Brands, Medical Use, Clinical Data
Drug Category
- Antiarrhythmic Agents
- Potassium Channel Blockers
Dosage Forms
Brands / Synonyms
Dofetilida; Dofetilida [Inn-Spanish]; Dofetilide [Usan:Ban:Inn]; Dofetilidum; Dofetilidum [Inn-Latin]; Tikosyn; Tikosyn
Indications
For the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm
Pharmacology
Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties and is indicated for the maintenance of normal sinus rhythm. Dofetilide increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. At concentrations covering several orders of magnitude, Dofetilide blocks only IKr with no relevant block of the other repolarizing potassium currents (e.g., IKs, IK1). At clinically relevant concentrations, Dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.
Mechanism of Action
The mechanism of action of Dofetilide is a blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, IKr. This inhibition of potassium channels results in a prolongation of action potential duration and the effective refractory period of accessory pathways (both anterograde and retrograde conduction in the accessory pathway).
Absorption
>90%
Toxicity
Not Available
Biotrnasformation / Drug Metabolism
Hepatic
Contraindications
TIKOSYN is contraindicated in patients with congenital oracquired long QT syndromes. TIKOSYN should not be used in
patients with a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction
abnormalities). TIKOSYN is also contraindicated in patients with severe renal impairment (calculated creatinine
clearance <20 mL/min).
The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in
combination with sulfamethoxazole) or ketoconazole with TIKOSYN is contraindicated, as each of these drugs cause a
substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation
transport system such as prochlorperazine and megestrol should not be used in patients on TIKOSYN.
The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with TIKOSYN is
contraindicated because this has been shown to significantly increase dofetilide plasma concentrations and QT
interval prolongation.
TIKOSYN is also contraindicated in patients with a known hypersensitivity to the drug.
Drug Interactions
Drug/Laboratory Test Interactions
None known.
Drug-Drug Interactions
Cimetidine: Concomitant use of cimetidine is contraindicated. Cimetidine at 400 mg BID (the usual
prescription dose) co-administered with TIKOSYN (500 mcg BID) for 7 days has been shown to increase dofetilide plasma
levels by 58%. Cimetidine at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide plasma levels
(500 mcg single dose). No studies have been conducted at intermediate doses of cimetidine. If a patient requires
TIKOSYN and anti-ulcer therapy, it is suggested that omeprazole, ranitidine, or antacids (aluminum and magnesium
hydroxides) be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetic profile of
TIKOSYN.
Verapamil: Concomitant use of verapamil is contraindicated. Co-administration of TIKOSYN with verapamil
resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not
significantly increased. In an analysis of the supraventricular arrhythmia and DIAMOND patient populations, the
concomitant administration of verapamil with dofetilide was associated with a higher occurrence of torsade de
pointes.
Ketoconazole: Concomitant use of ketoconazole is contraindicated. Ketoconazole at 400 mg daily (the maximum
approved prescription dose) co-administered with TIKOSYN (500 mcg BID) for 7 days has been shown to increase
dofetilide Cmax by 53% in males and 97% in females, and AUC by 41% in males and 69% in females.
Trimethoprim Alone or in Combination with Sulfamethoxazole: Concomitant use of trimethoprim alone or in
combination with sulfamethoxazole is contraindicated. Trimethoprim 160 mg in combination with 800 mg sulfamethoxazole
co-administered BID with TIKOSYN (500 mcg BID) for 4 days has been shown to increase dofetilide AUC by 103% and
Cmax by 93%.
Hydrochlorothiazide (HCTZ) Alone or in Combination with Triamterene: Concomitant use of HCTZ alone or in
combination with triamterene is contraindicated. HCTZ 50 mg QD or HCTZ/triamterene 50/100 mg QD was co-administered
with TIKOSYN (500 mcg BID) for 5 days (following 2 days of diuretic use at half dose). In patients receiving HCTZ
alone, dofetilide AUC increased by 27% and Cmax by 21%. However, the pharmacodynamic effect increased by
197% (QTc increase over time) and by 95% (maximum QTc increase). In patients receiving HCTZ in combination with
triamterene, dofetilide AUC increased by 30% and Cmax by 16%. However, the pharmacodynamic effect increased by 190%
(QTc increase over time) and by 84% (Maximum QTc increase). The pharmacodynamic effects can be explained by a
combination of the increase in dofetilide exposure and the reductions in serum potassium. In the DIAMOND trials, 1252
patients were treated with TIKOSYN and diuretics concomitantly of whom 493 died compared to 508 deaths among the 1248
patients receiving placebo and diuretics. Of the 229 patients who had potassium depleting diuretics added to their
concomitant medications in the DIAMOND trials, the patients on TIKOSYN had a non-significantly reduced relative risk
for death of 0.68 (95% CI 0.376, 1.230).
Potential Drug Interactions
Dofetilide is eliminated in the kidney by cationic secretion. Inhibitors of renal cationic secretion are
contraindicated with TIKOSYN. In addition, drugs that are actively secreted via this route (e.g., triamterene,
metformin and amiloride) should be co-administered with care as they might increase dofetilide levels.
Dofetilide is metabolized to a small extent by the CYP3A4 isoenzyme of the cytochrome P450 system. Inhibitors of
the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of this isoenzyme (e.g., macrolide
antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids,
diltiazem, grapefruit juice, nefazadone, norfloxacin, quinine, zafirlukast) should be cautiously coadministered with
TIKOSYN as they can potentially increase dofetilide levels. Dofetilide is not an inhibitor of CYP3A4 nor of other
cytochrome P450 isoenzymes (e.g., CYP2C9, CYP2D6) and is not expected to increase levels of drugs metabolized by
CYP3A4.
Other Drug Interaction Information
Digoxin: Studies in healthy volunteers have shown that TIKOSYN does not affect the pharmacokinetics of
digoxin. In patients, the concomitant administration of digoxin with dofetilide was associated with a higher
occurrence of torsade de pointes. It is not clear whether this represents an interaction with TIKOSYN or the presence
of more severe structural heart disease in patients on digoxin; structural heart disease is a known risk factor for
arrhythmia. No increase in mortality was observed in patients taking digoxin as concomitant medication.
Other Drugs: In healthy volunteers, amlodipine, phenytoin, glyburide, ranitidine, omeprazole, hormone
replacement therapy (a combination of conjugated estrogens and medroxyprogesterone), antacid (aluminum and magnesium
hydroxides) and theophylline did not affect the pharmacokinetics of TIKOSYN. In addition, studies in healthy
volunteers have shown that TIKOSYN does not affect the pharmacokinetics or pharmacodynamics of warfarin, or the
pharmacokinetics of propranolol (40 mg twice daily), phenytoin, theophylline, or oral contraceptives.
Population pharmacokinetic analyses were conducted on plasma concentration data from 1445 patients in clinical
trials to examine the effects of concomitant medications on clearance or volume of distribution of dofetilide.
Concomitant medications were grouped as ACE inhibitors, oral anticoagulants, calcium channel blockers, beta blockers,
cardiac glycosides, inducers of CYP3A4, substrates and inhibitors of CYP3A4, substrates and inhibitors of
P-glycoprotein, nitrates, sulphonylureas, loop diuretics, potassium sparing diuretics, thiazide diuretics, substrates
and inhibitors of tubular organic cation transport, and QTc-prolonging drugs. Differences in clearance between
patients on these medications (at any occasion in the study) and those off medications varied between -16% and +3%.
The mean clearances of dofetilide were 16% and 15% lower in patients on thiazide diuretics and inhibitors of tubular
organic cation transport, respectively.
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