ikosyn (dofetilide), an antiarrhythmic drug with pure Vaughn Williams Class III properties, has recently been approved for clinical use by the Food and Drug Administration.
The drug has been approved for the maintenance of sinus rhythm (SR) in patients with atrial fibrillation/flutter (AF/FL) of >1 week duration who have converted to SR and for the conversion of AF/FL to SR. However, because of risks associated with use of Tikosyn, this approval is contingent upon and emphasizes that initiation and re-initiation of the drug can be done only in hospital with continuous cardiac monitoring of at least 3 days duration. In addition, because of safety concerns, Tikosyn is only available to hospitals and prescribers who have received appropriate education regarding dosing. This issue of The Arrhythmia News will discuss this new drug, but is not intended to serve as official education/certification.
Dosing
Tikosyn comes in tablets of 500, 250 and 125 mcg. And is typically administered BID. The recommended dose is 500 mcg BID. However, the dose should be modified according to the corrected QT interval (QTc). If the QTc is >440 ms at pre drug baseline (500 ms with conduction abnormalities), Tikosyn is contraindicated. Likewise, if the QTc prolongs >15% or to >500 ms after initiation, the dose should be halved. Persistent QTc prolongation requires discontinuation of the drug.
Dosing must also be adjusted according to creatinine clearance (Clcr). For Clcr >60 ml/min, the usual Tikosyn dose of 500 mcg BID can be prescribed. For Clcr <20 ml/min, Tikosyn is contraindicated. Intermediate Clcrs require appropriate dose adjustments.
Clinical Efficacy
The clinical efficacy of Tikosyn in the treatment of AF/Fl has been well documented in several large studies. In the EMERALD Trial which evaluated dosing strategies of the drug in 382 patients, 29% of patients had converted to SR within three days. At that dose, 66% of patients remain in SR at 12 months following either pharmacological or electrical cardioversion as compared to 21% on placebo (p=0.001). This effect appeared to be dose dependent, as smaller doses were less effective. The SAFIRE-D trial with 325 patients demonstrated similar results.
The utility of Tikosyn for ventricular arrhythmias has not been documented and the drug is not indicated to treat these arrhythmias. However, the DIAMOND-CHF and the DIAMOND-MI Trials which included 3028 patients, produced some interesting results. These studies were designed to evaluate the sudden cardiac death in a high risk population. No difference in mortality was noted between drug and placebo, suggesting at least that the drug could be used safely to treat AF/FL in these high risk populations post-MI and with congestive heart failure. Of note, the effect of this smaller dose of Tikosyn in AF/FL was not statistically significant.
Safety
The safety of Tikosyn has been extensively documented in trials leading up to FDA approval. Tikosyn is associated with a significant risk (3-4%) of ventricular proarrhythmia when given at conventional dosages. However, the risk of Torsade des Pointes can be specifically minimized by careful QTc monitoring and dose adjustment as outlined above. One major advantage to the drug is that is does not have negative inotropic effects and is not associated with worsening heart failure or other hemodynamic effect.
Tikosyn is both actively excreted by the kidney and metabolized by the cytochrome P450 system of the liver. As such, drug interactions can be a significant problem and bear careful monitoring. The concomitant use of Tikosyn with cimetidine, verapamil, ketoconizole or trimethaprim/sulfamethoxizole is absolutely contraindicated. Drugs such as triamiterene, metaformin and amiloride, which are secreted by the same renal mechanism, must be used with caution. Drugs such as macrolide antibiotics, "azole" antifungal agents, serotonin reuptake inhibitors and other drugs which inhibit the cytochrome P450 system must also be used with caution.
Summary
Tikosyn (dofetilide), a pure class III antiarrhythmic drug has recently been approved for the treatment of AF/FL. Special precautions including in-hospital cardiac monitoring for 3 days when initiated are necessary for its use. Nonetheless, its efficacy and its safety for use in patients with structural heart disease make it an important new therapy for AF/FL.
Reproduced with permission. Published by the Arrhythmia Service of St.Luke's-Roosevelt Hospital Center, New York, New York.
Volume 6, Issue 2
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