Flecainide

Mechanism of Action

Flecainide is classified as a Class Ic antiarrhythmic agent according to the Vaughan–Williams classification. Flecainide acts on the fast-inward Na+ ion channel and has a high affinity for activated or open Na+ channels. It prolongs depolarization and increases refractoriness due to slow release from its binding site. It potently acts on the His-Purkinje system. It also works by inhibiting IKr channels, thereby delaying the potassium rectifier current and resulting in the prolongation of action potential duration in both ventricular and atrial muscle fibers. Flecainide blocks ryanodine receptor opening, reducing calcium release from the sarcoplasmic reticulum and leading to afterdepolarizations and triggered activity.[10] Hence, indications for flecainide include CPVT (see Image. Effects of Class Ic Sodium Channel Blockers on Cardiac Action Potential).[5] 

Class Ic antiarrhythmic agents exert their effects primarily by potently blocking the fast sodium current (INa). These agents preferentially bind to the open and inactivated states of sodium channels, producing a state-dependent (use-dependent) block with slow dissociation kinetics, thereby prolonging their effects across heart rates. This action markedly reduces the maximal upstroke velocity (dV/dt or Vmax), resulting in slowed conduction velocity, decreased action potential amplitude, and widening of the QRS complex on the electrocardiogram (ECG), with minimal effect on the QT interval.

Pharmacokinetics

Absorption: Following oral administration, flecainide is nearly completely absorbed. Peak plasma levels are reached approximately 3 hours after administration (range 1 to 6 hours). Steady-state levels are attained within 3 to 5 days. Flecainide does not undergo significant presystemic biotransformation, and its absorption is not affected by food or antacids. Milk may inhibit absorption in infants, so reducing the dose when milk is removed from their diet should be considered.[11]

Distribution: Once at steady state, no additional (or unexpected) accumulation of drug in plasma occurs during chronic therapy. The extent of flecainide binding to human plasma proteins is approximately 40% and remains constant across a plasma drug concentration range of 0.015 to approximately 3.4 mcg/mL. Therefore, significant drug interactions due to protein binding are unlikely.

Metabolism: Flecainide is metabolized hepatically via the CYP450 system; flecainide is a CYP2D6 substrate.[12] The extent of metabolism may vary depending on genetic polymorphisms that affect CYP2D6 activity.

Excretion: The elimination half-life of flecainide varies with age. The elimination half-life is age-dependent; in adults, it averages 12 to 24 hours. It is typically shortest in young children (eg, 6 to 8 hours) and prolonged in newborns due to immature clearance mechanisms. Flecainide is excreted primarily in the urine (about 30%) and to a lesser extent in feces (approximately 5%).[13][14][15][16]

Administration

Available Dosage Forms and Strengths

Flecainide is available in 50 mg, 100 mg, and 150 mg tablets.

Adult Dosage

Dosing regimens for specific conditions are as follows:

Paroxysmal atrial fibrillation/paroxysmal supraventricular tachycardia (per ACC/AHA/HRS guidelines):

• 50 to 300 mg daily by mouth, divided into 8- to 12-hour intervals.
  • Start with 50 mg orally every 12 hours, then increase by 100 mg per day every 4 days. The maximum recommended daily dose is 300 mg. Dose adjustment is made based on serum levels.

Ventricular arrhythmia prophylaxis:

• 100 to 400 mg daily by mouth, divided into 8- or 12-hour intervals.
  • Start with 100 mg orally every 12 hours, and increase the dose by 100 mg per day every 4 days. The maximum recommended daily dose is 400 mg. Dose adjustment is made based on serum levels.

Specific Patient Populations

Hepatic impairment: According to the manufacturer, no dosage adjustment is necessary in patients with liver disease. Dosage adjustment is recommended in patients with severe hepatic impairment, and caution and close monitoring are advised.

Renal impairment: In cases where urinary pH is markedly alkaline (8 or higher), which may occur in rare conditions such as renal tubular acidosis or with a strict vegetarian diet, the elimination of flecainide from plasma occurs at a significantly slower rate. In patients with renal impairment and a creatinine clearance below 35 mL/min/1.73 m², caution must be exercised.

Pregnancy considerations: Using flecainide during pregnancy may pose some risk to the fetus; therefore, clinicians should perform a risk-benefit analysis. Fetal risks include reduced fetal heart rate variability, impaired acceleration, and QT interval abnormalities.[17] Neonates exposed to flecainide in utero have been reported to develop hyperbilirubinemia after birth, although data are limited.

