Skip to main content

Dofetilide (Monograph)

Brand name: Tikosyn
Drug class: Class III Antiarrhythmics
VA class: CV300
Chemical name: N-[4-[2-[Methyl[2-[4-[(methylsulfonyl)amino]phenoxy]ethyl]amino]ethyl]phenyl] methanesulfonamide
Molecular formula: C19H27N3O5S2
CAS number: 115256-11-6

Medically reviewed by Drugs.com on May 23, 2024. Written by ASHP.

Warning

Risk Evaluation and Mitigation Strategy (REMS):

FDA approved a REMS for dofetilide to ensure that the benefits outweigh the risks. However, FDA later rescinded REMS requirements. See https://www.accessdata.fda.gov/scripts/cder/rems/.

Warning

  • Because of the arrhythmogenic potential, hospitalize and monitor closely (provision of Clcr calculations, continuous ECG monitoring, and cardiac resuscitation) patients for 3 days during treatment initiation. (See Arrhythmogenic Effects under Cautions.)

  • Clinicians and pharmacies in institutions must confirm their participation in a designated Tikosyn educational program before prescribing or ordering the drug. (See Restricted Distribution Program under Dosage and Administration.)

Introduction

Class III antiarrhythmic agent; a methanesulfonamide derivative.

Uses for Dofetilide

Supraventricular Tachyarrhythmias

Maintenance of normal sinus rhythm in patients with previous atrial fibrillation/atrial flutter of >1 week’s duration. Reserve for patients in whom atrial fibrillation/atrial flutter was highly symptomatic.

Conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. Has not been shown to be effective in patients with paroxysmal atrial fibrillation.

Dofetilide Dosage and Administration

General

Restricted Distribution Program

Renal Function Assessment

Ccr male = [(140 - age) × weight (in kg)] / [72 × serum creatinine (in mg/dL)] Ccr female = 0.85 × Ccr male

QT Interval Determination

Drug Transfer

Administration

Administer orally twice daily without regard to meals.

Dosage

Adults

Supraventricular Tachyarrhythmias
Oral

Initially, 500 mcg twice daily; modify dosage according to Clcr and QTc interval. (See Table 1 and Table 2.)

Table 1. Initial Dosage in Adults Based on Renal Function

Calculated Clcr (mL/minute)

Dosage

>60

500 mcg twice daily

40–60

250 mcg twice daily

20 to <40

125 mcg twice daily

<20

Dofetilide is contraindicated

Within 2–3 hours after administration of the first dose, determine the QTc interval. If QTc interval has increased by >15% or >500 msec (550 msec in patients with ventricular conduction abnormalities), adjust subsequent dosages as follows:

Table 2. Dosage Modification for QTc Prolongation

Initial Dosage (Based on Clcr)

Adjusted Dosage (for QTc Prolongation)

500 mcg twice daily

250 mcg twice daily

250 mcg twice daily

125 mcg twice daily

125 mcg twice daily

125 mcg once daily

For subsequent monitoring of the QT interval, see QT Interval Determination under Dosage and Administration.

Therapy may be initiated at lower dosages due to the risk of torsades de pointes.

Prescribing Limits

Adults

Supraventricular Tachyarrhythmias
Oral

Dosages >500 mcg twice daily have been associated with an increased incidence of torsades de pointes. (See Arrhythmogenic Effects under Cautions.)

Special Populations

Hepatic Impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh class A or B). Use with particular caution in patients with severe hepatic insufficiency (Child-Pugh class C).

Renal Impairment

Modify dosage according to the degree of renal impairment. (See Table 1.) For calculation of the patient’s Clcr, see Renal Function Assessment under Dosage and Administration.

Not studied in those undergoing dialysis; dosage recommendations are not known.

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function. (See Table 1.)

Cautions for Dofetilide

Contraindications

Warnings/Precautions

Warnings

Arrhythmogenic Effects

May cause serious ventricular arrhythmias, principally polymorphic ventricular tachycardia associated with QT interval prolongation (i.e., torsades de pointes). Generally occurs within the first 3 days of initiation of therapy. The risk is threefold greater in women than in men. (See Boxed Warnings.)

Reduce risk of torsades de pointes by controlling the plasma concentration (e.g., adjustment of initial dofetilide dosage according to Clcr, avoiding certain drug interactions) and monitoring the ECG for excessive increases in the QT interval.

Mortality

Limited evidence suggests a possible excess mortality as a result of dofetilide use.

General Precautions

Cardiovascular Conduction

No apparent adverse effects on conduction velocity. AV nodal conduction unaffected in normal volunteers or in patients with first degree heart block. Used safely in conjunction with pacemakers.

