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Dofetilide

Pronunciation

(doe FET il ide)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Tikosyn: 125 mcg, 250 mcg, 500 mcg

Brand Names: U.S.

  • Tikosyn

Pharmacologic Category

  • Antiarrhythmic Agent, Class III

Pharmacology

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 preexisting heart block and or sick sinus syndrome.

Absorption

Well absorbed

Distribution

Vd: 3 L/kg

Metabolism

Hepatic via CYP3A4 (low affinity); metabolites formed by N-dealkylation and N-oxidation

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

Time to Peak

Serum: Fasting: 2 to 3 hours

Half-Life Elimination

~10 hours; prolonged with renal impairment

Protein Binding

60% to 70%

Special Populations: Renal Function Impairment

Clearance is decreased and half-life is prolonged with decreasing CrCl.

Special Populations: Gender

Women have approximately 12% to 18% lower clearance.

Use: Labeled Indications

Atrial fibrillation/atrial flutter: 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.

Use: Unlabeled

Alternative antiarrhythmic for the treatment of atrial fibrillation in patients with hypertrophic cardiomyopathy (HCM)

Contraindications

Hypersensitivity to dofetilide or any component of the formulation; congenital or acquired long QT syndromes; patients with baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities); severe renal impairment (CrCl <20 mL/minute); concurrent use with cimetidine, dolutegravir, hydrochlorothiazide (alone or in combinations), itraconazole (according to itraconazole prescribing information), ketoconazole, megestrol, prochlorperazine, trimethoprim (alone or in combination), or verapamil

Dosing: Adult

Note: CrCl and QTc (or QT interval if heart rate is <60 beats/minute) must be determined prior to first dose. If QTc >440 msec (>500 msec in patients with ventricular conduction abnormalities), dofetilide is contraindicated.

Atrial fibrillation/atrial flutter: Oral:

Initial: 500 mcg twice daily (maximum dose: 500 mcg twice daily). Initial dosage must be adjusted in patients with estimated CrCl <60 mL/minute (see dosage adjustment in renal impairment). Dofetilide may be initiated at lower doses than recommended based on health care provider discretion.

Modification of dosage in response to initial dose: QTc interval should be measured 2 to 3 hours after the initial dose. If the QTc increases to more than 15% above baseline QTc or if the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), dofetilide dose should be reduced. If the starting dose was 500 mcg twice daily, then reduce to 250 mcg twice daily. If the starting dose was 250 mcg twice daily, then reduce to 125 mcg twice daily. If the starting dose was 125 mcg twice daily, then reduce to 125 mcg once daily. If at any time after the second dose is given the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), dofetilide should be discontinued.

Maintenance therapy: No further down titration of dose based on QTc is recommended following modification of initial dose. Renal function and QTc should be re-evaluated every 3 months or as medically warranted. If QTc >500 msec (>550 msec in patients with ventricular conduction abnormalities), discontinue therapy. If renal function deteriorates, adjust dose as described in dosage adjustment in renal impairment.

Dosing: Geriatric

Refer to adult dosing. No specific dosage adjustments are recommended based on age; however, careful assessment of renal function is particularly important in this population.

Dosing: Renal Impairment

Note: Using the Modification of Diet in Renal Disease (MDRD) equation and subsequent eGFR to determine dose may lead to overestimation of CrCl and overdose of medication; use only the Cockcroft-Gault equation to estimate CrCl (Denetclaw 2011). Use actual body weight when using the Cockcroft-Gault equation to calculate CrCl (weight range of patients enrolled in clinical trials: 40 to 134 kg).

CrCl >60 mL/minute: No dosage adjustment necessary.

CrCl 40 to 60 mL/minute: 250 mcg twice daily.

CrCl 20 to 39 mL/minute: 125 mcg twice daily.

CrCl <20 mL/minute: Use is contraindicated.

Dosing: Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe hepatic impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use with caution.

Administration

Oral: Administer with or without food.

Storage

Store at 15°C to 30°C (59°F to 86°F). Protect from moisture and humidity.

Drug Interactions

AMILoride: May increase the serum concentration of Dofetilide. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Dofetilide. Exceptions: Fluconazole; Isavuconazonium Sulfate. Avoid combination

Cimetidine: May increase the serum concentration of Dofetilide. This is likely via inhibition of dofetilide renal tubular secretion (primarily) and inhibition of dofetilide metabolism. Avoid combination

Cobicistat: May increase the serum concentration of Dofetilide. Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Dofetilide. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Dofetilide. Monitor therapy

CYP3A4 Inhibitors (Weak): May increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: May increase the serum concentration of Dofetilide. Avoid combination

Fingolimod: May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class III). Avoid combination

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

LamoTRIgine: May increase the serum concentration of Dofetilide. Avoid combination

Lidocaine (Topical): May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class III). Antiarrhythmic Agents (Class III) may increase the serum concentration of Lidocaine (Topical). This mechanism specifically applies to amiodarone and dronedarone. Monitor therapy

Loop Diuretics: May enhance the QTc-prolonging effect of Dofetilide. Monitor therapy

Megestrol: May increase the serum concentration of Dofetilide. Avoid combination

MetFORMIN: May increase the serum concentration of Dofetilide. Monitor therapy

Mifepristone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Prochlorperazine: May increase the serum concentration of Dofetilide. Avoid combination