Breastfeeding considerations: Flecainide is present in breast milk; the relative infant dose is 8% when the maternal dosing is 200 mg per day. The relative infant dosing is calculated using the highest average breast milk concentration compared to the maternal dosage. Breastfeeding is considered acceptable as long as the relative infant dose is less than 10%.[17] 

Pediatric patients: The FDA has not approved the use of flecainide in children. Its proarrhythmic effects, as previously mentioned, are also relevant in pediatric patients. In children with structural heart disease, flecainide has been associated with cases of cardiac arrest and sudden death. Therefore, initiation of flecainide treatment should occur in a hospital setting with rhythm monitoring. Any administration of flecainide acetate in children must be supervised by a cardiologist experienced in pediatric arrhythmia treatment. Consult institutional guidelines or manufacturer prescribing information for pediatric dosing regimens. Flecainide may be used off-label for the treatment of fetal supraventricular tachycardia; however, additional research is required.[18][19]

Older patients: According to manufacturer labeling, flecainide is eliminated more slowly from plasma in older individuals than in younger individuals. Patients aged 80 and older have been safely treated with standard dosages.

Adverse Effects

Cardiac Toxicity

Flecainide has proarrhythmic effects with an increased incidence of mortality and nonfatal cardiac arrest in patients with a history of myocardial infarction and asymptomatic premature ventricular contractions/non-sustained ventricular tachycardia. Flecainide prolongs depolarization and can slow conduction in the atrioventricular node and the His-Purkinje system. These changes can result in prolonged PR intervals and first-degree and second-degree heart blocks. Preexisting sinus node disease can result in profound bradycardia. It does not affect repolarization, exerting a mild effect on the QT interval.

Flecainide has a negative inotropic effect on cardiac muscles. Therefore, its use is contraindicated in patients with heart failure. Flecainide can convert atrial fibrillation to atrial flutter with 1:1 conduction or provoke ventricular tachyarrhythmias; therefore, a beta-blocker or a calcium channel blocker should be used concurrently.[15][20]

Common reactions to flecainide include dizziness, arrhythmias, dyspnea, visual disturbances, palpitations, chest pain, tremor, asthenia, abdominal pain, and constipation.

Drug-Drug Interactions

Significant drug interactions include ritonavir, cisapride, desipramine, dronedarone, quinidine, saquinavir, and tipranavir. Concurrent use with these agents should be avoided. Flecainide interacts with many other drugs, and therapy modification may be necessary; therefore, thorough medication reconciliation is important, as with all medications.

• Digoxin: Flecainide has been administered to patients receiving digoxin without significant adverse effects; however, during multiple-dose administration, plasma digoxin concentrations may increase, requiring additional monitoring.[13] 

• Amiodarone: When amiodarone is added to ongoing flecainide therapy, plasma flecainide levels may increase twofold or more. Therefore, reducing the flecainide dose and carefully monitoring for toxicity are advised.[21]

• Disopyramide/verapamil: The combined use of disopyramide or verapamil with flecainide should be approached cautiously. Since all three medications have negative inotropic effects, they should be used together only if the benefits clearly outweigh the risks.

• Calcium channel blockers: The combination of nifedipine or diltiazem with flecainide has not been studied, and concurrent use is not routinely recommended until further data are available.

• CYP450 enzyme inducers: Enzyme inducers, such as phenytoin, phenobarbital, and carbamazepine, modestly increase flecainide elimination by approximately 30%, potentially necessitating minor dosage adjustments in chronic therapy.

• CYP2D6 inhibitors: CYP2D6 inhibitors such as quinidine may increase plasma flecainide levels by inhibiting its metabolism. Antidepressants such as fluoxetine, paroxetine, and duloxetine are potent CYP2D6 inhibitors, and their coadministration with flecainide has been shown to increase plasma flecainide concentrations by 16% to 28%.[22][23][24]

Contraindications

According to the AHA/ACC/HRS 2017 guidelines, flecainide is contraindicated in patients with structural heart disease.[3] Other contraindications include hypersensitivity, documented second- or third-degree atrioventricular block, sick sinus syndrome, bundle branch block, cardiogenic shock, and acquired or congenital QT prolongation with a history of torsades de pointes.

