FLECAINIDE ACETATE

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Food does not effect the absorption of flecainide; however, milk may inhibit absorption. During times of reduced milk consumption (e.g., illness or weaning) in neonates and infants on primarily milk-based diets, closer monitoring and dose reduction may be necessary.
Oral Liquid Formulations
-Extemporaneous Oral suspension: Shake well before administering. Measure dosage with calibrated measuring device.

Extemporaneous Compounding-Oral
Extemporaneous 20 mg/ml flecainide oral suspension preparation:
-Add twenty four (24) flecainide 100 mg tablets to a large glass mortar.
-Grind tablets into a fine powder.
-Add approximately 20 ml of the chosen vehicle and mix to a uniform paste. Vehicle choices include: 1) a 1:1 mixture of Ora-Sweet and Ora-Plus; 2) a 1:1 mixture of Ora-Sweet SF and Ora-Plus; or 3) cherry syrup.
-Add geometric portions of the vehicle almost to volume and mix thoroughly after each addition.
-Transfer the contents to a calibrated bottle and add enough vehicle to bring to a total volume of 120 ml.
-Storage: The resulting suspension is reported stable for 60 days at 5 and 25 degrees C when protected from light.

Flecainide can cause or exacerbate cardiac arrhythmias (arrhythmia exacerbation). The proarrhythmic potential is the most serious risk of flecainide therapy. The risk of proarrhythmia in pediatric patients with supraventricular tachycardia has been reported as approximately 7%; however, the risk of serious proarrhythmia appears to be less than 1%. Serious cardiac adverse events, including cardiac arrest and death, have been reported in pediatric patients receiving flecainide, especially those with atrial flutter after surgical repair of congenital heart defects or structural heart disease. In adult patients, new or worsened arrhythmias occurred in 1% to 7% of patients with supraventricular arrhythmias and 7% to 13% of patients with ventricular arrhythmias. Eighty percent (51/64) of proarrhythmic events occurred within 14 days of the onset of therapy in patients treated with flecainide for sustained ventricular tachycardia. The results of the Cardiac Arrhythmia Suppression Trial (CAST) indicate that the rates of nonfatal cardiac arrest and total mortality in patients with recent myocardial infarction, asymptomatic or symptomatic ventricular arrhythmias, and mild to moderate left ventricular dysfunction were significantly increased in patients who received flecainide. These implications led to the recommendation that flecainide therapy be reserved for cases of documented life-threatening arrhythmias. Most commonly, ventricular tachycardia, which can deteriorate into ventricular fibrillation, has occurred and, in some cases, has resulted in death despite resuscitative measures. The risk of flecainide-induced arrhythmias is increased in patients with a history of structural heart disease or ventricular tachycardia. In a small study, the efficacy of flecainide in controlling ventricular tachycardia was poor and arrhythmia control worsened in several other patients. Sinus bradycardia (1.2%) and flecainide-induced QT prolongation with ventricular tachycardia have been reported. Torsade de pointes has also been reported rarely during therapy with flecainide. First-degree AV block occurs in 30% to 40% of patients on flecainide therapy; second- or third-degree block also occur, but much less frequently (second-degree AV block: 0.5%; third-degree AV block: 0.4%).

The most common gastrointestinal adverse reactions reported in adult ventricular arrhythmia patients treated with flecainide 200-400 mg/day include: nausea (8.9%), constipation (4.4%), and abdominal pain (3.3%). Other gastrointestinal adverse reactions possibly related to use of flecainide, occurring in 1 to < 3% of adult patients include: diarrhea, dyspepsia, anorexia, and vomiting. Adverse reactions reported in < 1% of flecainide-treated adult patients include: flatulence, dysgeusia, and xerostomia.

Flecainide exhibits a mild to moderate negative inotropic effect and can cause or worsen congestive heart failure. These effects occur particularly in patients with cardiomyopathy, preexisting severe heart failure, or decreased left ventricular ejection fractions. In adult patients, new or worsened heart failure occurred in 6.3% of 1046 patients with premature ventricular contractions (PVCs), non-sustained or sustained ventricular tachycardia, 9.1% of 297 patients with sustained ventricular tachycardia, and 0.4% of 225 patients with supraventricular arrhythmias. Exacerbation of preexisting heart failure occurred more commonly in studies which included patients with class III or IV failure than in studies that excluded such patients. Use flecainide cautiously in patients with a known history of heart failure or myocardial dysfunction. Chest pain (unspecified) (5.4%), palpitations (6.1%), and dyspnea (10.3%) have also been reported in adults. Sinus tachycardia, sinus pause or arrest were reported at an incidence of 1 to < 3% in acute and chronic studies. Angina pectoris, hypertension, and hypotension were reported in < 1% of patients and were considered possibly related to flecainide.

