VA Class:CV300
Ibutilide fumarate is a class III antiarrhythmic agent.1, 2, 3, 4, 7
Supraventricular Tachyarrhythmias
Ibutilide fumarate is used IV for the rapid conversion of recent-onset atrial fibrillation or atrial flutter to sinus rhythm.1, 7, 300, 301 Ibutilide is considered a drug of choice for pharmacologic cardioversion of atrial fibrillation or flutter.300, 301 Some experts also state that ibutilide may be useful for restoring sinus rhythm or slowing ventricular rate in hemodynamically stable patients with preexcited atrial fibrillation and rapid ventricular response (e.g., Wolff-Parkinson-White syndrome)†, although direct-current (DC) cardioversion is the intervention of choice for this indication when the patient is hemodynamically compromised.300, 301 In addition, IV ibutilide may be considered for the treatment of focal atrial tachycardia†, usually after failure of other preferred therapies (e.g., diltiazem, verapamil, β-adrenergic blocking agents).300 Atrial arrhythmias that are not of recent onset are less likely to respond to the drug, and ibutilide's effectiveness has not been determined in atrial arrhythmias of more than 90 days' duration.1
Ibutilide may cause potentially fatal arrhythmias, particularly sustained polymorphic ventricular tachycardia, usually associated with QT prolongation (i.e., torsades de pointes), but occasionally without documented QT interval prolongation;1, 7 such ventricular arrhythmias that were severe enough to require treatment with DC cardioversion occurred during or within a few hours of ibutilide fumarate administration in 1.7% of patients in clinical trials.1, 10 The risk of torsades de pointes may be increased in patients with bradycardia, varying heart rate, or hypokalemia.1 In addition, patients with a history of congestive heart failure or low ventricular ejection fraction appear to have a higher incidence of sustained polymorphic ventricular tachycardia.1 Therefore, it is essential that the drug be administered in a setting of continuous ECG monitoring and by personnel trained in the identification and treatment of acute ventricular arrhythmias, especially polymorphic ventricular tachycardia.1 In addition, the manufacturer states that patients with atrial fibrillation of more than 2 to 3 days' duration must be adequately anticoagulated, generally for at least 2 weeks before administration of ibutilide.1 Conversion of atrial fibrillation or flutter to normal sinus rhythm may be associated with embolism, particularly when the arrhythmia has been present for more than 48 hours, unless the patient is adequately anticoagulated.301 (See Uses: Cardioversion of Atrial Fibrillation/Flutter, in Heparin 20:12.04.16.) Ibutilide is not recommended for use in patients with a history of polymorphic ventricular tachycardia (e.g., torsades de pointes).1
Chronic atrial fibrillation that has been converted by treatment such as ibutilide to sinus rhythm has a strong tendency to revert, and therapy required to maintain sinus rhythm is associated with risks.1 Therefore, patients for whom parenteral ibutilide therapy is considered should be selected carefully such that the expected benefits of conversion to sinus rhythm and continuous treatment to maintain it outweigh the immediate risks associated with use of ibutilide and the risks of maintenance therapy, and that they are likely to offer an advantage compared with alternative management methods for atrial flutter or fibrillation.1
Because of their potential to prolong refractoriness, class Ia (e.g., disopyramide, quinidine, procainamide) or III (e.g., amiodarone, sotalol) antiarrhythmic agents should not be administered concomitantly with, or within 4 hours after completion of, ibutilide administration.1 In clinical trials, class I or III agents were withheld for at least 5 half-lives prior to, and 4 hours after completion of, ibutilide infusion, but thereafter were permitted at the clinician's discretion.1 The possibility that drugs that prolong the QT interval (e.g., certain antihistamines such as terfenadine [no longer commercially available in the US] and astemizole [no longer commercially available in the US], phenothiazines, tricyclic or tetracyclic antidepressants) may potentiate the proarrhythmic effects of ibutilide should be considered.1
Current evidence of safety and efficacy of ibutilide in the acute termination of recent-onset atrial arrhythmias is based on several placebo-controlled studies that included hundreds of patients with atrial flutter and/or fibrillation of 3 hours' to 90 days' duration and in one active treatment (i.e., sotalol)-controlled study that included 319 patients with such arrhythmias of 3 hours' to 45 days' duration.1, 7, 10 In one study comparing single doses of ibutilide and sotalol, conversion to sinus rhythm reportedly occurred in 53 or 70% of patients with atrial flutter, and in 22 or 43% of patients with atrial fibrillation receiving a 1 or 2 mg of ibutilide fumarate IV, respectively;1, 7, 10 conversion to sinus rhythm occurred in 18% of those with atrial flutter, and 10% of patients with atrial fibrillation receiving 1.5 mg/kg of sotalol hydrochloride, respectively.1, 7 In another placebo-controlled study, 14, 30, 58, or 55 % of patients with atrial flutter, and 10, 35, 32, or 40% of those with atrial fibrillation reportedly experienced conversion to sinus rhythm after receiving a single IV ibutilide fumarate dose of 0.005, 0.01, 0.015, or 0.025 mg/kg, respectively.1, 10 In the other placebo-controlled study in which patients received up to 2 doses of ibutilide (i.e., an initial IV ibutilide fumarate dose of 1 mg followed by a second IV dose of either 0.5 or 1 mg), 48 or 63% of eligible patients with atrial flutter and 38 or 25% of those with atrial fibrillation receiving a total dose of 1.5 or 2 mg, respectively, converted to sinus rhythm.1, 10
