What is the recommended washout period for amiodarone before starting dofetilide?

Amiodarone Washout Period Before Starting Dofetilide

Dofetilide should not be initiated until amiodarone plasma levels are below 0.3 mcg/mL or until amiodarone has been withdrawn for at least 3 months. 1

FDA-Mandated Requirements

The FDA drug label for dofetilide explicitly states that due to amiodarone's unpredictable pharmacokinetics, dofetilide initiation must wait until either:

• Amiodarone plasma levels fall below 0.3 mcg/mL, OR
• A minimum of 3 months has elapsed since amiodarone discontinuation 1

This requirement exists because amiodarone is contraindicated during dofetilide initiation due to its effects on renal tubular secretion and potential for dangerous QTc prolongation when combined with dofetilide. 2, 1

Pharmacokinetic Rationale

The 3-month washout period is based on amiodarone's extraordinarily long elimination half-life:

• Terminal elimination half-life: 55-100 days after chronic therapy 3, 4, 5
• After steady-state is reached, cessation produces only a 25% serum concentration reduction in 3 days and 50% reduction in 36 days 5
• The drug's extensive tissue accumulation (particularly in adipose tissue, skeletal muscle, and myocardium) means interactions can persist for months after discontinuation 6, 4
• Amiodarone's half-life ranges from 15-100 days depending on duration of therapy, with an average of approximately 58 days 6, 3

Clinical Algorithm for Transition

Step 1: Discontinue Amiodarone

• Stop amiodarone immediately when the decision is made to transition to dofetilide 1

Step 2: Wait Minimum 3 Months

• The standard approach is to wait the full 3-month washout period 1
• This accounts for the drug's prolonged tissue stores and unpredictable elimination 4, 5

Step 3: Consider Plasma Level Monitoring (Optional)

• If earlier initiation is clinically necessary, measure amiodarone plasma levels 1
• Dofetilide can only be started if levels are documented below 0.3 mcg/mL 1
• However, given amiodarone's tissue accumulation, plasma levels may not fully reflect tissue stores 4

Step 4: Initiate Dofetilide with Mandatory Hospitalization

• Once the washout period is complete, dofetilide requires inpatient initiation with continuous ECG monitoring for minimum 3 days 2, 1
• Baseline QTc must be <440 msec (or <500 msec with ventricular conduction abnormalities) 1, 7

Critical Pitfalls to Avoid

Do not attempt early transition: The 3-month washout is not negotiable unless plasma levels are definitively below 0.3 mcg/mL. 1 Attempting earlier initiation risks severe QTc prolongation and torsades de pointes, as both drugs prolong the QT interval through different mechanisms. 2, 1

Do not rely solely on symptom resolution: Amiodarone's antiarrhythmic effects persist long after discontinuation due to tissue stores, and this same property drives the interaction risk. 3, 4

Account for desethylamiodarone: The active metabolite desethylamiodarone also accumulates and has a similarly prolonged half-life, contributing to the extended washout requirement. 4, 5

Monitoring During Washout Period

During the 3-month washout:

• Monitor for arrhythmia recurrence, as amiodarone's antiarrhythmic effects gradually wane 3
• Consider temporary rate control agents (beta-blockers, calcium channel blockers) if needed 2
• Continue monitoring thyroid function and liver enzymes, as amiodarone toxicity can emerge even after discontinuation 6
• Adjust warfarin dosing if applicable, as amiodarone's effect on INR persists during washout 2, 4