Ibutilide
CHOICE OF PATIENTS
Patients with chronic atrial fibrillation have a strong tendency to revert after conversion to sinus rhythm and treatments to maintain sinus rhythm carry risks. Patients to be treated with CORVERT, therefore, should be carefully selected such that the expected benefits of maintaining sinus rhythm outweigh the immediate risks of CORVERT, and the risks of maintenance therapy, and are likely to offer an advantage compared with alternative management.

# Atrial Fibrillation or Atrial Flutter
- Dosing information
- The recommended dose based on controlled trials is outlined in the Table below. Ibutilide infusion should be stopped as soon as the presenting arrhythmia is terminated or in the event of sustained or nonsustained ventricular tachycardia, or marked QT prolongation or QTc.
- In a trial comparing ibutilide and sotalol, 2 mg ibutilide fumarate administered as a single infusion to patients weighing more than 60 kg was also effective in terminating atrial fibrillation or atrial flutter.
- In the post-cardiac surgery study, one or two intravenous infusions of 0.5 mg (0.005 mg/kg per dose for patients weighing less than 60 kg) was effective in terminating atrial fibrillation or atrial flutter.
- 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. Skilled personnel and proper equipment, Proarrhythmia), such as a cardioverter/defibrillator, and medication for treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, must be available during administration of CORVERT and subsequent monitoring of the patient.
- CORVERT Injection may be administered undiluted or diluted in 50 mL of diluent. CORVERT may be added to 0.9% Sodium Chloride Injection or 5% Dextrose Injection before infusion. The contents of one 10 mL vial (0.1 mg/mL) may be added to a 50 mL infusion bag to form an admixture of approximately 0.017 mg/mL ibutilide fumarate. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

# Wolff-Parkinson-White syndrome
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) and Heart Rhythm Society (HRS)
- Class of Recommendation: Class I
- Level of Evidence: Level C
- Dosing Information
- 1 mg IV over 10 minutes; repeat 1 mg when needed
- Developed by: American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) and Heart Rhythm Society (HRS)
- Class of Recommendation: Class IIb
- Level of Evidence: Level B
- Dosing Information
- 1 mg IV over 10 minutes; repeat 1 mg when needed
- Dosing Information
- Loading dosage: 0.005-0.02 mg/kg
- Maintenance doses: 0.001-0.004 mg/kg. 
- Like other antiarrhythmic agents, CORVERT 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 CORVERT has on cardiac repolarization, but CORVERT 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 >440 msec were not usually allowed to participate, and serum potassium had to be above 4.0 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. CORVERT 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 CORVERT developed sustained polymorphic ventricular tachycardia requiring cardioversion. In these clinical trials, many initial episodes of polymorphic ventricular tachycardia occurred after the infusion of CORVERT 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.
- 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 CORVERT. Before treatment with CORVERT, 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.
- Class Ia antiarrhythmic drugs (Vaughan Williams Classification), such as disopyramide, quinidine, and procainamide, and other class III drugs, such as amiodarone and sotalol, should not be given concomitantly with CORVERT Injection or within 4 hours postinfusion because of their potential to prolong refractoriness. In the clinical trials, class I or other class III antiarrhythmic agents were withheld for at least 5 half-lives prior to ibutilide infusion and for 4 hours after dosing, but thereafter were allowed at the physician's discretion.
- The potential for proarrhythmia may increase with the administration of CORVERT Injection to patients who are being treated with drugs that prolong the QT interval, such as phenothiazines, tricyclic antidepressants, tetracyclic antidepressants, and certain antihistamine drugs (H1 receptor antagonists).
- Of the nine (1.5%) ibutilide-treated patients with reports of reversible heart block, five had first degree, three had second degree, and one had complete heart block.
