Antiarrhythmic Agent, Class III

Maintenance of normal sinus rhythm in patients with atrial fibrillation/atrial flutter of longer than 1-week duration who have been converted to normal sinus rhythm; conversion of atrial fibrillation and atrial flutter to normal sinus rhythm

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Dofetilide has been shown to adversely affect in utero growth, organogenesis, and survival of rats and mice. There are no adequate and well controlled studies in pregnant women. Dofetilide should be used with extreme caution in pregnant women and in women of childbearing age only when the benefit to the patient unequivocally justifies the potential risk to the fetus.

Patients with paroxysmal atrial fibrillation; patients with congenital or acquired long QT syndromes, do not use if a baseline QT interval or QTc is >440 msec (500 msec in patients with ventricular conduction abnormalities); severe renal impairment (estimated Cl_cr <20 mL/minute); concurrent use with verapamil, cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), ketoconazole, prochlorperazine, or megestrol; known hypersensitivity to dofetilide, baseline heart rate <50 beats/minute; other drugs that prolong QT intervals (phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides: sparfloxacin, gatifloxacin, moxifloxacin); hypokalemia or hypomagnesemia; concurrent amiodarone

Note: Must be initiated (or reinitiated) in a setting with continuous monitoring and staff familiar with the recognition and treatment of life-threatening arrhythmias. Patients must be monitored with continuous EKG for a minimum of 3 days, or for a minimum of 12 hours after electrical or pharmacological cardioversion to normal sinus rhythm, whichever is greater. Patients should be readmitted for continuous monitoring if dosage is later increased.

Patients with sick sinus syndrome or with second or third-degree heart block should not receive dofetilide unless a functional pacemaker is in place. Defibrillation threshold is reduced in patients with ventricular tachycardia or ventricular fibrillation undergoing implantation of a cardioverter-defibrillator device. Safety and efficacy in children (<18 years old) have not been established. Use with caution in renal impairment; not recommended in patients receiving drugs which may compete for renal secretion via cationic transport. Use with caution in patients with severe hepatic impairment.

Supraventricular arrhythmia patients (incidence > placebo)

>10%: Central nervous system: Headache (11%)

2% to 10%:

Central nervous system: Dizziness (8%), insomnia (4%)

Cardiovascular: Ventricular tachycardia (2.6% to 3.7%), chest pain (10%), torsade de pointes (3.3% in CHF patients and 0.9% in patients with a recent MI; up to 10.5% in patients receiving doses in excess of those recommended). Torsade de pointes occurs most frequently within the first 3 days of therapy.

Dermatologic: Rash (3%)

Gastrointestinal: Nausea (5%), diarrhea (3%), abdominal pain (3%)

Neuromuscular & skeletal: Back pain (3%)

Respiratory: Dyspnea (6%), respiratory tract infection (7%)

Miscellaneous: Flu syndrome (4%)

<2%:

Central nervous system: CVA, facial paralysis, flaccid paralysis, migraine, paralysis

Cardiovascular: AV block (0.4% to 1.5%), ventricular fibrillation (0% to 0.4%), bundle branch block, heart block, edema, heart arrest, myocardial infarct, sudden death, syncope

Dermatologic: Angioedema

Gastrointestinal: Liver damage

Neuromuscular & skeletal: Paresthesia

Respiratory: Cough

>2% (incidence less than or equal to placebo): Anxiety, pain, angina, atrial fibrillation, hypertension, palpitation, supraventricular tachycardia, peripheral edema, urinary tract infection, weakness, arthralgia, sweating

The major dose-related toxicity is torsade de pointes. Treatment should be symptomatic and supportive. Watch for excessive prolongation of the QT interval in overdose situations. Continuous cardiac monitoring is necessary. A charcoal slurry is helpful when given early (15 minutes) after the overdose. Isoproterenol infusion into anesthetized dogs with cardiac pacing corrects the atrial and ventricular effective refractory periods caused by dofetilide. General treatment measures, override pacing, and magnesium therapy appear to be effective in the management of dofetilide-induced torsade de pointes.

CYP3A3/4 enzyme substrate (minor).

Cimetidine, a cation transport system inhibitor, inhibits dofetilide's elimination and can cause a 58% increase in dofetilide's plasma levels; concomitant use is contraindicated.

Drugs which prolong QT interval (including bepridil, cisapride, erythromycin, tricyclic antidepressants, phenothiazines, sparfloxacin, gatifloxacin, moxifloxacin): Use is contraindicated.

Verapamil causes an increase in dofetilide's peak plasma levels by 42%. In the supraventricular arrhythmia and a higher incidence of torsade de pointes was seen in patients on verapamil; concomitant use is contraindicated.

Ketoconazole increases dofetilide's C_max (53% males, 97% females) and the AUC (41% males, 69% females) when used concurrently; concomitant use is contraindicated.

Trimethoprim (alone or in combination with sulfamethoxazole) increases dofetilide's C_max (103%) and AUC (93%); concomitant use is contraindicated.

Renal cationic transport inhibitors (including triamterene, metformin, amiloride, prochlorperazine, megestrol) may increase dofetilide levels; coadminister with caution.

Diuretics and other drugs (aminoglycosides) which deplete potassium or magnesium may increase dofetilide toxicity (torsade de pointes).

Drugs which have been reported not to affect dofetilide include digoxin, amlodipine, phenytoin, glyburide, ranitidine, omeprazole, hormone replacement therapy (conjugated estrogens/medroxyprogesterone), antacid (aluminum/magnesium hydroxide), and theophylline.

