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 weeks if atrial fibrillation was present more than 3 days, had serum potassium of at least 4.0 mEq/L and QTc below 440 msec, and were monitored by telemetry for at least 24 hours. Patients could not be on class I or other class III antiarrhythmics (these had to be discontinued at least 5 half-lives prior to infusion) but could be on calcium channel blockers, beta blockers, or digoxin. In one trial, single 10-minute infusions of 0.005 to 0.025 mg/kg were tested in parallel groups (0.3 to 1.5 mg in a 60 kg person). In the second trial, up to two infusions of ibutilide fumarate were eva luated—the first 1.0 mg, the second given 10 minutes after completion of the first infusion, either 0.5 or 1.0 mg. In a third double-blind study, 319 patients with atrial fibrillation or atrial flutter of 3 hours to 45 days duration were randomized to receive single, 10-minute intravenous infusions of either sotalol (1.5 mg/kg) or CORVERT (1 mg or 2 mg). Among patients with atrial flutter, 53% receiving 1 mg ibutilide fumarate and 70% receiving 2 mg ibutilide fumarate converted, compared to 18% of those receiving sotalol. In patients with atrial fibrillation, 22% receiving 1 mg ibutilide fumarate and 43% receiving 2 mg ibutilide fumarate converted compared to 10% of patients receiving sotalol.
Patients in registration trials were hemodynamically stable. Patients with specific cardiovascular conditions such as symptomatic heart failure, recent acute myocardi |