Propafenone: May enhance the arrhythmogenic effect of Antiarrhythmic Agents (Class III). Management: Concurrent use of propafenone with quinidine, amiodarone, or other class IA or class III antiarrhythmics should be avoided. Treatment with such agents should be withheld for at least 5 half-lives prior to initiation of propafenone. Avoid combination

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Saquinavir: May enhance the arrhythmogenic effect of Dofetilide. Saquinavir may increase the serum concentration of Dofetilide. Avoid combination

Thiazide and Thiazide-Like Diuretics: May enhance the QTc-prolonging effect of Dofetilide. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Dofetilide. Avoid combination

Triamterene: May increase the serum concentration of Dofetilide. Monitor therapy

Trimethoprim: May decrease the excretion of Dofetilide. Avoid combination

Verapamil: May increase the serum concentration of Dofetilide. Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Torsades de pointes (patients receiving doses in excess of those recommended: ≤11%; cardiac failure patients: 3%; patients with recent myocardial infarction: <1%; occurs most frequently within the first 3 days of therapy)

Central nervous system: Headache (11%)

1% to 10%:

Cardiovascular: Chest pain (10%), ventricular fibrillation (≤5%), ventricular tachycardia (3% to 4%), bradycardia (≤2%), cardiac arrest (≤2%), cerebral ischemia (≤2%), cerebrovascular accident (≤2%), edema (≤2%), myocardial infarction (≤2%), syncope (≤2%), atrioventricular block (<2%), heart block (1%)

Central nervous system: Dizziness (8%), insomnia (4%), facial paralysis (≤2%), flaccid paralysis (≤2%), migraine (≤2%), paralysis (≤2%), paresthesia (≤2%)

Dermatologic: Skin rash (3%)

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

Hepatic: Hepatotoxicity (≤2%), hepatic injury (<2%)

Hypersensitivity: Angioedema (≤2%)

Neuromuscular & skeletal: Back pain (3%)

Respiratory: Respiratory tract infection (7%), dyspnea (6%), flu-like symptoms (4%), increased cough (≤2%), cough (<2%)

Miscellaneous: Accidental injury (3%), surgery (3%)

<1% (Limited to important or life-threatening): Bundle branch block

ALERT: U.S. Boxed Warning

Arrhythmias:

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on dofetilide should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation.

Warnings/Precautions

Concerns related to adverse effects:

• Proarrhythmic effects: May cause serious ventricular arrhythmias, primarily torsades de pointes (TdP). Watch for proarrhythmic effects; monitor and adjust dose to prevent QTc prolongation; reduced CrCl or certain dofetilide drug interactions will increase dofetilide plasma concentration. Risk of TdP significantly increases with doses greater than the maximum dose of 500 mcg twice daily. The risk of TdP may be higher in certain patient subgroups (eg, patients with heart failure). Most episodes of TdP occur within the first 3 days of therapy.

Disease-related concerns:

• Arrhythmias: Appropriate use: Reserve for patients who are highly symptomatic with atrial fibrillation/atrial flutter. [US Boxed Warning]: Must be initiated (or reinitiated) in a setting that can provide continuous monitoring of CrCl and ECG monitoring and cardiac resuscitation with staff familiar with the recognition and treatment of life-threatening arrhythmias 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: Use with caution in patients with second or third-degree heart block and/or sick sinus syndrome unless a functional pacemaker is in place; these patients were not included in phase 3 clinical trials. However, no effect on AV nodal conduction seen in patients with normal conduction and those with first-degree heart block. 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 (has not been studied).

• Renal impairment: Use with caution in patients with renal impairment; systemic clearance of dofetilide is decreased and plasma concentration increased with decreasing CrCl. Dose adjustment is required for patients with CrCl ≤60 mL/minute.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Monitoring Parameters

ECG monitoring with attention to QT (if heart rate <60 beats per minute) or QTc and occurrence of ventricular arrhythmias, baseline serum creatinine and changes in serum creatinine. Upon initiation (or reinitiation) continuous ECG monitoring recommended for a minimum of 3 days, or for at least 12 hours after electrical or pharmacological conversion to normal sinus rhythm, whichever is greater. Monitor serum potassium and magnesium levels at baseline and throughout therapy. QT or QTc must be monitored at baseline prior to the first dose and 2 to 3 hours afterwards. If at baseline, QTc >440 msec (>500 msec in patients with ventricular conduction abnormalities), use is contraindicated. If dofetilide initiated, QTc interval must be determined 2 to 3 hours after each subsequent dose of dofetilide for in-hospital doses 2 to 5. Thereafter, QT or QTc and CrCl should be evaluated every 3 months. If at any time during therapy after the second dose the measured QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), dofetilide should be discontinued.

Consult individual institutional policies and procedures.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache or nausea. Have patient report immediately to prescriber signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of severe cerebrovascular disease (change in strength on one side is greater than the other, trouble speaking or thinking, change in balance, or change in eyesight), sweating a lot, dehydration, vomiting, diarrhea, lack of appetite, thirsty, burning or numbness feeling, angina, severe dizziness, passing out, bradycardia, tachycardia, arrhythmia, shortness of breath, or swelling of arm or leg (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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