Drug Interactions between Contrave and dabrafenib

GENERALLY AVOID: Coadministration of naltrexone with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Naltrexone, especially in larger than recommended doses (more than 50 mg/day), has been associated with hepatocellular injury, hepatitis, and elevations in liver transaminases and bilirubin. Other potential causative or contributory etiologies identified include preexisting alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other hepatotoxic drugs.

MANAGEMENT: The use of naltrexone with other potentially hepatotoxic agents should be avoided whenever possible (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, malaise, right upper quadrant pain, dark urine, pale stools, and jaundice. Periodic monitoring of hepatic function is advisable.

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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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