Box Warnings

Flecainide has an FDA Black Box Warning recommending that its use be restricted to life-threatening ventricular arrhythmias, as data show no survival benefits without such arrhythmias. Proarrhythmic effects may occur in patients with atrial flutter or atrial fibrillation; the drug is not recommended for chronic atrial fibrillation. The warning also notes increased mortality and non-fatal cardiac arrest rates in asymptomatic patients with non–life-threatening ventricular arrhythmias and a prior history of myocardial infarction occurring 6 days to 2 years earlier.[25]

Warnings and Precautions

Caution is also advised in patients with myocardial dysfunction, congestive heart failure, QT prolongation, electrolyte abnormalities, and pacemakers.[26] In patients with a preexisting QRS duration of greater than 130 ms, Class Ic drugs should be prescribed with caution.[27]

Flecainide remains contraindicated in patients with structural heart disease based on the Cardiac Arrhythmia Suppression Trial (CAST trial) data; however, limited observational reports have raised cautious interest in its potential use in highly selected cases, such as stable coronary artery disease without active ischemia and preserved ventricular function. Robust prospective studies are essential before any reconsideration of current safety restrictions can be made.[1][28][29]

Monitoring

Narrow Therapeutic Index

There is an increased response and a steep relationship between dose and concentration. Plasma levels require monitoring in patients with severe renal impairment or hepatic disease. Flecainide overdose could be fatal. The prescriber should adjust the dose based on the clinical response.[13]

Monitoring Parameters

In patients with renal or hepatic impairment, it is prudent to monitor ECG and blood pressure and to obtain periodic serum trough concentrations. The therapeutic trough concentration is between 0.2 and 1 mcg/mL. Lower trough concentration may be sufficient in pediatric patients. Because of its narrow therapeutic index, slight differences in dose or blood concentration can cause serious therapeutic failures or life-threatening adverse drug reactions. Therefore, it is crucial to monitor all hemodynamic parameters, vital signs, ECG, and serum flecainide levels.[30]

Toxicity

Signs and Symptoms of Overdose

There is no specific antidote for flecainide overdose. Ingestion of doses up to 8000 mg has been survived, with reported plasma concentrations as high as 5.3 mcg/mL. Clinical features may include nausea, vomiting, seizures, hypotension, bradycardia, syncope, and pronounced ECG abnormalities such as marked QRS widening, QT and PR prolongation, ventricular tachycardia, atrioventricular block, asystole, bundle branch block, heart failure, or cardiac arrest. Fatal outcomes have occurred following ingestion of as little as 1000 mg, often in the context of co-ingestion with other medications or alcohol. Flecainide plasma levels should be obtained to confirm toxicity.

The therapeutic window for flecainide is narrow, ranging from 0.2 to 1.0 mcg/mL.[30] A patient with atrial tachyarrhythmia and pacemaker therapy developed a wide-QRS tachycardia that mimicked ventricular tachycardia. Pacemaker interrogation confirmed atrial flutter with pacemaker-mediated ventricular pacing, consistent with flecainide toxicity.[31][32] Infrequent cases of suicide by intentional flecainide overdose have been reported in the literature.[33][34][35]

Management of Overdose

Management of an overdose is mainly supportive, and there is no antidote for flecainide overdose. According to the review of literature, the documented mortality rate from overdose of Class Ic Vaughan Williams antiarrhythmics stands at 22.5%. Standard treatments include aggressive fluid resuscitation, administration of hypertonic sodium bicarbonate, and intravenous magnesium.[36] The initial management of toxicity involves administering a sodium bicarbonate infusion to promptly counteract the effects of flecainide, thereby preventing potentially life-threatening arrhythmias. Case reports indicate that sodium bicarbonate can be used as monotherapy and is commonly given as first-line treatment for a QRS duration of greater than 100 ms, in increments of 1 to 2 mEq/kg. Sodium bicarbonate raises serum pH and increases extracellular sodium levels, enabling it to compete with flecainide for sodium channel binding and strengthening the electrochemical gradient across cell membranes.[37] Consult a medical toxicologist and contact the national poison control center for up-to-date information.

Lipid emulsion therapy can also be used in conjunction with sodium bicarbonate for flecainide toxicity. The "lipid sink" theory suggests that it removes lipophilic flecainide from toxicity sites by increasing blood lipid levels.[38] Management is mainly supportive. Prompt gastrointestinal decontamination should be considered to limit absorption. Hemodynamic instability may respond to inotropic or chronotropic agents. Mechanical ventilation may be required in patients with severe cardiac and respiratory depression. Advanced supportive measures, including intra-aortic balloon counterpulsation or transvenous pacing, may be indicated in cases of refractory conduction block or profound hemodynamic compromise.[39] Due to flecainide's prolonged elimination half-life (approximately 12–27 hours) and potential for nonlinear kinetics at toxic concentrations, extended monitoring and supportive care are essential. Hemodialysis does not enhance clearance.

