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flecainide acetate 50 mg tab

Out of Stock Manufacturer ANI PHARMACEUTI 62559038001
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Uses

Ventricular Arrhythmias

Flecainide acetate is used orally to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia). Based on information from the National Heart, Lung, and Blood Institute (NHLBI) describing interim results of the Cardiac Arrhythmia Suppression Trial (CAST) (see the opening discussion in Cautions), FDA and the manufacturer have notified health-care professionals that flecainide therapy should be reserved for the suppression and prevention of documented ventricular arrhythmias that, in the clinician's judgment, are considered life-threatening.

Because of the drug's arrhythmogenic potential and associated risk of death identified in CAST, use of flecainide for less severe arrhythmias (e.g., nonsustained ventricular tachycardia, frequent ventricular premature complexes [VPCs]), even when they are symptomatic, no longer is recommended. The findings of CAST involved a select patient population with recent myocardial infarction, mild-to-moderate left ventricular dysfunction (e.g., mean baseline ejection fraction of 0.4), and asymptomatic or mildly symptomatic ventricular arrhythmias (mean baseline VPCs of 127/hour as evidenced via ambulatory ECG [Holter] monitoring during at least 18 hours of analyzable time, with about 20% of patients exhibiting at least one run of nonsustained ventricular tachycardia during such monitoring); such patients also had demonstrated drug-induced suppressibility of VPCs during the initial phase of the open trial. It currently is not known whether the findings of CAST can be extrapolated to other patient populations with nonlife-threatening ventricular arrhythmias (e.g., patients with arrhythmias in the absence of ventricular dysfunction, myocardial ischemia, or recent myocardial infarction). CAST principally involved suppression and prevention of VPCs, with only about 10% of patients exhibiting more than a single run of tachycardia at baseline. Some clinicians also question whether the results of CAST even can be extrapolated to patients with recurrent nonsustained ventricular tachycardia and ventricular dysfunction, since these patients are known to be at high risk of sudden death if untreated, and since CAST did not include sufficient numbers of such patients to clearly determine the benefit-to-risk ratio. However, despite the limitations of the CAST findings, the manufacturer, FDA, and other experts consider the potential risks of flecainide therapy substantial and currently do not recommend use of the drug in any patient with nonlife-threatening ventricular arrhythmias in the absence of substantial evidence of safety and efficacy. They state that it is prudent to consider the risks of class IC antiarrhythmic agents and current lack of evidence of improved survival unacceptable in patients without life-threatening ventricular arrhythmias, even in patients experiencing unpleasant but nonlife-threatening signs and symptoms. However, some clinicians, while recognizing the strong evidence of risk in the patient population studied in CAST and the substantial limitations of current evidence on safety and efficacy in other patient populations, question such an extreme limitation of usage.

Life-threatening Ventricular Arrhythmias

The optimum role of flecainide in the suppression and prevention of ventricular arrhythmias remains to be clearly determined.

In addition, it remains to be determined whether antiarrhythmic agents, including flecainide, have a beneficial effect on mortality or sudden death. Although flecainide has been used as a first-line agent for chronic suppression and prevention of ventricular arrhythmias in carefully selected patients, further studies are needed to evaluate the long-term efficacy and safety and the relative role of the drug. Therefore, it is recommended that flecainide generally be reserved for patients who have an insufficient therapeutic response to, or who do not tolerate, conventional orally administered antiarrhythmic agents (e.g., class IA agents). In addition, because of flecainide's arrhythmogenic potential, some clinicians would avoid use of the drug as a first-line agent in patients with life-threatening ventricular arrhythmias who also have congestive heart failure or substantial ventricular dysfunction. While it currently is not known whether the findings of the CAST study apply to class IC antiarrhythmic agents other than flecainide and encainide, some experts state that, in the absence of specific evidence of safety and efficacy, other class IC drugs should be considered to share the risks of flecainide and encainide.

There is relatively limited experience with the use of flecainide for suppression and prevention of recurrent life-threatening ventricular arrhythmias. In the management of severe refractory arrhythmias, the efficacy of flecainide appears to be comparable to that of other first-line antiarrhythmic agents, with the drug being effective in up to about 40% of patients. Younger patients and patients without coronary heart disease and/or substantial ventricular dysfunction appear to have a greater likelihood of responding to flecainide. Further studies, including comparative studies with other antiarrhythmic agents, are needed to evaluate the use of flecainide in the management of life-threatening ventricular arrhythmias.

Limited information is available on the use of flecainide in conjunction with other antiarrhythmic agents for the management of severe refractory ventricular arrhythmias.(See Drug Interactions: Antiarrhythmic Agents.) In a limited number of patients, flecainide has been combined with amiodarone, with good results in selected patients; however, use of these two agents in combination requires extreme caution and is generally reserved for patients with life-threatening ventricular arrhythmias inadequately controlled by single-agent therapy with amiodarone or another antiarrhythmic agent. Combination antiarrhythmic therapy for severe refractory ventricular arrhythmias is generally empiric and must be individualized.

