Drug Interactions between clopidogrel and isoniazid / pyrazinamide / rifampin

MONITOR CLOSELY: The risk of hepatotoxicity is greater when rifampin and isoniazid (INH) are given concomitantly, than when either drug is given alone. The proposed mechanism is rifampin's induction of isoniazid hydrolase, an enzyme involved in the conversion of INH to isonicotinic acid and hydrazine. Hydrazine is the proposed toxic metabolite of INH, which has been shown in animal studies to cause steatosis, hepatocyte vacuolation and glutathione depletion. Some studies have also shown that slow acetylators have a two-fold increased risk of developing antituberculosis drug-induced hepatotoxicity (ATDH) as compared with fast acetylators due to more available INH for direct hydrolysis to hydrazine. Theoretically, a similar reaction may occur with rifabutin and isoniazid. Additional risk factors for developing hepatotoxicity include patients with advanced age, malnutrition, existing hepatic impairment, daily alcohol consumption, female gender, HIV infection, extra-pulmonary tuberculosis and/or patients who are taking other potent CYP450-inducing agents.

MANAGEMENT: Caution and close monitoring should be considered if isoniazid (INH) is coadministered with rifampin or rifabutin. In cases where coadministration is required, careful monitoring of liver function, especially ALT and AST, should be done at baseline and then every 2 to 4 weeks during therapy, or in accordance with individual product labeling. Some manufacturers of INH recommend strongly considering its discontinuation if serum aminotransferase concentrations (AST or SGOT, ALT or SGPT) exceed 3 to 5 times the upper limit of normal. Product labeling for rifampin also recommends the immediate discontinuation of therapy if hepatic damage is suspected. INH product labeling suggests alternate drugs be used if hepatitis is attributed to INH in patients with tuberculosis. However, if INH must be used, it should only be resumed after the patient's symptoms and laboratory abnormalities have cleared. It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement. Patients should be counseled to immediately report signs or symptoms consistent with liver damage and notified that prodromal symptoms usually consist of fatigue, weakness, malaise, anorexia, nausea, and/or vomiting.

GENERALLY AVOID: A two-month regimen consisting of rifampin (RIF) and pyrazinamide (PZA) for the treatment of latent tuberculosis infection (LTBI) has been associated with liver injury resulting in high rates of hospitalization and death. The exact mechanism of interaction is unknown, although both agents are individually hepatotoxic and may have additive effects on the liver during coadministration. In one prospective cohort study of 224 patients in a community setting between 1999 and 2001, investigators found that the risk of hepatotoxicity in patients receiving the RIF-PZA regimen was increased threefold compared to patients receiving six months of isoniazid (INH). When patients were monitored more intensively, severe hepatotoxicity did not develop, but the difference did not reach statistical significance.

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. U.S. healthcare providers should report possible cases of RIF-PZA hepatotoxicity to CDC's Division of Tuberculosis Elimination, telephone 404-639-8442.

GENERALLY AVOID: Coadministration with potent inducers of CYP450 2C19 may enhance the metabolic activation of clopidogrel, resulting in increased platelet inhibition and possibly bleeding risk. Clopidogrel is a prodrug that is converted to its active metabolite (AM) primarily by CYP450 2C19, with contributions from several other CYP450 isoenzymes including CYP450 3A, 2B6, and 1A2. When clopidogrel (600 mg loading dose followed by 75 mg once daily for 7 days) was coadministered with the potent CYP450 2C19 and 3A4 inducer rifampin (300 mg twice daily for 14 days) in twelve healthy volunteers, mean clopidogrel AM peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 3.8-fold. Mean inhibition of platelet aggregation at 4 hours post loading dose was 34% higher in the presence of rifampin compared to clopidogrel administered alone. When clopidogrel (75 mg once daily for 6 days) was coadministered with rifampin (300 mg twice daily for 10 days) in another study of ten healthy volunteers, platelet aggregation was 33% as compared to 56% following clopidogrel alone for 6 days and 94% at baseline.

MANAGEMENT: Concomitant use of clopidogrel with potent CYP450 2C19 inducers should be avoided when possible. If coadministration is required, patients should be monitored closely for signs of bleeding.

