dofetilide
Tikosyn

Available forms
Available by prescription only
Capsules: 125 mcg (0.125 mg), 250 mcg (0.25 mg), 500 mcg (0.5 mg)

Indications and dosages
 Maintenance of normal sinus rhythm in patients with symptomatic atrial fibrillation or atrial flutter for longer than 1 week; conversion of atrial fibrillation and atrial flutter to normal sinus rhythm. Adults: Dosage is individualized and based on creatinine clearance and QTc interval, which must be determined before first dose. Usual recommended dosage is 500 mcg P.O. b.i.d. for patients with creatinine clearance greater than 60 ml/minute.
≡ Dosage adjustment. Adjust dosage based on the following schedule.

Creatinine clearance (ml/min) Starting dose 40-60 250 mcg P.O. b.i.d. 20-39 125 mcg P.O. b.i.d.

 At 2 to 3 hours after first dose, determine QTc interval. If it has increased by more than 15% over baseline, or if it’s more than 500 msec (550 msec in patients with ventricular conduction abnormalities), adjust dosage as follows: If starting dose based on creatinine clearance was 500 mcg P.O. b.i.d., give 250 mcg P.O. b.i.d. If starting dose based on creatinine clearance was 250 mcg P.O. b.i.d., give 125 mcg P.O. b.i.d. If starting dose based on creatinine clearance was 125 mcg P.O. b.i.d., give 125 mcg P.O. once daily.
 Determine QTc interval 2 to 3 hours after each subsequent dose while patient is hospitalized. If at any time after second dose QTc interval is more than 500 msec (550 msec in patients with ventricular conduction abnormalities), stop drug.

Pharmacodynamics
Antiarrhythmic action: Drug prolongs repolarization without affecting conduction velocity by blocking the cardiac ion channel carrying potassium current. No effect is seen on sodium channels, alpha-adrenergic receptors, or beta-adrenergic receptors.

Pharmacokinetics
Absorption: Bioavailability after oral administration is greater than 90% with plasma levels peaking in 2 to 3 hours. Steady state plasma levels are achieved in 2 to 3 days. Absorption unaffected by food or antacid.
Distribution: Widely distributed throughout body; has a distribution volume of 3 L/kg. Plasma protein- binding is 60% to 70%.
Metabolism: Metabolized to a small extent by CYP3A4 isoenzyme of cytochrome P-450 system of the liver.
Excretion: About 80% is excreted in urine, of which 80% is excreted as unchanged drug with remaining 20% as inactive or minimally active metabolites.

Contraindications and precautions
Contraindicated in patients with creatinine clearance less than 20 ml/minute and in those with congenital or acquired long QT interval syndrome. Don’t use in patients with baseline QTc interval greater than 440 msec (500 msec in patients with ventricular conduction abnormalities). Use cautiously in patients with severe hepatic impairment.
  Drug is distributed only to hospitals and other institutions confirmed to have received applicable dosing and treatment initiation programs. Such confirmation is also needed for inpatient and subsequent outpatient discharge and refill prescriptions.

Interactions
Drug-drug. Amiloride, amiodarone, diltiazem, macrolide antibiotics, metformin, nefazodone, norfloxacin, protease inhibitors, quinine, serotonin reuptake inhibitors, triamterene, zafirlukast: May increase plasma dofetilide levels. Use together cautiously.
Class I, class III antiarrhythmics: Effect hasn’t been studied; concomitant use isn’t recommended. Hold antiarrhythmics for at least three half-lives before giving dofetilide.
Digoxin: May increase risk of torsades de pointes. Monitor ECG closely if used together.
Drugs that inhibit renal cation transport system (cimetidine, ketoconazole, megestrol, prochlorperazine, sulfamethoxazole, trimethoprim), verapamil: Decreases dofetilide metabolism and excretion and increases plasma levels. Don’t use together.
Drugs that prolong QT interval (bepridil, oral macrolides, phenothiazines, tricyclic antidepressants): May enhance QT interval prolongation. Don’t use together.
Inhibitors of the CYP3A4 isoenzyme (amiodarone, azole antifungals, cannabinoids, diltiazem, macrolides, nefazodone, norfloxacin, protease inhibitors, quinine, serotonin reuptake inhibitors, zafirlukast): May increase dofetilide levels. Monitor patient for toxicity.
Potassium-wasting diuretics: Increases risk of torsades de pointes. Maintain potassium levels within normal range before and throughout drug therapy.
Drug-food. Grapefruit juice: May decrease hepatic metabolism and increase plasma levels. Tell patient not to use together.