Other Ventricular Arrhythmias

Controlled and uncontrolled clinical studies in patients with chronic stable ventricular arrhythmias have shown that flecainide is highly effective in suppressing and preventing nonsustained ventricular tachycardia and frequent VPCs, including complex VPCs. In short-term clinical studies, flecainide therapy produced at least 80-90% suppression of VPCs in about 80-90% of patients; in many patients, essentially complete suppression of uniform and multiform VPCs, complex VPCs, and/or nonsustained ventricular tachycardia may occur. However, despite such documented evidence of efficacy in suppressing and preventing these arrhythmias, there currently is no evidence of beneficial effect on mortality, and in at least one patient population (those with mild-to-moderate ventricular dysfunction and recent myocardial infarction) with such arrhythmias, there was evidence of substantial risk (including mortality and nonfatal cardiac arrest) associated with flecainide or encainide therapy.(See the opening discussion of Cautions.) Therefore, use of flecainide in nonlife-threatening ventricular arrhythmias currently is not recommended by the manufacturer, FDA, and other experts.

Supraventricular Tachyarrhythmias

Flecainide is used for the prevention of paroxysmal supraventricular tachyarrhythmias (PSVT), including atrioventricular (AV) nodal reentrant tachycardia and AV reentrant tachycardia (Wolff-Parkinson-White syndrome); other symptomatic, disabling supraventricular tachycardias of unspecified mechanisms; and symptomatic, disabling supraventricular arrhythmias (paroxysmal atrial fibrillation/flutter [PAF]) in patients without structural heart disease. Controlled and uncontrolled clinical studies have shown that flecainide may prevent or delay recurrence of PSVT and PAF episodes or may increase the interval between episodes of PSVT and PAF in 31-81% of patients, depending on the type of arrhythmia; suppression of arrhythmias refractory to other antiarrhythmic agents also has occurred. In some patients with atrial fibrillation or flutter associated with ventricular preexcitation and Wolff-Parkinson-White syndrome, flecainide may slow the ventricular rate or possibly restore and maintain normal sinus rhythm. Because of the risk of proarrhythmia, flecainide should not be used in patients with structural heart disease or ischemic heart disease.

Based on findings from the CAST study of substantial flecainide/encainide-associated risk in certain patients with ventricular arrhythmias, some experts currently caution that use of flecainide in supraventricular arrhythmias be limited to the management of symptomatic, disabling supraventricular arrhythmias (paroxysmal atrial fibrillation, AV junctional tachycardias) in patients without structural heart disease. However, some clinicians state that even these patients may be at risk of developing drug-induced arrhythmogenic effects (e.g., during exercise testing). The risks versus benefits of flecainide for the management of such arrhythmias in patients with structural heart defects remains to be elucidated, and assessment of the possible risks and potential benefits in such patients must be individualized.

Paroxysmal Supraventricular Tachycardia

For acute conversion of PSVT, vagal maneuvers, IV adenosine, AV nodal blocking agents (e.g., calcium-channel blocking agents, β-adrenergic blocking agents), and/or synchronized cardioversion are the treatments of choice. Oral flecainide is one of several drugs that may be used for the ongoing management of patients with PSVT who do not have structural or ischemic heart disease; use of flecainide generally is reserved for patients in whom other therapies are ineffective or contraindicated. In a randomized, placebo-controlled, crossover study in 34 patients with symptomatic PSVT, episodes of PSVT occurred in 85% of patients receiving placebo but in only about 21% of patients receiving flecainide acetate in a median dosage of 300 mg daily (range: 100-400 mg daily in 2 divided doses) during the 16-week study period. The median time before initial recurrence of PSVT exceeded 55 days in patients receiving flecainide compared with 11 days in those receiving placebo, while median intervals between episodes of PSVT exceeded 55 days in patients receiving flecainide compared with 12 days in those receiving placebo.

Paroxysmal Atrial Fibrillation and Flutter

In another randomized, crossover placebo-controlled study in 48 patients with PAF, episodes of PAF occurred in 92% of patients receiving placebo versus 69% of patients who received flecainide acetate daily in a median dosage of 300 mg daily (range: 100-600 mg daily in 2 divided doses) during the 8-week study period. The median time before initial recurrence of PAF was approximately 15 days in patients receiving flecainide versus 3 days in those receiving placebo, while the median interval between episodes of PAF was 27 days in patients receiving flecainide and approximately 6 days in patients receiving placebo.

