indication

For the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm

pharmacology

Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.

mechanism of action

The mechanism of action of Dofetilide is a blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. This inhibition of potassium channels results in a prolongation of action potential duration and the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway).

biotransformation

Hepatic

absorption

>90%

half life

10 hours

drug interactions

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Bendroflumethiazide: Increased risk of cardiotoxicity and arrhythmias

Chlorothiazide: Thiazide diuretics such as chlorothiazide may enhance the QTc-prolonging effect of dofetilide. Thiazide diuretics may increase the serum concentration of dofetilide. The concomitant use of hydrochlorothiazide and dofetilide is contraindicated by the manufacturer of dofetilide. Monitor for increased risk of QTc-prolongation and associated ventricular arrythmias during concomitant use of dofetilide and thiazide diuretics.

Chlorthalidone: Increased risk of cardiotoxicity and arrythmias

Cimetidine: Increases effect/toxicity of dofetilide

Clarithromycin: Increased risk of cardiotoxicity and arrhythmias

Erythromycin: Increased risk of cardiotoxicity and arrhythmias

Hydrochlorothiazide: Increased risk of cardiotoxicity and arrhythmias

Indapamide: Increased risk of cardiotoxicity and arrhythmias

Itraconazole: This strong CYP3A4 inhibitor increases the effect and toxicity of dofetilide

Ketoconazole: This strong CYP3A4 inhibitor increases the effect and toxicity of dofetilide

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias

Metolazone: Increased risk of cardiotoxicity and arrhythmias

Quinupristin: This combination presents an increased risk of toxicity

Ranolazine: Possible additive effect on QT prolongation

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Telithromycin: Increased risk of cardiotoxicity and arrhythmias

Thioridazine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Trichlormethiazide: Trichlormethiazide may increase Dofetilide serum concentrations and increase the QTc-prolonging effect of Dofetilide. Increased risk of ventricular arrhythmias.

Trimethoprim: Trimethoprim may significantly reduced the clearance of Dofetilide. Trimethoprim is a cation transport inhibitor and may interfere with renal excretion of Dofetilide. Concomitant use is contraindicated.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Verapamil: Verapamil may increase the plamsa levels of Dofetilide. Increased risk of torsade de pointes. Concomitant therapy is contraindicated.

Voriconazole: Voriconazole may increase the serum concentration of dofetilide by decreasing its metabolism. Concomitant therapy is contraindicated.

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).