Continuing Education Activity

Clinical uses of dofetilide include maintaining sinus rhythm in patients with atrial fibrillation. Dofetilide is indicated in adults for the conversion of atrial fibrillation or atrial flutter to normal sinus rhythm and the preservation of normal sinus rhythm in patients with highly symptomatic atrial fibrillation or atrial flutter of more than one week whose pathological sinus rhythm has converted to normal. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of dofetilide, pertinent for interprofessional team members in treating patients with cardiac disorders that will respond to such therapy.

Objectives:

• Identify the mechanism of action of dofetilide.
• Review the indications for dofetilide.
• Outline the potential adverse effects of dofetilide use.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients when using dofetilide.

Indications

It is an oral medication containing dofetilide as the active ingredient. The formula also contains inactive ingredients of microcrystalline cellulose, corn starch, colloidal silicon dioxide, magnesium stearate, gelatin, titanium dioxide, and FDC Yellow 6.[1][2][3]

Clinical Uses of Dofetilide

Dofetilide is effective in maintaining sinus rhythm in patients with atrial fibrillation. In the DIAMOND studies (Torp-Pedersen C et al., 1999), dofetilide did not affect mortality in patients with advanced heart failure or those convalescing from acute myocardial infarction.[4]

Dofetilide is indicated in adults for the conversion of atrial fibrillation or atrial flutter to normal sinus rhythm (NSR) and the preservation of normal sinus rhythm in patients with highly symptomatic atrial fibrillation or atrial flutter of more than one week whose pathological sinus rhythm has converted to normal.[5]

Azimilide and sematilide are also class III antiarrhythmics, but they are not available in the United States.

Because induction of severe ventricular arrhythmias is possible with dofetilide, it was available through a restricted distribution system that includes only clinicians, hospitals, and other institutions that have received special educational programs covering proper dosing and in-hospital treatment initiation, which is called Risk Evaluation and Mitigation Strategy (REMS). However, in January 2016, although the safety risks for Tikosyn (dofetilide) continued to be present by FDA's determination, the agency also decided that the REMS program is no longer compulsory because the risk-benefit ratio tilts to the side of the benefits of the drug.[6]

Off-Label Uses of Dofetilide

Clinicians have used dofetilide as an off-label prescription for supraventricular arrhythmias, ventricular tachycardia, and Wolff-Parkinson-White syndrome.[7]

Mechanism of Action

As with other class III antiarrhythmic drugs, dofetilide blocks potassium channels in phase 3 of the action potential and slows the efflux of potassium cation back out of the myocyte, slowing the repolarization rate of the cell and widening the action potential's plateau phase. The refractory periods of atrial, ventricular, and Purkinje cells are increased, leading to lengthening of the QT interval on the ECG. The increased widening of the QT interval is possibly due to the inhibition of phosphoinositide 3–kinase, which increases the late sodium current.[8][9]

Dofetilide is a class III antiarrhythmic agent. By inhibiting a component of the time-dependent potassium current, dofetilide increases the effective refractory period and action potential without affecting the conduction velocity.[10]

Administration

Pharmacodynamics/Pharmacokinetics

Adult

Dofetilide dosing is based on creatinine clearance: (CrCl greater than 60 mL/min) 500 mcg bid (CrCl 40 mL/min to 60 mL/min) 250 mcg bid; (CrCl 20 mL/min to less than 40 mL/min) 125 mcg bid; (CrCl less than 20 mL/min) contraindicated.

Pediatric

Safety and efficacy have not been established in children.

Route of Administration

Oral absorption is approximately 100%.

Oral bioavailability is not affected by food or antacid. Steady-state plasma concentrations are attainable within 2 to 3 days. Plasma concentrations are dose-proportional.

Onset of Action

Dofetilide takes 2 to 3 hours to reach maximum plasma concentration in the fasted state on a single dose. Therefore, this means it takes 2 to 3 hours for the onset of action for dofetilide.

