly INH, or six months of either daily or twice-weekly INH. Twice-weekly therapy must be administered under direct observed therapy (DOT), and the six-month regimens should generally not be used in HIV-infected individuals, those with fibrotic lesions on chest radiographs, and children. Four months of daily RIF may be considered for persons who are contacts of patients with INH-resistant, RIF-susceptible TB. The RIF-PZA regimen should never be offered to patients who are taking concomitant medications associated with liver injury patients who drink alcohol excessively (even if alcohol use is discontinued during treatment) patients with underlying liver disease and patients with a history of INH-associated liver injury. RIF-PZA may be considered in carefully selected patients if there is reason to believe they are not likely to complete the preferred six- or nine-month regimens. If RIF-PZA is prescribed, the PZA dosage should be no more than 20 mg/kg/day (up to a maximum of 2 g/day) or 50 mg/kg twice weekly (up to a maximum of 4 g twice weekly), and no more than a two-week supply of the medications should be dispensed at any given time. Patients should be evaluated in person by a healthcare provider at 2, 4, and 6 weeks of treatment for adherence, tolerance and adverse effects, and at 8 weeks to document treatment completion. Patients should also be instructed to discontinue the drugs promptly and seek medical attention if signs and symptoms of hepatic injury develop, including fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. Serum transaminases and bilirubin should be measured at baseline and at 2, 4, 6, and 8 weeks of treatment in patients taking RIF-PZA. Therapy should be withdrawn and not resumed if transaminase levels exceed five times the upper limit of normal or are anywhere above the normal range when accompanied by symptoms of hepatitis, or if serum bilirubin is greater than the normal range.

References
1 Kunimoto D, Warman A, Beckon A, Doering D, Melenka L "Severe hepatotoxicity associated with rifampin-pyrazinamide preventative therapy requiring transplantation in an individual at low risk for hepatotoxicity." Clin Infect Dis 36 (2003): E158-61. [PMID: 12802781]
2 Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide treatment for latent tuberculosis infection. MMWR Morb Mortal Wkly Rep 51 (2002): 998-9. [PMID: 12455909]
3 CDC. 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 52 (2003): 735-9. [PMID: 12904741]