Ibutilide Fumarate

Class: Class III Antiarrhythmics
VA Class: CV300
Chemical Name: (±)-N-[4-[4-(ethylheptylamino)-1-hydroxybutyl]phenyl]-methanesulfonamide (E)-2-butenedioate (2:1) (salt)
Molecular Formula: C₂₀H₃₆N₂O₃S•½C₄H₄ O₄
CAS Number: 122647-32-9
Brands: Corvert

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  May cause potentially fatal arrhythmias.^{1 7} 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 VT are available during and after drug administration.¹ (See Arrhythmogenic Effects under Cautions.)

  
  


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  Adequate anticoagulation recommended for patients with atrial fibrillation of more than 2–3 days’ duration.¹

  
  


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  Select patients carefully such that the expected benefits of conversion to sinus rhythm outweigh the immediate risks of ibutilide therapy.¹ Use ibutilide when it is likely to offer an advantage compared with alternative management methods for atrial flutter or fibrillation.¹ (See Supraventricular Tachyarrhythmias under Uses.)

  
  

Introduction

Class III antiarrhythmic agent;^{1 2 3 4 7} a methanesulfonanilide derivative.^{1 2 3}

Uses for Ibutilide Fumarate

Supraventricular Tachyarrhythmias

Used for the rapid conversion of recent-onset (≤48 hours’ duration) atrial flutter or fibrillation to sinus rhythm in patients with normal cardiac function.^{1 7 12}

Rhythm control in atrial flutter or fibrillation† in patients with preserved ventricular function when calcium-channel blocking agents or β-adrenergic blocking agents not effective.¹²

Used for rapid conversion of recent-onset (≤48 hours’ duration) atrial flutter or fibrillation to sinus rhythm in patients with Wolff-Parkinson-White syndrome† and preserved ventricular function; direct-current (DC) cardioversion is the intervention of choice for this indication.¹²

Atrial arrhythmias that are not of recent onset are less likely to respond to the drug.¹ Efficacy not determined in atrial arrhythmias of >90 days’ duration.¹

Ibutilide Fumarate Dosage and Administration

General

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  Adjust dosage carefully according to individual requirements and response.¹

  
  


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  Cardiac monitoring equipment, intracardiac pacing facilities, a cardioverter/defibrillator, and therapy for sustained VT (e.g., polymorphic VT) must be available during and after ibutilide administration.¹

  
  


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  Continuous ECG monitoring recommended for at least 4 hours after completion of ibutilide administration or until the corrected QT interval (QT_c) has returned to baseline.¹ May require longer monitoring if arrhythmic activity is noted.¹

  
  

Administration

Administer by IV infusion.¹

IV Administration

May be administered undiluted or diluted.¹

Dilution

Add the contents of a 10-mL vial of ibutilide fumarate to 50 mL of 0.9% sodium chloride or 5% dextrose injection, resulting in a final concentration of about 0.017 mg/mL (17 mcg/mL).¹

Rate of Administration

Administer over 10 minutes.¹

Dosage

Available as ibutilide fumarate; dosage expressed in terms of the hemifumarate salt.¹

Adults

Supraventricular Tachyarrhythmias

Atrial Flutter and/or Fibrillation

IV

Adults weighing ≥60 kg: Initially, 1 mg.^{1 7 12} Alternatively, 2 mg has been used.¹

Adults weighing <60 kg: Initially, 0.01 mg/kg (10 mcg/kg).^{1 7 12}

If arrhythmia does not terminate within 10 minutes after completion of initial infusion, repeat initial dose.^{1 7 12} Value and patient tolerance of additional doses not established.^{1 10}

Atrial Flutter and/or Fibrillation following Coronary Bypass Graft or Valvular Surgery

IV

Adults weighing ≥60 kg: 1 or 2 infusions of 0.5 mg each (given 10 minutes apart) have been used.^{1 7}

Adults weighing <60 kg: 1 or 2 infusions of 0.005 mg/kg (5 mcg/kg) each (given 10 minutes apart) have been used.^{1 7}

Prescribing Limits

Adults

Supraventricular Tachyarrhythmias

IV

Adults weighing ≥60 kg: Maximum 2 mg (e.g., 2 infusions of 1 mg each given 10 minutes apart).¹ Value and patient tolerance of additional doses not established.^{1 10}

Adults weighing <60 kg: Maximum 0.02 mg/kg (2 infusions of 0.01 mg/kg each given 10 minutes apart).¹ Value and patient tolerance of additional doses not established.^{1 10}

Special Populations

Hepatic Impairment

Dosage adjustment unlikely to be required.¹

Renal Impairment

Dosage adjustment unlikely to be required.¹

Geriatric Patients

Select dosage with caution, usually initiating therapy at the low end of the dosing range because of age-related decrease in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Ibutilide Fumarate

Contraindications

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  History of polymorphic VT (e.g., torsades de pointes).¹ (See Arrhythmogenic Effects under Cautions.)

  
  


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  Known hypersensitivity to ibutilide or any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Arrhythmogenic Effects

May cause serious or potentially fatal ventricular arrhythmias, particularly sustained polymorphic VT, usually associated with QT prolongation (i.e., torsades de pointes).^{1 7}

Possible increased risk of torsades de pointes in patients with a history of CHF, low left ventricular ejection fraction, bradycardia, varying heart rate, or hypokalemia.¹ Use not recommended in patients with a history of sustained polymorphic VT that required cardioversion.¹

If polymorphic VT occurs, discontinue the drug, correct electrolyte abnormalities (especially potassium and magnesium), and undertake overdrive cardiac pacing, electrical cardioversion, and/or defibrillation as necessary.¹ Generally should avoid treatment with antiarrhythmic drugs, although magnesium sulfate infusions may be beneficial.¹

Metabolic Effects

Hypokalemia or hypomagnesemia may increase the risk of torsades de pointes.¹ Evaluate patient for potassium or magnesium deficiency; if present, correct deficiency prior to initiation of therapy.¹ (See Arrhythmogenic Effects under Cautions.)

