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IBUTILIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ibutilide for injection is an antiarrhythmic drug with predominantly class III (cardiac potential prolongation) properties according to the Vaughan Williams Classification. Ibutilide delays repolarization by activation of a slow, inward current (predominantly sodium), leading to a prolongation of atrial and ventricular action potential duration and refractory periods.

Specific Substances

    1) U-70226E
    2) CAS 122647-31-8 (ibutilide)
    3) CAS 122647-32-9 (ibutilide fumarate)
    1.2.1) MOLECULAR FORMULA
    1) IBUTILIDE FUMARATE: C22H38N2O5S

Available Forms Sources

    A) FORMS
    1) Ibutilide fumarate is available 10 mL vials (1 mg/10 mL) in acetate-buffered (pH 4.6) isotonic solution (Prod Info ibutilide fumarate IV injection, 2009).
    B) USES
    1) Ibutilide fumarate for injection is used for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm (Prod Info ibutilide fumarate IV injection, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ibutilide fumarate is used for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm.
    B) PHARMACOLOGY: Ibutilide for injection is an antiarrhythmic drug with predominantly class III (cardiac potential prolongation) properties. It delays repolarization by activation of a slow, inward current (predominantly sodium), leading to a prolongation of atrial and ventricular action potential duration and refractory periods.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Nausea has been reported in ibutilide-treated patients with twice the incidence of controls. TORSADES de POINTES: Ibutilide may induce or worsen ventricular dysrhythmias, producing life threatening polymorphic ventricular tachycardia. Patients with a history of torsades de pointes, prolonged QTc (greater than 440 msec), and serum potassium below 4.0 mEq/L are at increased risk of developing ventricular dysrhythmias.
    E) WITH POISONING/EXPOSURE
    1) Overdose experience is limited. Effects reported include nausea, QT prolongation, ventricular ectopy, ventricular tachycardia, torsades de pointes, and complete heart block.
    0.2.20) REPRODUCTIVE
    A) Ibutilide is classified as FDA pregnancy category C. In animal studies, there was evidence of teratogenicity.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturers do not report any carcinogenic potential of ibutilide in humans.

Laboratory Monitoring

    A) Monitor vital signs.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor serum electrolytes, including potassium and magnesium (correct underlying abnormalities).

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat patients with torsades de pointes with IV magnesium sulfate; correct electrolyte abnormalities; overdrive pacing may be necessary.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not necessary as ibutilide is administered intravenously.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias.
    E) ANTIDOTE
    1) None.
    F) VENTRICULAR DYSRHYTHMIAS
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia and hypomagnesemia). Lidocaine may be used if dysrhythmias persist.
    G) TORSADES DE POINTES
    1) Therapeutic doses of ibutilide may cause prolongation of the QT interval. Concomitant use of ibutilide and other drugs that prolong the QT interval may increase the risk of torsades de pointes. Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium, atrial overdrive pacing may be necessary. Correct electrolyte abnormalities (hypomagnesemia, hypokalemia, hypocalcemia). MAGNESIUM SULFATE/DOSE: ADULTS: 1 to 2 g IV (mixed in 50 to 100 mL D5W) infused over 5 min, repeat 2 g bolus and begin infusion of 0.5 to 1 g/hr if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 min. OVERDRIVE PACING: Begin at 130 to 150 beats/min, decrease as tolerated. Rates of 100 to 120 beats/min may terminate torsades. Avoid class Ia (quinidine, disopyramide, procainamide), class Ic (flecainide, encainide, propafenone) and most class III antidysrhythmics (N-acetylprocainamide, sotalol).
    H) ENHANCED ELIMINATION PROCEDURE
    1) Although no studies report the use of dialysis, it is unlikely to remove significant amounts of ibutilide because of its large volume of distribution.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management, and ibutilide is generally only used in the hospital setting.
    2) OBSERVATION CRITERIA: Any patient with ibutilide overdose should be observed in an ICU setting with continuous ECG monitoring and frequent monitoring of vital signs.
    3) ADMISSION CRITERIA: Patients should be admitted to an intensive care setting for further observation.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    K) PHARMACOKINETICS
    1) Protein binding: approximately 40%. Vd: 11 L/kg. Renal excretion: about 82% of a 0.01 mg/kg dose was excreted in the urine (about 7% of the dose as parent drug). Feces: about 19% of the dose (0.01 mg/kg) excreted in the feces. Elimination half-life: range from 2 to 12 hours (average, 6 hours).
    L) DIFFERENTIAL DIAGNOSIS
    1) Overdose with block-blockers, digoxin; intrinsic cardiac disease.