The most common nervous system adverse reactions reported in adult ventricular arrhythmia patients treated with flecainide 200-400 mg/day include: dizziness (18.9%), headache (9.6%), fatigue (7.7%), asthenia (4.9%), and tremor (4.7%). Other adverse effects possibly related to use of flecainide, occurring in 1 to < 3% of patients include: hypoesthesia, paresthesias, paresis, ataxia, malaise, vertigo, syncope, drowsiness, tinnitus, anxiety, insomnia, and depression. Adverse reactions reported in < 1% of flecainide-treated patients include: twitching, weakness, convulsions, speech disorder, stupor, neuropathy, amnesia, confusion, depersonalization, euphoria, nightmares, and apathy.

There have been rare reports of isolated asymptomatic elevated hepatic enzymes. In foreign postmarketing surveillance studies, there have been rare reports of hepatic dysfunction including cholestasis and hepatic failure, and extremely rare reports of blood dyscrasias. Although a causal relationship has not been established, the manufacturer advises that clinicians discontinue flecainide in patients who develop unexplained jaundice or signs of hepatic dysfunction or blood dyscrasias in order to eliminate flecainide as the possible causative agent.

Visual impairment was reported in 15.9% of adult ventricular arrhythmia patients treated with flecainide 200-400 mg/day. Diplopia was reported at an incidence of 1 to < 3% in acute and chronic studies. Adverse reactions reported in < 1% of flecainide-treated patients include: ocular pain or ocular irritation, photophobia, and nystagmus.

Edema was reported in 3.5% of adult ventricular arrhythmia patients treated with flecainide 200-400 mg/day. Other general adverse reactions possibly related to use of flecainide, occurring in 1 to < 3% of adult patients include: fever, flushing, and diaphoresis. Adverse reactions reported in < 1% of flecainide-treated patients include: swollen lips, tongue and mouth, arthralgia, myalgia, polyuria, and urinary retention.

Rash (unspecified) was reported in 1 to < 3% of adult patients in acute and chronic studies. Other dermatologic adverse reactions reported in < 1% of flecainide-treated patients include: urticaria, exfoliative dermatitis, pruritus, and alopecia.

Hematologic adverse reactions reported in < 1% of flecainide-treated adult patients include: leukopenia, granulocytopenia, and thrombocytopenia.

Respiratory adverse reactions reported in < 1% of flecainide-treated adult patients include: bronchospasm and pneumonitis/pulmonary infiltration possibly due to chronic flecainide treatment.

Flecainide is contraindicated for use in patients with cardiogenic shock. Due to its potential negative inotropic effects, flecainide may worsen preexisting congestive heart failure (CHF), particularly in patients with cardiomyopathy, severe heart failure (NYHA class III or IV), or ventricular dysfunction (LVEF less than 30%). Worsening of CHF may occur within a few hours to several months after starting flecainide and has been reported in a higher percentage of adult patients with sustained ventricular tachycaridia (25.7%) compared to patients with supraventricular arrhythmias (0.4%). Plasma drug concentration monitoring is suggested for patients with CHF. Heart failure may increase the risk of prolonging the QT interval.