Metabolic Effects

Hypokalemia or hypomagnesemia may increase the risk of torsades de pointes. Closely monitor patients experiencing prolonged or excessive diarrhea, sweating, vomiting, loss of appetite, or thirst. Closely monitor patients receiving concomitant therapy with drugs that may increase the risk of such electrolyte imbalance (e.g., diuretics). (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category C.

Lactation

Not known whether dofetilide is distributed into milk. Use not recommended.

Pediatric Use

Safety and efficacy not established.

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults. Select dosage with caution because of age-related decreases in renal function.

Renal Impairment

If clearance is decreased, dosage adjustments are necessary depending on degree of renal impairment. Safety and efficacy not established in patients with Clcr <20 mL/minute. (See Table 1 under Dosage and Administration for dosage adjustment based on Clcr.)

Hepatic Impairment

Not studied in patients with severe hepatic impairment; use with particular caution in these patients. (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Headache, chest pain, dizziness.

Drug Interactions

Metabolized by CYP3A4, but has a low affinity for this isoenzyme. Does not inhibit CYP isoenzymes.

Carefully screen patient’s medication history, including all OTC, prescription, and herbal/natural preparations with emphasis on those that may affect dofetilide pharmacokinetics. If discontinuance of dofetilide is necessary to permit administration of potentially interacting drug(s), allow a washout period of at least 2 days.

Drugs Inhibiting Renal Tubular Cationic Transport

Pharmacokinetic interaction (decreased dofetilide elimination). May increase the risk of torsades de pointes (See Elimination under Pharmacokinetics, and see Contraindications under Cautions.) Use concurrent therapy with care.

Drugs Secreted by Renal Tubular Cationic Transport

Potential pharmacokinetic interaction (decreased dofetilide elimination and increased plasma concentration). May increase risk of torsades de pointes.

Use concurrent therapy with care.

Substances Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (decreased dofetilide metabolism and possible increased systemic exposure). Concomitant use not recommended.

Drugs that Prolong QT Interval

Potential pharmacodynamic interaction (increased risk of ventricular arrhythmias). Concomitant use not recommended.

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiloride

Potential decreased dofetilide elimination and increased plasma dofetilide concentrations; possible increased risk of torsades de pointes

Use concomitantly with caution

Amiodarone

Potential increased plasma dofetilide concentrations; possible increased risk of ventricular arrhythmias

Withhold amiodarone for at least 3 months or until serum amiodarone concentrations are <0.3 mcg/mL prior to administering dofetilide

Amlodipine

Pharmacokinetic interaction unlikely

Antacids (aluminum or magnesium hydroxides)

Pharmacokinetic interaction unlikely

Consider as alternative therapy for cimetidine

Antiarrhythmic agents

Possible increased risk of ventricular arrhythmias

Concomitant use not recommended. Withhold class I and class III antiarrhythmic agents for at least 3 half-lives prior to initiating dofetilide

Antidepressants, tricyclic

Possible increased risk of ventricular arrhythmias

Concomitant use not recommended

Antifungal agents, azole

Potential decreased dofetilide metabolism and possible increased systemic exposure; possible increased risk of torsades de pointes

Use certain azoles concomitantly with caution

Concomitant use of ketoconazole is contraindicated

Antiretroviral agents, HIV protease inhibitors

Potential decreased dofetilide metabolism and possible increased systemic exposure; possible increased risk of torsades de pointes

Use concomitantly with caution

Bepridil

Possible increased risk of ventricular arrhythmias

Concomitant use not recommended

Cannabinoids

Potential decreased dofetilide metabolism and possible increased systemic exposure; possible increased risk of torsades de pointes

Use concomitantly with caution

Cimetidine

Decreased dofetilide elimination; possible increased risk of torsades de pointes

Concomitant use contraindicated

Cisapride

Possible increased risk of ventricular arrhythmias

Concomitant use not recommended

Digoxin

Pharmacokinetic interaction unlikely. Uncertain potential pharmacodynamic interaction (increased risk of torsades de pointes).

