Interactions between Dofetilide and Joenja

Contraindicated

Coadministration with inhibitors of organic cation transporter 2 (OCT-2) may increase the plasma concentrations of dofetilide, which is primarily eliminated by glomerular filtration and active tubular secretion via OCT-2, with minor contribution from CYP450 3A4-mediated metabolism. In 20 healthy male subjects given a 500 mcg oral dose of dofetilide on day 2 of treatment with cimetidine (an OCT-2 and weak CYP450 3A4 inhibitor) 100 mg or 400 mg twice daily for 4 days, dofetilide peak plasma concentration (Cmax) increased by 11% and 29%, respectively, while systemic exposure (AUC) increased by 11% and 48%, respectively, compared to dofetilide plus placebo. Renal clearance of dofetilide decreased by 13% and 33%, respectively, and nonrenal clearance decreased by 5% and 21%, respectively. In addition, the mean maximum change in QTc interval from baseline increased by 22% and 33%, respectively. In another study with 24 healthy volunteers, coadministration of dofetilide 500 mcg twice daily with cimetidine 400 mg twice daily for 7 days increased Cmax and AUC of dofetilide by 50% and 58%, respectively. However, QTc interval was not significantly altered compared to dofetilide alone. In a similar study with 12 healthy male volunteers, dofetilide 500 mcg twice daily given with verapamil (an OCT-2 and moderate CYP450 3A4 inhibitor) 80 mg three times daily for 3 days resulted in a 43% increase in Cmax and 26% increase in AUC (0 to 4 hours) of dofetilide, which corresponded to a 6 msec increase in mean maximum change in QTc from baseline relative to dofetilide alone. In an analysis of patient data from the dofetilide clinical development program, concomitant administration with verapamil was also found to be associated with a higher occurrence of torsade de pointes according to the manufacturer. Dofetilide 500 mcg twice daily given with ketoconazole (an OCT-2 and potent CYP450 3A4 inhibitor) 400 mg daily for 7 days increased dofetilide Cmax and AUC by 53% and 41% respectively, in males, and 97% and 69%, respectively, in females. The same dosage of dofetilide coadministered with trimethoprim (an OCT-2 inhibitor) 160 mg and sulfamethoxazole 800 mg twice daily for 4 days increased dofetilide Cmax by 93% and AUC by 103%.

Management

Given the risk of concentration-dependent QT prolongation, concomitant use of dofetilide with OCT-2 inhibitors is considered contraindicated.

Monitor

Coadministration with inhibitors of CYP450 3A4 including grapefruit or grapefruit juice may increase the plasma concentrations of leniolisib, which undergoes extensive CYP450 3A4-mediated first-pass metabolism in the gut wall and liver. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

Management

Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of leniolisib. Some authorities recommend to avoid grapefruit products during leniolisib treatment (UK).

In vitro data suggest that grapefruit juice may inhibit the CYP450 3A4 first-pass metabolism of dofetilide. Decreased first-pass metabolism may increase dofetilide concentrations and increase the risk of QT interval prolongation and arrhythmias. The clinical significance is unknown, since dofetilide has a high oral bioavailability and a low affinity for CYP450 3A4. The manufacturer recommends caution.