Drug Interactions between bupropion and IsonaRif

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 It should also be restarted in very small, gradually increasing doses and immediately withdrawn if there is any indication of recurrent liver involvement.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.

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MONITOR: Coadministration with inducers of CYP450 2B6 may decrease the plasma concentrations of bupropion. In vitro findings suggest that CYP450 2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, one of three active metabolites of bupropion. In 12 study patients with mood disorders, administration of a single 150 mg dose of bupropion during treatment with the potent CYP450 2B6 inducer carbamazepine (mean dose 942 mg/day for at least 3 weeks) decreased mean bupropion peak plasma concentration (Cmax) and systemic exposure (AUC) by 87% and 90%, respectively, compared to administration with placebo. Mean Cmax and AUC of two active metabolites were also significantly reduced (86% and 96%, respectively, for erythrohydrobupropion; 81% and 86%, respectively, for threohydrobupropion), while Cmax and AUC of hydroxybupropion increased by 71% and 50%, respectively. In another 13 study subjects administered a 150 mg dose of sustained-release bupropion during treatment with the moderate CYP450 2B6 inducer efavirenz (600 mg once daily for 14 days), bupropion Cmax and AUC decreased by an average of 34% and 55%, respectively, while the Cmax of hydroxybupropion increased by 50% with no change in AUC. Although reduced therapeutic effects of bupropion may be anticipated from these interactions, the full clinical impact is uncertain, since metabolites are present in substantially higher plasma levels than the parent drug but have reduced potencies and possibly varied pharmacologic effects. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized in humans. In an antidepressant screening test performed on mice, hydroxybupropion was found to be one-half as potent as bupropion and both erythrohydrobupropion and threohydrobupropion were 5-fold less potent than bupropion. Another CYP450 2B6 inducer, ritonavir, has also been studied but resulted in decreased plasma concentrations of bupropion and all three metabolites. When coadministered with ritonavir 100 mg twice daily for 17 days, bupropion Cmax and AUC decreased by 21% and 22%, respectively; erythrohydrobupropion Cmax and AUC decreased by 28% and 48%, respectively, threohydrobupropion Cmax and AUC decreased by 39% and 38%, respectively; and hydroxybupropion AUC decreased by 23% with no change in Cmax. When coadministered with ritonavir 600 mg twice daily for 8 days, bupropion Cmax and AUC decreased by 62% and 66%, respectively; erythrohydrobupropion Cmax and AUC decreased by 48% and 68%, respectively, threohydrobupropion Cmax and AUC decreased by 58% and 50%, respectively; and hydroxybupropion Cmax and AUC decreased by 42% and 78%, respectively. When coadministered with lopinavir-ritonavir 400 mg-100 mg twice daily for 14 days, bupropion Cmax and AUC decreased by 57% each, while hydroxybupropion Cmax and AUC decreased by 31% and 50%, respectively.

MANAGEMENT: Pharmacologic response to bupropion should be monitored more closely whenever a CYP450 2B6 inducer is added to or withdrawn from therapy, and the bupropion dosage adjusted as necessary. Concomitant use of potent and moderate CYP450 2B6 inducers such as carbamazepine, efavirenz, rifampin, ritonavir, and lopinavir-ritonavir should be avoided with fixed-dose combination products such as bupropion-naltrexone or bupropion-dextromethorphan. For other bupropion products, increases in bupropion dosage should be guided by clinical response; however, the maximum recommended dosage should not be exceeded.

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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.

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