Duration of Action

The half-life of dofetilide was reported to be 4.8 to 13.5 hours. The most-reported half-life in the literature for dofetilide is 10 hours. From a pharmacokinetic principle, it takes 4.5 to 5 half-lives to eliminate approximately 100% of a single dose administration of any drug. Hence, it takes 4.5 to 5 half-lives to eliminate a single dose of dofetilide from the human body, which is 45 to 50 hours. Therefore, the duration of action of a single dose of dofetilide is 45 to 50 hours.[11]

Distribution

The volume of distribution: 3.1 L/kg to 4.0 L/kg, indicating that dofetilide does not get sequestered in fatty tissues.

Protein Binding

Plasma protein binding of dofetilide is 60% to 70%, is independent of plasma concentration, and is unaffected by renal impairment—the volume of distribution: 3.1 L/kg to 4.0 L/kg.

Metabolism

Fifty percent of dofetilide metabolism is in the liver into inactive metabolites. Dofetilide is metabolized to a small extent by the CYP3A4 isoenzyme of the cytochrome P450 system. Inhibitors of the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of this isoenzyme (e.g., macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazodone, norfloxacin, quinine, zafirlukast) should be cautiously coadministered with Tikosyn as they can potentially increase dofetilide levels. Dofetilide is not an inhibitor of CYP3A4 or other cytochrome P450 isoenzymes and is not expected to increase levels of drugs metabolized by CYP3A4.

Clearance

Renal

Excretion of about 80% of a single dose of dofetilide is in urine, with 80% as unchanged drug and the remaining 20% consisting of inactive or minimally active metabolites. Dofetilide gets eliminated in the kidney by cationic secretion. Inhibitors of renal cationic secretion are contraindicated with dofetilide. Also, drugs that get actively secreted via this route (e.g., triamterene, metformin, and amiloride) should be co-administered with care as they might increase dofetilide levels. The elimination half-life is 4.8 to 13.5 hours.

Adverse Effects

The drug has virtually no extracardiac pharmacological effects.[12]

Torsades de pointes occurred in 1% to 3% of patients in clinical trials where strict exclusion criteria (e.g., hypokalemia) were applied, and continuous ECG monitoring was used to detect marked QT prolongation in the hospital.

Dofetilide may induce or worsen ventricular dysrhythmias with therapeutic use, producing life-threatening polymorphic ventricular tachycardia. Patients with a history of torsade de pointes, prolonged QTc (greater than 440 milliseconds), hypomagnesemia, or serum potassium below 4.0 mEq/L show an increased risk of developing ventricular dysrhythmias. Other potential adverse effects of dofetilide administration include chest pain, nausea, abdominal pain, flatulence, diarrhea, headache, dizziness, and fatigue.

Overdose experience is limited. Effects reported include QT prolongation, torsade de pointes, and complete heart block. The most common side effects are headaches, chest pain, and dizziness.

Adverse Reactions Severe

• Fast, pounding, or irregular heartbeat
• Rash
• Severe diarrhea
• Dizziness or fainting
• Unusual sweating
• Vomiting
• Loss of appetite
• Increased thirst (drinking more than normal)

Adverse Reactions Mild

• Headache
• Chest pain
• Shortness of breath
• Nausea
• Flu-like symptoms
• Stomach pain
• Back pain
• Difficulty falling asleep or staying asleep

Pregnancy

Dofetilide is classified as FDA pregnancy category C under the recently replaced system. Therefore, pregnant patients should not receive dofetilide.[13]

Drug Interactions

Approximately 80% of a single dose of dofetilide gets excreted in the urine, of which approximately 80% is excreted as unchanged dofetilide, with the remaining 20% consisting of inactive or minimally active metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the cation transport system, a process that can be inhibited by cimetidine, trimethoprim, prochlorperazine, megestrol, ketoconazole, and dolutegravir). In vitro studies with the human liver microsomes show that CYP3A4 can metabolize dofetilide, but it has a low affinity for this isoenzyme. N-dealkylation and N-oxidation form metabolites.[14]

The following list of drugs are known to have significant interactions with dofetilide by inhibiting renal elimination:

• Cimetidine
• Verapamil
•  Ketoconazole
• Trimethoprim alone or in combination with sulfamethoxazole
• Prochlorperazine
• Megestrol
• Dolutegravir
• Hydrochlorothiazide alone or in combination with other medicines

Contraindications

Dofetilide contraindications include patients with long QT syndrome. It is also contraindicated in patients on kidney dialysis or with renal diseases.

