How do you safely convert a patient from amiodarone to Tikosyn (dofetilide)?

Converting from Amiodarone to Tikosyn (Dofetilide)

You must wait at least 3 months after stopping amiodarone before initiating Tikosyn, or until amiodarone plasma levels fall below 0.3 mcg/mL. 1

Critical Safety Requirement

The FDA label for Tikosyn explicitly states that dofetilide should not be initiated following amiodarone therapy until amiodarone plasma levels are below 0.3 mcg/mL or until amiodarone has been withdrawn for at least three months. 1 This is due to amiodarone's unpredictable pharmacokinetics and extremely long half-life (up to 100 days). 2

Why This Extended Washout Period is Necessary

• Amiodarone has an extraordinarily long elimination half-life that can extend up to 100 days, meaning the drug persists in tissues for months after discontinuation. 2

• Both amiodarone and dofetilide prolong the QT interval, creating additive risk for torsades de pointes if overlapped. 3, 1

• The risk of torsades de pointes with dofetilide ranges from 0.8% to 3.3% in clinical trials, and this risk is dose-dependent and increased by factors that prolong QT interval. 4, 5, 6

• Amiodarone's tissue stores and active metabolites continue to exert electrophysiologic effects long after serum levels become undetectable, making the washout period unpredictable. 1

Step-by-Step Conversion Algorithm

Step 1: Discontinue Amiodarone

• Stop amiodarone therapy completely
• Document the date of discontinuation
• Continue rate control with alternative agents (beta-blockers, calcium channel blockers, or digoxin) as needed during the washout period 3

Step 2: Monitor During Washout Period

• Wait a minimum of 3 months before considering Tikosyn initiation 1
• If available, measure amiodarone plasma levels and confirm they are below 0.3 mcg/mL before proceeding 1
• Monitor QTc interval during this period to ensure it returns toward baseline 1

Step 3: Pre-Tikosyn Assessment

Before initiating Tikosyn, verify the following:

• Calculate creatinine clearance using the Cockcroft-Gault equation (Tikosyn is contraindicated if CrCl <20 mL/min) 1
• Measure baseline QTc interval (must be <440 msec; contraindicated if >440 msec or >500 msec with ventricular conduction abnormalities) 1
• Check serum potassium and magnesium and correct any deficiencies (hypokalemia increases torsades risk) 1, 7
• Review all medications for potential interactions, particularly cimetidine, verapamil, trimethoprim, ketoconazole, and other drugs that affect renal elimination 1, 7

Step 4: Initiate Tikosyn in Hospital

Tikosyn must be initiated in an inpatient setting with continuous ECG monitoring for a minimum of 3 days. 1, 4, 5

Dose based on 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

Step 5: QTc Monitoring Protocol

• Measure QTc at 2-3 hours after each dose for the first 5 doses 1
• If QTc increases by >15% from baseline OR exceeds 500 msec (550 msec with ventricular conduction abnormalities), reduce the dose: 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 at any time after the second dose, discontinue Tikosyn permanently 1

Step 6: Continue Monitoring

• Maintain continuous ECG monitoring for minimum 3 days or 12 hours after conversion to sinus rhythm, whichever is greater 1
• Monitor for bradycardia, hypotension, and signs of heart block 1

Common Pitfalls to Avoid

Do not attempt to shorten the washout period. Even if the patient appears to have no residual amiodarone effects clinically, tissue stores remain and create unpredictable drug interactions. 1

Do not initiate Tikosyn as an outpatient. The FDA mandates inpatient initiation with continuous monitoring due to the risk of torsades de pointes, which typically occurs within the first 3 days. 1, 4, 5

Do not overlook renal function. Dofetilide is renally eliminated, and even mild renal impairment requires dose adjustment. 1, 7

Do not forget to adjust other medications. If the patient is on digoxin or warfarin, these were likely dose-adjusted during amiodarone therapy and will need readjustment after amiodarone washout. 2, 8

Alternative Considerations

If the 3-month washout period is clinically unacceptable:

• Consider other antiarrhythmic options that do not have the same contraindication with recent amiodarone use, such as flecainide or propafenone in patients without structural heart disease 3, 9
• In patients with structural heart disease or heart failure, amiodarone remains the safest option and could be continued rather than switched 3, 9
• Rate control with cardioversion may be preferable to antiarrhythmic drug switching in some cases 3

Efficacy Expectations

Once safely initiated, dofetilide demonstrates:

• 30% pharmacological conversion rate for atrial fibrillation 4, 6
• 71-75% maintenance of sinus rhythm at 6-12 months after conversion 4, 6, 9
• Superior efficacy for atrial flutter compared to atrial fibrillation 3, 5, 6
• Neutral effect on mortality in high-risk patients with heart failure or post-MI, similar to amiodarone 4, 6, 9