Dofetilide

Dofetilide
Names
Trade namesTikosyn
IUPAC name
  • N-[4-(2-{[2-(4-methane sulfonamidophenoxy)ethyl] (methyl)amino}ethyl)phenyl]methanesulfonamide
Clinical data
Drug classClass III antiarrhythmic agent[1]
Main usesAtrial fibrillation, atrial flutter[1]
Side effectsHeadache, chest pain, dizziness[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
External links
AHFS/Drugs.comMonograph
MedlinePlusa601235
Pharmacokinetics
Bioavailability96% (by mouth)
Protein binding60% -70%
Elimination half-life10 hours
Chemical and physical data
FormulaC19H27N3O5S2
Molar mass441.56 g·mol−1
3D model (JSmol)
SMILES
  • O=S(=O)(Nc1ccc(cc1)CCN(CCOc2ccc(cc2)NS(=O)(=O)C)C)C
InChI
  • InChI=1S/C19H27N3O5S2/c1-22(13-12-16-4-6-17(7-5-16)20-28(2,23)24)14-15-27-19-10-8-18(9-11-19)21-29(3,25)26/h4-11,20-21H,12-15H2,1-3H3 checkY
  • Key:IXTMWRCNAAVVAI-UHFFFAOYSA-N checkY

Dofetilide, sold under the brand name Tikosyn, is a medication used to keep people with atrial fibrillation or atrial flutter in sinus rhythm.[1] It is only indicated in those who have been in an abnormal rhythm for more than a week and have significant symptoms.[2] It is taken by mouth.[1]

Common side effects include headache, chest pain, and dizziness.[1] Other side effects may include QT prolongation and potentially an increased risk of death.[1] It should not be used in people with severe kidney problems.[1] Safety in pregnancy is unclear.[1] It is a class III antiarrhythmic agent.[1]

Dofetilide was approved for medical use in the United States in 1999.[1] While it was approved in Europe in 1999, this was withdrawn in 2004.[3] In the United States it costs about 25 USD per month.[4]

Medical uses

Dofetilide is used for the maintenance of sinus rhythm in individuals prone to the occurrence of atrial fibrillation and flutter arrhythmias, and for chemical cardioversion to sinus rhythm from atrial fibrillation and flutter.[5][6]

Dofetilide does not affect mortality in the treatment of people post-myocardial infarction with left ventricular dysfunction, however it was shown to decrease all-cause readmissions as well as CHF-related readmissions.[7][8] Some physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction, however use appears limited.

It has 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.[9]

Dosage

It is taken at a dose of 500 mcg twice per day in those with normal kidney function.[1]

Contraindications

Prior to administration of the first dose, the corrected QT (QTc) must be determined. If the QTc is greater than 440 msec (or 500 msec in patients with ventricular conduction abnormalities), dofetilide is contraindicated. If heart rate is less than 60 bpm, the uncorrected QT 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. [10]

Side effects

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.[11]

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 serial creatinine measurement, continuous telemetry monitoring and availability of cardiac resuscitation.

Pharmacology

Mechanism of action

Dofetilide works by selectively blocking the rapid component of the delayed rectifier outward potassium current (IKr).[12]

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 (the slope of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential.

Dofetilide synthesis

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.

Pharmacokinetics

Peak plasma concentrations are seen two to three hours after oral dosing when fasting. Dofetilide is well absorbed in its oral form, with a bioavailability of >90%. Intravenous administration of dofetilide is not available in the United States. [13]

The elimination half-life of dofetilide is roughly 10 hours; however, this varies based on many physiologic factors (most significantly creatinine 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.[14]

Dofetilide is metabolized predominantly by CYP3A4 enzymes predominantly in the liver and GI tract. This means that it is likely to interact with drugs that inhibit CYP3A4, such as erythromycin, clarithromycin, or ketoconazole, resulting in higher and potentially toxic levels of dofetilide. [15]

Metabolism

A steady-state plasma level of dofetilide is achieved in 2–3 days.

80% of dofetilide is excreted by the kidneys, so the dose of dofetilide should be adjusted in individuals with chronic kidney disease, based on creatinine clearance.

In the kidneys, dofetilide is eliminated via cation exchange (secretion). Agents that interfere with the renal cation exchange system, such as verapamil, cimetidine, hydrochlorothiazide, itraconazole, ketoconazole, prochlorperazine, and trimethoprim should not be administered to individuals taking dofetilide.

