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Author: Kristin Watson, PharmD, BCCP

A boxed warning is included in medication product labeling to draw attention to serious adverse reactions and provide guidance on steps that can be taken to minimize risks of therapy and/or ensure safety.1 The number of new and updated boxed warnings has grown incrementally over recent years.2 However, compliance with boxed warning ranges from 0.7 to 93.7%, depending on the type of warning.3–6 Adherence to drug-disease state boxed warnings appears to be substantially greater when compared to drug-laboratory warnings.4,6 Nonadherence appears to be more likely in older patients.4,6

Several cardiac medications have a boxed warning and clinicians should be aware of these to minimize the risk of serious consequences. In this two-part blog series, we’ll review the literature that supports the boxed warnings for cilostazol (PletalÒ), dofetilide (TikosynÒ), edoxaban (SavaysaÒ), prasugrel (EffientÒ) and ticagrelor (BrilintaÒ) (summarized in the Table).7–11 Practical considerations will also be discussed, including recommendations for alternative therapies when criteria for a boxed warning is met. Cilostazol and dofetilide will be covered in this post. Stay tuned for part two of this series on the boxed warnings for edoxaban, prasugrel, and ticagrelor.

Cilostazol is a phosphodiesterase (PDE) III inhibitor with vasodilatory and antiplatelet activity. Cilostazol is recommended for select patients with lower extremity peripheral arterial disease (PAD) to improve walking distance.8, 12-13 Although walking distance is marginally improved (50 -60 meters) with cilostazol, a reduction in cardiovascular events has not been observed.8,13–16 Consequently, use should be reserved for those who remain symptomatic despite other therapies that may improve walking distance (i.e., exercise and smoking cessation).13,16 Improvement in symptoms, if any, will typically occur after 2 to 4 weeks of cilostazol therapy. Treatment should be discontinued if no improvement is seen within 3 months.8

Because other PDE III inhibitors (e.g., milrinone) have been shown to increase the risk of death in patients with New York Heart Association class III/IV heart failure (HF), the boxed warning for cilostazol states that therapy is contraindicated in patients with any HF severity.17-18 No trials have specifically evaluated the use of cilostazol in patients with HF, but data from a case-crossover study suggests that it use may increase the risk of HF hospitalization in those with PAD and diabetes.19

Patients with PAD and HF should be managed similarly to others with symptomatic PAD, with the exception of cilostazol. This includes antiplatelet therapy, smoking cessation, exercise, statin therapy, and blood pressure and glycemic control. Revascularization can be considered for those with claudication symptoms that impair quality of life despite optimized guideline directed medical therapy. The management of patients with critical or acute limb ischemia is beyond the scope of this post but detailed recommendations are provided elsewhere.13,16 Since HF is a progressive disease, recommend against cilostazol in patients with reduced left ventricular ejection fraction (LVEF) (i.e., < 40%), even if no HF symptoms are present.

Dofetilide is a Vaughn Williams Class III antiarrhythmic used to pharmacologically cardiovert to and/or maintain sinus rhythm in patients with atrial fibrillation/flutter (AF/AFL).  Although dofetilide, like many antiarrhythmics, increases the risk of ventricular arrhythmias, it is one of the few antiarrhythmics that can be safely used in patients with AF/AFL and reduced LVEF and/or structural heart disease.10,20–24

The boxed warning for dofetilide specifies that it must be initiated or re-initiated in an inpatient setting to allow for close monitoring during the first three days due to the risk of a life-threatening arrhythmia known as torsades de pointes (TdP).10,23 The risk of TdP ranges 0.8 to 3.3%, and is highest in those with HF. 10,22–24   Although the risk of TdP is greatest with the initiation of therapy, it can occur at any time, and patients should be admitted for re-initiation of therapy if dofetilide is held for any reason. Although dofetilide is no longer regulated by a Risk Evaluation and Mitigation Strategy (REMS), institutions should continue to follow the manufacturer’s dosing guide to reduce the risk of TdP.10,25

It is essential to follow the manufacturer’s recommendations to reduce the risk of QTc prolongation and TdP. Even when these instructions are followed, women are more likely to require dose reductions or treatment discontinuation due to 14-22% higher concentrations compared to men.10,27 Be sure to always run a drug interaction check before prescribing or dispensing dofetilide. A “Guideline for Use” should be considered, as dofetilide is not common and the risk of therapy can be life-threatening. Pharmacists can play a role in developing such a guideline and assuring the appropriate use of dofetilide.28,29 Restricting inpatient prescribing to electrophysiology or a cardiology provider should also be considered.