Adverse reactions
CNS: headache, dizziness, syncope, paresthesia, insomnia, anxiety, migraine, cerebral ischemia, facial paralysis, CVA.
CV: ventricular fibrillation, ventricular tachycardia, torsades de pointes, AV block,chest pain, bradycardia, edema, cardiac arrest, sudden death, MI, QT prolongation, atrial fibrillation, hypertension.
GI: nausea, diarrhea, abdominal pain.
GU: urinary tract infection.
Hepatic: liver damage.
Musculoskeletal: back pain, arthralgia, flaccid paralysis.
Respiratory: respiratory tract infection, dyspnea, increased cough.
Skin: rash.
Other: flulike syndrome, accidental injury, angioedema.

Effects on lab test results
None reported.

Overdose and treatment
The most likely effect of overdose is excessive prolongation of the QT interval.
 There’s no known antidote. Treatment is symptomatic and supportive. Start cardiac monitoring. Charcoal slurry may be given and is useful especially within first 15 minutes after administration. Treatment of torsades de pointes or overdose may include isoproterenol, with or without cardiac pacing. Magnesium sulfate also may be effective.

Special considerations
• Patients in atrial fibrillation should be anticoagulated according to usual practice before electrical or pharmacologic cardioversion. Anticoagulation therapy may be continued after cardioversion according to usual medical practice.
 ALERT For at least 3 days, patient must be in a facility equipped with ECG monitoring and a staff trained in managing ventricular arrhythmias or patient must be monitored for a minimum of 12 hours after pharmacologic or electrical conversions to normal sinus rhythm, whichever is longer.
 ALERT Patient needs to be hospitalized with every dosage change.
• If a dose is missed, patient shouldn’t double next dose. Instead, patient should skip that dose and wait until the next administration time for regularly scheduled dose.
• Drug is only available to hospitals and prescribers who participated in the Tikosyn education program (877-TIKOSYN).
• Monitor patient for prolonged diarrhea, sweating, or vomiting. These symptoms may indicate an electrolyte imbalance that may increase potential for arrhythmia.
• Monitor renal function and QTc interval routinely (at least every 3 months) and creatinine clearance. • Withhold class I or III antiarrhythmics for at least 3 half-lives before starting drug.
Breast-feeding patients
• Drug’s effects in breast-fed infants aren’t known; advise women not to breast-feed while taking drug.
Pediatric patients
• Safety and effectiveness in patients younger than age 18 haven’t been established.
Geriatric patients
• There’s no change in elimination based on age when dosage is adjusted for renal function.

Patient education
• Urge patient to report any change in OTC, prescription, or supplement or herb use.
• Tell patient not to use OTC Tagamet-HB for ulcers or heartburn and that antacids, Zantac 75 mg, and other acid-reduction drugs, such as Pepcid, Prilosec, Axid, and Prevacid, can be used.
• Inform patient that dofetilide can be taken without regard to meals or antacid administration.
• Inform patient that grapefruit juice can decrease metabolism of drug and lead to toxicity.
• Advise patient that, if a dose is missed, not to double next dose. Instead, tell patient to skip that dose and wait until the next administration time for regularly scheduled dose.
• Instruct woman to call if she becomes pregnant.
• Advise woman not to breast-feed while taking drug.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use