Diltiazem

Potential decreased dofetilide metabolism and possible increased systemic exposure; possible increased risk of torsades de pointes

Use concomitantly with caution

Diuretics, potassium-depleting

Possible increased risk of electrolyte imbalance (i.e., hypokalemia or hypomagnesemia) and increased risk of torsades de pointes

Close monitoring recommended during concomitant therapy

Concomitant use of hydrochlorothiazide or in combination with triamterene is contraindicated

Glyburide

Pharmacokinetic interaction with dofetilide unlikely

Grapefruit juice

Potential decreased dofetilide metabolism and possible increased systemic exposure; possible increased risk of torsades de pointes

Use concomitantly with caution

Hormone replacement therapy

Pharmacokinetic interaction unlikely

Hydrochlorothiazide (with or without triamterene)

Increased dofetilide AUC and peak plasma concentrations; possible increased risk of QT interval prolongation

Concomitant use contraindicated

Ketoconazole

Decreased dofetilide elimination; possible increased risk of torsades de pointes

Concomitant use contraindicated

Macrolides, oral

Possible increased risk of ventricular arrhythmias

Concomitant use not recommended

Megestrol

Decreased dofetilide elimination; possible increased risk of torsades de pointes

Concomitant use contraindicated

Metformin

Decreased dofetilide elimination and increased plasma dofetilide concentration; possible increased risk of torsades de pointes

Use concomitantly with caution

Nefazodone

Potential decreased dofetilide metabolism and increased systemic exposure; possible increased risk of torsades de pointes

Use concomitantly with caution

Norfloxacin

Potential decreased dofetilide metabolism and increased systemic exposure; possible increased risk of torsades de pointes

Use concomitantly with caution

Omeprazole

Pharmacokinetic interaction unlikely

Consider as alternative therapy for cimetidine

Oral contraceptives

Pharmacokinetic interaction unlikely

Phenothiazines

Possible increased risk of ventricular arrhythmias

Concomitant use not recommended

Phenytoin

Pharmacokinetic interaction unlikely

Prochlorperazine

Decreased dofetilide elimination; possible increased risk of torsades de pointes

Concomitant use contraindicated

Propranolol

Pharmacokinetic interaction unlikely

Quinine

Potential decreased dofetilide metabolism and increased systemic exposure; possible increased risk of torsades de pointes

Use concomitantly with caution

Ranitidine

Pharmacokinetic interaction unlikely

Consider ranitidine as alternative therapy for cimetidine

SSRIs

Potential decreased dofetilide metabolism and increased systemic exposure; possible increased risk of torsades de pointes

Use concomitantly with caution

Theophylline

Pharmacokinetic interaction unlikely

Triamterene

Potential decreased dofetilide elimination and increased plasma concentrations

Use concomitantly with caution

Concomitant use of hydrochlorothiazide in combination with triamterene is contraindicated

Trimethoprim (with or without sulfamethoxazole)

Decreased dofetilide elimination; possible increased risk of torsades de pointes

Concomitant use contraindicated

Verapamil

Increased plasma dofetilide concentrations; possible increased risk of torsades de pointes

Concomitant use contraindicated

Warfarin

Pharmacodynamic or pharmacokinetic interaction unlikely

Zafirlukast

Potential decreased dofetilide metabolism and possible increased systemic exposure; possible increased risk of torsades de pointes

Use concomitantly with caution

Dofetilide Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is >90%. Peak plasma concentrations are attained within 2–3 hours. Steady-state plasma concentrations are attained within 2–3 days.

Food

Food delays absorption but does not affect total bioavailability.

Distribution

Extent

Apparent volume of distribution is 3 L/kg. In animal studies, in utero growth and survival is affected adversely. Not known whether dofetilide is distributed into human milk.

Plasma Protein Binding

60–70%.

Elimination

Metabolism

Metabolized by CYP3A4, but the drug has a low affinity for this isoenzyme.

Elimination Route

Excreted principally in urine (80%); urinary excretion is mainly as unchanged drug (80%) and inactive or minimally active metabolites (20%). Eliminated via glomerular filtration and active tubular secretion.

Half-life

Terminal half-life is approximately 10 hours.

Special Populations

With decreasing Clcr (renal impairment), the overall drug systemic clearance is decreased and plasma concentration increased. Not known whether hemodialysis removes dofetilide from plasma.

Pharmacokinetics not altered in patients with mild to moderate hepatic insufficiency (Child-Pugh class C). Pharmacokinetics not studied in patients with severe hepatic insufficiency (Child-Pugh class C).

Stability

Storage

Oral

Capsules and Tablets

15–30°C in tight, well closed containers. Protect from moisture and humidity.

Actions

Advice to Patients

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of dofetilide is restricted. (See Restricted Distribution Program under Dosage and Administration.)

Dofetilide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

0.125 mg

Tikosyn

Pfizer

0.25 mg

Tikosyn

Pfizer

0.5 mg

Tikosyn

Pfizer

AHFS DI Essentials™. © Copyright 2024, Selected Revisions June 2, 2016. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

Reload page with references included