Vaughan Williams Class III antiarrhythmic activity. Blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current. Dofetilide has no effect on sodium channels, adrenergic alpha-receptors, or adrenergic beta-receptors. It increases the monophasic action potential duration due to delayed repolarization. The increase in the QT interval is a function of prolongation of both effective and functional refractory periods in the His-Purkinje system and the ventricles. Changes in cardiac conduction velocity and sinus node function have not been observed in patients with or without structural heart disease. PR and QRS width remain the same in patients with pre-existing heart block and or sick sinus syndrome.

Absorption: >90%

Distribution: V_d: 3 L/kg

Protein binding: 60% to 70%

Metabolism: Dofetilide can be metabolized by CYP3A3/4, but has a low affinity for it. Metabolites are formed by N-dealkylation and N-oxidation.

Bioavailability: >90%

Half-life: 10 hours

Time to peak: 2-3 hours after ingested in the fasting state

Elimination: 80% excreted in the urine, of which 80% is excreted unchanged, and 20% is inactive or minimally active metabolites. Renal elimination consists of glomerular filtration and active tubular secretion via cationic transport system.

Adults: Oral:

Initial: 500 mcg orally twice daily. Initial dosage must be adjusted in patients with estimated Cl_cr <60 mL/minute. Dofetilide may be initiated at lower doses than recommended based on physician discretion.

Modification of dosage in response to initial dose:

QTc interval should be measured 2-3 hours after the initial dose. If the QTc >15% of baseline, or if the QTc is >500 msec (550 msec in patients with ventricular conduction abnormalities) dofetilide should be adjusted. If the starting dose is 500 mcg twice daily, then adjust to 250 mcg twice daily. If the starting dose was 250 mcg twice daily, then adjust to 125 mcg twice daily. If the starting dose was 125 mcg twice daily then adjust to 125 mcg every day.

Continued monitoring for doses 2-5:

QTc interval must be determined 2-3 hours after each subsequent dose of dofetilide for in-hospital doses 2-5. If the measured QTc is >500 msec (550 msec in patients with ventricular conduction abnormalities) dofetilide should be stopped.

Dosage adjustment in renal impairment:

Cl_cr >60 mL/minute: Administer 500 mcg twice daily.

Cl_cr 40-60 mL/minute: Administer 250 mcg twice daily.

Cl_cr 20-39 mL/minute: Administer 125 mcg twice daily.

Cl_cr <20 mL/minute: Contraindicated in this group.

Dosage adjustment in hepatic impairment: No dosage adjustments required in Child-Pugh Class A and B. Patients with severe hepatic impairment were not studied.

Elderly: No specific dosage adjustments are recommended based on age, however careful assessment of renal function is particularly important in this population.

EKG monitoring with attention to QTc and occurrence of ventricular arrhythmias, baseline serum creatinine and changes in serum creatinine. Check serum potassium and magnesium levels if on medications where these electrolyte disturbances can occur, or if patient has a history of hypokalemia or hypomagnesemia.

The management of atrial fibrillation deserves careful consideration in patients with heart failure, because the loss of atrial assistance to ventricular filling may have greater negative effects on cardiac output. The choice of antiarrhythmic is important because of the risk that antiarrhythmic therapy may increase mortality in this setting.

No information available to require special precautions

No effects or complications reported

Take with or without food; take exactly the way it was prescribed; do not stop this medicine without talking with your physician; never take an extra dose; if you miss a dose just take your normal amount at the next scheduled time. If you take more medicine than you should call your physician immediately. If you cannot reach your physician, go to the nearest emergency room (take your medicine with you). Tell your physician about any new medicines before taking them; not all medicines mix well with this one. Call your physician immediately if you faint, become dizzy, have fast heartbeats, severe diarrhea, unusual sweating, vomiting, no appetite, or more thirst than normal. You may feel tired, weak, or have numbness, tingling, muscle cramps, constipation, vomiting, or rapid heartbeats if you have a low potassium level.

Patient must be carefully instructed concerning how to take this medicine, what to do if a dose is missed, and the recognition of serious adverse events. Patients should be cautioned not to stop taking this medication without talking with their physician. Measure QTc as outlined in dosing information and discuss results with physician, monitor EKG for any tachyarrhythmias, and monitor for changes in renal function and signs/symptoms of electrolyte imbalance.

Capsule: 125 mcg, 250 mcg, 500 mcg

Buxton AE, Lee KL, Fisher JD, et al, "A Randomized Study of the Prevention of Sudden Death in Patients With Coronary Artery Disease," N Engl J Med, 1999, 341(25):1882-90.

Choy AM, Darbar D, Dell'Orto S, et al, "Exaggerated QT Prolongation After Cardioversion of Arterial Fibrillation," J Am Coll Cardiol, 1999, 34(2):396-401.

Falk RH, Pollak A, Singh SN, et al, "Intravenous Dofetilide, A Class III Antiarrhythmic Agent, for the Termination of Sustained Atrial Fibrillation or Flutter. Intravenous Dofetilide Investigators," J Am Coll Cardiol, 1997, 29(2):385-90.

Norgaard BL, Wachtell K, Christensen PD, et al, "Efficacy and Safety of Intravenously Administered Dofetilide in Acute Termination of Atrial Fibrillation and Flutter: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial. Danish Dofetilide in Atrial Fibrillation and Flutter Study Group," Am Heart J, 1999, 137(6):1062-9.

Prystowsky EN, Benson DW Jr, Fuster V, et al, "Management of Patients With Atrial Fibrillation: A Statement for Healthcare Professionals. From the Subcommittee on Electrocardiography and Electrophysiology, American Heart Association," Circulation, 1996, 93(6):1262-77.

Torp-Pederson C, Moller M, Bloch-Thomsen PE, et al, "Dofetilide in Patients with Congestive Heart Failure and Left Ventricular Dysfunction," N Engl J Med, 1999, 341(12):857-65.