An alternative antiarrhythmic may be considered if dofetilide must be discontinued due to side effects or lack of efficacy. Decisions regarding an alternative antiarrhythmic, if any, should be made in conjunction with a cardiology provider, preferably an electrophysiology specialist.



  • Hypersensitivity to the medication
  • Creatinine Clearance < 20 mL/min
    • Calculated using the actual body wt. in the Cockcroft-Gault equation
    • Patients with creatinine clearance > 20 mL/min were excluded from clinical trials; QTc prolongation risk increases with increased plasma concentrations
    • Over 60% of dofetilide is eliminated in the urine as active drug
  • Baseline QT interval/QTc > 440 msec or 500 msec in patients with ventricular conduction abnormalities (e.g., bundle branch block)
    • Elevated baseline QT interval/QTc is an independent risk factor for drug-induced TdP
  • Concomitant use of verapamil
    • Dofetilide peak plasma concentrations are increased when co-administered with verapamil; the exact mechanism for this interaction is not known
    • Combined use increased the risk of TdP in clinical trials
  • Concomitant use of medications that inhibit renal cation transport
    • Dofetilide is eliminated via cationic renal system and inhibitors can significantly increase dofetilide concentrations, thus increasing the risk for TdP
    • Renal cation transport inhibitors include cimetidine, dolutegravir, ketoconazole, megestrol, prochlorperazine, and trimethoprim +/- sulfamethoxazole
  • Concomitant use of hydrochlorothiazide (alone or in combination with other agents)
    • Hydrochlorothiazide inhibits tubular secretion of dofetilide and increases the AUC of dofetilide by 27%

Additional considerations

  • Hypomagnesemia and hypokalemia should be corrected before initiation of therapy
    • Hypomagnesemia and hypokalemia increase the risk of drug-induced TdP
    • Careful monitoring should be performed in patients receiving medications that can deplete these electrolytes; normal magnesium and potassium levels should be maintained during the course of therapy
    • Patients receiving diuretic therapy for HF are at increased risk for TdP; frequent electrolyte monitoring is warranted
  • Use is not recommended in patients receiving other agents that prolong the QT interval/QTc
  • Withhold Vaugh Williams Class I/III medications for at least three half-lives prior to initiation of dofetilide.
    • Concomitant use may increase the risk of ventricular arrhythmias
    • Oral amiodarone should discontinued at least three months prior to dofetilide initiation, or serum amiodarone concentrations should be < 0.3 mg/L, per product labeling
    • Recent data suggests that dofetilide may be safely administered 7 days after amiodarone discontinuation if the patient has an implantable cardioverter defibrillator; more data, especially in woman, is necessary before determining the optimal “washout” period
    • Concomitant antiarrhythmic use was not permitted in clinical trials

CILOSTAZOL – Should not be prescribed to patients with LVEF < 40%, regardless of HF symptoms, as chronic use of other PDE III inhibitors increases the risk of death in patients with HF.

DOFETILIDE – Follow dosing and drug-drug interaction recommendations in product labeling to minimize the risk of TdP. Ensure that potassium and magnesium are repleted before initiation/re-initiation of therapy and that normal levels are maintained throughout the course of therapy. Evaluate potassium and magnesium concentrations regularly with closer monitoring in patients receiving medications that lower potassium and/or magnesium. Take advantage of the resources on  and considering developing a “Guideline for Use” at your inpatient facility if one does not exist.

Stay tuned for part 2 of this blog, where the boxed warnings for edoxaban, prasugrel and ticagrelor will be discussed!

Kristin Watson, PharmD, BCCP

Dr. Watson is an associate professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy, and practices as a clinical pharmacy specialist in the ambulatory heart failure clinic at the Veterans Affairs Medical Center in Baltimore, MD. Follow her on Twitter @cards_pharm_gal