- Other clinically important adverse events with an uncertain relationship to CORVERT include the following (0.2% represents one patient): sustained monomorphic ventricular tachycardia (0.2%), nonsustained monomorphic ventricular tachycardia (4.9%), AV block (1.5%), bundle branch block (1.9%), ventricular extrasystoles (5.1%), supraventricular extrasystoles (0.9%), hypotension/postural hypotension (2.0%), bradycardia/sinus bradycardia (1.2%), nodal arrhythmia (0.7%), congestive heart failure (0.5%), tachycardia/sinus tachycardia/supraventricular tachycardia (2.7%), idioventricular rhythm (0.2%), syncope (0.3%), and renal failure (0.3%). The incidence of these events, except for syncope, was greater in the group treated with CORVERT than in the placebo group.
- Another adverse reaction that may be associated with the administration of CORVERT was nausea, which occurred with a frequency greater than 1% more in ibutilide-treated patients than those treated with placebo.
- The medical events reported for more than 1% of the placebo- and ibutilide-treated patients are shown in the following Table.
- In the post-cardiac surgery study, 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.
- 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. Coadministration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials.
- Calcium channel blocking agents
- Coadministration 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
- Coadministration of beta-adrenergic blocking agents did not have any effect on either the safety or efficacy of ibutilide in the clinical trials.
In 285 patients with atrial fibrillation or atrial flutter who were treated with CORVERT, the clearance of ibutilide was independent of renal function, as assessed by creatinine clearance (range 21 to 140 mL/min).
- 5% Dextrose Injection
- 0.9% Sodium Chloride Injection
- The following intravenous solution containers are compatible with admixtures of CORVERT Injection (0.1 mg/mL):
- polyvinyl chloride plastic bags
- polyolefin bags
- Admixtures of the product, with approved diluents, are chemically and physically stable for 24 hours at room temperature (15 to 30 C or 59 to 86 F) and for 48 hours at refrigerated temperatures (2 to 8C or 36 to 46F). Strict adherence to the use of aseptic technique during the preparation of the admixture is recommended in order to maintain sterility.
- 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/m2 basis, at least 250 times the maximum recommended human dose.
- In the registration trials with CORVERT 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 block3rd 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.
- CORVERT 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 C22H38N2O5S, 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:
- 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.
- In healthy male volunteers, about 82% of a 0.01 mg/kg dose of  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 -oxidation followed by sequential -oxidation of the heptyl side chain of ibutilide. Of the eight metabolites, only the -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.
- 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 evaluatedthe 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 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%).
- 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.
- In a double-blind, parallel group study, 302 patients with atrial fibrillation (n=201) or atrial flutter (n=101) that occurred 1 to 7 days after coronary artery bypass graft or valvular surgery and lasted 1 hour to 3 days were randomized to receive two 10-minute infusions of placebo, or 0.25, 0.5 or 1 mg of ibutilide fumarate. Among patients with atrial flutter, conversion rates at 1.5 hours were: placebo, 4%; 0.25 mg ibutilide fumarate, 56%; 0.5 mg ibutilide fumarate, 61%; and 1 mg ibutilide fumarate, 78%. Among patients with atrial fibrillation, conversion rates at 1.5 hours were: placebo, 20%; 0.25 mg ibutilide fumarate, 28%; 0.5 mg ibutilide fumarate, 42%, and 1 mg ibutilide fumarate, 44%. The majority of patients (53% and 72% in the 0.5-mg and 1-mg dose groups, respectively) converted to sinus rhythm remained in sinus rhythm for 24 hours. Patients were not given other antiarrhythmic drugs within 24 hours of ibutilide fumarate infusion in this study.
- Single-dose 10 mL vial, 1 mg /10 mL (0.1 mg/mL)            NDC 0009-3794-01
-  Wood MA, Stambler BS, Ellenbogen KA, Gilligan DM, Perry KT, Wakefield LK et al. (1998) Suppression of inducible ventricular tachycardia by ibutilide in patients with coronary artery disease. Ibutilide Investigators. Am Heart J 135 (6 Pt 1):1048-54. PMID: 9630110