Drug Interactions between dronedarone and letrozole / ribociclib

CONTRAINDICATED: Dronedarone may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In healthy subjects given repeated oral doses, dronedarone induced a QTc prolongation of about 10 ms at 400 mg twice daily and up to 25 ms at 1600 mg twice daily. In clinical trials using a dosage of 400 mg twice daily, premature discontinuation of therapy due to QT prolongation occurred in 1.5% of dronedarone patients versus 0.5% of placebo patients. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of dronedarone with other drugs that can prolong the QT interval is considered contraindicated.

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MONITOR: Coadministration with dronedarone may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme, CYP450 3A4 isoenzyme, and/or P-glycoprotein (P-gp) efflux transporter. The mechanism is decreased clearance via these routes due to inhibition by dronedarone. When given with the CYP450 2D6 substrates metoprolol and propranolol, dronedarone increased metoprolol systemic exposure (AUC) by 1.6-fold and propranolol AUC by 1.3-fold. Similarly, dronedarone coadministration led to 1.4- to 1.5-fold increases in the AUC of diltiazem, nifedipine and verapamil, which are CYP450 3A4 substrates. Dronedarone also increased the AUC of digoxin, a P-glycoprotein substrate, by 2.5-fold.

MANAGEMENT: Caution is advised when dronedarone is used concomitantly with drugs that are substrates of CYP450 2D6, CYP450 3A4 and/or P-gp, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever dronedarone is added to or withdrawn from therapy.

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MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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