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Generic Name: Dofetilide
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

Warning(s)

  • 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.1 2 (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.1 2 9 10 12 (See Restricted Distribution Program under Dosage and Administration.)

REMS:

FDA approved a REMS for dofetilide to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of dofetilide and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center ().

Introduction

Class III antiarrhythmic agent; a methanesulfonamide derivative.1 2 3 4 5

Uses for Tikosyn

Supraventricular Tachyarrhythmias

Maintenance of normal sinus rhythm in patients with previous atrial fibrillation/atrial flutter of >1 week’s duration.1 2 4 5 11 Reserve for patients in whom atrial fibrillation/atrial flutter was highly symptomatic.1 2 4

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Conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.1 2 4 5 11 Has not been shown to be effective in patients with paroxysmal atrial fibrillation.1 2

Tikosyn 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.1 2 (See Boxed Warnings.) Closely monitor patients for 3 days (until steady-state plasma concentrations are obtained) whenever treatment is initiated or dosage is increased.1 2 12 When the dosage is increased, the need for rehospitalization is not eliminated by previously successful use of such dosages.1 2

  • Individualize dosage carefully according to calculated Clcr and QTc interval.1 2 Prior to treatment initiation, calculate the Clcr and determine QTc interval.1 2 (See QT Interval Determination under Dosage and Administration.)

  • Administer appropriate anticoagulant therapy in patients with atrial fibrillation.1 2

  • Maintain serum potassium concentrations within the normal range before treatment initiation and during therapy.1 2

Restricted Distribution Program

  • Must be obtained through a restricted distribution program.1 2 3 4 5 9 10 Not available through community pharmacies.1 2 9 10 12

  • May verify the status of clinicians who have participated in required education programs via the Internet ().9 10 12 b

  • For information regarding participation in such educational programs, contact the manufacturer at 877-845-6796.9 10 12 b

Renal Function Assessment

  • Prior to treatment initiation, calculate the Clcr.1 2 Reduce initial dosage if Clcr <60 mL/minute.1 2 (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 Clcr.1 2

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

  • Reevaluate renal function every 3 months or as medically warranted.1 If renal function deteriorates, adjust dosage.1 (See Table 1.)1 2

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 QTc interval using an average of 5–10 beats or the QT interval, if the heart rate is <60 bpm.1 2

  • Use is contraindicated if the QTc interval >440 msec (500 msec in patients with ventricular conduction abnormalities).1 2 (See Contraindications under Cautions.)

  • Within 2–3 hours after administering the first dose, determine the QTc interval again.1 2 Adjust subsequent dosage based on the QTc interval.1 2 (See Table 2.)

  • Within 2–3 hours after each subsequent dose (for in-hospital doses 2–5), determine the QTc interval.1 2 12 No further downward titration of dosage based on QTc interval is recommended.1 2 However, if at any time after the second dose is given the QTc >500 msec (550 msec in patients with ventricular conduction abnormalities), discontinue use.1 2

  • 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.1 2

  • Reevaluate QTc interval every 3 months or as medically warranted.1 If QTc >500 msec (550 msec in patients with ventricular conduction abnormalities), discontinue use and carefully monitor the patient until the QTc interval returns to baseline values.1 2

Drug Transfer

  • A transition period is recommended prior to initiating therapy in patients receiving other antiarrhythmic agents.1 2 Withhold class I and class III antiarrhythmic agents for ≥3 half-lives prior to initiating dofetilide.1 Withhold amiodarone for ≥3 months or until serum amiodarone concentrations are <0.3 mcg/mL prior to administering dofetilide.1 (See Drugs that Prolong QT Interval under Interactions.)