Self-administration for Conversion of Paroxysmal Atrial Fibrillation

Limited evidence suggests that out-of-hospital self-administration of a single oral loading dose of flecainide or propafenone (''pill-in-the-pocket'' approach) is safe and effective for terminating recent-onset paroxysmal atrial fibrillation and can reduce hospitalizations and emergency room visits in carefully selected patients who have mild or no heart disease. In-hospital administration of flecainide or propafenone (as immediate-release tablets) as a single oral dose for terminating acute atrial fibrillation has been shown to be effective with a low incidence of adverse effects in several randomized, controlled studies; however, the safety of such treatment without initial evaluation in a hospital setting or in patients with substantial structural heart disease has not been established. In addition, additional study and experience are required to assess the possible need for concomitant antithrombotic (e.g., warfarin) therapy and potential for adverse drug interactions (e.g., with warfarin or digoxin) in patients self-administering antiarrhythmic agents for recent-onset paroxysmal atrial fibrillation on an out-of-hospital basis.

In a prospective, uncontrolled study, 268 patients (18-75 years of age) with mild or no heart disease who had hemodynamically well-tolerated atrial fibrillation of recent (less than 48 hours) onset were treated in-hospital (i.e., in the emergency room or cardiology ward) with a single oral dose of flecainide or immediate-release propafenone (according to clinician preference) to restore normal sinus rhythm. Patients weighing 70 kg or more received 300 mg of flecainide acetate or 600 mg of propafenone hydrochloride and those weighing less than 70 kg received 200 mg of flecainide acetate or 450 mg of propafenone hydrochloride. In-hospital treatment was considered effective if conversion of atrial fibrillation to sinus rhythm occurred within 6 hours of administration of the antiarrhythmic agent without clinically important adverse effects (i.e., symptomatic hypotension, symptomatic bradycardia after restoration of sinus rhythm, dyspnea, presyncope, syncope, conversion to atrial flutter or atrial tachycardia, or episodes of sustained or unsustained ventricular tachycardia). The time to conversion to sinus rhythm following in-hospital treatment with flecainide or propafenone in these patients averaged 135 minutes (median: 120 minutes). Patients in whom inpatient administration of these antiarrhythmics was effective and who were not excluded during subsequent examination were discharged and given flecainide or propafenone for treatment of subsequent episodes of palpitations (presumed recurrent atrial fibrillation) on an outpatient basis. These patients were instructed to take a single oral dose of the assigned antiarrhythmic drug 5 minutes after noting the onset of palpitations (self-assessed) and then to assume a resting state (e.g., a supine or sitting position) until resolution of the palpitations or for at least four hours.

Analysis of data from 2 of the study sites indicated that 12% of patients presenting to the emergency room for recent-onset atrial fibrillation were candidates for out-of-hospital treatment with propafenone or flecainide. During a mean follow-up period of 15 months (range: 7-19 months), 79% of patients included in the out-of-hospital phase of the study experienced episodes of palpitations (presumed atrial fibrillation); patients self-administered propafenone hydrochloride (mean dose: 555 mg) or flecainide acetate (mean dose: 263 mg) within a mean of 36 minutes (median: 10 minutes) after the onset of symptoms in 92% of such episodes. Each antiarrhythmic agent was effective in interrupting 94% of episodes of palpitations (a primary end point); time to resolution of symptoms after drug administration averaged 113 minutes (median: 98 minutes). In patients who had multiple recurrences of palpitations during the follow-up period, self-administration of flecainide or propafenone terminated all such episodes in 84% of patients. Self-administration of oral flecainide or propafenone also was associated with reductions in emergency room visits and hospital admissions (secondary end points); calls for emergency room intervention during the study averaged 4.9 per month compared with 45.6 per month during the year prior to the study, while the number of hospitalizations averaged 1.6 per month during the study compared with 15 per month during the prior year.

Atrial Fibrillation and Flutter

Flecainide is considered a drug of choice for pharmacologic cardioversion of atrial fibrillation or atrial flutter. Conversion of atrial fibrillation or flutter to normal sinus rhythm may be associated with embolism, particularly when the arrhythmia has been present for more than 48 hours, unless the patient is adequately anticoagulated.

Limited data suggest that oral flecainide may also improve control of ventricular rate at rest and during exercise in digitalized patients with atrial fibrillation in whom cardiac glycosides alone may not provide adequate control.

Some clinicians do not recommend the use of antiarrhythmic agents in patients with atrial fibrillation or flutter, because increased mortality has been reported in patients receiving antiarrhythmic therapy after conversion of atrial fibrillation to normal sinus rhythm.

Atrial Tachycardias

Flecainide is one of several drugs that may be used for the ongoing management of focal atrial tachycardia or junctional tachycardia in patients without structural or ischemic heart disease. Limited data suggest that oral flecainide may be effective in suppressing and preventing recurrent atrial tachycardia.

Dosage and Administration

Administration

Flecainide acetate is administered orally. Flecainide acetate has also been administered IV, but a parenteral dosage form of the drug is currently not commercially available in the US.

Flecainide acetate is usually administered orally in 2 equally divided doses daily at 12-hour intervals; however, in patients in whom arrhythmias are not adequately controlled or the drug is not well tolerated with twice-daily dosing, the drug may be given in 3 divided doses daily at 8-hour intervals. The elimination half-life of flecainide suggests that once-daily oral dosing may be possible in some patients, but once-daily dosing regimens of the drug have not been evaluated to date.