Range Of Toxicity

    A) TOXICITY: Five cases of acute overdoses (0.020 to 0.038 mg/kg) have been reported without deaths. The largest dose was 3.4 mg administered over 15 minutes. One patient developed increased ventricular ectopy and monomorphic ventricular tachycardia after receiving 0.025 mg/kg of ibutilide. Another patient developed complete heart block and nonsustained polymorphic VT after receiving 0.032 mg/kg of ibutilide. The remaining two patients did not develop any adverse effects after receiving 0.038 and 0.020 mg.kg of ibutilide, respectively.
    B) THERAPEUTIC DOSES: ADULTS: WEIGHT 60 KG (132 POUNDS) OR GREATER: 1 mg over 10 minutes. WEIGHT LESS THAN 60 KG (132 POUNDS): 0.1 mL/kg (0.01 mg/kg) over 10 minutes. CHILDREN: Safety and effectiveness have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Ibutilide fumarate is used for the rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm.
    B) PHARMACOLOGY: Ibutilide for injection is an antiarrhythmic drug with predominantly class III (cardiac potential prolongation) properties. It delays repolarization by activation of a slow, inward current (predominantly sodium), leading to a prolongation of atrial and ventricular action potential duration and refractory periods.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Nausea has been reported in ibutilide-treated patients with twice the incidence of controls. TORSADES de POINTES: Ibutilide may induce or worsen ventricular dysrhythmias, producing life threatening polymorphic ventricular tachycardia. Patients with a history of torsades de pointes, prolonged QTc (greater than 440 msec), and serum potassium below 4.0 mEq/L are at increased risk of developing ventricular dysrhythmias.
    E) WITH POISONING/EXPOSURE
    1) Overdose experience is limited. Effects reported include nausea, QT prolongation, ventricular ectopy, ventricular tachycardia, torsades de pointes, and complete heart block.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Of the 586 patients with atrial flutter or atrial fibrillation who received ibutilide in phase II/III studies, 25% reported adverse events related to the cardiovascular system, compared with 7.1% (127 patients) who received placebo. Ibutilide fumarate injection can induce or worsen ventricular arrhythmias in some patients (Prod Info Corvert(R), ibutilide, 2002; Kowey et al, 1996).
    b) In one efficacy and safety study, 15 of 219 patients experienced 16 serious medical events following the therapeutic use of ibutilide. There was 9 cases of ventricular dysrhythmia, 2 cerebrovascular accidents, 1 patient with junctional premature beats, 1 case or AV block, 1 cardiac arrest, 1 patient with supraventricular tachycardia, and 1 case of pulmonary edema (Abi-Mansour et al, 1998).
    c) SUSTAINED POLYMORPHIC VENTRICULAR TACHYCARDIA: A potential hazard of ibutilide is the risk of QT interval prolongation, thus leading to torsades de pointes (Podrid, 1999). Torsades developed in 1.7% (control 0%) of ibutilide treated patients (Prod Info Corvert(R), ibutilide, 2002; Kowey et al, 1996); developed in 2.7% of patients (n=209) (Abi-Mansour et al, 1998).
    1) A higher incidence of sustained polymorphic ventricular tachycardia (PVT) has been observed in patients with a history of low ejection fraction or congestive heart failure. Sustained PVT has been reported in 5.4% of patients with a history of heart failure compared to 0.8% without this underlying complication (Prod Info Corvert(R), ibutilide, 2002).
    2) Polymorphic ventricular tachycardia (PVT) has coincided with maximal ibutilide levels (and maximum changes in QTc), and PVT is usually seen within 40 minutes of the start of infusion. However, plasma levels at the time of PVT occurrence in patients developing this dysrhythmia have been similar to levels in patients not developing PVT, and there is no apparent threshold at which the risk of its occurrence would be significantly higher (Prod Info Corvert(R), ibutilide, 2002).
    d) Stambler et al (1996) identified risk factors for polymorphic ventricular tachycardia in patients receiving ibutilide: women (4 times more likely than men), nonwhites (4 times more likely than whites), heart failure (people with history of heart failure were 3 times more susceptible), and slower heart rate (mean pulse in patients who developed polymorphic VT = 78 versus 95 in those who did not develop polymorphic VT) (Stambler et al, 1996).
