Tikosyn

Increase in QT interval is directly related to dofetilide dose and plasma concentration. Figure 1 shows that the relationship in normal volunteers between dofetilide plasma concentrations and change in QTc is linear, with a positive slope of approximately 1525 msec/(ng/mL) after the first dose and approximately 1015 msec/(ng/mL) at Day 23 (reflecti... ng a steady state of dosing). A linear relationship between mean QTc increase and dofetilide dose was also seen in patients with renal impairment, in patients with ischemic heart disease, and in patients with supraventricular and ventricular arrhythmias. Note: The range of dofetilide plasma concentrations achieved with the 500 mcg BID dose adjusted for creatinine clearance is 13.5 ng/mL. The relationship between dose, efficacy, and the increase in QTc from baseline at steady state for the two randomized, placebo-controlled studies (described further below) is shown in Figure 2. The studies examined the effectiveness of TIKOSYN in conversion to sinus rhythm and maintenance of normal sinus rhythm after conversion in patients with atrial fibrillation/flutter of 1 week duration. As shown, both the probability of a patient's remaining in sinus rhythm at six months and the change in QTc from baseline at steady state of dosing increased in an approximately linear fashion with increasing dose of TIKOSYN. Note that in these studies, doses were modified by results of creatinine clearance measurement and in-hospital QTc prolongation. Number of patients evaluated for maintenance of NSR: 503 TIKOSYN, 174 placebo. Number of patients evaluated for QTc change: 478 TIKOSYN, 167 placebo. Two randomized, parallel, double-blind, placebo-controlled, dose-response trials evaluated the ability of TIKOSYN 1) to convert patients with atrial fibrillation or atrial flutter (AF/AFl) of more than 1 week duration to normal sinus rhythm (NSR) and 2) to maintain NSR (delay time to recurrence of AF/AFl) after drug-induced or electrical cardioversion. A total of 996 patients with a one week to two ...Read More