Dosage

Dosage of flecainide acetate must be carefully adjusted according to individual requirements and response, patient tolerance, and the general condition and cardiovascular status of the patient. Clinical and ECG monitoring of cardiac function, including appropriate ambulatory ECG monitoring (e.g., Holter monitoring), is recommended during therapy with the drug. When feasible, plasma flecainide concentrations should be monitored, especially in patients with severe chronic renal failure or severe congestive heart failure in whom elimination of the drug may be impaired and in patients with life-threatening ventricular arrhythmias. Dosage should be adjusted to maintain trough plasma flecainide concentrations at less than 0.7-1 mcg/mL; the risk of adverse effects, particularly adverse cardiac effects, may increase with higher trough concentrations, especially when the trough concentration exceeds 1 mcg/mL. Since steady-state plasma concentrations of flecainide and the optimum therapeutic effect may not be attained for 3-5 days (or longer in some patients) at a given dosage in patients with normal renal and hepatic function, increases in flecainide dosage should be made at intervals of not less than 4 days. Once adequate control of arrhythmias has been attained, dosage reduction to minimize adverse effects or effects on cardiac conduction may be possible in some patients; however, the efficacy of the drug at the lower dosage should be evaluated. If congestive heart failure, myocardial dysfunction, or renal or hepatic failure develops in patients receiving flecainide, dosage reduction may be necessary. Many clinicians recommend the use of low initial dosages in geriatric patients.

Any use of flecainide in children should be supervised directly by a cardiologist experienced in the treatment of arrhythmias in this age group. Because of the evolving nature of flecainide use in children, specialized references should be consulted for the most recent information. The manufacturer recommends that infants younger than 6 months of age receive an initial flecainide acetate dosage of approximately 50 mg/m daily, divided into 2 or 3 equally divided doses. For older children, the manufacturer recommends an initial dosage of 100 mg/m daily. The maximum dosage recommended by the manufacturer for pediatric patients is 200 mg/m daily, and this dosage should not be exceeded. Plasma trough flecainide concentrations (less than 1 hour before dosing) and ECGs should be obtained at presumed steady state (after at least 5 doses) after initiation of therapy and any change in dosing, such as dosage increases for lack of effectiveness or for increased growth of the child. In some children receiving higher dosages, plasma drug concentrations are labile; while receiving the same dosage, plasma flecainide concentrations have increased rapidly to far above therapeutic concentrations, despite previously low plasma concentrations. Small changes in dosage also may lead to disproportionate increases in plasma drug concentrations. For the first year of flecainide treatment whenever the pediatric patient is seen for clinical follow-up, a 12-lead ECG and plasma trough flecainide concentrations are suggested. The usual therapeutic concentration of flecainide in children is 200-800 ng/mL, although concentrations up to 800 ng/mL may be required for adequate control in some children.

Since initial flecainide acetate dosages higher than those recommended and dosage adjustments at shorter intervals than recommended have resulted in an increased risk of arrhythmogenicity and congestive heart failure in patients with sustained ventricular tachycardia, especially during the first few days of flecainide therapy, a loading dose of the drug is not recommended. IV lidocaine has occasionally been used concomitantly and without any apparent adverse interaction until the therapeutic effect of oral flecainide therapy was attained; however, studies have not been performed to determine the value of this regimen. Based on theoretical considerations, it is recommended that, when transferring patients from therapy with another antiarrhythmic agent to flecainide, at least 2-4 elimination half-lives of the agent being discontinued be allowed to elapse before therapy with flecainide is initiated at the usual dosage. When withdrawal of another antiarrhythmic agent is likely to result in life-threatening arrhythmias, initiation of flecainide therapy in a hospital setting should be considered.

Life-threatening Ventricular Arrhythmias

For the suppression and prevention of life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia), the recommended initial adult dosage of flecainide acetate is 100 mg every 12 hours. Some clinicians suggest an initial dosage of 50 mg twice daily in these patients. Dosage may be increased in increments of 50 mg twice daily every 4 days until an effective response is attained or the maximum recommended dosage of 400 mg daily is reached. Most patients do not require dosages greater than 150 mg every 12 hours or 300 mg daily.

Supraventricular Arrhythmias

For the prevention of paroxysmal supraventricular tachycardias (PSVT), including atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia, and other disabling supraventricular tachycardias of unspecified mechanism, and disabling paroxysmal atrial fibrillation/flutter (PAF), the recommended initial adult dosage of flecainide acetate is 50 mg every 12 hours. Dosage may be increased in increments of 50 mg twice daily every 4 days until an effective response is attained. In patients with PAF who do not attain the desired response, the manufacturer states that increasing flecainide acetate dosage to 100 mg twice daily can increase effective response without increasing the incidence of adverse effects (which might lead to discontinuance of flecainide therapy). The maximum recommended dosage of flecainide in patients with PSVT is 300 mg daily.

