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Chapter: Pharmacovigilance: The Cardiovascular Spectrum of Adverse Drug Reactions

Dofetilide is a specific class III antiarrhythmic agent indicated for the maintenance of and conversion to normal sinus rhythm in highly symptomatic patients with persistent atrial fibrillation and atrial flutter.


Dofetilide is a specific class III antiarrhythmic agent indicated for the maintenance of and conversion to normal sinus rhythm in highly symptomatic patients with persistent atrial fibrillation and atrial flutter (Pfizer Inc., 1999). It prolongs action potential dura-tion and refractoriness of both the atrial and the ventricular myocardium (Boriani et al., 2004). As with most other drugs which prolong the action potential, dofetilide carries a risk of proarrhythmia. Following oral administration, there is a dose- and concentration-dependent increase in the corrected QT interval (QTc) that can lead to torsade des pointes (Boriani et al., 2004), a life-threatening arrhythmia. In the clinical development programme, the inci-dence of torsade des pointes was dramatically reduced when lower dosages were administered and when dosage was decreased for patients with impaired renal function (Torp-Pederson et al., 1999). Dofetilide is the first antiarrhythmic agent for which stud-ies of overall mortality risk were conducted before market approval was requested. These studies showed neutral effect on death in patients taking dofetilide who had heart failure or previous myocardial infarc-tion (Torp-Pederson et al., 1999; Kober et al. 2000), in contrast to some other antiarrhythmic agents for which overall mortality either has increased or has not been studied (Coplen et al. 1990; Teo, Yusuf and Furberg, 1993; Fuster et al., 2001). Dofetilide was approved by the Food and Drug Administration (FDA) in 1999. Because of the risk of torsade des pointes identified in the clinical development programme, the FDA mandated a risk management programme which required in-hospital initiation of dofetilide therapy, and restricted its availability to hospitals and prescribers who have received appropriate education on dofetilide treatment initiation and dosing.

Shortly after dofetilide was approved for use in the United States, the FDA also approved sotalol HCl, a new sotalol product with the same indi-cation as dofetilide (Berlex Laboratories, 2000). As with dofetilide, sotalol is also associated with a dose- and concentration-dependent incidence of QT-prolongation and torsade des pointes (Wang et al., 1986). Comparable incidence of torsade de pointes has been reported for sotalol and dofetilide (Bren-dorp, 2002). The product labelling for sotalol HCl contained detailed dosing and monitoring recommen-dations similar to the language in the product labelling for dofetilide. However, the FDA did not request a risk management programme for sotalol as this drug had already been marketed in the United States for the treatment of ventricular arrhythmias.s

Because of the uniqueness of the dofetilide risk management programme, a series of studies was conducted by the Duke Center for Education and Research on Therapeutics to evaluate the acceptance and effectiveness of the mandatory provider education programme for the use of dofetilide (LaPointe et al., 2002, 2003a,b). One study evaluated whether the mandated risk management programme for dofetilide was effective in improving adherence to labelled dosing and monitoring recommendations at Duke University Medical Center (LaPointe et al., 2003b). It was found that the recommended starting dose was prescribed more frequently in the dofetilide group than in the sotalol group and a higher number of patients in the dofetilide group when compared with the sotalol group received the baseline tests for potassium, magnesium, serum creatinine, and an electrocardio-gram. Dofetilide was used less often than sotalol during the study period (47 patients vs 117 patients). The investigators raised the issue that the low usage of dofetilide might reflect an unintended, negative consequence of the risk management programme.

Another study assessed the opinions and knowl-edge retention of practitioners after participation in the dofetilide risk management programme at Duke (LaPointe et al., 2002). In general, practitioners felt the risk management programme for dofetilide was necessary although they either disagreed or were undecided as to whether dofetilide was potentially more dangerous than other antiarrhythmic agents or whether a similar programme should be required for other antiarrhythmic agents. This study showed that the knowledge-retention questions were answered correctly more often by the physicians and pharma-cists than by the nurses. It was noted that the other two smaller community hospitals within the Duke Health Care system opted not to include dofetilide in their formularies, and thus did not complete the education programme. This may indicate the perceived burden of the programme, a lack of resources within smaller community hospitals to complete the risk management programme, or both.

The experience of implementing the dofetilide risk management programme was reported from several other institutions with different approaches (Tran et al., 2001; Freeland, Worthy and Zolnierz, 2003). The pharmacy and therapeutics committees at most institutions required that policies and procedures be developed for dofetilide use prior to putting the drug on the formulary. The dofetilide risk manage-ment programme has been successfully implemented in many institutions. However, some have been hesitant to incorporate dofetilide into their formu-laries, as the development of procedures for the dofetilide risk management programme is time-consuming and requires multidisciplinary expertise, including pharmacists, physicians and nurses.

Very limited data on postmarketing experience with dofetilide have been published. The reported postmar-keting clinical experience suggests that the conversion of persistent atrial fibrillation with dofetilide was comparable to the premarketing studies, and demon-strated a similar safety profile (Prystowsky et al., 2003; Guanzon and Crouch, 2004).

The experience with dofetilide illustrates one approach in which a postmarketing risk management programme can minimize the risk identified in a clin-ical development programme. The dofetilide experi-ence has also presented challenges in implementing risk management programmes intended to maximize benefits and minimize medication risks.

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