Flecainide Level

Flecainide is used mainly for treatment and prevention of ventricular arrhythmia, paroxysmal supraventricular tachycardia, paroxysmal atrial fibrillation, and paroxysmal atrial flutter.

In adults, the reference range of the therapeutic trough of flecainide is 0.2-1 µg/mL. ^[1]

In children, the reference range of the therapeutic trough is 200-800 ng/mL, although concentrations of up to 800 ng/mL may be required for adequate control in some children. ^[2]

Flecainide is used mainly for treatment and prevention of ventricular arrhythmia, paroxysmal supraventricular tachycardia, paroxysmal atrial fibrillation, and paroxysmal atrial flutter.

Plasma levels of flecainide should be monitored, when feasible, especially in patients with severe liver or kidney failure, severe congestive heart failure, or life-threatening ventricular arrhythmias. The goal is to control or prevent arrhythmia with the lowest therapeutic plasma flecainide level. Trough plasma concentrations are 0.2-1 µg/mL in most patients successfully treated with flecainide. ^[2]

A flecainide plasma trough level of less than 0.2 µg/mL is considered subtherapeutic.

Causes of increased plasma levels of flecainide include the following: ^[3]

• CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine, bupropion, amiodarone, cimetidine)

• Renal failure

• Liver failure

• Congestive heart failure

• Β-adrenergic–blocking agents

• Alkalinizing agents (eg, high-dose antacids, carbonic anhydrase inhibitors, sodium bicarbonate)

• Clozapine

Causes of decreased plasma levels of flecainide include the following: ^[3]

• CYP2D6 inducers (rifampicin, carbamazepine, phenytoin, phenobarbital)

• Acidifying agents (eg, ammonium chloride)

• Milk in infants

Adverse effects associated with flecainide

Increased adverse effects, particularly cardiac, are more common with plasma trough levels of more than 0.7-1 µg/mL, especially greater than 1 µg/mL. ^[2] Such cardiac effects may include the following:

• Proarrhythmia

• Cardiac arrest

• Atrioventricular block

• Sinus node dysfunction

• Negative inotropic effect that can cause or worsen heart failure

The following are other potential adverse effects associated with flecainide: ^[2]

• Neurotoxicity (eg, vertigo)

• Visual disturbances including diplopia

• Hallucination

• Dysarthria

• Generalized seizures

• Depersonalization

The flecainide trough level should be checked 3-5 days after starting the medication and less than one hour before the following dose. ^[4]

Sample material: Blood (3 mL)

Method of collection: Venipuncture

Container: Red-top tube

Method of test: High-performance liquid chromatography (HPLC)

Reject due to: Gross hemolysis or lipemia

Storing temperature: Refrigerating the sample is preferred (sample lasts up to 14 days); (in ambient temperature, sample might last up to 7 days)

Description

The chemical name for flecainide is N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide monoacetate, and its molecular formula is C₁₇ H₂₀ F₆ N₂ O₃ •C₂ H₄ O₂, which is a white crystalline powder. ^{[2, 3]}

Flecainide acetate is a membrane-stabilizing antiarrhythmic agent that exhibits a local anesthetic effects. Its principal effect on cardiac tissue is concentration-dependent inhibition of transmembrane influx of extracellular sodium ions via fast sodium channels, which decreases the maximal rate of depolarization of phase 0 of the action potential by combining with fast sodium channels in their inactive state and inhibiting recovery after repolarization (slowly attach to and dissociate from transmembrane sodium channels similar to other antiarrhythmic agents in class IC). This effect produces a dose-related decrease in intracardiac conduction throughout the heart, with the most marked effect on conduction within the His-Purkinje system.

Flecainide also increases PR, QRS, AH, and, to a lesser degree, QT intervals, in addition to having a mild to moderate negative inotropic effect.

Flecainide acetate is rapidly and almost completely absorbed from the gastrointestinal tract following oral administration.

The absolute bioavailability of the commercially available flecainide acetate tablets averages approximately 85%-90%.

The peak flecainide plasma concentration is generally reached within 2-3 hours. Flecainide does not undergo any significant first-pass metabolism.

In vitro, flecainide is approximately 40%-50% bound to plasma proteins. Following intravenous administration in rats, flecainide and its metabolites are distributed into many tissues, including the heart, but only minimally into the CNS.

Flecainide is metabolized in the liver (CYP2D6-mediated) into inactive metabolites.

Flecainide and metabolites are excreted unchanged almost completely in urine. The half-life is about 11.5-16 hours. The plasma clearance is decreased when the urine pH is 8 or more.

Indications/Applications

Steady-state plasma concentrations of flecainide and the optimum therapeutic effect takes up to 3-5 days (or longer in some patients) to be reached; thus, the flecainide trough should be checked after 3-5 days and less than one hour before the following dose.

Rechecking the trough is unnecessary after the steady-state plasma concentration has been reached, unless the dose needs to be adjusted or a factor that can affect the drug concentration has been introduced (eg, renal failure, heart failure, major changes in dietary milk in infants). ^{[2, 5]}

It is also suggested to check the flecainide level, along with electrocardiograph results, whenever the patient is seen for clinical follow-up during the first year of treatment. ^[5]

Considerations

The flecainide level is usually checked in combination with cardiac monitoring such as electrocardiography, telemetry, or Holter monitoring for better clinical interpretation. ^[2]

A study by Burnham et al found evidence that, even though consensus guidelines recommend that class-1C antiarrhythmics not be used in patients with stable coronary artery disease (CAD) due to adverse events reported in individuals with ventricular arrhythmia and a prior myocardial infarction, flecainide has a favorable safety profile in comparison with class-3 antiarrhythmics when used for treating atrial fibrillation in select patients with stable CAD. According to the investigators, at 3-year follow-up in such patients the mortality rates for flecainide versus the class-3 drugs were 9.1% vs 19.3%, respectively, with the rates for heart-failure hospitalization, major adverse cardiac events, and ventricular tachycardia being 12.5% vs 18.3%, respectively; 22.9% vs 36.6%, respectively; and 5.8% vs 8.5%, respectively. ^[6]