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Dofetilide

Pronouncation: (doe-FEH-till-ide)
Class: Antiarrhythmic agent

Trade Names:
Tikosyn
- Capsules 125 mcg
- Capsules 250 mcg
- Capsules 500 mcg

Pharmacology

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Blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium currents.

Pharmacokinetics

Absorption

Bioavailability greater than 90%. T _max is 2 to 3 h.

Distribution

60% to 70% protein bound. Vd is 3 L/kg.

Metabolism

Metabolized by N-delkylation and N-oxidation, and to a lesser extent by CYP3A4.

Elimination

t _½ approximately 10 h. Approximately 80% excreted in urine of which approximately 80% is unchanged drug.

Special Populations

Renal Function Impairment

Cl is decreased and t _½ is prolonged. Dosage adjustment recommended.

Gender

Women have approximately 12% to 18% lower Cl.

Indications and Usage

Maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with AF/AFl of more than 1 wk duration who have been converted to normal sinus rhythm; conversion of AF/AFl to normal sinus rhythm.

Unlabeled Uses

Ventricular arrhythmias.

Contraindications

Hypersensitivity to drug; congenital or acquired long QT syndromes; baseline QT interval of QTc greater than 440 msec (500 msec in patients with ventricular conduction abnormalities); severe renal function impairment (Ccr less than 20 mL/min); concurrent use of cimetidine, ketoconazole, trimethoprim (alone or in combination with sulfamethoxazole), or verapamil; concomitant use of known inhibitors of renal cation transport (eg, megestrol, prochlorperazine).

Dosage and Administration

Adults

PO The dose must be individualized according to calculated Ccr and QTc. Use the QT interval if the heart rate is less than 60 bpm. There are no data on use if the heart rate is less than 50 bpm. The usual recommended dose is 500 mcg twice daily, as modified by the dosing algorithm described in the manufacturer's prescribing information.

General Advice

Administer first 3 days of therapy to patient who is on continuous ECG monitoring.
If a dose is missed do not double up. Give next dose at scheduled time.

Storage/Stability

Store capsules at controlled room temperature. Protect from moisture.

Drug Interactions

Cimetidine, inhibitors of renal cationic exchange (eg, megestrol, phenothiazines), ketoconazole, trimethoprim (alone or in combination with sulfamethoxazole), verapamil

Contraindicated.

Drugs actively secreted by renal cationic secretion (eg, amiloride, metformin, triamterene), inhibitors of CYP3A4 isozymes (eg, amiodarone, azole antifungal agents, cannabinoids, diltiazem, grapefruit juice, macrolide antibiotics, nefazodone, norfloxacin, protease inhibitors, quinine, serotonin reuptake inhibitors, zafirlukast)

May increase dofetilide levels; use with caution.

Class I (eg, quinidine) or Class III (eg, sotalol) antiarrhythmics

Withhold for at least 3 half-lives prior to dosing with dofetilide.

Drugs that prolong the QT interval (eg, bepridil, cisapride, phenothiazines, tricyclic antidepressants, erythromycin)

Concurrent use not recommended.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Ventricular tachyarrhythmia; chest pain; torsades de pointes; AV block; bundle branch block; heart block; angioedema; bradycardia; cerebral ischemia; cerebrovascular accident; cardiac arrest; MI; syncope.

CNS

Headache; dizziness; insomnia; migraine.

Dermatologic

Rash.

EENT

Increased cough.

GI

Diarrhea; abdominal pain.

Hepatic

Liver damage.

Respiratory

Respiratory tract infection; dyspnea.

Miscellaneous

Flu syndrome; back pain; edema; facial paralysis; paralysis; paresthesia; sudden death.

Precautions

Warnings

Equipped facility

Administer in an equipped facility that can provide Ccr calculations, continuous ECG monitoring, and resuscitation for at least 3 days when therapy is initiated or restarted.

Restricted distribution

Restrict distribution to facilities/prescribers who have received approved educational program.

Monitor

Ensure that Ccr has been calculated and the QTc interval and serum potassium have been determined before initiating therapy and periodically (at least every 3 mo) during treatment. Determine QTc interval 2 to 3 h after first dose and note change from baseline QTc interval. Notify health care provider if it has increased more than 15% or is greater than 500 msec. Monitor ECG for arrhythmias and conduction changes.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

Select dose with caution, reflecting the greater frequency of decreased renal function.

Renal Function

Plasma concentrations of dofetilide may be increased; dosage must be adjusted based on Ccr.

Hepatic Function

Use with caution in patients with severe hepatic function impairment.

Potassium levels

Should be within normal range prior to and during administration of drug.

Torsades de pointes

Risk may be reduced by controlling plasma concentrations of dofetilide by dosing according to Ccr and monitoring ECG.

Overdosage

Symptoms

Prolongation of the QT interval, ventricular fibrillation, cardiac arrest.

Patient Information

Advise patient that each dose may be taken without regard to meals.
Instruct patient that if a dose is missed, do not double up. Advise patient to take the next dose at the usual time.
Caution patient NOT to change the dose or discontinue therapy unless advised to do so by health care provider.
Instruct patient in BP and pulse measurement skills.
Instruct patient to immediately report any of these symptoms to health care provider: dizziness or weakness associated with change in pulse; excessive or prolonged diarrhea, sweating or vomiting; loss of appetite or thirst.
Instruct patient to notify health care provider if they are hospitalized or prescribed a new medication for any condition.