Self-administration for Conversion of Paroxysmal Atrial Fibrillation

For self-administration on an outpatient basis for termination of atrial fibrillation of recent onset in carefully selected patients with mild or no heart disease, flecainide acetate has been given as a single oral loading dose of 300 mg in patients weighing 70 kg or more or 200 mg in patients weighing less than 70 kg.

Some clinicians suggest that flecainide be taken 5 minutes after noting the onset of palpitations and that patients remain in a supine or sitting position until resolution of palpitations or for a period of at least 4 hours following the dose. Patients should seek medical advice if palpitations do not resolve within 6-8 hours, if previously unexperienced symptoms (e.g., dyspnea, presyncope, syncope) occur, or if a marked increase in heart rate occurs after taking the antiarrhythmic drug. Patients should not take more than a single oral dose of flecainide during a 24-hour period.

Dosage in Renal and Hepatic Impairment

In adults with renal impairment, dosage of flecainide acetate must be carefully adjusted and may need to be modified in response to the degree of renal impairment. The recommended initial oral dosage of flecainide acetate in adults with renal impairment is 100 mg every 12 hours. Since the elimination half-life of the drug may be prolonged in patients with renal impairment, steady-state plasma concentrations with a given dosage may not be attained for longer than 4 days. Consequently, increases in dosage should be made with caution and at intervals of longer than 4 days, with the patient closely monitored for signs of adverse cardiac effects or other toxicity. It is recommended that plasma flecainide concentrations be monitored closely to guide dosage adjustments in these patients. In patients with severe renal impairment (creatinine clearances of 20 mL/minute per m or less), the usual dosage should be decreased by 25-50%.

Since flecainide is extensively metabolized, probably in the liver, elimination may be markedly prolonged in patients with substantial hepatic impairment, and therefore the drug should not be used in such patients unless the potential benefits are considered to clearly outweigh the risks. If flecainide is used in patients with hepatic impairment, plasma flecainide concentrations should be monitored closely and dosage reduced as necessary.

Cautions

While clinical studies have indicated that adverse reactions to flecainide occur frequently but are usually mild to moderate in severity and transient, and the drug is generally well tolerated in most patients, concerns about the long-term safety and efficacy of the drug in patients with nonlife-threatening arrhythmias have been raised by findings of the Cardiac Arrhythmia Suppression Trial (CAST). Findings from the CAST study after an average of 10 months of follow-up indicate that the rate of total mortality and nonfatal cardiac arrest in patients with recent myocardial infarction, mild-to-moderate left ventricular dysfunction, and asymptomatic or mildly symptomatic ventricular arrhythmias (principally frequent ventricular premature complexes [VPCs]) who received flecainide was increased substantially.

The CAST study, which began in 1987, was designed to evaluate the efficacy (in terms of reduced sudden cardiac death and total mortality) and safety of flecainide, encainide, and moricizine for the suppression and prevention of VPCs following recent myocardial infarction in patients with asymptomatic or mildly symptomatic ventricular arrhythmias. Findings from this large, multicenter, double-blind, placebo-controlled study, sponsored by the National Heart, Lung, and Blood Institute (NHLBI), indicate that the rates of total mortality (from arrhythmia, cardiac arrest, other cardiac causes, or noncardiac or unclassified causes) and nonfatal cardiac arrest combined in such patients receiving flecainide was increased substantially to 2.2 times that observed in patients receiving placebo. These findings were consistent across a variety of patient subgroups, and the degree of undesirable effects associated with flecainide or encainide was similar. When the effects of flecainide or encainide were considered together, the rate of total mortality and nonfatal cardiac arrest was 2.5 times that observed with placebo, and the rate of death secondary to arrhythmia or cardiac arrest for these drugs was 3.6 times that observed with placebo. Because there was evidence suggesting a potential harmful effect and no evidence of substantial benefit in the type of patient studied, flecainide and encainide were removed from the CAST study in early 1989. The relevance of the findings of the CAST study to patients with ventricular arrhythmias associated with a high risk of death currently is not known, and the manufacturers and FDA state that current evidence does not require discontinuance of flecainide or encainide in patients being treated for life-threatening arrhythmias.

The frequency of flecainide-induced adverse effects tends to decrease with time, and adverse effects tend to occur intermittently. Flecainide-induced adverse effects are often alleviated by dosage reduction, occasionally disappear despite continued treatment and without dosage reduction, and are usually reversible following discontinuance of the drug. The risk of adverse effects, particularly adverse cardiac effects, may increase when trough plasma flecainide concentrations increase above 0.7-1 mcg/mL, especially when the trough concentration exceeds 1 mcg/mL.

The most common adverse effects of flecainide are dizziness and visual disturbances, which are dose related, often occur concomitantly, and are also the most common adverse reactions requiring discontinuance of the drug. Adverse extracardiac effects requiring discontinuance of flecainide therapy occur in about 5-15% of patients. The need to discontinue flecainide results most often from multiple adverse effects rather than a single adverse effect, and adverse effects requiring discontinuance of the drug are most likely to occur during the first 2-4 weeks of therapy.