Flecainide is contraindicated in patients with preexisting second- or third-degree AV block, or bifascicular or trifascicular bundle-branch block, unless a pacemaker is in place that could sustain cardiac rhythm in the event of complete heart block. In general, use flecainide cautiously in patients with certain types of cardiac disease. Flecainide has proarrhythmic properties and can induce or worsen cardiac arrhythmias. In order to reduce the risk of proarrhythmia, hospitalization in a facility that can provide rhythm monitoring and direct supervision by a cardiologist skilled in the treatment of pediatric arrhythmias is recommended during therapy initiation. Use flecainide with extreme caution in pediatric patients with atrial flutter after surgery to correct congenital heart defects and in patients with structural heart disease as these populations appear to be at highest of risk of cardiovascular adverse events. Although flecainide has been shown to be highly effective in suppressing chronic stable ventricular arrhythmias in many patients, there is no documented beneficial effect on mortality. There is, however, evidence of an increased risk of mortality and non-fatal cardiac arrest with the use of flecainide after myocardial infarction in adult patients with asymptomatic PVCs or non-sustained ventricular tachycardia. Therefore, use is no longer recommended in patients without documented life-threatening ventricular arrhythmias. Consider dose reduction or discontinuation in patients who exhibit a prolonged QRS (more than 180 milliseconds) or PR (more than 300 milliseconds) interval. Although its effects on normal sinus node function are negligible, flecainide should be used only with extreme caution in patients with preexisting sick sinus syndrome or significant conduction delay because it may cause profound clinically low heart rate, sinus pause, or sinus arrest. Use in chronic atrial fibrillation has not been adequately studied and is not recommended by the manufacturer due to the reported risk of ventricular arrhythmias (about 10%) in this population. QT prolongation and torsade de pointes have occurred during therapy and flecainide should be avoided, when possible, in patients with congenital long QT syndrome or acquired QT prolongation syndromes or in patients with a history of torsade de pointes. Use flecainide with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, or in patients receiving medications known to prolong the QT interval. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. Flecainide can increase endocardial pacing thresholds, so it is not recommended for use in patients with nonprogrammable pacemakers unless pacing rescue is available. The effects on pacing threshold are reversible following cessation of therapy.

Correct any electrolyte imbalance, such as hyperkalemia, before initiating therapy with flecainide, as electrolyte imbalances may alter the antiarrhythmic effects of the drug. Use flecainide with caution in patients with conditions that may increase the risk of QT prolongation including hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to cause electrolyte imbalances.

Hepatic disease can alter the metabolism and/or excretion of flecainide, potentially resulting in drug accumulation and reduced dosage requirements. Plasma drug concentration monitoring is required for patients with severe hepatic disease. Adjust dosage at intervals that exceed 4 days, since steady-state conditions may take longer to achieve in these patients.

Renal impairment (e.g., renal disease, renal failure) can alter the excretion of flecainide, potentially resulting in drug accumulation and reduced dosage requirements. Approximately 30% of flecainide is excreted renally. In patients with renal impairment, adjust dosage at intervals that exceed 4 days since steady-state conditions may take longer to achieve in these patients. Plasma drug concentration monitoring is required for patients with severe renal disease and may also be helpful for patients with moderate renal disease.

Description: Flecainide is a class IC local anesthetic-type antiarrhythmic. It is used for the maintenance of normal sinus rhythm in patients with supraventricular arrhythmias associated with disabling symptoms and without structural heart disease or life-threatening ventricular tachycardia. Flecainide appears to be a safe and effective antiarrhythmic in pediatric patients with structurally normal hearts; however, due to the risk of proarrhythmia, direct supervision by a cardiologist skilled in the treatment of pediatric arrhythmias is recommended during therapy initiation. Close monitoring of flecainide plasma trough concentrations is also recommended in pediatric patients, especially during therapy initiation and dose adjustments. Cautious use is recommended in patients with structural heart disease, left ventricular dysfunction, or recent acute myocardial infarction. As a result of the Cardiac Arrhythmia Suppression Trial (CAST) in adult patients, flecainide is not considered a first-line agent to suppress ventricular arrhythmias because of its propensity for fatal proarrhythmic effects. Flecainide is FDA-approved in pediatric patients as young as neonates.

General dosing information:
-Due to the risk of proarrhythmia, hospitalization during drug initiation at a facility that can provide rhythm monitoring and direct supervision by a cardiologist skilled in the treatment of pediatric arrhythmias is recommended.
-When switching a patient from another antiarrhythmic to flecainide, the manufacturer suggests allowing 2-4 half-lives of the drug being discontinued to elapse before starting flecaindide.
-Milk may inhibit the absorption of flecainide; closer monitoring is recommended and dose adjustment may be required in patients during decreased consumption of milk or other dairy products (e.g., illness such as gastroenteritis or neonates/infants during periods of weaning).

