When can a change in a patient's condition be expected during the initial 3-day period of Tikosyn (dofetilide) loading?

Changes During Tikosyn (Dofetilide) Loading Period

During the initial 3-day loading period of Tikosyn (dofetilide), the majority of significant changes, particularly adverse events like Torsade de Pointes, occur within the first 3 days of treatment, with most cases (76%) occurring within this timeframe. 1

Timing of Significant Changes

• The most critical period for monitoring is the first 72 hours (3 days), which is why hospitalization with continuous telemetry monitoring is mandatory during this period 1
• In the DIAMOND studies, 76% of Torsade de Pointes cases occurred within the first 3 days of dosing 1
• In patients with myocardial infarction, 4 out of 7 cases of Torsade de Pointes occurred within the first 3 days 1
• For patients with atrial fibrillation, 2 out of 4 events in the DIAMOND AF subpopulation occurred within the first 3 days 1

QT Interval Changes

• QT interval changes are typically observed within hours after the first dose 1
• Per protocol, ECG should be checked 2-3 hours after administering the first dose to determine QTc changes 2
• If QTc increases by >15% compared to baseline or exceeds 500 ms (550 ms in patients with ventricular conduction abnormalities), subsequent dosing should be reduced by 50% 2
• QTc monitoring continues at 2-3 hours after each subsequent dose during the initial hospitalization period 2

Dose Adjustments During Loading Period

• In clinical studies, 23% of patients had their dose adjusted downward based on calculated creatinine clearance during the in-hospital initiation period 1
• 3% of patients required dose down-titration due to increased QT interval or QTc during this period 1
• Increased QT interval or QTc led to discontinuation of therapy in 3% of patients 1

Conversion to Normal Sinus Rhythm

• Most patients who convert to normal sinus rhythm do so within 24-36 hours of starting treatment 3
• In the DIAMOND studies, 12% of patients with atrial fibrillation or flutter at baseline converted to normal sinus rhythm after one month of Tikosyn treatment (compared to 2% with placebo) 1

Safety Considerations

• The risk of Torsade de Pointes is highest during the initial loading period, which necessitates the mandatory 3-day hospitalization 1, 3
• Patients with QTc greater than 460 msec, second or third degree AV block (unless with pacemaker), resting heart rate <50 bpm, or prior history of polymorphic ventricular tachycardia should be excluded from treatment 1
• Hypokalemia or hypomagnesemia increases the risk of Torsade de Pointes, so electrolyte levels should be normalized before starting Tikosyn and maintained during treatment 1

Monitoring Protocol

• Continuous ECG monitoring via telemetry is required for all patients during the entire 3-day loading period 1
• QT interval should be monitored 2-4 hours after each dose during initiation and titration 2
• If the QT interval prolongs to ≥500 ms, the dose must be reduced or the drug discontinued 2
• Renal function and serum electrolytes should be evaluated during this period 3

The mandatory 3-day hospitalization with continuous monitoring during Tikosyn initiation is specifically designed to address the highest-risk period for adverse events, particularly life-threatening arrhythmias like Torsade de Pointes 1, 3. This monitoring protocol has been shown to significantly reduce the risk of serious adverse events while allowing for appropriate dose adjustments based on individual patient response 1.