Professional Information
Ibutilide (Systemic)
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VA CLASSIFICATION
Primary: CV300
Commonly used brand name(s): Corvert.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antiarrhythmic{01}—
Indications
Accepted
Arrhythmias, atrial (treatment)—Ibutilide is indicated for the rapid conversion of recent-onset atrial fibrillation or atrial flutter to sinus rhythm.{01} Patients with atrial fibrillation or flutter of long duration are less likely to respond to ibutilide than patients with recent-onset atrial fibrillation or flutter{01} . It is not known if ibutilide is effective in patients with arrhythmias of more than 90 days duration{01} .
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
442.62 {01}
Mechanism of action/Effect:
Ibutilide prolongs atrial and ventricular action potential duration and refractory periods {01}. The mechanism of action may involve activation of a slow, inward, predominately sodium current, or blockage of outward potassium currents. Ibutilide slightly decreases the sinus rate and atrioventricular (AV) conduction {01}. On the electrocardiogram, ibutilide produces a dose-related prolongation of the QT interval {01}. In the Vaughan Williams classification of antiarrhythmics, ibutilide is considered to be a class III agent {01}.
Distribution:
Volume of distribution (Vol D)—Steady-state: 11 L per kg of body weight {01}. Ibutilide is highly distributed in patients with atrial fibrillation or flutter {01}.
Protein binding:
Moderate (40%) {01}.
Biotransformation:
Of eight metabolites, formed primarily by omega oxidation followed by sequential beta oxidation of the heptyl side chain of ibutilide, the omega-hydroxy metabolite appears to be the only active metabolite {01}. Plasma concentrations of the active metabolite are less than 10% of that of ibutilide {01}.
Half-life:
Elimination:
Average, 6 hours (range, 2 to 12 hours) {01}. Ibutilide is cleared rapidly, with a systemic plasma clearance similar to that of hepatic blood flow (about 29 mL per minute per kg of body weight) {01}.
Time to convert to normal sinus rhythm
30 to 90 minutes {01}.
Elimination:
Renal—Approximately 82% (about 7% unchanged) {01}.
Fecal—Approximately 19% {01}.
Precautions to Consider
Carcinogenicity
Studies in animals have not been done to evaluate the carcinogenic potential of ibutilide {01}.
Mutagenicity
Mutagenicity was not detected in the Ames test, mammalian cell forward gene mutation assay, unscheduled DNA synthesis assay, and mouse micronucleus assay {01}.
Pregnancy/Reproduction
Fertility—
No impairment of fertility was detected in a reproductive study in rats {01}.
Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.
Reproduction studies in rats have shown orally administered ibutilide to be teratogenic and embryocidal {01}.
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known whether ibutilide is distributed into breast milk {01}. However, breast-feeding is not recommended {01}.
Pediatrics
Appropriate studies on the relationship of age to the effects of ibutilide have not been performed in the pediatric population {01}. Safety and efficacy have not been established {01}.
Geriatrics
Use of ibutilide in patients with a mean age of 65 has not demonstrated geriatric-specific problems that would limit the usefulness of ibutilide in the elderly {01}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
» Medications that prolong the QT interval{01} , such as:
» Antiarrhythmics, other, such as
Amiodarone{01}
Disopyramide{01}
Procainamide{01}
Quinidine{01}
Sotalol{01}
Antidepressants, tricyclic{01}
Astemizole{01}
Maprotiline{01}
Phenothiazines{01} (concurrent use with ibutilide may have additive effects on prolongation of the QT interval, increasing the risk of cardiac proarrhythmia {01}; it is recommended that class Ia antiarrhythmic agents, such as disopyramide, quinidine, and procainamide, and other class III antiarrhythmic agents, such as amiodarone and sotalol, not be given concurrently with ibutilide {01}; additionally, these antiarrhythmic agents should be withheld for at least five half-lives prior to administration of ibutilide and for 4 hours postinfusion of ibutilide because of their potential for prolonging the refractory period {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to ibutilide{01}
Risk-benefit should be considered when the following medical problems exist
Atrial fibrillation, chronic (increased risk of recurrence after conversion to sinus rhythm {01})
» Bradycardia{01} or
» Hypokalemia{01} or
» Hypomagnesemia{01} (these condition may increase the risk for development of polymorphic ventricular tachycardia {01}; electrolyte abnormalities should be corrected prior to administration of ibutilide {01})
» Congestive heart failure (CHF), history of{01} or
» Low left ventricular ejection fraction, history of{01} (increased risk of sustained polymorphic ventricular tachycardia occurring with use of ibutilide {01}; in clinical trials, 5.4% of patients with a history of CHF experienced sustained polymorphic ventricular tachycardia [compared with 0.8% of patients without a history of CHF who experienced this effect] {01})
Hepatic function impairment{01} or
Renal function impairment{01} (the pharmacokinetics of ibutilide have not been studied in patients with hepatic or renal function impairment {01}; it is recommended that patients with abnormal hepatic function be monitored by telemetry for more than the recommended 4-hour period {01})
» QT interval prolongation, history of{01} or
