Ibutilide Fumarate

IBUTILIDE FUMARATE- ibutilide fumarate injection, solution
Mylan Institutional LLC

Rx only

FOR INTRAVENOUS INFUSION ONLY

DESCRIPTION

Ibutilide fumarate injection is an antiarrhythmic drug with predominantly class III (cardiac action potential prolongation) properties according to the Vaughan Williams Classification. Each milliliter of ibutilide fumarate injection contains 0.1 mg of ibutilide fumarate (equivalent to 0.087 mg ibutilide free base), 0.189 mg sodium acetate trihydrate, 8.9 mg sodium chloride, hydrochloric acid and/or sodium hydroxide to adjust pH to approximately 4.6, and water for injection.

Ibutilide fumarate injection is an isotonic, clear, colorless, sterile aqueous solution.

Ibutilide fumarate has one chiral center, and exists as a racemate of the (+) and (−) enantiomers.

The chemical name for ibutilide fumarate is Methanesulfonamide, N-{4-{4-(ethylheptylamino)-1 -hydroxybutyl}phenyl}, (+)(−), (E)-2-butenedioate (1:0.5) (hemifumarate salt). Its molecular formula is C₂₂ H₃₈ N₂ O₅ S, and its molecular weight is 442.62.

Ibutilide fumarate is a white to off-white powder with an aqueous solubility of over 100 mg/mL at pH 7 or lower.

The structural formula is represented below:

Ibutilide Fumerate

CLINICAL PHARMACOLOGY

Mechanism of Action

Ibutilide fumarate injection prolongs action potential duration in isolated adult cardiac myocytes and increases both atrial and ventricular refractoriness in vivo, i.e., class III electrophysiologic effects. Voltage clamp studies indicate that ibutilide fumarate injection, at nanomolar concentrations, delays repolarization by activation of a slow, inward current (predominantly sodium), rather than by blocking outward potassium currents, which is the mechanism by which most other class III antiarrhythmics act. These effects lead to prolongation of atrial and ventricular action potential duration and refractoriness, the predominant electrophysiologic properties of ibutilide fumarate injection in humans that are thought to be the basis for its antiarrhythmic effect.

Electrophysiologic Effects

Ibutilide fumarate injection produces mild slowing of the sinus rate and atrioventricular conduction. Ibutilide fumarate injection 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, ibutilide fumarate injection 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 ibutilide fumarate injection 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 ibutilide fumarate injection 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 ibutilide fumarate injection 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 ibutilide fumarate injection 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 ibutilide fumarate 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 [¹⁴ C] 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 evaluated 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 evaluated 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 ibutilide fumarate injection (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 myocardial infarction, and angina were excluded. About two thirds had cardiovascular symptoms, and the majority of patients had left atrial enlargement, decreased left ventricular ejection fraction, a history of valvular disease, or previous history of atrial fibrillation or flutter. Electrical cardioversion was allowed 90 minutes after the infusion was complete. Patients could be given other antiarrhythmic drugs 4 hours postinfusion.

Results of the first two studies are shown in the tables below. Conversion of atrial flutter/ fibrillation usually (70% of those who converted) occurred within 30 minutes of the start of infusion and was dose related. The latest conversion seen was at 90 minutes after the start of the infusion. Most converted patients remained in normal sinus rhythm for 24 hours. Overall responses in these patients, defined as termination of arrhythmias for any length of time during or within 1 hour following completed infusion of randomized dose, were in the range of 43% to 48% at doses above 0.0125 mg/kg (vs 2% for placebo). Twenty-four hour responses were similar. For these atrial arrhythmias, ibutilide was more effective in patients with flutter than fibrillation ( ≥ 48% vs ≤ 40%).

PERCENT OF PATIENTS WHO CONVERTED (Second Trial)
			Ibutilide
		Placebo	0.005 mg/mg	0.01 mg/kg	0.015 mg/kg	0.025 mg/kg
	n	41	41	40	38	40
* Percent of patients who converted within 70 minutes after the start of infusion. † Percent of patients who remained in sinus rhythm 24 hours after dosing.
Both	Initially *	2	12	33	45	48
	At 24 hours †	2	12	28	42	43
Atrial flutter	Initially *	0	14	30	58	55
	At 24 hours †	0	14	30	58	50
Atrial Fibrillation	Initially *	5	10	35	32	40
	At 24 hours †	5	10	25	26	35

PERCENT OF PATIENTS WHO CONVERTED (Second Trial)
			Ibutilide
		Placebo	1.0 mg/0.5 mg	1.0 mg/1.0 mg
	n	86	86	94
* Percent of patients who converted within 90 minutes after the start of infusion. † Percent of patients who remained in sinus rhythm 24 hours after dosing.
Both	Initially *	2	43	44
	At 24 hours †	2	34	37
Atrial flutter	Initially *	2	48	63
	At 24 hours †	2	45	59
Atrial Fibrillation	Initially *	2	38	25
	At 24 hours †	2	21	17

The numbers of patients who remained in the converted rhythm at the end of 24 hours were slightly less than those patients who converted initially, but the difference between conversion rates for ibutilide compared to placebo was still statistically significant. In long-term follow-up, approximately 40% of all patients remained recurrence free, usually with chronic prophylactic treatment, 400 to 500 days after acute treatment, regardless of the method of conversion.

Patients with more recent onset of arrhythmia had a higher rate of conversion. Response rates were 42% and 50% for patients with onset of atrial fibrillation/flutter for less than 30 days in the two efficacy studies compared to 16% and 31% in those with more chronic arrhythmias.

Ibutilide was equally effective in patients below and above 65 years of age and in men and women. Female patients constituted about 20% of patients in controlled studies.