Ibutilide Fumarate Drug Information
Generic name: IBUTILIDE FUMARATE
Uses of Ibutilide Fumarate
Ibutilide fumarate injection is indicated for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm. Patients with atrial arrhythmias of longer duration are less likely to respond to ibutilide fumarate. The effectiveness of ibutilide has not been determined in patients with arrhythmias of more than 90 days in duration.
LIFE-THREATENING ARRHYTHMIAS—APPROPRIATE TREATMENT ENVIRONMENT Ibutilide fumarate can cause potentially fatal arrhythmias, particularly sustained polymorphic ventricular tachycardia, usually in association with QT prolongation (torsades de pointes), but sometimes without documented QT prolongation. In registration studies, these arrhythmias, which require cardioversion, occurred in 1.7% of treated patients during, or within a number of hours of, use of Ibutilide fumarate. These arrhythmias can be reversed if treated promptly (see WARNINGS, Proarrhythmia ). It is essential that Ibutilide fumarate be administered in a setting of continuous ECG monitoring and by personnel trained in identification and treatment of acute ventricular arrhythmias, particularly polymorphic ventricular tachycardia.
Patients with atrial fibrillation of more than 2 to 3 days’ duration must be adequately anticoagulated, generally for at least 2 weeks. CHOICE OF PATIENTS Patients with chronic atrial fibrillation have a strong tendency to revert after conversion to sinus rhythm (see CLINICAL STUDIES ) and treatments to maintain sinus rhythm carry risks. Patients to be treated with Ibutilide fumarate, therefore, should be carefully selected such that the expected benefits of maintaining sinus rhythm outweigh the immediate risks of Ibutilide fumarate, and the risks of maintenance therapy, and are likely to offer an advantage compared with alternative management.
Dosage & Administration of Ibutilide Fumarate
Side Effects of Ibutilide Fumarate
Nonsustained monomorphic VT 1 0.8 29 4.9 Nonsustained polymorphic VT — —
16
Hypotension 2 1.6 12 2.0 Bundle branch block — — 11 1.9
Sustained polymorphic VT — — 10
AV block 1 0.8 9 1.5 Hypertension — — 7 1.2 QT
segment prolonged — — 7
Bradycardia 1 0.8 7 1.2 Palpitation 1 0.8 6 1.0 Tachycardia 1
0.8 16
GASTROINTESTINAL Nausea 1 0.8 11 1.9
CENTRAL NERVOUS SYSTEM Headache 4 3.1 21
In the post-cardiac surgery study (see
CLINICAL STUDIES ), similar types of medical events were reported. In the 1 mg ibutilide fumarate treatment group (N=70), 2 patients (2.9%) developed sustained polymorphic ventricular tachycardia and 2 other patients (2.9%) developed nonsustained polymorphic ventricular tachycardia. Polymorphic ventricular tachycardia was not reported in the 73 patients in the 0.5 mg dose group or in the 75 patients in the 0.25 mg dose group.
Warnings & Cautions for Ibutilide Fumarate
Proarrhythmia Like other antiarrhythmic agents, ibutilide fumarate injection can induce or worsen ventricular arrhythmias in some patients. This may have potentially fatal consequences. Torsades de pointes, a polymorphic ventricular tachycardia that develops in the setting of a prolonged QT interval, may occur because of the effect ibutilide fumarate has on cardiac repolarization, but ibutilide fumarate can also cause polymorphic VT in the absence of excessive prolongation of the QT interval.
In general, with drugs that prolong the QT interval, the risk of torsades de pointes is thought to increase progressively as the QT interval is prolonged and may be worsened with bradycardia, a varying heart rate, and hypokalemia. In clinical trials conducted in patients with atrial fibrillation and atrial flutter, those with QTc intervals greater than 440 msec were not usually allowed to participate, and serum potassium had to be above 4 mEq/L. Although change in QTc was dose dependent for ibutilide, there was no clear relationship between risk of serious proarrhythmia and dose in clinical studies, possibly due to the small number of events. In clinical trials of intravenous ibutilide, patients with a history of congestive heart failure (CHF) or low left ventricular ejection fraction appeared to have a higher incidence of sustained polymorphic ventricular tachycardia (VT), than those without such underlying conditions; for sustained polymorphic VT the rate was 5.4% in patients with a history of CHF and 0.8% without it.
There was also a suggestion that women had a higher risk of proarrhythmia, but the sex difference was not observed in all studies and was most prominent for nonsustained ventricular tachycardia. The incidence of sustained ventricular arrhythmias was similar in male (1.8%) and female (1.5%) patients, possibly due to the small number of events. Ibutilide fumarate is not recommended in patients who have previously demonstrated polymorphic ventricular tachycardia (eg, torsades de pointes). During registration trials, 1.7% of patients with atrial flutter or atrial fibrillation treated with Ibutilide fumarate developed sustained polymorphic ventricular tachycardia requiring cardioversion.