    e) Kowey (1996) identified three risk factors predictive of occurrence of torsades de pointes: bradycardia, low body weight, history of congestive heart failure (Kowey et al, 1996).
    f) SUSTAINED MONOMORPHIC VENTRICULAR TACHYCARDIA: Developed in 2.3% of patients (n=209) (Abi-Mansour et al, 1998).
    g) NONSUSTAINED POLYMORPHIC VENTRICULAR TACHYCARDIA: Developed in 2.7% (control 0%) of ibutilide treated patients (Prod Info Corvert(R), ibutilide, 2002); developed in 7.3% of patients (n=209) (Abi-Mansour et al, 1998).
    h) NONSUSTAINED MONOMORPHIC VENTRICULAR TACHYCARDIA: Developed in 4.9% (control 0.8%) of ibutilide treated patients (Prod Info Corvert(R), ibutilide, 2002); developed in 7.3% of patients (n=209) (Abi-Mansour et al, 1998).
    i) VENTRICULAR EXTRASYSTOLES: Developed in 5.1% (control 0.8%) of ibutilide treated patients (Prod Info Corvert(R), ibutilide, 2002).
    j) BUNDLE BRANCH BLOCK: Developed in 1.9% (control 0%) of ibutilide treated patients (Prod Info Corvert(R), ibutilide, 2002).
    k) HYPERTENSION, QT SEGMENT PROLONGED, AND TACHYCARDIA: All episodes occurred in approximately 1.2% to 2.7% of the study population (controls 0% to 0.8%, respectively) (Prod Info Corvert(R), ibutilide, 2002).
    l) COMPLETE HEART BLOCK: A patient with preexisting intermittent heart block inadvertently received 2.5 milligrams of ibutilide. He developed complete heart block, bradycardia, QTc prolongation and nonsustained polymorphic ventricular tachycardia (Stambler et al, 1996).
    m) SINUS ARREST AND SINUS BRADYCARDIA: A 79-year-old female was administered 1 mg of ibutilide over 10 minutes for conversion of atrial fibrillation. Ten minutes after infusion, she experienced 19 distinct episodes of sinus arrest (mean duration 3.1 seconds, range 2.2 to 4.5 seconds). During this period (17 minutes in duration), her heart rate varied from 49 to 58 beats per minute. The patient required a permanent pacemaker after sinus node dysfunction was diagnosed (Amin et al, 1998).
    n) Menstrual cycle and sex differences exist in the QTc response to ibutilide. In a study of 38 men and 20 women, there was statistically greater increase in the QTc in women vs men. Additionally, in women, a statistically greater increase was seen in the QTc in the first half of the menstrual cycle (menses and ovulatory phases) vs the luteal phase (Rodriguez et al, 2001).
    2) WITH POISONING/EXPOSURE
    a) In the registration trials, 4 patients were unintentionally overdosed with ibutilide (largest dose 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 block-3rd degree and nonsustained polymorphic VT; two patients (0.038 and 0.020 mg/kg) did not experience any adverse events (Prod Info Corvert(R), ibutilide, 2002).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) ACUTE LUNG INJURY
    1) WITH THERAPEUTIC USE
    a) In one efficacy and safety study, 15 of 219 patients experienced 16 serious medical events following the therapeutic use of ibutilide. One of these patients developed pulmonary edema (Abi-Mansour et al, 1998).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CEREBROVASCULAR DISEASE
    1) WITH THERAPEUTIC USE
    a) In one efficacy and safety study, 15 of 219 patients experienced 16 serious medical events following the therapeutic use of ibutilide. Two of these patients had cerebrovascular accidents (Abi-Mansour et al, 1998).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in ibutilide-treated patients with twice the incidence of controls (Prod Info Corvert(R), ibutilide, 2002).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) Renal failure has been described in association with intravenous ibutilide in less than 0.5% of patients (Prod Info Corvert(R), ibutilide, 2002).
    b) CASE REPORT: A 52-year-old man with a history of untreated borderline hypertension and hyperuricemia (treated with allopurinol 100 milligrams per day) experienced acute renal failure 6 days after he was treated with 2 doses of ibutilide (0.87 milligram intravenously) for atrial flutter. The authors believe that his renal failure was due to the combination of allopurinol, an ACE inhibitor, and ibutilide (Franz et al, 1999).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) BULLOUS ERUPTION
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Erythematous bullous lesions were reported in a medical resident after ibutilide injection was accidentally spilled on his hands (Dodds & Oberg, 1998).