Reviewed by: Brent Reed, PharmD, BCCP


  1. Food and Drug Administration. Guidance for Industry: Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription Drugs and Biological Products – Content and Format. Available at: Accessed October 15, 2019.
  2. Solotke MT, Dhruva SS, Downing NS, Shah ND, Ross JS. New and incremental FDA black box warnings from 2008 to 2015. Expert Opin Drug Saf. 2018;17(2):117-123. doi:10.1080/14740338.2018.1415323
  3. Wagner AK, Chan KA, Dashevsky I, et al. FDA drug prescribing warnings: is the black box half empty or half full? Pharmacoepi Drug Safety. 2006;15(6):369-386. doi:10.1002/pds.1193
  4. Savaysa (edoxaban) [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc.; 2015.
  5. Pletal (cilostazol) [package insert] Rockville, MD: Otsuka America Pharmaceutical, Inc.; 2017.
  6. Brilinta (ticagrelor) [package insert]. Wilmington, DE. AstraZeneca Pharmaceuticals LP.; 2016.
  7. Tikosyn (dofetilide) [package insert]. New York, NY. Pfizer Inc.; 2014.
  8. Effient (prasugrel) [package insert]. Indianapolis, IN. Eli Lilly and Company; 2019.
  9. Alonso-Colello P, Bellmunt, S, McGorrian C, et al. Antithrombotic Therapy in Peripheral Artery Disease Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141 (Suppl):e669-90s.
  10. Gerhard-Herman MD, Gornik HL, Barrett C, et al. 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease. J Am Coll Cardiol. 2017;69(11):e71-e126. doi:10.1016/j.jacc.2016.11.007
  11. Money SR, Herd JA, Isaacsohn JL, et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg. 1998;27(2):267-274; discussion 274-275. doi:10.1016/s0741-5214(98)70357-x
  12. Strandness DE, Dalman RL, Panian S, et al. Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study. Vasc Endovascular Surg. 2002;36(2):83-91. doi:10.1177/153857440203600202
  13. Anderson JL, Halperin JL, Albert N, et al. Management of Patients With Peripheral Artery Disease (Compilation of 2005 and 2011 ACCF/AHA Guideline Recommendations): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(14):1555-1570. doi:10.1016/j.jacc.2013.01.004.
  14. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991;325(21):1468-1475. doi:10.1056/NEJM199111213252103
  15. Feldman AM, Bristow MR, Parmley WW, et al. Effects of vesnarinone on morbidity and mortality in patients with heart failure. Vesnarinone Study Group. N Engl J Med. 1993;329(3):149-155. doi:10.1056/NEJM199307153290301
  16. Wu C-K, Lin J-W, Wu L-C, Chang C-H. Risk of Heart Failure Hospitalization Associated With Cilostazol in Diabetes: A Nationwide Case–Crossover Study. Front Pharmacol. 2019;9. doi:10.3389/fphar.2018.01467
  17. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Euro Heart J. 2016;37:2893-62.
  18. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. J Am Coll Cardiol. 2014;64(21):e1-e76. doi:10.1016/j.jacc.2014.03.022
  19. Køber L, Bloch Thomsen PE, Møller M, et al. Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction: a randomised trial. Lancet. 2000;356(9247):2052-2058. doi:10.1016/s0140-6736(00)03402-4
  20. 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. New Engl J Med. 1999;341(12):857-865. doi:10.1056/NEJM199909163411201
  21. Singh S, Zoble RG, Yellen L, et al. Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter: the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study. Circulation. 2000;102(19):2385-2390. doi:10.1161/01.cir.102.19.2385
  22. Food and Drug Administration. Information for Tikosyn (dofetilide). Accessed October 20, 2019.
  23. Pfizer Inc. Safety Profile. Accessed October 20, 2019.
  24. Pokorney SD, Yen DC, Campbell KB, et al. Dofetilide dose reductions and discontinuations in women compared with men. Heart Rhythm. 2018;15(4):478-484. doi:10.1016/j.hrthm.2018.01.027
  25. Quffa LH, Panna M, Kaufmann MR, McKillop M, Dietrich NM, Franck AJ. Impact of a Pharmacy-Cardiology Collaborative Practice on Dofetilide Safety Monitoring. Ann Pharmacother. 2017;51(1):39-43. doi:10.1177/1060028016669962
  26. Tisdale JE. Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management. Can Pharm J (Ott). 2016;149(3):139-152. doi:10.1177/1715163516641136
  27. Drew BJ, Ackerman MJ, Funk M, et al. Prevention of Torsade de Pointes in Hospital Settings. J Am Coll Cardiol. 2010;55(9):934-947. doi:10.1016/j.jacc.2010.01.001
  28. Sharma SP, Turagam M, Atkins D, et al. Safety of rapid switching from amiodarone to dofetilide in atrial fibrillation patients with an implantable cardioverter-defibrillator. Heart Rhythm. 2019;16(7):990-995. doi:10.1016/j.hrthm.2019.01.028
  29. Naksuk N, Sugrue AM, Padmanabhan D, et al. Potentially modifiable factors of dofetilide-associated risk of torsades de pointes among hospitalized patients with atrial fibrillation. J Interv Card Electrophysiol. 2019;54(2):189-196. doi:10.1007/s10840-018-0476-2
What’s in the Black Box? Examining the Evidence for Five Cardiac Medications? Part 1

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