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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(doe FET il ide)
Generic Available (U.S.)
No
Prescribing and Access Restrictions
Tikosyn® is deemed to have an approved REMS program. As a requirement of the REMS program, access to this medication is restricted. Tikosyn® is only available to prescribers and hospitals that have confirmed their participation in a designated Tikosyn® Education Program. The program provides comprehensive education about the importance of in-hospital treatment initiation and individualized dosing.
T.I.P.S. is the Tikosyn® In Pharmacy System designated to allow retail pharmacies to stock and dispense Tikosyn® once they have been enrolled. A participating pharmacy must confirm receipt of the T.I.P.S. program materials and educate its pharmacy staff about the procedures required to fill an outpatient prescription for Tikosyn®. The T.I.P.S. enrollment form is available at www.tikosyn.com. Tikosyn® is only available from a special mail order pharmacy, and enrolled retail pharmacies. Pharmacists must verify that the hospital/prescriber is a confirmed participant before Tikosyn® is provided. For participant verification, the pharmacist may call 1-800-788-7353 or use the web site located at www.tikosynlist.com. Further details and directions on the program are provided at www.tikosyn.com.
Dofetilide therapy must be initiated/adjusted in a hospital setting with proper monitoring under the guidance of experienced personnel.
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
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
C
Pregnancy Considerations
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 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), itraconazole, ketoconazole, prochlorperazine, or megestrol; baseline heart rate <50 beats/minute; other drugs that prolong QT intervals (phenothiazines, cisapride, bepridil, tricyclic antidepressants, moxifloxacin; hypokalemia or hypomagnesemia; concurrent amiodarone, clarithromycin, or erythromycin
Warnings/Precautions
Boxed warnings:
• Arrhythmias: Appropriate use: See “Disease-related concerns” below.
Concerns related to adverse effects:
• Proarrhythmic effects: Watch for proarrhythmic effects; monitor and adjust dose to prevent QTc prolongation. Torsade de pointes significantly increases with doses >500 mcg twice daily.
Disease-related concerns:
• Arrhythmias: Appropriate use: Reserve for patients who are highly symptomatic with atrial fibrillation/atrial flutter. [U.S. Boxed Warning]: 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.
• Conduction disturbances: Patients with second or third-degree heart block and/or sick sinus syndrome should not receive 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.
• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.
• Hepatic impairment: Use with caution in patients with severe hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
Concurrent drug therapy issues:
• Drugs with QT prolongation potential: Concurrent use with other drugs known to prolong QTc interval is not recommended. 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.
• Potassium-depleting diuretics: Risk of hypokalemia and/or hypomagnesemia may be increased by potassium-depleting diuretics, increasing the risk of malignant arrhythmias such as torsade de pointes.
Other warnings/precautions:
• CAST trial: In the Cardiac Arrhythmia Suppression Trial (CAST), recent (>6 days but <2 years ago) myocardial infarction patients with asymptomatic, non-life-threatening ventricular arrhythmias did not benefit and may have been harmed by attempts to suppress the arrhythmia with flecainide or encainide. An increased mortality or nonfatal cardiac arrest rate (7.7%) was seen in the active treatment group compared with patients in the placebo group (3%). The applicability of the CAST results to other populations is unknown. Antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.
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: Respiratory tract infection (7%), dyspnea (6%)
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, MI, 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
Metabolism/Transport Effects
Substrate of CYP3A4 (minor)
Drug Interactions
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
AMILoride: May increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Dofetilide. Risk X: Avoid combination
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of Dofetilide. This is likely via inhibition of dofetilide renal tubular secretion (primarily) and inhibition of dofetilide metabolism. Risk X: Avoid combination
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Management: Upon completion/discontinuation of conivaptan, allow at least 7 days before initiating therapy with drugs that are CYP3A4 substrates. Risk D: Consider therapy modification
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Eribulin: May enhance the QTc-prolonging effect of Antiarrhythmic Agents (Class III). Risk C: Monitor therapy
Fingolimod: May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class III). Management: Obtain baseline ECG (if not recently available) if initiating fingolimod during treatment with class III antiarrhythmic agents. Monitor for bradycardia and AV block. The Canadian labeling recommends avoiding concomitant use of these agents. Risk C: Monitor therapy
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Loop Diuretics: May enhance the QTc-prolonging effect of Dofetilide. Risk C: Monitor therapy
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Megestrol: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
MetFORMIN: May increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Prochlorperazine: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Saquinavir: May enhance the arrhythmogenic effect of Dofetilide. Saquinavir may increase the serum concentration of Dofetilide. Risk X: Avoid combination
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thiazide Diuretics: May enhance the QTc-prolonging effect of Dofetilide. Thiazide Diuretics may increase the serum concentration of Dofetilide. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Toremifene: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Toremifene. The risk for potentially dangerous arrhythmias may be increased. Risk X: Avoid combination
Triamterene: May increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Trimethoprim: May decrease the excretion of Dofetilide. Risk X: Avoid combination
Vandetanib: QTc-Prolonging Agents may enhance the arrhythmogenic effect of Vandetanib. Risk X: Avoid combination
Verapamil: May increase the serum concentration of Dofetilide. Risk X: Avoid combination
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
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: Well absorbed
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, serum: 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: Note: The manufacturer recommends using actual body weight when using the Cockcroft-Gault equation to calculate creatinine clearance.
