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Drug Interactions between amiodarone and dabrafenib

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Moderate

amiodarone dabrafenib

Applies to: amiodarone and dabrafenib

MONITOR: Coadministration with dabrafenib may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4 and/or 2C9. Dabrafenib has been found in vitro to be an inducer of these isoenzymes. Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib; however, transient inhibition of CYP450 isoenzymes may be observed during the first few days of treatment. In 12 study subjects, administration of the CYP450 3A4 probe substrate midazolam following repeat doses of dabrafenib 150 mg twice daily for 15 days reduced midazolam peak plasma concentration (Cmax) by 61% and systemic exposure (AUC) by 74%. When a single 15 mg dose of warfarin was coadministered similarly with dabrafenib, the AUC of S(-) warfarin decreased by 37% and that of R(+) decreased by 33%. S(-) warfarin, the biologically more active enantiomer, is primarily metabolized by CYP450 2C9, while R(+) warfarin is a substrate of CYP450 3A4 and 1A2.

MANAGEMENT: Caution is advised when dabrafenib is prescribed with drugs that undergo metabolism by CYP450 3A4 and/or 2C9. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever dabrafenib is added to or withdrawn from therapy. Significantly reduced plasma concentrations and loss of efficacy may occur with sensitive substrates of CYP450 3A4 or 2C9 such as hormonal contraceptives, immunosuppressants (cyclosporine, everolimus, sirolimus, tacrolimus), ivacaftor, and warfarin-type anticoagulants. Alternatives to these medications should be considered if possible.

References (2)
  1. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  2. (2013) "Product Information. Tafinlar (dabrafenib)." GlaxoSmithKline

Drug and food interactions

Major

amiodarone food

Applies to: amiodarone

GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered amiodarone. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In 11 nonsmoking, healthy volunteers, grapefruit juice (300 mL with drug administration, then 3 hours and 9 hours later) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amiodarone (17 mg/kg single dose) by 84% and 50%, respectively, compared to water. Formation of the pharmacologically active metabolite, N-desethylamiodarone (N-DEA), was completely inhibited. Clinically, this interaction can lead to altered efficacy of amiodarone, since antiarrhythmic properties of amiodarone and N-DEA appear to differ. In the study, mean increases in PR and QTc intervals of 17.9% and 11.3%, respectively, were observed 6 hours postdose with water, while increases of 10.2% and 3.3%, respectively, were observed after administration with grapefruit juice.

ADJUST DOSING INTERVAL: Food increases the rate and extent of absorption of amiodarone. The mechanism appears to involve the effect of food-induced physiologic changes on drug release from its formulation. In 30 healthy volunteers, administration of a single 600 mg dose of amiodarone following a high-fat meal resulted in a Cmax and AUC that were 3.8 and 2.4 times the respective values under fasting conditions. The time to reach peak plasma concentration (Tmax) was decreased by 37%, indicating an increased rate of absorption. Mean Cmax and AUC for the active metabolite, N-DEA, also increased by 32% and 55%, respectively, but there was no change in the Tmax.

MANAGEMENT: Patients treated with oral amiodarone should avoid consumption of grapefruits and grapefruit juice. In addition, oral amiodarone should be administered consistently with regard to meals.

References (3)
  1. (2002) "Product Information. Cordarone (amiodarone)." Wyeth-Ayerst Laboratories
  2. Libersa CC, Brique SA, Motte KB, et al. (2000) "Dramatic inhibition of amiodarone metabolism induced by grapefruit juice." Br J Clin Pharmacol, 49, p. 373-8
  3. Meng X, Mojaverian P, Doedee M, Lin E, Weinryb I, Chiang ST, Kowey PR (2001) "Bioavailability of Amiodarone tablets administered with and without food in healthy subjects." Am J Cardiol, 87, p. 432-5
Moderate

dabrafenib food

Applies to: dabrafenib

ADJUST DOSING INTERVAL: Food may reduce as well as delay the absorption of dabrafenib. In study subjects, administration of dabrafenib with a high-fat meal decreased peak plasma concentration (Cmax) and systemic exposure (AUC) by 51% and 31%, respectively, and delayed median Tmax by approximately 3.6 hours compared to administration in the fasted state.

MANAGEMENT: Dabrafenib should be taken at least 1 hour before or 2 hours after a meal.

References (1)
  1. (2013) "Product Information. Tafinlar (dabrafenib)." GlaxoSmithKline

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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