For the maintenance of normal sinus rhythm in patients with supraventricular arrhythmias (including atrial flutter, atrial fibrillation, paroxysmal supraventricular tachycardia (PSVT), and junction ectopic tachycardia (JET)*) associated with disabling symptoms and without structural heart disease or in patients with life-threatening ventricular tachycardia:
Oral dosage:
Neonates: Initially, 50 mg/m2/day PO given in 2 to 3 divided doses is recommended by the manufacturer; increase as needed every 4 days to achieve clinical goals (Max: 200 mg/m2/day PO). Alternatively, a dose of 2 mg/kg/day PO given in 2 divided doses and adjusted upward based on clinical response and weight gain was used in 20 neonatal patients (mean postnatal age 11.5 +/- 11.1 days, mean gestational age 36.8 +/- 3 weeks) with supraventricular tachycardia. A mean dose of 3.35 +/- 1.35 mg/kg/day PO was successful in controlling arrhythmias in 17 (85%) of the patients. A maximum dose of 8 mg/kg/day PO has been recommended.
Infants 6 months or younger: Initially, 50 mg/m2/day PO given in 2 to 3 divided doses is recommended by the manufacturer; increase as needed every 4 days to achieve clinical goals (Max: 200 mg/m2/day PO). Alternatively, 1 to 6 mg/kg/day PO given in 2 to 3 divided doses (Max: 8 mg/kg/day PO) has been recommended.
Infants > 6 months, Children, and Adolescents: Initially, 100 mg/m2/day PO given in 2 to 3 divided doses is recommended by the manufacturer; increase as needed every 4 days to achieve clinical goals (Max: 200 mg/m2/day PO). Alternatively, 1 to 6 mg/kg/day PO given in 2 to 3 divided doses (Max: 8 mg/kg/day PO) has been recommended. Although an absolute maximum dose has not been specified in pediatric patients, the manufacturer recommends 300 mg/day PO for supraventricular arrhythmias and 400 mg/day PO for ventricular tachycardia in adults.
-for the transplacental treatment of fetal supraventricular tachyarrhythmias*:
Oral dosage:
Pregnant Females: 200 to 450 mg/day PO given in 3 divided doses has been used. In a retrospective, multicenter study, thirty-five pregnant women with fetuses diagnosed with fetal atrial flutter (AF) or supraventricular tachycardia (SVT) (30 to 32 weeks mean gestational age at diagnosis) were treated with flecainide first-line. Other first-line agents used included sotalol and digoxin. Flecainide and digoxin were associated with a higher conversion of SVT to normal sinus rhythm compared to sotalol; however, sotalol was associated with higher rates of prenatal AF termination. In patients with incessant SVT or AF that persisted to 5 days, median ventricular rates declined more and to a better-tolerated rate with flecainide and digoxin compared to sotalol. Serious drug-related adverse effects were not reported.

Therapeutic Drug Monitoring:
The following information regarding therapeutic drug concentration monitoring is recommended by the manufacturer:
-Usual target trough concentration: 200-500 ng/mL; in some cases, up to 800 ng/mL may be required
-Monitoring of flecainide plasma concentrations may be used in addition to electrocardiogram (ECG) monitoring to guide maintenance dosage.
-A plasma trough concentration and ECG is recommended after therapy initiation or dose adjustment once steady-state is reached (after at least 5 doses).
-Plasma trough concentrations and ECGs are recommended at each follow-up visit during the first year of therapy.
-Small changes in dosage may lead to disproportionate increases in plasma concentrations. Toxicity is more frequent with trough plasma concentrations > 1000 ng/mL in adults.
-Frequent plasma drug concentration monitoring is required for patients with severe renal (i.e., CrCl < 35 ml/min/1.73m2) or hepatic disease, and may also be helpful in patients with congestive heart failure or in patients with moderate renal disease.
-Monitoring of flecainide plasma concentrations is strongly recommended in patients receiving amiodarone therapy.

Maximum Dosage Limits:
-Neonates
200 mg/m2/day PO or 8 mg/kg/day PO.
-Infants
200 mg/m2/day PO or 8 mg/kg/day PO.
-Children
200 mg/m2/day PO or 8 mg/kg/day PO.
-Adolescents
200 mg/m2/day PO or 8 mg/kg/day PO.

