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
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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