Dofetilide

Pronunciation

(doe FET il ide)

U.S. Brand Names

Tikosyn™

Generic Available

Canadian Brand Names

Tikosyn™

Use

Maintenance of normal sinus rhythm in patients with chronic 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

Pregnancy Risk Factor

Pregnancy Implications

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.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to dofetilide or any component of the formulation; 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 Clcr<20 mL/minute); concurrent use with verapamil, cimetidine, hydrochlorothiazide (alone or in combinations), trimethoprim (alone or in combination with sulfamethoxazole), ketoconazole, prochlorperazine, or megestrol; 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

Warnings/Precautions

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 ECG 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.

Reserve for patients who are highly symptomatic with atrial fibrillation/atrial flutter; torsade de pointes significantly increases with doses >500 mcg twice daily; hold class I or class III antiarrhythmics for at least three half-lives prior to starting dofetilide; use in patients on amiodarone therapy only if serum amiodarone level is <0.3 mg/L or if amiodarone was stopped for >3 months previously; correct hypokalemia or hypomagnesemia before initiating dofetilide and maintain within normal limits during treatment. Risk of hypokalemia and/or hypomagnesemia may be increased by potassium-depleting diuretics, increasing the risk of torsade de pointes. Concurrent use with other drugs known to prolong QTc interval is not recommended.

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.

Adverse Reactions

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 placebo): Anxiety, pain, angina, atrial fibrillation, hypertension, palpitation, supraventricular tachycardia, peripheral edema, urinary tract infection, weakness, arthralgia, diaphoresis

Overdosage/Toxicology

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.

Drug Interactions

Substrate of CYP3A4 (minor)

If dofetilide needs to be discontinued to allow dosing of other potentially interacting drug(s) (see below), a washout period of at least 2 days is needed before starting the other drug(s).

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.

Diuretics and other drugs (aminoglycosides) which deplete potassium or magnesium may increase dofetilide toxicity (torsade de pointes). Concurrent use of hydrochlorothiazide is contraindicated.

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

QTc-prolonging agents (including bepridil, cisapride, clarithromycin, erythromycin, tricyclic antidepressants, phenothiazines, sparfloxacin, gatifloxacin, moxifloxacin): Use is contraindicated.

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

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

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: St John's wort may decrease dofetilide levels. Avoid ephedra (may worsen arrhythmia).

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Absorption: >90%

Distribution: Vd: 3 L/kg

Protein binding: 60% to 70%

Metabolism: Hepatic via CYP3A4, but low affinity for it; metabolites formed by N-dealkylation and N-oxidation

Bioavailability: >90%

Half-life elimination: 10 hours

Time to peak: Fasting: 2-3 hours

Excretion: Urine (80%, 80% as unchanged drug, 20% as inactive or minimally active metabolites); renal elimination consists of glomerular filtration and active tubular secretion via cationic transport system

Dosage

Adults: Oral:

Note: QT or QTc must be determined prior to first dose. If QTc >440 msec (>500 msec in patients with ventricular conduction abnormalities), dofetilide is contraindicated (see Contraindications and Warnings/Precautions).

Initial: 500 mcg orally twice daily. Initial dosage must be adjusted in patients with estimated Clcr<60 mL/minute (see Dosage Adjustment in Renal Impairment). 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) at any time, dofetilide should be discontinued.

Chronic therapy (following the 5th dose):

QT or QTc and creatinine clearance should be evaluated every 3 months. If QTc >500 msec (>550 msec in patients with ventricular conduction abnormalities), dofetilide should be discontinued.

Dosage adjustment in renal impairment:

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

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

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

Clcr<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.

Monitoring Parameters

ECG 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. QT or QTc must be monitored at specific times prior to the first dose and during the first 3 days of therapy. Thereafter, QT or QTc and creatinine clearance must be evaluated at 3-month intervals.

Patient Education

Take exactly as directed; do not take additional doses or discontinue without consulting prescriber. Do not open capsules. If you miss a dose, take your normal amount at the next scheduled time. You will need regular cardiac checkups and blood tests when taking this medication. You may experience headache, dizziness, or difficulty sleeping (use caution when driving or engaging in tasks requiring alertness until response to drug is known); or abdominal pain, diarrhea, or nausea (small, frequent meals and increased dietary bulk may help). Inform prescriber immediately if you experience fainting; severe GI discomfort or diarrhea; chest palpitations, irregular heartbeat, or chest pain; increased thirst; respiratory difficulty; skin rash; back pain; or alteration in muscle strength or gait. Pregnancy/breast-feeding precautions: Inform your prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Nursing Implications

Patient must be carefully instructed concerning how to take this medicine, what to do if a dose is missed, which over-the-counter medications to avoid (eg, cimetidine), and the recognition of serious adverse events. Patients should be cautioned not to stop taking this medication without talking with their prescriber. Measure QTc as outlined in dosing information and discuss results with physician, monitor ECG for any tachyarrhythmias, and monitor for changes in renal function and signs/symptoms of electrolyte imbalance. A patient resource kit is available.

Cardiovascular Considerations

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.

The two DIAMOND studies were 3-year trials comparing mortality between dofetilide and placebo in patients with left ventricular dysfunction. One study included patients with moderate to severe CHF (60% of participants were NYHA Class III or IV) and the other study looked at patients with a recent MI (40% had NYHA class III or IV CHF). Dofetilide was an effective therapy for atrial fibrillation in carefully selected and monitored heart failure patients. Mortality was similar between those who received placebo and dofetilide; fewer patients on dofetilide were hospitalized for heart failure. It seems prudent, therefore, to carefully select and monitor patients in this situation.

Dofetilide can cause life-threatening ventricular arrhythmias and should therefore be used in select patients in whom atrial fibrillation/flutter is highly symptomatic. Physicians and pharmacists need to complete their Tikosyn™ educational program before dofetilide can be prescribed and dispensed.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Insomnia is common

Mental Health: Effects on Psychiatric Treatment

Contraindicated with drugs that prolong QTc (phenothiazines, TCAs, ziprasidone)

Dosage Forms

Capsule: 125 mcg, 250 mcg, 500 mcg

References

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.

International Brand Names

Tikosyn™ (CA)

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