Corvert
Generic: IBUTILIDE FUMARATE
Basic Information
Manufacturer
Pharmacia & Upjohn Company LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
b7d717ed-022d-4459-b5e6-098c2a8b7427
Indications & Usage
INDICATIONS AND USAGE CORVERT 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 CORVERT.
The effectiveness of ibutilide has not been determined in patients with arrhythmias of more than 90 days in duration.
Patients with atrial arrhythmias of longer duration are less likely to respond to CORVERT.
The effectiveness of ibutilide has not been determined in patients with arrhythmias of more than 90 days in duration.
Warnings
WARNINGS Proarrhythmia: 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 (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 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.
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 (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 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.
Adverse Reactions
ADVERSE REACTIONS CORVERT Injection was generally well tolerated in clinical trials.
Of the 586 patients with atrial fibrillation or atrial flutter who received CORVERT in phase II/III studies, 149 (25%) reported medical events related to the cardiovascular system, including sustained polymorphic ventricular tachycardia (1.7%) and nonsustained polymorphic ventricular tachycardia (2.7%).
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.
Treatment-Emergent Medical Events With Frequency of More Than 1% and Higher Than That of Placebo Event Placebo N=127 All Ibutilide N=586 Patients Patients n % n % CARDIOVASCULAR Ventricular extrasystoles 1 0.8 30 5.1 Nonsustained monomorphic VT 1 0.8 29 4.9 Nonsustained polymorphic VT — — 16 2.7 Hypotension 2 1.6 12 2.0 Bundle branch block — — 11 1.9 Sustained polymorphic VT — — 10 1.7 AV block 1 0.8 9 1.5 Hypertension — — 7 1.2 QT segment prolonged — — 7 1.2 Bradycardia 1 0.8 7 1.2 Palpitation 1 0.8 6 1.0 Tachycardia 1 0.8 16 2.7 GASTROINTESTINAL Nausea 1 0.8 11 1.9 CENTRAL NERVOUS SYSTEM Headache 4 3.1 21 3.6 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.
Of the 586 patients with atrial fibrillation or atrial flutter who received CORVERT in phase II/III studies, 149 (25%) reported medical events related to the cardiovascular system, including sustained polymorphic ventricular tachycardia (1.7%) and nonsustained polymorphic ventricular tachycardia (2.7%).
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.
Treatment-Emergent Medical Events With Frequency of More Than 1% and Higher Than That of Placebo Event Placebo N=127 All Ibutilide N=586 Patients Patients n % n % CARDIOVASCULAR Ventricular extrasystoles 1 0.8 30 5.1 Nonsustained monomorphic VT 1 0.8 29 4.9 Nonsustained polymorphic VT — — 16 2.7 Hypotension 2 1.6 12 2.0 Bundle branch block — — 11 1.9 Sustained polymorphic VT — — 10 1.7 AV block 1 0.8 9 1.5 Hypertension — — 7 1.2 QT segment prolonged — — 7 1.2 Bradycardia 1 0.8 7 1.2 Palpitation 1 0.8 6 1.0 Tachycardia 1 0.8 16 2.7 GASTROINTESTINAL Nausea 1 0.8 11 1.9 CENTRAL NERVOUS SYSTEM Headache 4 3.1 21 3.6 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.