Patients with Hepatic Impairment Dosing
Use in patients with hepatic impairment only if benefits clearly outweigh the risks as flecainide elimination is slower in these patients. Frequent and early plasma drug concentration monitoring is required for patients with severe hepatic disease. Adjust dosage at intervals > 4 days, since steady-state conditions may take longer to achieve in these patients.

Patients with Renal Impairment Dosing
Specific recommendations for dosage adjustment in pediatric patients with renal impairment are not available. The manufacturer recommends the following dose adjustments in adult patients with renal impairment:
CrCl > 35 ml/min/1.73m2: No dosage adjustment is required.
CrCl <= 35 ml/min/1.73m2: Initially, 100 mg PO once daily or 50 mg PO twice daily. Frequent plasma concentration monitoring is required. Adjust dosage at intervals > 4 days, since steady-state conditions may take longer to achieve in these patients.

Intermittent hemodialysis
No dosage supplement is needed for hemodialysis. Hemodialysis removes about 1% of an oral dose of unchanged flecainide.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: As a class, the IC agents have three primary electrophysiological effects. Potent inhibition of the fast sodium channels depresses the upstroke of the action potential, which is manifested as a decrease in the maximal rate of phase 0 depolarization. Secondly, the IC agents significantly slow His-Purkinje conduction and cause QRS widening. Finally, these agents shorten the action potential of Purkinje fibers.

Flecainide inhibits the fast sodium channels of the myocardial cell membrane, thereby increasing the recovery period after repolarization. The drug can inhibit extracellular calcium influx but only at high doses. Flecainide does not exhibit vagomimetic, vagolytic, or beta-adrenergic blocking properties. It slows intracardiac conduction and can slightly increase action potential duration in atrial and ventricular muscle. The PR, QRS, and QT intervals are usually prolonged.

Flecainide acts on the antegrade pathways of anomalous AV conduction, thereby terminating paroxysmal reentrant supraventricular tachycardias. In patients with Wolff-Parkinson-White syndrome, flecainide increases the refractoriness of the anterograde and/or retrograde pathways by decreasing conduction in these or accessory pathways. Although it may have mild to moderate negative inotropic effects , flecainide generally has only minimal cardiovascular effects; blood pressure, heart rate, and left ventricular function are usually unchanged.

Pharmacokinetics: Flecainide is administered orally. Flecainide is 40% bound to plasma proteins, primarily alpha-1-acid glycoprotein (AGP). Flecainide is metabolized by dealkylation and conjugation to at least 5 metabolites that are excreted in the urine. Approximately 30% (range 10-50%) of the drug is excreted via renal pathways and 5% is excreted fecally. The elimination of flecainide is slower in patients with a very alkaline urinary pH (> 8), such as patients with renal tubular acidosis or on a strict vegetarian diet.

Affected cytochrome P450 isoenzymes: CYP2D6
Flecainide is primarily metabolized by CYP2D6 isoenzymes.


-Route-Specific Pharmacokinetics
Oral Route
An oral dose of flecainide is almost completely absorbed. Peak plasma levels occur 1-4.8 hours after oral administration in pediatric patients. Although food does not effect the absorption of flecainide, milk may inhibit absorption. This may have an impact on dosing requirements in pediatric patients, particularly neonates and infants. In adult patients, steady-state concentrations of flecainide are reached in 3-5 days.


-Special Populations
Pediatrics
Neonates
Based on limited data, the elimination half-life is prolonged in neonatal patients compared to older pediatric patients and may be as long as 29 hours at birth decreasing to 11-12 hours by 3 months of age.

Infants, Children, and Adolescents
In a pharmacokinetic study of pediatric patients receiving flecainide (n = 26), the elimination half-life was longer and the plasma clearance slower in infants and adolescents compared to children. The elimination half-life was approximately 11-12 hours in infants, 8 hours in children, and 11-12 hours in adolescents. The mean volume of distribution was 9.5 L/kg and did not vary with age.

Hepatic Impairment
Clearance and/or elimination of flecainide is markedly prolonged in patients with hepatic insufficiency.

Renal Impairment
The half-life is increased in patients with renal impairment. Hemodialysis removes about 1% of an oral dose of unchanged flecainide.