Nervous System Effects

Dizziness (including dizziness, lightheadedness, faintness, unsteadiness, near syncope), which is dose related and often accompanied by visual disturbances, occurs in about 10-20% of patients receiving flecainide acetate dosages of 200-400 mg daily and about 30% of patients receiving 400-600 mg daily. Dizziness has required discontinuance of therapy in about 4-6% of patients. Flecainide-induced dizziness may also be associated with other adverse nervous system effects (e.g., nervousness) and probably results from an effect of the drug on the CNS.

Headache, which appears to be dose related, occurs in about 5-10% of patients receiving flecainide acetate dosages of 200-400 mg daily and about 10% of patients receiving 400-600 mg daily. Headache has required discontinuance of therapy in less than 1% of patients.

Fatigue has occurred in about 3-8% of patients receiving flecainide and required discontinuance in about 1% of patients. Tremor or nervousness has occurred in about 3-5% of patients and required discontinuance in less than 1% of patients. Hypoesthesia and paresthesia, which tend to occur in the perioral region or the extremities, occur in about 1-3% of patients receiving flecainide. Other adverse nervous system effects occurring in about 1-3% of patients receiving the drug include paresis, ataxia, vertigo, syncope, somnolence, tinnitus, anxiety,insomnia, and mental depression. Twitching, weakness, change in taste perception, dry mouth, speech disorder, stupor, seizures, amnesia, confusion, neuropathy, hallucinations, depersonalization, euphoria, morbid dreams, and apathy have been reported in less than 1% of patients.

Ocular Effects

Visual disturbances (including blurred vision, difficulty in focusing, spots before eyes), which are dose related and often associated with dizziness, occur in about 5-20% of patients receiving flecainide acetate dosages of 200-400 mg daily and about 30% of patients receiving 400-600 mg daily. Visual disturbances have required discontinuance of therapy in about 2-3% of patients. The most common visual disturbance is blurred vision on lateral gaze and/or turning the head to the side. Diplopia has occurred in about 1-3% of patients receiving flecainide, and photophobia, nystagmus, and ocular pain or irritation have occurred in less than 1% of patients.

Flecainide-induced visual disturbances tend to be mild to moderate in severity and transient; persistent disturbances often respond to dosage reduction. Visual disturbances occur intermittently, usually last only for a few seconds, and occur most often during the time of expected peak plasma concentrations following an individual dose. The mechanism(s) of flecainide-induced visual disturbances is not known, but blurred vision may result from difficulty in accommodation caused by a local anesthetic effect of the drug on the ciliary muscle, from an effect on vestibulo-ocular reflexes, or from an effect on the CNS.

Arrhythmogenic Effects

Like other antiarrhythmic agents, flecainide can worsen existing arrhythmias or cause new arrhythmias, and the arrhythmogenic potential is the most serious risk associated with the drug. Arrhythmogenic effects associated with flecainide range from an increased frequency of ventricular premature complexes (VPCs) to the development of new and/or more severe and potentially fatal ventricular tachyarrhythmias. About 75% of the arrhythmogenic effects associated with the drug have been new or worsened ventricular tachyarrhythmias (e.g., new occurrence of sustained or nonsustained ventricular tachycardia, including exercise-induced or spontaneous wide QRS complex tachycardia, or progression of ventricular tachycardia to ventricular fibrillation), with the remainder consisting of increased frequency of VPCs or new or worsened supraventricular arrhythmias. In some patients, principally those with factors predisposing them to the risk of arrhythmogenic effects, flecainide therapy has been associated with episodes of ventricular tachycardia or fibrillation that required prolonged or unusual resuscitative measures or that resulted in death despite resuscitative measures.

The risk of flecainide-induced arrhythmogenic effects appears to be directly related to dosage and underlying cardiac disease, including severity of the preexisting ventricular arrhythmia and myocardial dysfunction. Patients with atherosclerosis, cardiac disease, previous myocardial infarction, congestive heart failure, or nonsustained ventricular tachycardia appear to have approximately twice the risk of arrhythmogenic effects during flecainide therapy as those without these conditions. Patients with a history of sustained ventricular tachycardia appear to have about a 10-fold overall increased risk, and patients with both a history of sustained ventricular tachycardia and structural heart disease appear to have about a 14-fold increased risk compared with those with structural heart disease and only VPCs. When flecainide is given according to currently recommended dosage regimens and precautions, the risk of arrhythmogenic effects appears to be comparable to that associated with other antiarrhythmic agents.