Administration

Administer orally twice daily without regard to meals.1 2

Dosage

Adults

Supraventricular Tachyarrhythmias
Oral

Initially, 500 mcg twice daily; modify dosage according to Clcr and QTc interval.1 2 12 (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.1 2 If QTc interval has increased by >15% or >500 msec (550 msec in patients with ventricular conduction abnormalities), adjust subsequent dosages as follows:1 2

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.1 2

Prescribing Limits

Adults

Supraventricular Tachyarrhythmias
Oral

Dosages >500 mcg twice daily have been associated with an increased incidence of torsades de pointes.1 2 (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).1 2 Use with particular caution in patients with severe hepatic insufficiency (Child-Pugh class C).1 2

Renal Impairment

Modify dosage according to the degree of renal impairment.1 2 (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.1

Geriatric Patients

Select dosage with caution because of age-related decreases in renal function.1 2 12 (See Table 1.)

Cautions for Tikosyn

Contraindications

  • Congenital or acquired long QT syndromes; baseline QT or QTc interval >440 msec (500 msec in patients with ventricular conduction abnormalities).1 2

  • Severe renal impairment (calculated Clcr <20 mL/minute).1 2

  • Concomitant use of verapamil or cation transport system inhibitors (e.g., cimetidine, ketoconazole, megestrol, prochlorperazine, or trimethoprim [alone or in combination with sulfamethoxazole]).1 2 b (See Specific Drugs under Interactions.)

  • Concomitant use of hydrochlorothiazide alone or in combination with triamterene.1

  • Known hypersensitivity to dofetilide.1 2 12

Warnings/Precautions

Warnings

Arrhythmogenic Effects

May cause serious ventricular arrhythmias, principally polymorphic ventricular tachycardia associated with QT interval prolongation (i.e., torsades de pointes).1 2 3 4 5 6 7 8 11 Generally occurs within the first 3 days of initiation of therapy.1 2 The risk is threefold greater in women than in men.1 2 (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.1 2

Mortality

Limited evidence suggests a possible excess mortality as a result of dofetilide use.1

General Precautions

Cardiovascular Conduction

No apparent adverse effects on conduction velocity.1 2 AV nodal conduction unaffected in normal volunteers or in patients with first degree heart block.1 2 Used safely in conjunction with pacemakers.1 2

Metabolic Effects

Hypokalemia or hypomagnesemia may increase the risk of torsades de pointes.1 2 Closely monitor patients experiencing prolonged or excessive diarrhea, sweating, vomiting, loss of appetite, or thirst.1 2 Closely monitor patients receiving concomitant therapy with drugs that may increase the risk of such electrolyte imbalance (e.g., diuretics).1 2 (See Specific Drugs under Interactions.)

Specific Populations

Pregnancy

Category C.1 2

Lactation

Not known whether dofetilide is distributed into milk.1 2 Use not recommended.1 2

Pediatric Use

Safety and efficacy not established.1 2

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1 2 Select dosage with caution because of age-related decreases in renal function.1 2 12

Renal Impairment

If clearance is decreased, dosage adjustments are necessary depending on degree of renal impairment.1 b Safety and efficacy not established in patients with Clcr <20 mL/minute.1 2 (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.1 2 (See Hepatic Impairment under Dosage and Administration.)

Common Adverse Effects

Headache, chest pain, dizziness.1

Interactions for Tikosyn

Metabolized by CYP3A4,1 a but has a low affinity for this isoenzyme.1 Does not inhibit CYP isoenzymes.b

Carefully screen patient’s medication history, including all OTC, prescription, and herbal/natural preparations with emphasis on those that may affect dofetilide pharmacokinetics.1 b If discontinuance of dofetilide is necessary to permit administration of potentially interacting drug(s), allow a washout period of at least 2 days.1 b

Drugs Inhibiting Renal Tubular Cationic Transport

Pharmacokinetic interaction (decreased dofetilide elimination).1 2 12 May increase the risk of torsades de pointes1 2 12 (See Elimination under Pharmacokinetics, and see Contraindications under Cautions.) Use concurrent therapy with care.1

Drugs Secreted by Renal Tubular Cationic Transport

Potential pharmacokinetic interaction (decreased dofetilide elimination and increased plasma concentration).1 2 12 May increase risk of torsades de pointes.1 2 12