» Ventricular tachycardia (VT), polymorphic (i.e., torsades de pointes ), history of{01} (ibutilide is not recommended in patients who have a history of QT interval prolongation or polymorphic VT because it can cause potentially fatal arrhythmias, particularly sustained polymorphic ventricular tachycardia {01}; this proarrhythmic effect usually is in association with QT interval prolongation [i.e., torsades de pointes ] but can occur without documented QT interval prolongation {01})
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Electrocardiogram (ECG) (continuous monitoring is recommended during administration and for at least 4 hours following infusion or until the QT interval corrected for heart rate [QTc] has returned to baseline; if any arrhythmic activity is noted, longer monitoring is required {01}; patients with abnormal hepatic function should be monitored for more than the 4-hour period {01})
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent
Cardiovascular effects, including atrioventricular block {01}
bradycardia {01} (slow heartbeat), bundle branch block {01}
hypertension {01}
hypotension {01} (dizziness or lightheadedness when getting up from a lying or sitting position; sudden fainting), nonsustained monomorphic ventricular tachycardia {01}
palpitation {01}
QT segment prolongation {01}
sustained and nonsustained polymorphic ventricular tachycardia {01}
tachycardia {01}
and ventricular extrasystoles {01}
Incidence rare
Cardiovascular effects, including congestive heart failure {01}
idioventricular rhythm {01}
nodal arrhythmia {01}
and supraventricular extrasystoles {01}
renal failure {01}
syncope {01} (fainting)
Note: Cardiovascular side/adverse effects have occurred at therapeutic ibutilide plasma concentrations in approximately 25% of patients in clinical trials. These effects include sustained (1.7%) and nonsustained (2.7%) polymorphic ventricular tachycardia and nonsustained monomorphic ventricular tachycardias (4.9%) {01}. Initial episodes of polymorphic ventricular tachycardia have occurred after the ibutilide infusion was stopped, but usually not more than 40 minutes after the start of the first infusion {01}. Episodes of polymorphic ventricular tachycardia have recurred about 3 hours after the initial infusion of ibutilide, and, in two cases, the ventricular tachycardia degenerated into ventricular fibrillation {01}.
Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
Headache {01}
nausea {01}
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic
Atrioventricular (AV) block (third degree){01}
increased prolongation of repolarization{01}
increased ventricular ectopy{01}
ventricular tachycardia, monomorphic{01}
ventricular tachycardia, nonsustained polymorphic{01}
Treatment of overdose
Treatment is symptomatic and supportive.
General Dosing Information
The continuous infusion of ibutilide should be stopped upon the termination of the presenting arrhythmia or in the event of sustained or nonsustained ventricular tachycardia or marked prolongation of the QT interval or the QT interval corrected for heart rate (QTc) {01}.
The use of ibutilide requires continuous ECG monitoring for at least 4 hours following infusion or until QTc has returned to baseline {01}. Detection of any arrhythmic activity requires longer monitoring {01}. Proper resuscitative cardiovascular equipment and emergency medication for the treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, should be available {01}.
Treatment of adverse effects
Recommended treatment consists of the following: • For treatment of polymorphic ventricular tachycardia—Ibutilide should be discontinued and electrolyte abnormalities, especially potassium and magnesium, should be corrected {01}. Appropriate treatment, such as overdrive cardiac pacing, electrical cardioversion, or defibrillation, should be instituted {01}. Pharmacologic therapy may include magnesium sulfate infusions; however, treatment with antiarrhythmics generally should be avoided {01}.
Parenteral Dosage Forms
IBUTILIDE FUMARATE INJECTION
Usual adult dose
Antiarrhythmic
Patients weighing less than 60 kg: Intravenous infusion, 0.01 mg per kg of body weight administered over a ten-minute period {01}. Dose may be repeated ten minutes after the completion of the first infusion if the arrhythmia does not stop within ten minutes after the end of initial administration {01}.
Patients weighing 60 kg or more: Intravenous infusion, 1 mg administered over a ten-minute period {01}. Dose may be repeated ten minutes after the completion of the first infusion if the arrhythmia does not stop within ten minutes after the end of initial administration {01}.
Usual pediatric dose
Safety and efficacy have not been established {01}.
Strength(s) usually available
U.S.—
0.1 mg per mL (Rx) [Corvert]{01}
Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F). Store vial in carton until ready to use {01}.
Preparation of dosage form:
Ibutilide may be administered undiluted or diluted {01}. Ibutilide may be diluted in 50 mL of 0.9% sodium chloride injection or 5% dextrose injection {01}. The contents of one 10-mL (0.1 mg per mL) vial of ibutilide may be added to a 50-mL infusion bag to form an admixture of approximately 0.017 mg per mL {01}.
Stability:
Ibutilide admixtures are stable for 24 hours at room temperature (15 to 30 °C [59 to 86 °F]), and for 48 hours at refrigerated temperatures (2 to 8 °C [36 to 46 °F]) {01}.
Incompatibilities:
Only polyvinyl chloride plastic bags or polyolefin bags should be used for ibutilide admixtures {01}.
Revised: 01/04/1999
References
- Corvert package insert (Upjohn—US), Rev 1/96, Rec 2/96.
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