Because of difficulties in distinguishing spontaneous and drug-related variations in an underlying arrhythmia disorder in patients with complex arrhythmias, reported occurrence rates must be considered approximations. Arrhythmogenic effects associated with flecainide have reportedly occurred with an overall frequency of about 7%. In patients with sustained ventricular tachycardia who also often had heart failure, a low left ventricular ejection fraction, a history of myocardial infarction, and/or an episode of cardiac arrest, the incidence of arrhythmogenic effects during flecainide therapy was 13% when dosage was initiated at 200 mg daily, was titrated upward slowly, and did not exceed 300 mg daily in most patients; about half of the arrhythmogenic effects were serious. In early clinical studies in patients with sustained ventricular tachycardia who received an initial flecainide acetate dosage of 400 mg daily (twice the currently recommended initial dosage), the incidence of arrhythmogenic effects was 26%; about 75% of the arrhythmogenic effects were serious, and arrhythmogenic effects resulted in death in about 10% of patients receiving the drug, despite immediate medical attention. With the currently recommended initial dosage regimen in patients with sustained ventricular tachycardia, the incidence of arrhythmogenic effects resulting in death has decreased to about 0.5% of patients. In patients with less severe arrhythmias (chronic VPCs, nonsustained ventricular tachycardia) receiving flecainide, the overall incidence of arrhythmogenic effects appears to be approximately 3-4%; serious arrhythmogenic effects occur in about 0.4% of patients and result in death in about 0.1% of patients. It is not known whether the incidence of arrhythmogenic effects is increased in patients with chronic atrial fibrillation (CAF), high ventricular rate, and/or exercise. Wide complex tachycardia and ventricular fibrillation have been reported in about 17% of patients with CAF who were undergoing maximal exercise tolerance testing.

In patients with supraventricular arrhythmias including paroxysmal atrial fibrillation/flutter (PAF), the incidence of arrhythmogenic effects during flecainide therapy was about 4% and serious arrhythmogenic effects occurred in about 0.4%. The incidence of arrhythmogenic effects was about 11% in patients with chronic atrial fibrillation.

Flecainide-induced arrhythmogenic effects appear to be directly related to dosage and the rate of dosage escalation, particularly in patients with sustained ventricular tachycardia. A relationship with plasma concentrations of the drug has not been established; however, some data suggest that arrhythmogenicity may be associated with plasma concentrations higher than 1 mcg/mL. Arrhythmogenic effects appear to be most likely to occur within 1-4 weeks of initiation of flecainide therapy and/or within 1 week of an increase in dosage. In patients with sustained ventricular tachycardia, 80% of the arrhythmogenic effects occur within 14 days of initiation of flecainide therapy. The exact role is not clear, but concomitant use of other antiarrhythmic agents may increase the risk of arrhythmogenic effects during flecainide therapy. Because of the risk of arrhythmogenic effects, initiation of flecainide therapy in a hospital setting is recommended for patients with sustained ventricular tachycardia and should be considered for other patients with underlying structural heart disease.(See Cautions: Precautions and Contraindications.)

Cardiovascular Effects

Because of its mild to moderate negative inotropic effect, flecainide may cause or worsen congestive heart failure, particularly in patients with cardiomyopathy, preexisting severe heart failure (New York Heart Association [NYHA] class III or IV), or low left ventricular ejection fractions (less than 30%). New or worsened congestive heart failure associated with flecainide has occurred in about 6% of patients with PVCs, non-sustained or sustained ventricular tachycardia and with a frequency of about 1% in patients without a history of congestive heart failure. Worsened congestive heart failure associated with flecainide therapy occurred with a frequency of about 26% in patients with a history of congestive heart failure and sustained ventricular tachycardia. New or worsened congestive heart failure occurred in about 0.4% of patients with supraventricular arrhythmias. Congestive heart failure associated with flecainide has required discontinuance of the drug in about 1.4% of patients and possibly resulted in death in about 0.5% of patients. In most cases, fatalities were probably related to serious underlying heart disease; in addition, most of these patients had life-threatening ventricular arrhythmias and all had substantial myocardial dysfunction prior to flecainide therapy.

Exacerbation of preexisting congestive heart failure during flecainide therapy has occurred most frequently in patients with advanced stages of failure (i.e., NYHA class III or IV). When congestive heart failure has developed or worsened, the onset has occurred within hours to several months after initiation of therapy; the risk appears to be greatest during the first 1-4 weeks of treatment. Some patients who develop signs and/or symptoms of congestive heart failure during flecainide therapy can continue to receive the drug at the same dosage with adjustment of concomitant cardiac glycoside and/or diuretic therapy; however, others may require a reduction in flecainide dosage or discontinuance of the drug.

Palpitation has occurred in about 6%, chest pain in about 5%, and edema in about 3% of patients receiving flecainide. Tachycardia and flushing have occurred in about 1-3% of patients, and bradycardia, angina pectoris, hypertension, and hypotension have occurred in less than 1% of patients receiving the drug.