Use concurrent therapy with care.1

Substances Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP3A4: Potential pharmacokinetic interaction (decreased dofetilide metabolism and possible increased systemic exposure).1 2 12 Concomitant use not recommended.1 12 b

Drugs that Prolong QT Interval

Potential pharmacodynamic interaction (increased risk of ventricular arrhythmias).1 2 Concomitant use not recommended.1 12 b

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Amiloride

Potential decreased dofetilide elimination and increased plasma dofetilide concentrations;1 2 12 possible increased risk of torsades de pointes1 2 12

Use concomitantly with caution1

Amiodarone

Potential increased plasma dofetilide concentrations;1 possible increased risk of ventricular arrhythmias1

Withhold amiodarone for at least 3 months or until serum amiodarone concentrations are <0.3 mcg/mL prior to administering dofetilide1

Amlodipine

Pharmacokinetic interaction unlikely1 b

Antacids (aluminum or magnesium hydroxides)

Pharmacokinetic interaction unlikely1 b

Consider as alternative therapy for cimetidine1 b

Antiarrhythmic agents

Possible increased risk of ventricular arrhythmias1 2

Concomitant use not recommended.1 b 12 Withhold class I and class III antiarrhythmic agents for at least 3 half-lives prior to initiating dofetilide1

Antidepressants, tricyclic

Possible increased risk of ventricular arrhythmias1 2

Concomitant use not recommended1 b 12

Antifungal agents, azole

Potential decreased dofetilide metabolism and possible increased systemic exposure;1 2 12 possible increased risk of torsades de pointes1 2 12

Use certain azoles concomitantly with caution1 b

Concomitant use of ketoconazole is contraindicated1 2

Antiretroviral agents, HIV protease inhibitors

Potential decreased dofetilide metabolism and possible increased systemic exposure;1 2 12 possible increased risk of torsades de pointes2 12

Use concomitantly with caution1 b

Bepridil

Possible increased risk of ventricular arrhythmias1 2

Concomitant use not recommended1 b 12

Cannabinoids

Potential decreased dofetilide metabolism and possible increased systemic exposure;1 2 12 possible increased risk of torsades de pointes1 2 12

Use concomitantly with caution1 b

Cimetidine

Decreased dofetilide elimination; possible increased risk of torsades de pointes1 2 12

Concomitant use contraindicated1 2

Cisapride

Possible increased risk of ventricular arrhythmias1 2

Concomitant use not recommended1 b 12

Digoxin

Pharmacokinetic interaction unlikely.1 2 Uncertain potential pharmacodynamic interaction (increased risk of torsades de pointes).1

Diltiazem

Potential decreased dofetilide metabolism and possible increased systemic exposure;1 2 12 possible increased risk of torsades de pointes1 2 12

Use concomitantly with caution1 b

Diuretics, potassium-depleting

Possible increased risk of electrolyte imbalance (i.e., hypokalemia or hypomagnesemia) and increased risk of torsades de pointes1 2

Close monitoring recommended during concomitant therapy1 2

Concomitant use of hydrochlorothiazide or in combination with triamterene is contraindicated1 2

Glyburide

Pharmacokinetic interaction with dofetilide unlikely1

Grapefruit juice

Potential decreased dofetilide metabolism and possible increased systemic exposure;1 2 12 possible increased risk of torsades de pointes1 2 12

Use concomitantly with caution1 b

Hormone replacement therapy

Pharmacokinetic interaction unlikely1 b

Hydrochlorothiazide (with or without triamterene)

Increased dofetilide AUC and peak plasma concentrations;1 possible increased risk of QT interval prolongation1

Concomitant use contraindicated1

Ketoconazole

Decreased dofetilide elimination;1 2 possible increased risk of torsades de pointes1 2 12

Concomitant use contraindicated1 2

Macrolides, oral

Possible increased risk of ventricular arrhythmias1 2

Concomitant use not recommended1 b 12

Megestrol

Decreased dofetilide elimination;1 2 possible increased risk of torsades de pointes1 2 12