In a double-blind, placebo-controlled, dose-ranging study in patients with atrial flutter or fibrillation of 1 hour's to 3 days' duration that developed 1-7 days after coronary bypass graft or valvular surgery, 56, 61, or 78% of patients with atrial flutter and 28, 42, or 44% of those with atrial fibrillation treated with two 10-minute IV ibutilide fumarate infusions (10 minutes apart) of 0.25, 0.5, or 1 mg (each), respectively, reportedly experienced conversion to sinus rhythm at 90 minutes.1, 11 Four or 20% of patients with atrial flutter or atrial fibrillation, respectively, reportedly experienced conversion to sinus rhythm after receiving two 10-minute infusions of placebo.1, 11 The mean time to conversion to sinus rhythm decreased as the dose of ibutilide fumarate was increased.11 In addition, 53 or 72% of patients who experienced conversion to sinus rhythm after receiving 10-minute IV ibutilide fumarate infusions of 0.5 or 1 mg (each), respectively, remained in sinus rhythm for 24 hours without the use of additional antiarrhythmic agents.1, 11
Direct-current (DC) cardioversion often is the treatment of choice for patients with atrial flutter and/or fibrillation,8, 9 and up to 70-95% of such arrhythmias may initially be converted to sinus rhythm by DC cardioversion.7, 8 However, while ibutilide also can effectively convert such arrhythmias in many patients, the role of the drug, particularly in light of its proarrhythmic potential, relative to DC cardioversion for acute conversion of atrial flutter or fibrillation to sinus rhythm remains to be established.7
Ibutilide fumarate is administered by IV infusion.1 The commercially available injection containing 0.1 mg (100 mcg) of the drug per mL may be administered undiluted.1 Alternatively, ibutilide fumarate injection may be diluted prior to administration by adding the contents of a 10-mL vial of the drug to 50 mL of 0.9% sodium chloride or 5% dextrose injection, resulting in a final ibutilide fumarate concentration of about 0.017 mg/mL (17 mcg/mL).1 Undiluted or diluted infusion solutions of ibutilide should be administered IV over 10 minutes.1
Dosage of ibutilide fumarate is expressed in terms of the hemifumarate salt.1 Safety and efficacy of the drug in children younger than 18 years of age have not been established.1
Proarrhythmic effects of ibutilide must be anticipated, and the drug should be administered only by skilled personnel in a setting in which proper equipment (e.g., cardiac monitors, intracardiac pacing, cardioverter/defibrillator) and therapy for sustained ventricular tachycardia such as polymorphic ventricular tachycardia are available during and after administration of ibutilide.1 In clinical trials, many initial episodes of such proarrhythmic effects were observed after completion of the ibutilide infusion but no later than 40 minutes after initiation of the infusion.1 However, instances of recurrent polymorphic ventricular tachycardia occurring about 3 hours after the initial infusion also were observed in these trials.1 Therefore, patients should be observed with continuous ECG monitoring for at least 4-6 hours after completion of ibutilide administration or until the corrected QT interval (QTc) has returned to baseline.1 Longer monitoring may be required if any arrhythmic activity is noted.1 Most cases of ventricular tachycardia observed in clinical trials responded to cardiac pacing and magnesium sulfate infusions, although degeneration to ventricular fibrillation requiring immediate defibrillation also can occur.1 If polymorphic ventricular tachycardia occurs in patients receiving ibutilide, the manufacturer recommends that the drug be discontinued and that electrolyte abnormalities (especially potassium and magnesium) be corrected and overdrive cardiac pacing, electrical cardioversion, and/or defibrillation be undertaken as necessary.1 Treatment with antiarrhythmic drugs generally should be avoided, although pharmacologic intervention with magnesium sulfate infusions may prove beneficial.1
Supraventricular Tachyarrhythmias
For the acute management of recent-onset atrial flutter or fibrillation in adults weighing 60 kg or more, 1 mg of ibutilide fumarate should be given initially;1, 7 for adults weighing less than 60 kg, an initial dose of 0.01 mg/kg (10 mcg/kg) is recommended.1, 7 If the arrhythmia does not terminate within 10 minutes after completion of the initial infusion, the initial dose may be repeated 10 minutes after completion of such infusion.1, 7 In a clinical study comparing ibutilide with sotalol, 2 mg of ibutilide fumarate administered as a single infusion to patients weighing more than 60 kg also was effective in terminating atrial flutter or fibrillation.1 Results of a clinical study in patients who developed atrial flutter and/or fibrillation after undergoing coronary bypass graft or valvular surgery indicate that lower doses (i.e., 1 or 2 infusions of 0.5 mg each [0.005 mg/kg per dose for patients weighing less than 60 kg]) was effective in producing conversion to sinus rhythm in these patients.1 The value and patient tolerance of additional doses of the drug have not been established and currently are not recommended by the manufacturer.1, 10
