DOFETILIDE
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
Selectively blocks the rapid component of the delayed rectifier potassium current (Ikr) in cardiac myocytes, prolonging repolarization and the effective refractory period.
| Metabolism | Primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6; undergoes N-dealkylation and N-oxidation; 80% excreted renally as unchanged drug and metabolites. |
| Excretion | Renal: 80% unchanged; biliary/fecal: 20% as metabolites and unchanged drug. |
| Half-life | Terminal elimination half-life: 10 hours (range 7–13 hours) in patients with normal renal function; prolonged in renal impairment, up to 20 hours in moderate impairment and >30 hours in severe impairment. |
| Protein binding | 60–70% bound to plasma proteins (mainly albumin). |
| Volume of Distribution | 3–4 L/kg, indicating extensive extravascular distribution. |
| Bioavailability | Oral: >90% (well absorbed). |
| Onset of Action | Oral: 1–3 hours after administration. |
| Duration of Action | Therapeutic effect (QT prolongation) persists for approximately 8–12 hours after a dose; clinical effects may last longer due to active metabolites? No active metabolites; duration parallels half-life. |
250-500 mcg orally twice daily, based on creatinine clearance and QTc response.
| Dosage form | CAPSULE |
| Renal impairment | CrCl >60 mL/min: 500 mcg twice daily; CrCl 40-60 mL/min: 250 mcg twice daily; CrCl 20-39 mL/min: 125 mcg twice daily; CrCl <20 mL/min: contraindicated. |
| Liver impairment | No specific dose adjustment; use with caution in severe hepatic impairment. |
| Pediatric use | Not approved for use in children; safety and efficacy not established. |
| Geriatric use | Initiate at lower end of dosing range; monitor renal function and QTc closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Many drugs are contraindicated including verapamil and cimetidine as they inhibit secretion and increase levels Can cause life-threatening ventricular arrhythmias particularly torsades de pointes.
| Breastfeeding | No human data on dofetilide excretion in breast milk. M/P ratio unknown. Based on molecular weight (441.6 g/mol) and low protein binding (60–70%), excretion is possible. Discontinue breastfeeding or dofetilide due to potential for serious adverse effects in infant (e.g., arrhythmias). |
| Teratogenic Risk | Dofetilide is pregnancy category C. No adequate human studies; animal studies show fetal toxicity (reduced fetal weight, delayed ossification) at maternal toxic doses. Avoid in pregnancy unless benefit outweighs risk. |
■ FDA Black Box Warning
Dofetilide can cause life-threatening ventricular arrhythmias (e.g., torsade de pointes) due to QT prolongation. Must be initiated in a hospital setting with continuous ECG monitoring and creatinine clearance assessment. Dosage must be adjusted based on renal function and QT interval.
| Common Effects | Headache |
| Serious Effects |
Baseline QT interval >440 msec (or >500 msec with ventricular conduction abnormalities); severe renal impairment (CrCl <20 mL/min); concurrent use of verapamil, hydrochlorothiazide, cimetidine, ketoconazole, trimethoprim, prochlorperazine, or other QT-prolonging drugs; history of torsade de pointes; uncorrected hypokalemia or hypomagnesemia.
| Precautions | Hypokalemia and hypomagnesemia should be corrected before use; dose adjustment required for renal impairment; avoid concurrent use with drugs that prolong QT interval or inhibit CYP3A4; monitor ECG for QT prolongation; risk of ventricular arrhythmias increased with bradycardia or recent myocardial infarction. |
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| Fetal Monitoring | Monitor maternal ECG for QTc prolongation (baseline and during therapy), serum creatinine and potassium levels, and renal function. Fetal monitoring includes ultrasound for growth and amniotic fluid assessment if used during pregnancy. |
| Fertility Effects | No human data on fertility effects. In animal studies, dofetilide did not impair fertility in rats at doses up to 1 mg/kg/day. Effects on human fertility are unknown. |