Concomitant use contraindicated1 2

Metformin

Decreased dofetilide elimination and increased plasma dofetilide concentration;1 2 12 possible increased risk of torsades de pointes1 2 12

Use concomitantly with caution1 b

Nefazodone

Potential decreased dofetilide metabolism and increased systemic exposure;1 2 12 possible increased risk of torsades de pointes1 2 12

Use concomitantly with caution1 b

Norfloxacin

Potential decreased dofetilide metabolism and increased systemic exposure;1 2 12 possible increased risk of torsades de pointes1 2 12

Use concomitantly with caution1 b

Omeprazole

Pharmacokinetic interaction unlikely1 2

Consider as alternative therapy for cimetidine1 b

Oral contraceptives

Pharmacokinetic interaction unlikely1 b

Phenothiazines

Possible increased risk of ventricular arrhythmias1 2

Concomitant use not recommended1

Phenytoin

Pharmacokinetic interaction unlikely1 b

Prochlorperazine

Decreased dofetilide elimination;1 2 possible increased risk of torsades de pointes1 2 12

Concomitant use contraindicated1 2

Propranolol

Pharmacokinetic interaction unlikely1 b

Quinine

Potential decreased dofetilide metabolism and increased systemic exposure;1 2 12 possible increased risk of torsades de pointes1 2 12

Use concomitantly with caution1 b

Ranitidine

Pharmacokinetic interaction unlikely1 2

Consider ranitidine as alternative therapy for cimetidine1 b

SSRIs

Potential decreased dofetilide metabolism and increased systemic exposure;1 2 12 possible increased risk of torsades de pointes1 2 12

Use concomitantly with caution1 b

Theophylline

Pharmacokinetic interaction unlikely1 2

Triamterene

Potential decreased dofetilide elimination and increased plasma concentrations1 2 12

Use concomitantly with caution1 b

Concomitant use of hydrochlorothiazide in combination with triamterene is contraindicated1 2

Trimethoprim (with or without sulfamethoxazole)

Decreased dofetilide elimination;2 possible increased risk of torsades de pointes1 2 12

Concomitant use contraindicated1 2

Verapamil

Increased plasma dofetilide concentrations;1 2 possible increased risk of torsades de pointes1 2 12

Concomitant use contraindicated1 2

Warfarin

Pharmacodynamic or pharmacokinetic interaction unlikely1 2

Zafirlukast

Potential decreased dofetilide metabolism and possible increased systemic exposure;1 2 12 possible increased risk of torsades de pointes1 2 12

Use concomitantly with caution1 b

Tikosyn Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability is >90%.1 a Peak plasma concentrations are attained within 2–3 hours.a Steady-state plasma concentrations are attained within 2–3 days.1

Food

Food delays absorption but does not affect total bioavailability.2

Distribution

Extent

Apparent volume of distribution is 3 L/kg.1 In animal studies, in utero growth and survival is affected adversely.1 Not known whether dofetilide is distributed into human milk.1

Plasma Protein Binding

60–70%.1 a

Elimination

Metabolism

Metabolized by CYP3A4,1 a but the drug has a low affinity for this isoenzyme.1

Elimination Route

Excreted principally in urine (80%); urinary excretion is mainly as unchanged drug (80%) and inactive or minimally active metabolites (20%).1 Eliminated via glomerular filtration and active tubular secretion.1

Half-life

Terminal half-life is approximately 10 hours.1 2

Special Populations

With decreasing Clcr (renal impairment), the overall drug systemic clearance is decreased and plasma concentration increased.1 Not known whether hemodialysis removes dofetilide from plasma.1

Pharmacokinetics not altered in patients with mild to moderate hepatic insufficiency (Child-Pugh class C).1 Pharmacokinetics not studied in patients with severe hepatic insufficiency (Child-Pugh class C).1 2