Clinical studies of ibutilide did not include sufficient numbers of patients younger than 65 years of age to determine whether they respond differently than older patients.1 While other clinical experience has not revealed age-related differences in response, dosage of ibutilide should be selected with caution for geriatric patients, usually initiating therapy at the low end of the dosing range.1 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or other drug therapy observed in geriatric patients also should be considered.1
Dosage in Renal and Hepatic Impairment
The safety, efficacy, and pharmacokinetics of ibutilide fumarate in patients with renal and/or hepatic impairment have not been established.1 The manufacturer states that it is unlikely that dosing adjustments based on renal or hepatic function are necessary.1 Nonetheless, because the drug undergoes substantial hepatic clearance, the manufacturer recommends that patients with abnormal liver function undergo continuous ECG monitoring that extends beyond the usual 4-hour period recommended for other patients.1
Ibutilide fumarate is a class III antiarrhythmic agent.1, 2, 3, 4, 7 Like sotalol, ibutilide is a methanesulfonanilide derivative,1, 2, 3 and exhibits electrophysiologic effects characteristic of class III antiarrhythmic agents (e.g., prolongs repolarization and refractoriness without affecting conduction).1, 2, 3 However, unlike sotalol, ibutilide lacks β-adrenergic blocking activity.2, 3
Ibutilide fumarate prolongs repolarization of cardiac tissue by prolonging the action potential duration (APD) and effective refractory period (ERP) in both atrial and ventricular cardiac tissue.1, 2, 3, 4, 7 In vitro studies of its electrophysiologic effects suggest that the antiarrhythmic action of ibutilide may result at least in part from activation of a slow, predominantly sodium, inward current at very low (i.e., less than nanomolar) concentrations,1, 3, 5, 6 and/or from inhibition of the rapidly activating component of the potassium channel involved in repolarization of cardiac cells (i.e., the rapidly activated component of the delayed rectifier potassium current IKr) at higher (100-fold) concentrations.1, 2, 3, 4, 5, 6 However, the exact mechanism of action of the drug remains to be more fully elucidated.7 Like other class III antiarrhythmics, effects on cardiac repolarization induced by the drug can result in proarrhythmic effects (principally torsades de pointes).1, 3 (See Uses.)
Ibutilide appears to be more selective in its cellular actions than some other currently available class III antiarrhythmic agents (e.g., amiodarone, sotalol), and therefore has been referred to as a “pure” class III antiarrhythmic.3 Ibutilide has negligible effects on heart rate, cardiac contractility, or blood pressure.3
Additional Information
SumMon® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the labeling be consulted for detailed information on the usual cautions, precautions, and contraindications.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion | 1 mg (0.1 mg/mL)* | ||
Ibutilide Fumarate Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. Pharmacia & Upjohn Company. Corvert® (ibutilide fumarate) injection for intravenous infusion only prescribing information. Kalamazoo, MI; 2002 Jul.
2. Yang T, Snyders DJ, Roden DM. Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Circulation . 1995: 91:1799-806.
3. Colatsky TJ, Argentieri. Potassium channel blockers as antiarrhythmic drugs. Drug Dev Res . 1994; 33:235-49.
4. Lynch JJ, Baskin EP, Nutt EM et al. Comparison of binding to rapidly activating delayed rectifier K+ channel, IKr , and effects on myocardial refractoriness for class III antiarrhythmic agents. J Cardiovasc Pharmacol . 1995; 25:336-40. [PubMed 7752661]
5. Lee KS, Gibson JK. Unique ionic mechanism of action of ibutilide on freshly isolated heart cells. Circulation . 1995; 92:2755-6. [PubMed 7586381]
6. Yang T, Snyders DJ, Roden DM. Unique ionic mechanism of action of ibutilide on freshly isolated heart cells: Response. Circulation . 1995; 92:2756-7.
7. Anonymous. Ibutilide. Med Lett Drugs Ther . 1996; 38:38. [PubMed 8606678]
8. Zipes DP. Management of cardiac arrhythmias: Pharmacological, electrical, and surgical techniques. In: Braunwald E, ed. Heart disease. A textbook of cardiovascular medicine. 4th ed. Philadelphia, PA: W. B. Saunders; 1992:628-66.
9. Emergency Cardiac Care Committee and Subcommittees, American Heart Association. Guidelines for cardiopulmonary resuscitation and emergency cardiac care. JAMA . 1992; 268:2171-302. [PubMed 1404767]
10. Pharmacia & Upjohn Company, Kalamazoo, MI: Personal communication.
11. Howard PA. Ibutilide: an antiarrhytmic agent for the treatment of atrial fibrillation or flutter. Ann Pharmacother . 1999; 33:38-47. [PubMed 9972384]
300. Page RL, Joglar JA, Caldwell MA et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol . 2016; 67:e27-e115.
301. January CT, Wann LS, Alpert JS et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol . 2014; 64:e1-76. [PubMed 24685669]