Dofetilide

Dofetilide is a prescription drug that is prescribed to patients with irregular heartbeats (atrial fibrillation/flutter). It enables the heart to beat more regularly.

Dofetilide is marketed as Tikosyn by Pfizer.

Uses

Maintenance of Normal Sinus Rhythm in the Heart

Dofetilide is used for the maintenance of normal sinus rhythm in patients with atrial fibrillation/flutter of greater than one week duration who have been converted to normal sinus rhythm.

Conversion of Atrial Fibrillation/Flutter in the Heart

Dofetilide is indicated for the conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.

How Dofetilide is Taken

Dofetilide is available in 125, 250, and 500 mcg oral capsules.

The dose of Dofetilide must be individualized according to calculated creatinine clearance and QTc (corrected QT interval). The usual recommended dose of Dofetilide is 500 mcg twice daily; however, the dose of Tikosyn must be individualized according to creatinine clearance and QTc.

How Dofetilide Works

Dofetilide blocks the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. 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.

How the Body Affects Dofetilide

Peak circulating levels occur at 2-3 hours after dosing. The terminal half life of dofetilide is approximately 10 hours; steady state circulating levels are attained within 2-3 days after dosing.

Metabolites of dofetilide are formed by the chemical processes N-dealkylation and N-oxidation. Approximately 80% of the original dofetilide dose is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide with the remaining 20% consisting of inactive or minimally active metabolites.

Side Effects

Risks and Precautions

Drug Interactions

Cimetidine: Concurrent use of cimetidine is contraindicated. Cimetidine at 400 mg BID (the usual prescription dose) co-administered with dofetilide (500 mcg BID) for 7 days has been shown to increase dofetilide levels by 58%. Cimetidine at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide levels (500 mcg single dose).

Verapamil: Concurrent use of verapamil is contraindicated. Co-administration of TIKOSYN with verapamil resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not significantly increased.

Ketoconazole: Concurrent use of ketoconazole is contraindicated. Ketoconazole at 400 mg daily (the maximum approved prescription dose) co-administered with dofetilide (500 mcg BID) for 7 days has been shown to increase dofetilide Cmax by 53% in males and 97% in females, and AUC by 41% in males and 69% in females.

Trimethoprim Alone or in Combination with Sulfamethoxazole: Concurrent use of trimethoprim alone or in combination with sulfamethoxazole is contraindicated. Trimethoprim 160 mg in combination with 800 mg sulfamethoxazole co-administered BID with dofetilide (500 mcg BID) for 4 days has been shown to increase dofetilide AUC by 103% and Cmax by 93%.

Hydrochlorothiazide (HCTZ) Alone or in Combination with Triamterene: Concurrent use of HCTZ alone or in combination with triamterene is contraindicated. HCTZ 50 mg QD or HCTZ/triamterene 50/100 mg QD was co-administered with dofetilide (500 mcg BID) for 5 days (following 2 days of diuretic use at half dose). In patients receiving HCTZ alone, dofetilide AUC increased by 27% and Cmax by 21%. However, the pharmacodynamic effect increased by 197% (QTc increase over time) and by 95% (maximum QTc increase). In patients receiving HCTZ in combination with triamterene, dofetilide AUC increased by 30% and Cmax by 16%. However, the pharmacodynamic effect increased by 190% (QTc increase over time) and by 84% (Maximum QTc increase). The pharmacodynamic effects can be explained by a combination of the increase in dofetilide exposure and the reductions in serum potassium. In the DIAMOND trials, 1252 patients were treated with dofetilide and diuretics concomitantly of whom 493 died compared to 508 deaths among the 1248 patients receiving placebo and diuretics. Of the 229 patients who had potassium depleting diuretics added to their concomitant medications in the DIAMOND trials, the patients on dofetilide had a non-significantly reduced relative risk for death of 0.68 (95% CI 0.376, 1.230).

Effectiveness

Two trials evaluated the effectiveness of dofetilide in:

converting patients with atrial fibrillation or atrial flutter (AF/AFl) of more than 1 week duration to normal sinus rhythm (NSR)
maintaining NSR (delay time to recurrence of AF/AFl) after drug-induced or electrical cardioversion

A total of 996 patients with a history of atrial fibrillation/atrial flutter were enrolled. Both studies randomized patients to placebo or to doses of dofetilide 125 mcg, 250 mcg, 500 mcg or in one study a comparator drug.

Of patients who converted pharmacologically, approximately 70% converted within 24-36 hours.