Stability

Storage

Oral

Capsules and Tablets

15–30°C in tight, well closed containers.1 Protect from moisture and humidity.1

Actions

  • More selective in its cellular actions than some other class III antiarrhythmic agents (e.g., amiodarone, sotalol).4 5 7 11

  • Prolongs the action potential duration and effective refractory period in both atrial and ventricular cardiac tissue, principally due to delayed repolarization.1 2 4 5 11 Selectively inhibits the rapidly activating component of the potassium channel (delayed rectifier potassium current IKr) involved in repolarization of cardiac cells.1 2 3 4 5 8 11

  • Does not affect cardiac conduction velocity and sinus node function.1 2 4 5 7 11 Has no effect on sodium channels (associated with class I antiarrhythmic agents) or β- or α-adrenergic receptors at clinically relevant concentrations.1 2 4 11

  • Negligible effects on heart rate or BP.2 4 5 11 12 May improve slightly cardiac contractility.2 4 5 11 12

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.1 2 (See REMS.)

  • Importance of informing a clinician immediately if new rapid heartbeats, lightheadedness, or fainting occur.1 2 If a clinician cannot be contacted, proceed to the nearest hospital emergency room.1 2

  • Importance of informing a clinician immediately if excessive or prolonged diarrhea, sweating, vomiting, or loss of appetite or thirst occurs.1

  • Importance of adherence to dosage and medical appointment schedule.1 2 Take drug at same time each day and omit any missed doses.1 2

  • 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.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 2

  • 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.

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Tikosyn 125MCG Capsules (PFIZER U.S.): 60/$245.15 or 180/$714.17

Tikosyn 250MCG Capsules (PFIZER U.S.): 60/$246.98 or 180/$719.96

Tikosyn 500MCG Capsules (PFIZER U.S.): 60/$245.99 or 120/$479.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions July 27, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer. Tikosyn (dofetilide) capsules prescribing information. New York, NY; 2004 Mar.

2. Pfizer. Tikosyn (dofetilide) product monograph and confirmation of education. New York, NY. From Tikosyn web site (). 2000 March.

3. Anon. Dofetilide for atrial fibrillation. Med Lett Drugs Ther. 2000; 42:41-2.

4. Kalus JS, Mauro VF. Dofetilide: a class III-specific antiarrhythmic agent. Ann Pharmacother. 2000; 34:44-56. [IDIS 439892] [PubMed 10669186]

5. Lenz TL, Hilleman DE. Dofetilide, a new class III antiarrhythmic agent. Pharmacotherapy. 2000; 20:776-86. [IDIS 449491] [PubMed 10907968]

6. Greenbaum RA, Campbell TJ, Channer KS et al. Conversion of atrial fibrillation and maintenance of sinus rhythm by dofetilide: the EMERALD (European and Australian Multicenter Evaluative Research on Atrial Fibrillation Dofetilide) study. Circulation. 1998; 98(Suppl I):I-633. Abstract No. 3326.

7. Torp-Pedersen C, Moller M, Bloch-Thomsen PE et al for the Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. N Engl J Med. 1999; 341:857-65.

8. Stevenson WG, Stevenson LW. Atrial fibrillation in heart failure. N Engl J Med. 1999; 341:910-1. Editorial. [IDIS 434468] [PubMed 10486424]

9. Pfizer. Become a confirmed TIKOSYN prescriber. From web site. Accessed October 11, 2000.

10. Pfizer. Become a confirmed TIKOSYN institution. From web site. Accessed October 11, 2000.

11. McClellan KJ, Markham A. Dofetilide: a review of its use in atrial fibrillation and atrial flutter. Drugs. 1999; 58:1043-59. [PubMed 10651390]

12. Pfizer, New York, NY: Personal communication.

a. Mounsey JP, DiMarco JP. Dofetilide Circulation. 2000; 102:2665-70.

b. Pfizer. Tikosyn (dofetilide) product monograph and confirmation of education. New York, NY. From Tikosyn web site. 2002 March.

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