Reproductive

    3.20.1) SUMMARY
    A) Ibutilide is classified as FDA pregnancy category C. In animal studies, there was evidence of teratogenicity.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS: There was evidence of teratogenicity (adactyly, interventricular septal defects, and scoliosis) when rats were given oral 20 mg/kg/day doses (about 4 times the maximum recommended human dose (MRHD) on a mg/m(2) basis). The oral "no effect dose", corrected for 3% bioavailability, in rats was 5 mg/kg/day (approximately equal to the MRHD) (Prod Info ibutilide fumarate intravenous injection, 2012).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified ibutilide as FDA pregnancy category C (Prod Info ibutilide fumarate intravenous injection, 2012).
    2) This drug should not be administered to a pregnant woman unless the potential maternal benefit outweighs the fetal risk (Prod Info ibutilide fumarate intravenous injection, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Nursing should be avoided during ibutilide fumarate treatment (Prod Info ibutilide fumarate intravenous injection, 2012).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) RATS: There was no effect on mating or fertility when male and female rats were given doses up to 20 mg/kg/day (approximately 4 times the maximum recommended human dose on a mg/m(2) basis) (Prod Info ibutilide fumarate intravenous injection, 2012).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturers do not report any carcinogenic potential of ibutilide in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturer does not report any carcinogenic potential of ibutilide in animals (Prod Info CORVERT(R) IV injection, 2006).

Genotoxicity

    A) There was no evidence of mutagenicity in the following tests: Ames assay, mammalian cell forward gene mutation assay, unscheduled DNA synthesis assay, and mouse micronucleus assay (Prod Info CORVERT(R) IV injection, 2006).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor serum electrolytes, including potassium and magnesium (correct underlying abnormalities).
    4.1.2) SERUM/BLOOD
    A) Monitor serum electrolytes, including potassium and magnesium and correct any underlying abnormalities.
    4.1.4) OTHER
    A) OTHER
    1) Obtain and ECG and institute continuous cardiac monitoring.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients should be admitted to an intensive care setting for further observation.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management, and ibutilide is generally only used in the hospital setting.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Any patient with Ibutilide overdose should be observed in an intensive care setting continuous ECG monitoring and frequent monitoring of vital signs.

Monitoring

    A) Monitor vital signs.
    B) Obtain an ECG, and institute continuous cardiac monitoring.
    C) Monitor serum electrolytes, including potassium and magnesium (correct underlying abnormalities).

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not necessary as ibutilide is administered intravenously.

