Strategies for Mitigating Dofetilide-Induced Ventricular Arrhythmias

In recent years, the Patient Safety Authority has received several reports of QT prolongation in patients receiving dofetilide. Approximately half of these reports were associated with serious adverse events, including torsades de pointes and other types of ventricular arrhythmias and cardiac arrest, some requiring a transfer to a higher level of care and at least one resulting in death. Some of these reports described a failure to adequately monitor electrocardiograms (EKGs) and adjust therapy in a timely manner. Others indicated concomitant use of medications contraindicated with dofetilide¹ and/or those known to prolong the QT interval,² such as azithromycin, fluconazole, hydrochlorothiazide, indapamide, levofloxacin, ondansetron, promethazine, and sulfamethoxazole/trimethoprim.

Dofetilide, also marketed under the brand name Tikosyn, is a class III antiarrhythmic agent used to treat irregular heartbeat in certain patients with atrial fibrillation or atrial flutter.¹ Due to the linear relationship between QTc interval and serum dofetilide concentrations, and its potential to induce life-threatening ventricular arrhythmias, the black box warning recommends starting or restarting dofetilide therapy in a facility that provides continuous EKG monitoring, serum creatinine monitoring, and access to cardiac resuscitation for a minimum of three days.¹ Contraindications include preexisting prolonged QTc interval, renal impairment, and concomitant medications or disease states that may further prolong the QTc interval or elevate serum dofetilide levels.¹

Until 2016, the U.S. Food and Drug Administration’s Risk Evaluation and Mitigation Strategy (REMS)^[1] program mandated certification of prescribers, pharmacies, and healthcare facilities in a national registry to ensure safe prescribing and dispensing of dofetilide.⁴ Although the dofetilide REMS program no longer exists, we strongly encourage healthcare facilities and providers to reevaluate their current protocols for dofetilide and ensure that they align with the information provided in the package insert¹ and documented in literature,^5,6 including dosage calculations, documented and potential drug interactions, patient-specific risk factors, and instructions for monitoring EKG and lab values, to ensure its safe and effective use.

To enhance the safety of dofetilide administration and mitigate the risk of ventricular arrhythmias, healthcare facilities are advised to consider implementing the action items below.

• Accurate medication reconciliation

  • Conduct a thorough medication reconciliation process to verify the correct dofetilide dose for newly admitted patients who are continuing their chronic therapy from home.

• Engagement of specialized practitioners

  • Restrict the prescribing of dofetilide (re)initiation therapy to cardiology.

  • Engage the clinical pharmacists (e.g., in pharmacy-driven protocol) to monitor, evaluate, and adjust therapy based on risk factors and patient response to dose.⁷

• Optimization of electronic health records (EHR) and computerized provider order entry (CPOE)

  • Incorporate clear and specific ordering instructions and monitoring parameters for EKG. If applicable, preselect within CPOE order panel by default to ensure timely EKG acquisition. For (re)initiation of therapy, EKG should be obtained at baseline and two to three hours after administration of each of the first five doses.¹

  • Include instructions for dose modifications per package insert: dose should be decreased if increase in QTc or QT is >15% or >500 milliseconds after the first dose, and the therapy should be discontinued if at any time after the second dose QTc or QT increases >500 msec.¹ Refer to the package insert for detailed instructions on dose modifications and therapy adjustments.

  • Activate interaction alerts for dofetilide within CPOE and EHR to notify healthcare providers of potential risks when dofetilide is ordered concurrently with medications known to prolong the QT interval or alter potassium levels. Employ a risk stratification strategy for these alerts to minimize alert fatigue and prioritize interactions with the greatest potential for adverse effects. Ensure that these alerts are prominently displayed for the prescribing and verifying providers.

  • Integrate prompts and reminders for nurses to alert prescribers if magnesium, potassium, and serum creatinine levels deviate from their normal range.^1,5–7

• Additional instructions for monitoring

  • Emphasize the importance of communicating the need for EKG monitoring, changes in lab values, and vigilance for potential arrhythmias during hand-offs.

• Competency training

  • Provide competency training to all healthcare providers involved in the medication-use process, encompassing prescribing, verification, dispensing, administration, and monitoring of dofetilide.

• Patient education

  • Empower patients to actively participate in their care by advising them to thoroughly review the dofetilide Medication Guide.¹ Emphasize the importance of correct administration, adherence to the dosing schedule, and recognition of potential adverse effects. Stress the need to maintain an accurate and accessible medication list. Furthermore, educate the patients on the requirement for readmission if they miss more than two consecutive doses of dofetilide.⁸

Disclosure

The author declares that they have no relevant or material financial interests.

This article was previously distributed in a March 5, 2025, newsletter of the Patient Safety Authority, available at https://conta.cc/4i0eawX.

About the Author

Myungsun (Sunny) Ro (mro@pa.gov) is a research scientist on the Data Science & Research team at the Patient Safety Authority (PSA). Her responsibilities include analyzing and synthesizing data from various sources to identify opportunities to improve patient safety, as well as writing scientific articles for publication in the PSA’s peer-reviewed journal, Patient Safety.