ophysiologic Effects
CORVERT produces mild slowing of the sinus rate and atrioventricular conduction. CORVERT produces no clinically significant effect on QRS duration at intravenous doses up to 0.03 mg/kg administered over a 10-minute period. Although there is no established relationship between plasma concentration and antiarrhythmic effect, CORVERT produces dose-related prolongation of the QT interval, which is thought to be associated with its antiarrhythmic activity. (See WARNINGS for relationship between QTc prolongation and torsades de pointes-type arrhythmias.) In a study in healthy volunteers, intravenous infusions of CORVERT resulted in prolongation of the QT interval that was directly correlated with ibutilide plasma concentration during and after 10-minute and 8-hour infusions. A steep ibutilide concentration/response (QT prolongation) relationship was shown. The maximum effect was a function of both the dose of CORVERT and the infusion rate.
Hemodynamic Effects
A study of hemodynamic function in patients with ejection fractions both above and below 35% showed no clinically significant effects on cardiac output, mean pulmonary arterial pressure, or pulmonary capillary wedge pressure at doses of CORVERT up to 0.03 mg/kg.
Pharmacokinetics
After intravenous infusion, ibutilide plasma concentrations rapidly decrease in a multiexponential fashion. The pharmacokinetics of ibutilide are highly variable among subjects. Ibutilide has a high systemic plasma clearance that approximates liver blood flow (about 29 mL/min/kg), a large steady-state volume of distribution (about 11 L/kg) in healthy volunteers, and minimal (about 40%) protein binding. Ibutilide is also cleared rapidly and highly distributed in patients being treated for atrial flutter or atrial fibrillation. The elimination half-life averages about 6 hours (range from 2 to 12 hours). The pharmacokinetics of ibutilide are linear with respect to the dose of CORVERT over the dose range of 0.01 mg/kg to 0.10 mg/kg. The enantiomers of ibutilide fumarate have pharmacokinetic properties similar to each other and to ibutilide fumarate.
The pharmacokinetics of CORVERT Injection in patients with atrial flutter or atrial fibrillation are similar regardless of the type of arrhythmia, patient age, sex, or the concomitant use of digoxin, calcium channel blockers, or beta blockers.
Metabolism and elimination
In healthy male volunteers, about 82% of a 0.01 mg/kg dose of [14C] ibutilide fumarate was excreted in the urine (about 7% of the dose as unchanged ibutilide) and the remainder (about 19%) was recovered in the feces.
Eight metabolites of ibutilide were detected in metabolic profiling of urine. These metabolites are thought to be formed primarily by ω-oxidation followed by sequential β-oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the ω-hydroxy metabolite possesses class III electrophysiologic properties similar to that of ibutilide in an in vitro isolated rabbit myocardium model. The plasma concentrations of this active metabolite, however, are less than 10% of that of ibutilide.
Clinical Studies
Treatment with intravenous ibutilide fumarate for acute termination of recent onset atrial flutter/fibrillation was eva luated in 466 patients participating in two randomized, double-blind, placebo-controlled clinical trials. Patients had had their arrhythmias for 3 hours to 90 days, were anticoagulated for at least 2 |