Range Of Toxicity

Summary

    A) TOXICITY: Five cases of acute overdoses (0.020 to 0.038 mg/kg) have been reported without deaths. The largest dose was 3.4 mg administered over 15 minutes. One patient developed increased ventricular ectopy and monomorphic ventricular tachycardia after receiving 0.025 mg/kg of ibutilide. Another patient developed complete heart block and nonsustained polymorphic VT after receiving 0.032 mg/kg of ibutilide. The remaining two patients did not develop any adverse effects after receiving 0.038 and 0.020 mg.kg of ibutilide, respectively.
    B) THERAPEUTIC DOSES: ADULTS: WEIGHT 60 KG (132 POUNDS) OR GREATER: 1 mg over 10 minutes. WEIGHT LESS THAN 60 KG (132 POUNDS): 0.1 mL/kg (0.01 mg/kg) over 10 minutes. CHILDREN: Safety and effectiveness have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) IV ROUTE
    1) INITIAL INFUSION:
    a) WEIGHT 60 KG OR GREATER: 1 mg over 10 minutes (Prod Info ibutilide fumarate intravenous injection, 2012).
    b) WEIGHT LESS THAN 60 KG: 0.1 mL/kg (0.01 mg/kg) over 10 minutes (Prod Info ibutilide fumarate intravenous injection, 2012).
    2) SECOND INFUSION: May administer a second 10-minute infusion of equal strength 10 minutes after completion of first infusion if arrhythmia has not abated (Prod Info ibutilide fumarate intravenous injection, 2012).
    7.2.2) PEDIATRIC
    A) IV ROUTE
    1) Safety and effectiveness have not been established in pediatric patients (Prod Info ibutilide fumarate intravenous injection, 2012).

Maximum Tolerated Exposure

    A) Five cases of acute overdoses (0.020 to 0.038 mg/kg) have been reported without deaths (Prod Info ibutilide fumarate IV injection, 2009; Stambler et al, 1996). The largest dose was 3.4 mg administered over 15 minutes (Prod Info ibutilide fumarate IV injection, 2009).
    1) One patient developed increased ventricular ectopy and monomorphic ventricular tachycardia after receiving 0.025 mg/kg of ibutilide (Prod Info ibutilide fumarate IV injection, 2009).
    2) Another patient developed complete heart block and nonsustained polymorphic VT after receiving 0.032 mg/kg of ibutilide(Prod Info ibutilide fumarate IV injection, 2009).
    3) The remaining two patients did not develop any adverse effects after receiving 0.038 and 0.020 mg.kg of ibutilide, respectively (Prod Info ibutilide fumarate IV injection, 2009).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ibutilide for injection is an antiarrhythmic drug with predominantly class III (cardiac potential prolongation) properties. It delays repolarization by activation of a slow, inward current (predominantly sodium), leading to a prolongation of atrial and ventricular action potential duration and refractory periods (Prod Info ibutilide fumarate IV injection, 2009).

Physicochemical

Ph

    A) Approximately 4.6 (Prod Info CORVERT(R) IV injection, 2006).
    B) Ibutilide fumarate is a white to off-white powder that has an aqueous solubility of over 100 mg/mL at pH 7 or lower (Prod Info CORVERT(R) IV injection, 2006).

Molecular Weight

    A) IBUTILIDE FUMARATE: 442.62 (Prod Info CORVERT(R) IV injection, 2006)

