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.

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

• Initiate therapy and adjust dosage in a hospital setting where the patient can be monitored by personnel trained in the management of serious ventricular arrhythmias. (See Boxed Warnings.) Closely monitor patients for 3 days (until steady-state plasma concentrations are obtained) whenever treatment is initiated or dosage is increased. When the dosage is increased, the need for rehospitalization is not eliminated by previously successful use of such dosages.

• Individualize dosage carefully according to calculated Cl_cr and QT_c interval. Prior to treatment initiation, calculate the Cl_cr and determine QT_c interval. (See QT Interval Determination under Dosage and Administration.)

• Administer appropriate anticoagulant therapy in patients with atrial fibrillation.

• Maintain serum potassium concentrations within the normal range before treatment initiation and during therapy.

Restricted Distribution Program

• Must be obtained through a restricted distribution program. Not available through community pharmacies.

• May verify the status of clinicians who have participated in required education programs via the Internet ([Web]).

• For information regarding participation in such educational programs, contact the manufacturer at 877-845-6796.

Renal Function Assessment

• Prior to treatment initiation, calculate the Cl_cr. Reduce initial dosage if Cl_cr <60 mL/minute. (See Table 1.)

• Because the increase in the QT interval and the risk of ventricular arrhythmias are directly related to plasma drug concentrations, adjust dosage based on calculated Cl_cr.

• Estimate the patient’s Cl_cr by using the following formulas:

• Reevaluate renal function every 3 months or as medically warranted. If renal function deteriorates, adjust dosage. (See Table 1.)

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

QT Interval Determination

• Prior to treatment initiation, determine the QT_c interval using an average of 5–10 beats or the QT interval, if the heart rate is <60 bpm.

• Use is contraindicated if the QT_c interval >440 msec (500 msec in patients with ventricular conduction abnormalities). (See Contraindications under Cautions.)

• Within 2–3 hours after administering the first dose, determine the QT_c interval again. Adjust subsequent dosage based on the QT_c interval. (See Table 2.)

• Within 2–3 hours after each subsequent dose (for in-hospital doses 2–5), determine the QT_c interval. No further downward titration of dosage based on QT_c interval is recommended. However, if at any time after the second dose is given the QT_c >500 msec (550 msec in patients with ventricular conduction abnormalities), discontinue use.

• Perform continuous ECG monitoring for a minimum of 3 days or for a minimum of 12 hours after electrical or pharmacologic conversion to normal sinus rhythm, whichever is greater.

• Reevaluate QT_c interval every 3 months or as medically warranted. If QT_c >500 msec (550 msec in patients with ventricular conduction abnormalities), discontinue use and carefully monitor the patient until the QT_c interval returns to baseline values.

Drug Transfer

• A transition period is recommended prior to initiating therapy in patients receiving other antiarrhythmic agents. Withhold class I and class III antiarrhythmic agents for ≥3 half-lives prior to initiating dofetilide. Withhold amiodarone for ≥3 months or until serum amiodarone concentrations are <0.3 mcg/mL prior to administering dofetilide. (See Drugs that Prolong QT Interval under Interactions.)

Administration

Administer orally twice daily without regard to meals.

Dosage

Adults

Supraventricular Tachyarrhythmias

Oral

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

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

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 Cl_cr, 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

• Congenital or acquired long QT syndromes; baseline QT or QT_c interval >440 msec (500 msec in patients with ventricular conduction abnormalities).

• Severe renal impairment (calculated Cl_cr <20 mL/minute).

• Concomitant use of verapamil or cation transport system inhibitors (e.g., cimetidine, ketoconazole, megestrol, prochlorperazine, or trimethoprim [alone or in combination with sulfamethoxazole]). (See Specific Drugs under Interactions.)

• Concomitant use of hydrochlorothiazide alone or in combination with triamterene.

• Known hypersensitivity to dofetilide.

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 Cl_cr, 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 Cl_cr <20 mL/minute. (See Table 1 under Dosage and Administration for dosage adjustment based on Cl_cr.)

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

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 Cl_cr (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

• More selective in its cellular actions than some other class III antiarrhythmic agents (e.g., amiodarone, sotalol).

• Prolongs the action potential duration and effective refractory period in both atrial and ventricular cardiac tissue, principally due to delayed repolarization. Selectively inhibits the rapidly activating component of the potassium channel (delayed rectifier potassium current I_Kr) involved in repolarization of cardiac cells.

• Does not affect cardiac conduction velocity and sinus node function. Has no effect on sodium channels (associated with class I antiarrhythmic agents) or β- or α-adrenergic receptors at clinically relevant concentrations.

• Negligible effects on heart rate or BP. May improve slightly cardiac contractility.

Advice to Patients

• Importance of reading the manufacturer’s patient information prior to beginning therapy and rereading it each time the prescription is refilled in case patient status has changed. (See REMS.)

• Importance of informing a clinician immediately if new rapid heartbeats, lightheadedness, or fainting occur. If a clinician cannot be contacted, proceed to the nearest hospital emergency room.

• Importance of informing a clinician immediately if excessive or prolonged diarrhea, sweating, vomiting, or loss of appetite or thirst occurs.

• Importance of adherence to dosage and medical appointment schedule. Take drug at same time each day and omit any missed doses.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

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.)

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