DOFETILDE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DOFETILDE (DOFETILDE).
Selective class III antiarrhythmic agent that blocks the rapid component of the delayed rectifier potassium current (I_Kr), prolonging atrial and ventricular repolarization and refractory periods.
| Metabolism | Hepatic metabolism via CYP3A4 (minor), with 80% excreted unchanged in urine via renal tubular secretion. |
| Excretion | Approximately 80% of the dose is excreted unchanged in the urine via active tubular secretion; the remainder is metabolized (hepatic) and excreted in feces. Biliary excretion is minimal. |
| Half-life | Terminal elimination half-life is approximately 10 hours (range 6.7–13.5 hours) in patients with normal renal function; prolonged in renal impairment (up to 20–30 hours in severe impairment). |
| Protein binding | 60–70% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Vd is approximately 3 L/kg (range 2–5 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is >90%. |
| Onset of Action | Oral: Peak effect on QT prolongation occurs within 2–3 hours after a dose; clinical antiarrhythmic effect (conversion of atrial fibrillation/flutter) typically observed within 24–72 hours after starting therapy. |
| Duration of Action | Duration of QT prolongation is dose- and concentration-dependent; effects persist for at least 12 hours, requiring twice-daily dosing. Continuous electrocardiographic monitoring recommended for 3 days at initiation. |
125 to 500 mcg orally twice daily; initial dose based on creatinine clearance and QTc interval; maximum 500 mcg twice daily.
| 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 recommended for hepatic impairment; monitor QTc interval. |
| Pediatric use | Safety and efficacy not established; no standard pediatric dosing. |
| Geriatric use | Start at lower end of dosing range based on renal function; monitor renal function and QTc interval. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DOFETILDE (DOFETILDE).
| Breastfeeding | Unknown if excreted in human milk. M/P ratio not established. Due to potential for serious adverse reactions (e.g., arrhythmias) in nursing infants, discontinue nursing or discontinue drug, taking into account importance of drug to mother. |
| Teratogenic Risk | Pregnancy Category C. No adequate studies in pregnant women. In animal studies, dofetilide caused fetal toxicity (increased post-implantation loss, decreased fetal weight, and skeletal variations) at doses 5-10 times the maximum human dose. Risk cannot be ruled out. Use only if potential benefit justifies potential risk to fetus. First trimester: unknown risk; second and third trimesters: limited data, theoretical risk of QT prolongation. |
■ FDA Black Box Warning
Torsades de pointes (TdP) due to QT prolongation; must be initiated in a hospital setting with continuous ECG monitoring; dose adjustment required based on creatinine clearance and QT interval; interactions with drugs that increase dofetilide levels or prolong QT.
| 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, cimetidine, trimethoprim, ketoconazole, or other QT-prolonging drugs; hypokalemia or hypomagnesemia; history of TdP or congenital long QT syndrome; breastfeeding.
| Precautions | QT prolongation and TdP risk; renal impairment requires dose adjustment; electrolyte disturbances (hypokalemia, hypomagnesemia) must be corrected; bradycardia; use with other QT-prolonging drugs is contraindicated; monitoring of ECG and renal function required. |
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| Fetal Monitoring | Monitor maternal ECG for QTc interval prolongation (baseline and during therapy; adjust dose if QTc > 500 msec). Monitor serum potassium and magnesium levels (correct deficiencies before use). Monitor renal function (CrCl) for dose adjustment. Fetal monitoring: consider fetal echocardiography for potential arrhythmia detection. |
| Fertility Effects | No human data on fertility. In animal studies, no impaired fertility was observed in rats at exposures up to 5 times the clinical exposure. Effects on human fertility are unknown. |