References

General Bibliography

    1) Abi-Mansour P, Carberry PA, & McCowan RJ: Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and atrial fibrillation. Am heart J 1998; 163:632-642.
    2) American Heart Association: 2005 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2005; 112(24 Suppl):IV 1-203. Available from URL: http://circ.ahajournals.org/content/vol112/24_suppl/. As accessed 12/14/2005.
    3) Amin NB, Borzak S, Housholder S, et al: Sinus bradycardia and multiple episodes of sinus arrest following administration of ibutilide. Heart 1998; 79(6):628-629.
    4) Charlton NP , Lawrence DT , Brady WJ , et al: Termination of drug-induced torsades de pointes with overdrive pacing. Am J Emerg Med 2010; 28(1):95-102.
    5) Dodds ES & Oberg KC: Erythematous bullous lesions on the dorsa of the hands due to contact exposure to ibutilide fumarate for injection. Pharmacother 1998; 18(4):880-882.
    6) Drew BJ, Ackerman MJ, Funk M, et al: Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2010; 55(9):934-947.
    7) Franz M, Geppert A, & Kain R: Acute renal failure after ibutilide (letter). Lancet 1999; 353:467.
    8) Keren A, Tzivoni D, & Gavish D: Etiology, warning signs and therapy of torsade de pointes: a study of 10 patients. Circulation 1981; 64:1167-1174.
    9) Khan IA & Gowda RM: Novel therapeutics for treatment of long-QT syndrome and torsade de pointes. Int J Cardiol 2004; 95(1):1-6.
    10) Kowey PR, VanderLugt JT, & Luderer JR: Safety and risk/benefit analysis of ibutilide for acute conversion of atrial fibrillation/flutter. Am J Cardiol 1996; 78:46-52.
    11) Link MS, Berkow LC, Kudenchuk PJ, et al: Part 7: Adult Advanced Cardiovascular Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S444-S464.
    12) Neumar RW , Otto CW , Link MS , et al: Part 8: adult advanced cardiovascular life support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S729-S767.
    13) Perticone F, Ceravolo R, & Cuccurullo O: Prolonged magnesium sulfate infusion in the treatment of ventricular tachycardia in acquired long QT syndrome. Clin Drug Inverst 1997; 13:229-236.
    14) Podrid PJ: Redefining the Role of Antiarrhythmic Drugs. N Eng J Med 1999; 340(24):1910-1912.
    15) Product Information: CORVERT(R) IV injection, ibutilide fumarate IV injection. Pharmacia & Upjohn Company, New York, NY, 2006.
    16) Product Information: Corvert(R), ibutilide. Pharmacia & Upjohn Company, Kalamazoo, MI, 2002.
    17) Product Information: Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, isoproterenol HCl intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection. Hospira, Inc. (per FDA), Lake Forest, IL, 2013.
    18) Product Information: Lidocaine HCl intravenous injection solution, lidocaine HCl intravenous injection solution. Hospira (per manufacturer), Lake Forest, IL, 2006.
    19) Product Information: ibutilide fumarate IV injection, ibutilide fumarate IV injection. Bioniche Pharma USA (per Manufacturer), Lake Forest, IL, 2009.
    20) Product Information: ibutilide fumarate intravenous injection, ibutilide fumarate intravenous injection. Mylan Institutional LLC (per DailyMed), Rockford, IL, 2012.
    21) Product Information: magnesium sulfate heptahydrate IV, IM injection, solution, magnesium sulfate heptahydrate IV, IM injection, solution. Hospira, Inc. (per DailyMed), Lake Forest, IL, 2009.
    22) RTECS : Registry of Toxic Effects of Chemical Substances. National Institute for Occupational Safety and Health. Cincinnati, OH (Internet Version). Edition expires July/31/2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    23) Roden DM: Ibutilide and the treatment of atrial arrhythmias: A new drug-almost unheralded-is now available to US physicians, (Edit). Circulation 1996; 94:1499-1502.
    24) Rodriguez I, Kilborn MJ, Liu XK, et al: Drug-induced QT prolongation in women during the menstrual cycle. JAMA 2001; 285(10):1322-1326.
    25) Smith WM & Gallagher JJ: "Les torsades de pointes": an unusual ventricular arrhythmia. Ann Intern Med 1980; 93:578-584.
    26) Stambler BS, Wood MA, & Ellenbogen KA: Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Circulation 1996; 94:1613-1621.
    27) Vanden Hoek TL, Morrison LJ, Shuster M, et al: Part 12: cardiac arrest in special situations: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010; 122(18 Suppl 3):S829-S861.
    28) de Caen AR, Berg MD, Chameides L, et al: Part 12: Pediatric Advanced Life Support: 2015 American Heart Association Guidelines Update for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2015; 132(18 Suppl 2):S526-S542.