DIQTA 1.0: Drug-Induced QT Prolongation Atlas

IBUTILIDE FUMARATE

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Most-DIQT concern

Severity Score:5.0

Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF

BOXED WARNING
LIFE-THREATENING ARRHYTHMIAS-APPROPRIATE TREATMENT ENVIRONMENT
Ibutilide fumarate injection 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 injection. These arrhythmias can be reversed if treated promptly (see WARNINGS, PROARRHYTHMIA). It is essential that ibutilide fumarate injection 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.
WARNINGS
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 injection has on cardiac repolarization, but ibutilide fumarate injection 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. Ibutilide fumarate injection is not recommended in patients who have previously demonstrated polymorphic ventricular tachycardia (e.g., torsades de pointes).
PRECAUTIONS
Other drugs that prolong the QT interval
The potential for proarrhythmia may increase with the administration of ibutilide fumarate 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).
DOSAGE AND ADMINISTRATION
The recommended dose based on controlled trials (see CLINICAL PHARMACOLOGY: CLINICAL STUDIES) 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 prolongation of QT or QTc.
CLINICAL PHARMACOLOGY
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.

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24085

Other ADRs

38381537

Odds Ratio = 223.103

Drug Property Information

ATC Code(s):

C01BD05 - ibutilide fumarate

C01BD - "Antiarrhythmics, class III"
C01B - "ANTIARRHYTHMICS, CLASS I AND III"
C01 - CARDIAC THERAPY
C - CARDIOVASCULAR SYSTEM

Active Ingredient:IBUTILIDE FUMARATE

Active Ingredient UNII:9L5X4M5L6I

Drugbank ID:DB00308

PubChem Compound:60753

CTD ID:C067192

PharmGKB:PA449958

CAS Number:122647-31-8

Dosage Form(s):injection, solution

Route(s) Of Administrator:intravenous

Daily Dose:

1.0 mg/day C01BD05

Chemical Structure:

SMILE Code:
CCCCCCCN(CC)CCCC(O)C1=CC=C(NS(C)(=O)=O)C=C1

Reference

1: Efficacy and safety of ibutilide for the conversion of monomorphic atrial tachycardia.

[Eidher Ulrike,Freihoff Fritz,Kaltenbrunner Wilhelm,Steinbach Konrad]
Pacing Clin Electrophysiol,2006 Apr;29(4):358-62. PMID: 16650262

2: Electrophysiology and pharmacology of ibutilide.

[Naccarelli G V,Lee K S,Gibson J K,VanderLugt J]
Am J Cardiol,1996 Oct 17;78(8A):12-6. PMID: 8903270

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