In these clinical trials, many initial episodes of polymorphic ventricular tachycardia occurred after the infusion of ibutilide fumarate was stopped but generally not more than 40 minutes after the start of the first infusion. There were, however, instances of recurrent polymorphic VT that occurred about 3 hours after the initial infusion. In two cases, the VT degenerated into ventricular fibrillation, requiring immediate defibrillation.
Other cases were managed with cardiac pacing and magnesium sulfate infusions. Nonsustained polymorphic ventricular tachycardia occurred in 2.7% of patients and nonsustained monomorphic ventricular tachycardias occurred in 4.9% of the patients (see ADVERSE REACTIONS ). Proarrhythmic events must be anticipated. Skilled personnel and proper equipment, including cardiac monitoring equipment, intracardiac pacing facilities, a cardioverter/defibrillator, and medication for treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, must be available during and after administration of ibutilide fumarate.
Before treatment with ibutilide fumarate, hypokalemia and hypomagnesemia should be corrected to reduce the potential for proarrhythmia. Patients should be observed with continuous ECG monitoring for at least 4 hours following infusion or until QTc has returned to baseline. Longer monitoring is required if any arrhythmic activity is noted.
Management of polymorphic ventricular tachycardia includes discontinuation of ibutilide, correction of electrolyte abnormalities, especially potassium and magnesium, and overdrive cardiac pacing, electrical cardioversion, or defibrillation. Pharmacologic therapies include magnesium sulfate infusions. Treatment with antiarrhythmics should generally be avoided.
Drug Interactions with Ibutilide Fumarate
Drug Interactions No specific pharmacokinetic or other formal drug interaction studies were conducted. Digoxin Supraventricular arrhythmias may mask the cardiotoxicity associated with excessive digoxin levels. Therefore, it is advisable to be particularly cautious in patients whose plasma digoxin levels are above or suspected to be above the usual therapeutic range.
Co-administration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials. Calcium channel blocking agents Co-administration of calcium channel blockers did not have any effect on either the safety or efficacy of ibutilide in the clinical trials. Beta-adrenergic blocking agents Co-administration of beta-adrenergic blocking agents did not have any effect on either the safety or efficacy of ibutilide in the clinical trials.
Pregnancy Safety for Ibutilide Fumarate
Pregnancy Ibutilide administered orally was teratogenic (abnormalities included adactyly, interventricular septal defects, and scoliosis) and embryocidal in reproduction studies in rats. On a mg/m 2 basis, corrected for the 3% oral bioavailability, the “no adverse effect dose” (5 mg/kg/day given orally) was approximately the same as the maximum recommended human dose (MRHD); the teratogenic dose (20 mg/kg/day given orally) was about four times the MRHD on a mg/m 2 basis, or 16 times the MRHD on a mg/kg basis. Ibutilide fumarate should not be administered to a pregnant woman unless clinical benefit outweighs potential risk to the fetus.
Pediatric Use of Ibutilide Fumarate
Pediatric Use Clinical trials with ibutilide fumarate in patients with atrial fibrillation and atrial flutter did not include anyone under the age of 18. Safety and effectiveness of ibutilide in pediatric patients has not been established.
Contraindications for Ibutilide Fumarate
Ibutilide fumarate injection is contraindicated in patients who have previously demonstrated hypersensitivity to ibutilide fumarate or any of the other product components.
Overdosage Information for Ibutilide Fumarate
Acute Experience in Animals Acute overdose in animals results in CNS toxicity; notably, CNS depression, rapid gasping breathing, and convulsions. The intravenous median lethal dose in the rat was more than 50 mg/kg which is, on a mg/m 2 basis, at least 250 times the maximum recommended human dose. Human Experience In the registration trials with ibutilide fumarate injection, four patients were unintentionally overdosed.
The largest dose was 3.4 mg administered over 15 minutes. One patient (0.025 mg/kg) developed increased ventricular ectopy and monomorphic ventricular tachycardia, another patient (0.032 mg/kg) developed AV block—3rd degree and nonsustained polymorphic VT, and two patients (0.038 and 0.020 mg/kg) had no medical event reports. Based on known pharmacology, the clinical effects of an overdosage with ibutilide could exaggerate the expected prolongation of repolarization seen at usual clinical doses.
Medical events (eg, proarrhythmia, AV block) that occur after the overdosage should be treated with measures appropriate for that condition.
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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