About 20 percent of dofetilide is metabolized in the liver via the CYP3A4 isoenzyme of the cytochrome P450 enzyme system. Drugs that interfere with the activity of the CYP3A4 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 the CYP3A4 isoenzyme system.

History

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. [16]

After initially receiving marketing approval in Europe in 1999, Pfizer voluntarily withdrew this approval in 2004 for commercial reasons[17] and it is not registered in other first world countries.

Society and culture

It is not available in Europe or Australia.[18] In the United States it is only available by mail order or through specially trained local pharmacies.[10]

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 "Dofetilide Monograph for Professionals". Drugs.com. Archived from the original on 10 August 2020. Retrieved 26 December 2021.
  2. ↑ "DailyMed - DOFETILIDE capsule". dailymed.nlm.nih.gov. Archived from the original on 11 January 2022. Retrieved 26 December 2021.
  3. ↑ "Tikosyn". Archived from the original on 11 January 2022. Retrieved 26 December 2021.
  4. ↑ "Dofetilide Prices and Dofetilide Coupons - GoodRx". GoodRx. Archived from the original on 5 November 2016. Retrieved 26 December 2021.
  5. ↑ Banchs JE; Wolbrette DL; Samii SM; et al. (November 2008). "Efficacy and safety of dofetilide in patients with atrial fibrillation and atrial flutter". J Interv Card Electrophysiol. 23 (2): 111–5. doi:10.1007/s10840-008-9290-6. PMID 18688699. S2CID 25162347.
  6. ↑ Lenz TL; Hilleman DE (November 2000). "Dofetilide: A new antiarrhythmic agent approved for conversion and/or maintenance of atrial fibrillation/atrial flutter". Drugs Today. 36 (11): 759–71. doi:10.1358/dot.2000.36.11.601530. PMID 12845335.
  7. ↑ Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. (September 1999). "Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group". The New England Journal of Medicine. 341 (12): 857–65. doi:10.1056/NEJM199909163411201. PMID 10486417.
  8. ↑ Torp-Pedersen C; ller M; Mø Bloch-Thomsen PE; et al. (September 1999). "Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group". N. Engl. J. Med. 341 (12): 857–65. doi:10.1056/NEJM199909163411201. PMID 10486417.
  9. ↑ Micromedex Drugdex drug evaluations micromedex.com
  10. 1 2 TIKOSYN® (dofetilide). Pfizer. <http://www.tikosyn.com/ Archived 2019-08-02 at the Wayback Machine>.
  11. ↑ Torp-Pedersen C, Møller M, Bloch-Thomsen PE, et al. Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigations of Arrhythmia and Mortality on Dofetilide Study Group. N Engl J Med 1999; 341:857.
  12. ↑ Roukoz H; Saliba W (January 2007). "Dofetilide: a new class III antiarrhythmic agent". Expert Rev Cardiovasc Ther. 5 (1): 9–19. doi:10.1586/14779072.5.1.9. PMID 17187453. S2CID 11255636.
  13. ↑ 1Rasmussen HS, Allen MJ, Blackburn KJ, et al. Dofetilide, a novel class III antiarrhythmic agent. J Cardiovasc Pharmacol 1992; 20 Suppl 2:S96.
  14. ↑ "Dofetilide." Lexicomp. Wulters Kluwer Health, n.d. Web. <online.lexi.com>.
  15. ↑ Walker DK, Alabaster CT, Congrave GS, et al. Significance of metabolism in the disposition and action of the antidysrhythmic drug, dofetilide. In vitro studies and correlation with in vivo data. Drug Metab Dispos 1996; 24:447.
  16. ↑ "Information for Tikosyn (dofetilide)". US Food and Drug Administration. 2016-03-09. Archived from the original on 2019-04-23. Retrieved 2021-03-05.
  17. ↑ Wathion, Noel (2004-04-13). "Public Statement on Tikosyn (dofetilide): Voluntary Withdrawal of the Marketing Authorisation in the European Union" (PDF). European Agency for the Evaluation of Medicinal Products. Archived (PDF) from the original on 2017-10-13. Retrieved 2021-03-05.
  18. ↑ Australian Medicines Handbook 2014
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