TIKOSYN is indicated for the conversion and maintenance of normal sinus rhythm in highly symptomatic patients with atrial fibrillation/atrial fluter
of greater than 1 week.
TIKOSYN is contraindicated with verapamil, and with cation transport inhibitors such as cimetidine, ketoconazole, trimethoprim (alone or in
combination with sulfamethoxazole). These drugs will increase plasma concentrations of dofetilide.
HCTZ (alone or in combination such as with Triamterene), prochlorperazine, and megestrol. These drugs will inhibit renal cation transport of
Long QT syndrome, If QTc >440 msec (>500 msec in patients with ventricular conduction abnormalities), dofetilide is
Creatinine clearance < 20
Bradycardia (HR < 40 bpm)
Inhibitors of CYP3A4, renal cation transports, drugs that prolong the QT interval, and other antiarrhythmics may increase the risk of proarrhythmia
either by increasing dofetilide exposure or by adding to its QT-prolonging effect.
Class I or III AntiArrhythmics should be witheld at least 3 half-lives before starting Tikosyn
Amiodarone: if level < 0.3 mg/dl or if stopped for 3 months can start Tikosyn
Digoxin: not affected
Check QTc when co-administering these medications as they might increase dofetilide levels: azole antifungal antibiotics, protease inhibitors,
SSRIs, amiodarone, cannabinoids, diltiazem, nefazodone, zafirlukast, norfloxacin, quinine, metformin, amiloride, and grapefruit juice.
Dofetilide is Pregnancy category C (Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in
humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks).
Dofetilide is contraindicated in lactating mothers.
MECHANISM OF ACTION
Dofetilide is a class III antiarrhythmic drug. It increases monophasic Action Potential. It has no effects on Na+ channels, adrenergic alpha
receptors, or adrenergic Beta receptors.
HEMODYNAMIC AND EKG EFFECTS
Dofetilide has no effects on inotropy, Cardiac Output, Stroke Volume, Systemic Vascular Resistance, Blood Pressure, Heart Rate (was
decreased by 4-6 bpm in studies). It has no effect on PR interval, QRS interval, conduction velocity and sinus function.
Dofetilide did not increase the electrical energy needed to CV Vfib and reduce the Vfib threshold in patients with VT/Vf.
The QTc effect prolongation seen on surface EKG is secondary to prolongation of both effective and functional refractory periods in His-Purkinje
system and ventricle.
The QTc prolongation is proportional to the dose and greater on day 1.
Ventricular arrhythmias (Torsades de Pointe, polymorphic VT)
Half-life is 10 hours.
Bioavailability is > 90% (not affected by food).
Protein binding: 60-70%.
Renal excretion: 80%. Metabolised to a small extent by CYP 450. Affected by inhibition of CYP3A9
Dofetilide was evaluated in 3 major trials: DIAMOND-CHF (III, IV), DIAMOND-MI, and EMERALD. (Danish Investigation of Arrhythmia and Mortality ON Dofetilide)
Dofetilide 500 mg twice daily converted 30% of patients to Normal Sinus Rhythm (vs 1% for placebo). 70% of these patients were converted
within 24-36 hours. Probability of remaining in sinus rhythm at 12 months was 58% (vs 25 % placebo) - 37% for the 250 mg twice daily dosage.
There was no significant Mortality and Morbidity in patients with structural heart disease.
Arrhythmia incidence was 0.9% (at the 500mg twice daily dosage)
Headaches, Chest Pain, dizziness
PRIOR TO STARTING
Discontinue all other antiarrhythmic therapy for a minimum of 3 plamsa half-lives
Discontinue amiodarone for at least 3 months or until amiodarone plasma levels are < 0.3 mcg/ml
Patient should be anticoagulated for at least 3 weeks
Telemetry monitoring should continue for a minimum of 3 days or for 12 hours after conversion to normal sinus rhythm
Digoxin is not contraindicated, however the concomitant administration of digoxin was associated with a higher incidence of torsades de pointe.
(It is not clear whether this represents an interaction with TIKOSYN or the presence of more severe structural heart disease in patients taking digoxin).
Replace K+ to > 4.0 prior to starting Dofetilide.
Ensure the patient will receive a bottle with 14 capsules from the hospital pharmacy
Schedule blood work and ECG re-evaluation every 3 months
Make sure the patient's pharmacy has Tikosyn in stock (pharmacy must be enrolled in the T.I.P.S. program. harmacies may not have TIKOSYN
stocked and may require 24 hours notice.
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CrCl >60 mL/minute: Administer 500 mcg twice daily.
CrCl 40-60 mL/minute: Administer 250 mcg twice daily.
CrCl 20-39 mL/minute: Administer 125 mcg twice daily.
CrCl <20 mL/minute: Contraindicated.
QTc interval should be measured 2-3 hours after the initial dose. If the QTc is
>15% of baseline, or if the QTc is >500 msec (550 msec in patients with
ventricular conduction abnormalities), dofetilide should be reduced. If the
starting dose was 500 mcg twice daily, then reduce to 250 mcg twice daily. If the
starting dose was 250 mcg twice daily, then reduce to 125 mcg twice daily. If the
starting dose was 125 mcg twice daily, then reduce to 125 mcg once daily. If at
any time after the second dose is given the QTc is >500 msec (550 msec in
patients with ventricular conduction abnormalities), dofetilide should be