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| Clinical data | |
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| Trade names | Tikosyn |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a601235 |
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| Pharmacokinetic data | |
| Bioavailability | 96% (oral) |
| Protein binding | 60% -70% |
| Eliminationhalf-life | 10 hours |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.166.441 |
| Chemical and physical data | |
| Formula | C19H27N3O5S2 |
| Molar mass | 441.56 g·mol−1 |
| 3D model (JSmol) | |
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Dofetilide is a class IIIantiarrhythmic agent.[1] It is marketed under the trade nameTikosyn byPfizer, and is available in theUnited States in capsules containing 125, 250, and 500μg of dofetilide. It is not available in Europe[2] or Australia.[3]
Dofetilide is used for the maintenance ofsinus rhythm in individuals prone to the occurrence ofatrial fibrillation andflutter arrhythmias, and for chemicalcardioversion to sinus rhythm fromatrial fibrillation andflutter.[4][5]
Based on the results of the Danish Investigations of Arrhythmias and Mortality on Dofetilide ("DIAMOND") study,[6] dofetilide does not affect mortality in the treatment of patients post-myocardial infarction withleft ventricular dysfunction, however it was shown to decrease all-cause readmissions as well asCHF-related readmissions.[6] Because of the results of the DIAMOND study, some physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction, however use appears limited: After initially receiving marketing approval in Europe in 1999, Pfizer voluntarily withdrew this approval in 2004 for commercial reasons[2] and it is not registered in other first world countries.
It has clinical advantages over other class III antiarrhythmics in chemical cardioversion of atrial fibrillation, and maintenance of sinus rhythm, and does not have the pulmonary or hepatotoxicity of amiodarone, however atrial fibrillation is not generally considered life-threatening, and dofetilide causes an increased rate of potentially life-threatening arrhythmias in comparison to other therapies.[7]
Prior to administration of the first dose, thecorrected QT (QTc) must be determined. If the QTc is greater than 440 msec (or 500 msec in patients withventricular conduction abnormalities), dofetilide is contraindicated. If heart rate is less than 60 bpm, the uncorrectedQT interval should be used. After each subsequent dose of dofetilide, QTc should be determined and dosing should be adjusted.
If at any time after the second dose of dofetilide the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), dofetilide should be discontinued.[8]
Torsades de pointes is the most serious side effect of dofetilide therapy. The incidence of torsades de pointes is 0.3-10.5% and is dose-related, with increased incidence associated with higher doses. The majority of episodes of torsades de pointes have occurred within the first three days of initial dosing. Patients should be hospitalized and monitored for the first three days after starting dofetilide.[6]
The risk of inducing torsades de pointes can be decreased by taking precautions when initiating therapy, such as hospitalizing individuals for a minimum of three days for serialcreatinine measurement, continuoustelemetry monitoring and availability of cardiac resuscitation.
Dofetilide works by selectively blocking the rapid component of thedelayed rectifier outward potassium current (IKr).[9]
This causes the refractory period of atrial tissue to increase, hence its effectiveness in the treatment of atrial fibrillation and atrial flutter.
Dofetilide does not affect dV/dTmax (theslope of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential.
There is a dose-dependent increase in the QT interval and the corrected QT interval (QTc). Because of this, many practitioners will initiate dofetilide therapy only on individuals under telemetry monitoring or if serial EKG measurements of QT and QTc can be performed.
Peak plasma concentrations are seen two to three hours after oral dosing whenfasting. Dofetilide is well absorbed in its oral form, with abioavailability of >90%. Intravenous administration of dofetilide is not available in the United States.[10]
The eliminationhalf-life of dofetilide is roughly 10 hours; however, this varies based on many physiologic factors (most significantlycreatinine clearance), and ranges from 4.8 to 13.5 hours. Due to the significant level of renal elimination (80% unchanged, 20% metabolites), the dose of dofetilide must be adjusted to prevent toxicity due to impaired renal function.[11]
Dofetilide is metabolized predominantly byCYP3A4enzymes predominantly in theliver andGI tract. This means that it is likely to interact with drugs that inhibit CYP3A4, such aserythromycin,clarithromycin, orketoconazole, resulting in higher and potentially toxic levels of dofetilide.[12]
A steady-state plasma level of dofetilide is achieved in 2–3 days.
80% of dofetilide is excreted by thekidneys, so the dose of dofetilide should be adjusted in individuals withchronic kidney disease, based oncreatinine clearance.
In the kidneys, dofetilide is eliminated via cation exchange (secretion). Agents that interfere with the renal cation exchange system, such asverapamil,cimetidine,hydrochlorothiazide,itraconazole,ketoconazole,prochlorperazine, andtrimethoprim should not be administered to individuals taking dofetilide.
About 20 percent of dofetilide is metabolized in the liver via theCYP3A4 isoenzyme of thecytochrome P450 enzyme system. Drugs that interfere with the activity of theCYP3A4 isoenzyme can increase serum dofetilide levels. If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via theCYP3A4 isoenzyme system.
After its initial US FDA approval, due to the pro-arrhythmic potential, it was only made available to hospitals and prescribers that had received education and undergone specific training in the risks of treatment with dofetilide; however, this restriction was subsequently removed in 2016.[13]
