What are the guidelines for managing a patient on Tikosyn (dofetilide)?

Management of Tikosyn (Dofetilide)

Tikosyn must be initiated in a hospital setting with continuous ECG monitoring for a minimum of 3 days, and patients cannot be discharged within 12 hours of cardioversion to normal sinus rhythm. 1

Mandatory Inpatient Initiation Protocol

Pre-Initiation Requirements

• Calculate creatinine clearance before the first dose using the Cockcroft-Gault equation, as renal function directly determines dosing and toxicity risk 2, 1
• Measure baseline QTc interval (average of 5-10 beats); if QTc >440 msec (>500 msec with ventricular conduction abnormalities), dofetilide is absolutely contraindicated 2, 1
• Correct electrolyte abnormalities before initiation—hypokalemia and hypomagnesemia must be normalized, with potassium maintained >3.6-4.0 mEq/L throughout therapy 2, 1
• Ensure anticoagulation is established per usual practice before cardioversion in atrial fibrillation patients 1

Initial Dosing Algorithm

The starting dose is determined strictly by creatinine clearance 1:

• CrCl >60 mL/min: 500 mcg twice daily
• CrCl 40-60 mL/min: 250 mcg twice daily
• CrCl 20-<40 mL/min: 125 mcg twice daily
• CrCl <20 mL/min: Contraindicated 2, 1

Critical Monitoring During Initiation

• Measure QTc 2-3 hours after each of the first 5 doses under continuous ECG monitoring 2, 1
• If QTc increases >15% from baseline OR exceeds 500 msec (550 msec with ventricular conduction abnormalities), reduce the dose by 50% 2, 1:
  • 500 mcg BID → 250 mcg BID
  • 250 mcg BID → 125 mcg BID
  • 125 mcg BID → 125 mcg once daily
• If QTc exceeds 500 msec after the second dose, permanently discontinue dofetilide 2, 1
• 76% of torsades de pointes episodes occur within the first 3 days, justifying this intensive monitoring period 2

Ongoing Maintenance Management

Regular Monitoring Schedule

• Reassess renal function and QTc every 3 months or whenever clinically indicated 1
• If QTc exceeds 500 msec (550 msec with ventricular conduction abnormalities) during maintenance, discontinue dofetilide and monitor until QTc returns to baseline 1
• If renal function deteriorates, adjust dose according to the creatinine clearance-based algorithm above 1

Critical Drug Interactions—Absolute Contraindications

The following medications are absolutely contraindicated with dofetilide and must be discontinued before initiation 1:

• Cimetidine (increases dofetilide levels by 58% at prescription doses) 1
• Verapamil (increases peak levels by 42% and associated with higher torsades risk) 1
• Ketoconazole (increases Cmax by 53-97% and AUC by 41-69%) 1
• Trimethoprim (alone or with sulfamethoxazole) 1
• Prochlorperazine 1
• Megestrol 1
• Dolutegravir 1
• Hydrochlorothiazide (alone or in combinations) 1

Safe Alternative Medications

• For acid suppression: Use omeprazole, ranitidine, or antacids (aluminum/magnesium hydroxide) instead of cimetidine 1
• Dofetilide can be safely co-administered with digoxin and beta-blockers 3

Special Population Considerations

Heart Failure and Structural Heart Disease

• Dofetilide and amiodarone are the only antiarrhythmics proven safe in patients with ejection fraction ≤35% 2
• In the DIAMOND CHF trial, dofetilide reduced AF incidence (1.9% vs 6.6% placebo) and heart failure hospitalizations without increasing mortality 2
• Torsades de pointes risk is 3.3% in heart failure patients, higher than other populations 2
• Unlike other antiarrhythmics, dofetilide has no effect on heart rate or blood pressure, making it advantageous when AV nodal blockade must be avoided 2, 4

Renal Impairment

• Overall systemic clearance decreases with declining creatinine clearance, requiring strict dose adjustment 1
• Patients on dialysis were not studied—appropriate dosing is unknown, and hemodialysis effectiveness in removing dofetilide is uncertain 1

Hepatic Impairment

• No additional dose adjustment needed for mild-to-moderate hepatic impairment after creatinine clearance adjustment 1
• Severe hepatic impairment patients were not studied—use with extreme caution 1

Clinical Efficacy Expectations

• Real-world acute conversion rates are higher than clinical trials reported, with most conversions occurring within 24-36 hours 5, 6
• Dofetilide is more effective for atrial flutter than atrial fibrillation (70% vs 29% conversion rates) 5
• After cardioversion, median time to relapse exceeds one year, with 75% probability of maintaining sinus rhythm 3
• At 3-year follow-up, 49% of patients remain on dofetilide, with waning effect being the most common reason for discontinuation (57%) 7

Safety Profile and Risk Mitigation

Torsades de Pointes Risk

• Overall torsades risk ranges from 0.8-1.5% with oral therapy and 3-4% with IV therapy 4
• Risk is dose-related and highest in women, patients with bradycardia, hypokalemia, hypomagnesemia, and renal dysfunction 4
• The mandatory 3-day inpatient monitoring protocol with QTc-guided dose adjustment is designed to minimize this risk 5

Common Pitfalls to Avoid

• Never initiate dofetilide outside a hospital setting 2
• Always verify all medications and supplements before initiation—patients must inform all healthcare providers of ongoing dofetilide therapy 1
• Correct electrolyte abnormalities before starting therapy—potassium-depleting diuretics significantly increase torsades risk 2
• If a dose is missed, do NOT double the next dose—take the next scheduled dose at the usual time 1
• Patients must report symptoms of electrolyte imbalance (excessive diarrhea, vomiting, sweating, loss of appetite/thirst) immediately 1

Role in Treatment Algorithm

• Dofetilide is a second-line agent for SVT management when beta-blockers, diltiazem, flecainide, verapamil, or propafenone are ineffective or contraindicated 8
• For atrial fibrillation in heart failure or post-MI patients, dofetilide is a first-line option alongside amiodarone, as these are the only agents with proven safety in this population 2, 3
• Dofetilide is particularly useful when AV nodal blockade needs to be avoided due to its lack of effect on heart rate and blood pressure 6