General Precautions

Effects on Cardiac Conduction

Possible AV block, bundle branch block, or bradycardia.¹

Risk of torsades de pointes is thought to increase in part with bradycardia or a varying heart rate.¹ (See Arrhythmogenic Effects under Cautions.)

Specific Populations

Pregnancy

Category C.¹

Lactation

Distribution into milk not studied.¹ Use not recommended.¹

Pediatric Use

Safety and efficacy in children <18 years of age not established.¹

Geriatric Use

No differences in efficacy or safety parameters relative to younger adults.¹ However, use with caution due to the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.¹ (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Extend continuous ECG monitoring beyond the usual 4-hour period recommended for other patients.¹

Common Adverse Effects

Generally well tolerated.¹ Adverse events affecting the cardiovascular system (e.g., arrhythmogenic affects, affects on cardiac conduction, palpitation, hypotension, hypertension), nausea, and headache reported in ≤5.1% of patients.¹

Interactions for Ibutilide Fumarate

Drugs Affecting QT Interval

Potential pharmacodynamic interaction (increased risk of ventricular arrhythmias).¹

Specific Drugs

Drug	Interaction	Comments
Amiodarone	Possible potentiation of refractoriness and increased risk of arrhythmias1	Class Ia or III antiarrhythmic agents should not be administered concomitantly with, or within 4 hours after completion of, ibutilide administration1
Antidepressants, tricyclic or tetracyclic	Possible increased risk of ventricular arrhythmias1
Antihistamines (H1-receptor antagonists)	Possible increased risk of ventricular arrhythmias1
β-adrenergic blocking agents	Pharmacokinetic interaction unlikely1
Calcium-channel blocking agents	Pharmacokinetic interaction unlikely1
Digoxin	Pharmacokinetic interaction unlikely1
Disopyramide	Possible potentiation of refractoriness and increased risk of arrhythmias1	Class Ia or III antiarrhythmic agents should not be administered concomitantly with, or within 4 hours after completion of, ibutilide administration1
Phenothiazines	Possible increased risk of ventricular arrhythmias1
Procainamide	Possible potentiation of refractoriness and increased risk of arrhythmias1	Class Ia or III antiarrhythmic agents should not be administered concomitantly with, or within 4 hours after completion of, ibutilide administration1
Quinidine	Possible potentiation of refractoriness and increased risk of arrhythmias1	Should not be administered concomitantly with, or within 4 hours after completion of, ibutilide administration1

Ibutilide Fumarate Pharmacokinetics

Distribution

Extent

Following IV administration, rapidly cleared and widely distributed.¹ Steady-state volume of distribution is 11 L/kg.¹

Distribution appears to be one of the primary mechanisms for termination of pharmacologic effects.¹

Plasma Protein Binding

Approximately 40%.¹

Elimination

Metabolism

Extensively metabolized to numerous metabolites including one active metabolite.¹ Undergoes substantial hepatic clearance.¹

Elimination Route

Excreted in urine (about 82%) and feces (about 19%) principally as metabolites.¹

Half-life

Averages about 6 hours.¹

Special Populations

Clearance is independent of renal function.¹

Pharmacokinetics not affected by patient age or gender.¹

Stability

Storage

Parenteral

Solution for Injection

20–25°C.¹ Diluted solutions are stable for 24 hours at 15–30°C or for 48 hours under refrigeration (2–8°C).¹

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Compatible with polyvinyl chloride plastic IV solution bags or polyolefin IV solution bags.¹

ActionsActions

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  Exhibits electrophysiologic effects characteristic of class III antiarrhythmic agents (e.g., prolongs repolarization and refractoriness without appreciably affecting conduction).^{1 2 3}

  
  


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  More selective in its cellular actions than some other class III antiarrhythmic agents (e.g., amiodarone, sotalol).³

  
  


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  Prolongs the action potential duration and effective refractory period (ERP) in both atrial and ventricular cardiac tissue.^{1 2 3 4 7 12}

  
  


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  Delays repolarization by activating a slow, predominantly sodium, inward current.^{1 3 5 6}

  
  


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  Produces dose-related prolongation of the QT interval, which is thought to be associated with the antiarrhythmic activity.¹ (See Arrhythmogenic Effects under Cautions.)

  
  


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  Negligible effects on heart rate, cardiac contractility, or BP.³ Lacks β-adrenergic blocking activity.^{2 3 12}

  
  

Advice to Patients

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  Importance of patients informing clinicians of existing or contemplated therapy, including prescription and OTC drugs, dietary supplements, and/or herbal products, as well as any concomitant illnesses.¹

  
  


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  Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.¹

  
  


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  Importance of advising patients of other important precautionary information.¹ (See Cautions.)

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Ibutilide Fumarate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for IV infusion	1 mg (0.1 mg/mL)	Corvert	Pfizer

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions August 2009. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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. [IDIS 421290] [PubMed 9972384]

12. The American Heart Association. Guidelines 2005 for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2005; 112(Suppl I): IV1-211.

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