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.
Administration: Oral
Do not open capsules.
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
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, difficulty sleeping, abdominal pain, diarrhea, or nausea. Inform prescriber immediately if you experience fainting, severe GI discomfort or diarrhea, chest palpitations, irregular heartbeat, chest pain, increased thirst, respiratory difficulty, skin rash, back pain, or alteration in muscle strength or gait.
Geriatric Considerations
No specific dosage adjustments are recommended based on age; however, evaluation for use of this drug in the elderly is imperative. A complete review of medications, to assure there is no inadvertent use of contraindicated medications and those with potential drug interactions, can be re-evaluated for continued need. Laboratory values must be assessed prior to initiating medication; careful assessment of renal function is particularly important in the elderly population.
Anesthesia and Critical Care Concerns/Other Considerations
Clinical Pearl/Comments: Since dofetilide is ~80% renally eliminated and the QT interval is sensitive to changes in heart rate and electrolyte disturbances, the critically-ill patient continued on dofetilide should be closely monitored for QTc prolongation, hypomagnesemia, hypokalemia, and hypocalcemia. Dosage adjustments should be made based on Clcr (Cockcroft-Gault method). Dofetilide should be discontinued if QTc-prolongation exceeds 500 msec (or 550 msec in patients with ventricular conduction abnormalities) or if Clcr is <20 mL/minute given the elevated risk of torsade de pointes. QTc should be determined using Bazett's formula if heart rate exceeds 60 bpm. The QT interval should be used to guide dosage adjustment if heart rate is <60 bpm.
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.
There are limited studies evaluating the efficacy of dofetilide in patients with paroxysmal atrial fibrillation (PAF). While the efficacy data have not been statistically significant, positive trends have been noted and further study is required. In heart failure patients, dofetilide has been reported to preserve inotropic and end-systolic indices. Considering the neutral survival data from the DIAMOND trials and the positive influence on hemodynamic function, dofetilide is recommended by the most recently published ACC/AHA/ESC guidelines as an appropriate second- or third-line agent for PAF, particularly in the setting of ventricular dysfunction.
Dofetilide can cause life-threatening ventricular arrhythmias and should therefore be used in select patients in whom atrial fibrillation/flutter is highly symptomatic. Hospitals and physicians 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
Dofetilide is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.
Dental Comment
Dofetilide is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Dofetilide is considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.
Mental Health: Effects on Mental Status
Insomnia is common
Mental Health: Effects on Psychiatric Treatment
Contraindicated with drugs that prolong QTc (phenothiazines, TCAs, ziprasidone)
Nursing: Physical Assessment/Monitoring
Must be initiated or reinitiated by a cardiologist in a setting with continuous ECG monitoring for a period of time at beginning or adjustment of therapy. Monitor for signs of electrolyte imbalance.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, oral:
Tikosyn®: 125 mcg, 250 mcg, 500 mcg
Pricing: U.S. (www.drugstore.com)
Capsules (Tikosyn)
125 mcg (60): $233.48
250 mcg (60): $234.85
500 mcg (60): $242.18
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.
Fuster V, Ryden LE, Cannom DS, et al, “ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation-Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society,” J Am Coll Cardiol, 2006, 48(4):854-906.
Mounsey JP and DiMarco JP, “Dofetilide,” Circulation, 2000, 102(21):2665-70.
Naccarelli GV, Wolbrette DL, Khan M, et al, “Old and New Antiarrhythmic Drugs for Converting and Maintaining Sinus Rhythm in Atrial Fibrillation: Comparative Efficacy and Results of Trials,” Am J Cardiol, 2003, 91(6A):15D-26D.
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.
Wann SL, Curtis AB, January CT, et al, “2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Updating the 2006 Guideline): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines,” Circulation, 2011, 123 (1):104-23.
International Brand Names
Lexi-Comp.com
Last full review/revision May 2011
Content last modified May 2011
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