Dofetilide is contraindicated in patients with a low potassium level in the blood, vomiting and/or diarrhea, sweating, loss of appetite, decreased thirst, and whether the patients have ever had heart or liver disease. Dofetilide is contraindicated in patients planning to become pregnant, pregnant, or breastfeeding.

Monitoring

Central Nervous System Effects

Headache, dizziness, syncope, paresthesia, insomnia, anxiety, migraine, cerebral ischemia, facial paralysis, CVA.

Cardiovascular Effects

Ventricular fibrillation, ventricular tachycardia, torsades de pointes, AV block, chest pain, bradycardia, edema, cardiac arrest, sudden death, MI, QT prolongation, atrial fibrillation, hypertension.

Respiratory Effects

Ensuring adequate ventilation is necessary, and endotracheal intubation is performed early in patients with life-threatening cardiac arrhythmias.

Additional Monitoring Requirements/Precautions

• Gastrointestinal (GI): nausea, diarrhea, abdominal pain
• GU: urinary tract infection
• Hepatic: liver damage
• Musculoskeletal: back pain, arthralgia, flaccid paralysis
• Respiratory: respiratory tract infection, dyspnea, increased cough
• Skin: rash
• Other: flu-like syndrome, accidental injury, angioedema

Toxicity

All class III (potassium channel blockers) antiarrhythmic drugs are proarrhythmic. Therefore, physicians should take extreme care when prescribing dofetilide to patients.

Toxic manifestations are usually an extension of pharmacological activity (e.g., torsade de pointes). Oral dofetilide doses of 500 mcg twice daily have correlations with an increased risk of developing torsades de pointes; there is a report of sudden death in one patient. A patient received two 500 mcg dofetilide doses one hour apart and developed ventricular fibrillation and cardiac arrest 2 hours after the second dose.[15] During a clinical study, one subject ingested twenty-eight 500 mcg capsules and received treatment with gastric lavage within 30 minutes of exposure, with reports of no adverse effects.

The most likely side effect of overdose is the excessive lengthening of the QT interval.

There is no known remedy for dofetilide overdoses; treatment of dofetilide overdose is supportive and symptomatic. Start cardiac monitoring with ECG. A charcoal slurry given within the first 15 minutes of administration is useful. Pharmacological management of dofetilide overdose and torsades de pointes may include isoproterenol, with or without cardiac pacing, and magnesium sulfate; beta-blockers have also been used.

Enhancing Healthcare Team Outcomes

Dofetilide is a class III antiarrhythmic agent usually prescribed by the cardiologist. However, these patients are often followed and monitored by the primary care provider, cardiac nurse, and internist. Healthcare providers who look after patients with arrhythmias must know the adverse effects of these agents; this extends to the nursing staff who will administer the drug and most likely perform the initial observation of any adverse effects or drug interactions.

Pharmacists should verify dosing and perform thorough medication reconciliation to rule out drug interactions and ensure proper dosing, preventing potentially severe adverse effects. They should communicate any concerns to the physician or nursing staff to initiate appropriate corrective action.

All class III (potassium channel blockers) antiarrhythmic drugs are proarrhythmic as well. Therefore, extreme care should is necessary for clinicians when prescribing dofetilide.

All healthcare workers, including the cardiac nurse and pharmacist, should consult with a cardiologist regarding any potential changes in dosing or administration schedule.[16]

As demonstrated above, an interprofessional team approach with open lines of communication is the optimal approach to dofetilide therapy so that patients can achieve the best possible outcomes. [Level 5]