Drug Interaction Report

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.

Switch to consumer interaction data

Limited data suggest that sulfamethoxazole-trimethoprim (SMX-TMP) may rarely prolong the QT interval of the electrocardiogram. 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. There have been isolated reports of QT prolongation and ventricular arrhythmias occurring in patients treated with SMX-TMP intravenously. However, a causal relationship has not been established, and the risk of clinically significant QT prolongation is unlikely at recommended dosages of SMX-TMP. 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). Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

Switch to consumer interaction data

MONITOR: Two cases have been reported in which patients on sulfamethoxazole-trimethoprim therapy, after consuming beer, reported flushing, heart palpitations, dyspnea, headache, and nausea (disulfiram - alcohol type reactions). First-generation sulfonylureas have been reported to cause facial flushing when administered with alcohol by inhibiting acetaldehyde dehydrogenase and subsequently causing acetaldehyde accumulation. Since sulfamethoxazole is chemically related to first-generation sulfonylureas, a disulfiram-like reaction with products containing sulfamethoxazole is theoretically possible. However, pharmacokinetic/pharmacodynamic data are lacking and in addition, the two reported cases cannot be clearly attributed to the concomitant use of sulfamethoxazole-trimethoprim and alcohol.

MANAGEMENT: Patients should be alerted to the potential for this interaction and although the risk for this interaction is minimal, caution is recommended while taking sulfamethoxazole-trimethoprim concomitantly with alcohol.

Switch to consumer interaction data

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.

Switch to consumer interaction data