Enhancing Healthcare Team Outcomes

This section discusses the evidence-based use and outcomes of flecainide across various clinical settings.

CAST Trial

Initially, it was thought to be effective in the treatment of premature ventricular contractions and nonsustained ventricular tachycardia after myocardial infarction to reduce the incidence of sudden death. However, in a multicenter randomized placebo-controlled trial on patients after myocardial infarction, the use of flecainide was associated with increased mortality due to fatal arrhythmias. Therefore, flecainide is considered for patients without coronary artery disease and left ventricular dysfunction. Currently, contraindications to flecainide include patients with left ventricular hypertrophy, ischemic heart disease, hypertrophic obstructive cardiomyopathy, high-degree atrioventricular block, and complete heart block.[40]

PITAGORA Trial

A multicenter, single-blind, prospective randomized trial compared amiodarone with Class Ic (propafenone and flecainide) in patients with atrial fibrillation and a pacemaker due to sinus node disease for maintaining sinus rhythm as a goal. Flecainide was found to be noninferior and equally efficacious in preventing episodes lasting more than 10 minutes or those lasting for 1 day.[41]

Pill-in-the-Pocket Approach

According to the NEJM study published in 2004, flecainide is one of the drugs, apart from propafenone, used in outpatient or emergency department settings to treat symptomatic atrial fibrillation. In some patients, oral prophylaxis or catheter ablation may not be feasible; therefore, a single dose of an antiarrhythmic medication at the time of symptom onset is an appropriate option. The dose of flecainide was 300 mg for patients of more than 70 kg or 200 mg otherwise. Around 165 patients were followed for 2 years; 94% were successfully treated after the onset of symptoms within 2 hours. Recurrences were successfully treated in up to 84% of cases. The number of emergency room visits and hospitalizations was significantly lower during the study period compared to the year before the treatment period.[42]

Acute Cardioversion in Emergency Departments

Based on recent meta-analyses, IV flecainide is superior to other antiarrhythmics, such as ibutilide, amiodarone, sotalol, propafenone, and procainamide. Eleven randomized controlled trials were analyzed, and it was found that flecainide was highly effective for cardioversion within 2 hours. There is no statistically significant difference in proarrhythmic behavior compared to placebo or other antiarrhythmics.[43]

Effect on Atrial Remodeling

Structural changes in the atria occur due to atrial fibrillation, leading to myocardial remodeling and mitochondrial dysfunction caused by oxidative stress. During atrial fibrillation, atrial activation rapidly leads to intracellular calcium accumulation via the Na+/Ca2+ exchanger. Flecainide inhibits intracellular Ca2+ accumulation, which reduces atrial remodeling and oxidative stress.[44]

Fetal Tachycardia

Flecainide has been shown to be effective in the transplacental treatment of fetal tachycardia. Flecainide was found to be superior to digoxin and sotalol in the termination of fetal tachycardia, especially supraventricular tachycardia. The placental transfer is not affected in hydrops fetalis.[45]

Catecholaminergic Polymorphic Ventricular Tachycardia

As discussed above, flecainide inhibits cardiac ryanodine receptors in their open state, which are responsible for calcium release and lead to CPVT. Flecainide suppresses 76% of exercise-induced ventricular arrhythmias in 33 genotype-positive patients. It is also efficacious in suppressing ventricular tachyarrhythmias in genotype-negative patients.[46]

Practical Aspects Before and During Initiation of Flecainide

1. An exercise stress test should be performed before initiating flecainide therapy to rule out coronary artery disease and repeated during treatment if resting QRS prolongation is observed.
2. ECG monitoring is recommended to assess QRS duration. The flecainide dose should be reduced to half the initial dose if the QRS duration increases by 25%.
3. Patients should be screened for sinus node dysfunction and atrioventricular node disease prior to treatment initiation.
4. Concurrent administration of negative chronotropic agents, such as beta-blockers, is recommended.

While pharmaceutical therapy with flecainide should be initiated only by a cardiologist, it requires an interprofessional team approach, including the patient, other clinicians and specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient outcomes. As a narrow therapeutic index medication, all healthcare team members must be aware of the patient's therapy, recognize signs of toxicity or inadequate response, and communicate openly with other interprofessional team members regarding treatment progress and adverse events to optimize therapeutic outcomes and improve the patient's condition.