MONITOR: Coadministration of isoniazid (INH) with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. INH-associated hepatotoxicity is believed to be due to an accumulation of toxic metabolites and may also be partly immune mediated, though the exact mechanisms are not universally agreed upon. INH is metabolized by N-acetyltransferase and CYP450 2E1. The rate of INH's acetylation is genetically determined and generally classified as slow or rapid, with slow acetylators characterized by a relative lack of N-acetyltransferase. While the rate of acetylation does not significantly alter INH's effectiveness, it can lead to higher blood levels of INH and an increase of adverse reactions. In addition, INH is an in vitro inhibitor of several CYP450 isoenzymes (2C9, 2C19, 2E1, and 3A4). Coadministration of hepatotoxic drugs eliminated by one or more of these pathways may lead to elevated concentrations of the concomitant drug and increase the risk of hepatotoxicity. Most of the INH-associated hepatitis cases occur during the first 3 months of treatment, but may occur at any time and have been reported to be severe or even fatal. INH is reported in medical literature to cause clinically apparent acute liver injury with jaundice in 0.5% to 1% and fatality in 0.05% to 0.1% of recipients. A United States Public Health Service Surveillance Study of 13,838 people taking INH reported 8 deaths among 174 cases of hepatitis. Risk factors for INH related liver injury may include: age > 35 years, female gender, postpartum period, daily consumption of alcohol, injection drug user, slow acetylator phenotype, malnutrition, HIV infection, pre-existing liver disease, extra-pulmonary tuberculosis, and concomitant use of hepatotoxic medications. Clinical data have been reported with concurrent use of acetaminophen, alcohol, carbamazepine, phenobarbital, phenytoin, and rifampin.

MANAGEMENT: Coadministration of isoniazid (INH) with other hepatotoxic medications should be done with caution and close clinical monitoring. Some authorities recommend avoiding concurrent use when possible. If coadministration is needed, baseline and monthly liver function testing as well as monthly interviewing of the patient to check for signs and symptoms of adverse effects is recommended. More frequent testing may be advisable in patients at increased risk of INH-associated liver injury. Some manufacturers of INH recommend strongly considering its discontinuation if serum aminotransferase concentrations (AST or SGOT, ALT or SGPT) exceed 3 to 5 times the upper limit of normal. Patients should be counseled to immediately report signs or symptoms consistent with liver damage and notified that prodromal symptoms usually consist of fatigue, weakness, malaise, anorexia, nausea, and/or vomiting. If hepatic damage is suspected, INH should be immediately discontinued as continuation may lead to more severe damage. If hepatitis is attributed to INH in patients with tuberculosis, alternative drugs should be used. However, if INH must be used, it should only be resumed after the patient's symptoms and laboratory abnormalities have cleared. It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement. Consultation with product labeling and relevant guidelines is advisable.

MONITOR: Coadministration with inhibitors of CYP450 2C19 may reduce the efficacy of clopidogrel, whose antiplatelet effect is dependent in part on bioactivation by the isoenzyme to a pharmacologically active metabolite. This is consistent with studies that reported decreased effectiveness of clopidogrel and poorer clinical outcome in patients who have common genetic polymorphisms of CYP450 2C19 resulting in reduced or absent enzyme activity. The interaction has been studied with omeprazole, a potent CYP450 2C19 inhibitor. In 72 healthy subjects administered clopidogrel (300 mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg) simultaneously for 5 days, systemic exposure to the active metabolite of clopidogrel decreased by 46% (Day 1) and 42% (Day 5) during coadministration with omeprazole, while mean inhibition of platelet aggregation (IPA) diminished by 47% (24 hours) and 30% (Day 5). Similar results were reported when the same doses of clopidogrel and omeprazole were administered 12 hours apart in another study. Data are not available for less potent inhibitors of CYP450 2C19. However, ineffective inhibition of platelet aggregation has been reported in association with a potential interaction with amiodarone, whose active metabolite, desethylamiodarone, has been shown to inhibit CYP450 2C19 in vitro.

MANAGEMENT: Based on existing data, it may be advisable to closely monitor the therapeutic efficacy of clopidogrel during concomitant treatment with CYP450 2C19 inhibitors.