Effects on Cardiac Conduction

Clinically important conduction disturbances occur infrequently during flecainide therapy in patients without preexisting conduction abnormalities; however, the risk of adverse cardiac effects probably increases progressively as plasma flecainide concentrations increase above 0.7-1 mcg/mL. Sinus bradycardia, pause, and arrest have occurred collectively in about 1.2% of patients. First-degree AV block occurs in about 30-40% of patients receiving flecainide. Second-degree AV block occurs in about 0.5% of patients and third-degree AV block in about 0.4% of patients. New bundle-branch block may develop rarely. Paradoxically, an extremely rapid ventricular rate may occur when flecainide is used in the treatment of atrial flutter or fibrillation, due to a reduction in the degree of AV nodal block to a 1:1 ratio. Risk of this tachycardia may be reduced by administration of a cardiac glycoside or a β-adrenergic blocking agent. Less than half of the clinically important flecainide-induced conduction disturbances have resulted in symptoms, which were usually mild, and about one-third of patients who developed substantial conduction disturbances continued to receive the drug, usually after insertion of an artificial pacemaker. However, discontinuance of the drug may be necessary in some patients unless a temporary or permanent artificial pacemaker is in place.(See Cautions: Precautions and Contraindications.) Syncope has also occurred rarely as a result of sinus node dysfunction, almost exclusively in patients with known preexisting sinus node dysfunction. An atypical ventricular tachycardia-like (torsades de pointes-like) arrhythmia associated with flecainide-induced QT-interval prolongation and bradycardia has also been reported.

Flecainide-induced increases in PR and QRS intervals are usually not clinically important. There is a correlation between dosage of flecainide and the degree of lengthening of PR and QRS intervals during the initial dosage titration period; however, ECG changes tend to remain constant during long-term therapy. The degree of lengthening of PR and QRS intervals does not allow prediction of therapeutic efficacy or the development of adverse cardiac effects, although some data suggest that absolute increases in PR and QRS intervals (at least 40 ms) may be associated with adverse cardiac effects. Patients with preexisting PR and QRS prolongation tend to develop the same absolute increase in these intervals during flecainide therapy as those with normal intervals at baseline. Although prolongation of PR and QRS intervals is to be expected during therapy with the drug and is usually not clinically important, substantial increases require caution and consideration of dosage reduction.(See Cautions: Precautions and Contraindications.) Rarely, substantial prolongation of QTc may occur and also require caution and dosage reduction.

GI Effects

Nausea occurs in about 9-10% of patients receiving flecainide and has required discontinuance of the drug in about 1% of patients. Dyspepsia, anorexia, vomiting, constipation, and diarrhea have occurred in about 1-3% of patients and flatulence in less than 1% of patients.

Dermatologic Effects

Rash occurs in about 1-3% of patients receiving flecainide. Urticaria, pruritus, and exfoliative dermatitis have occurred in less than 1% of patients.

Other Adverse Effects

Dyspnea has occurred in about 5-10% of patients receiving flecainide. Malaise, fever, and increased sweating have occurred in about 1-3% of patients receiving the drug. Decreased libido, impotence, polyuria, urinary retention, arthralgia, myalgia, bronchospasm, and swelling of the lips, tongue, and mouth have been reported in less than 1% of patients.

There have been rare reports of asymptomatic, isolated increases in serum alkaline phosphatase or aminotransferase concentrations in patients receiving long-term flecainide therapy; however, a causal relationship to the drug has not been established. There have also been rare reports of hepatic dysfunction, including cholestasis and hepatic failure, and extremely rare reports of blood dyscrasias (leukopenia, thrombocytopenia) in patients receiving flecainide, but these effects have not been directly attributed to the drug.(See Cautions: Precautions and Contraindications.) However, in one patient who developed granulocytopenia, there was evidence of a specific IgG antibody directed against a flecainide (hapten)-neutrophil complex.

Precautions and Contraindications

Findings from the CAST study indicate that use of flecainide and other class I antiarrhythmic agents (e.g., disopyramide, quinidine, procainamide, and tocainide) may be associated with substantial risk in certain patients with ventricular arrhythmias. Therefore, the manufacturer, FDA, and some experts currently recommend that use of flecainide and other class I agents in patients with ventricular arrhythmias be limited to those with life-threatening arrhythmias.(See Uses.) Use in less severe ventricular arrhythmias, even when symptomatic, currently is not recommended. In addition, it has been recommended that use of these drugs in patients with supraventricular arrhythmias be limited to those with symptomatic disabling arrhythmias. It is essential that patients not alter their antiarrhythmic therapy without first consulting their physician. The decision to discontinue therapy with flecainide (or encainide) must be made by the physician, and physicians have been advised by FDA and the manufacturers to contact their patients receiving either of these drugs and determine whether alternative therapy is indicated, reserving therapy with flecainide or encainide only for arrhythmias considered life-threatening. Some experts state that discontinuing therapy with these drugs in patients with symptomatic sustained ventricular arrhythmias that have been treated effectively for prolonged periods seems unwarranted and is potentially dangerous. However, if withdrawal of therapy with flecainide or encainide is contemplated in these or other patients with sustained arrhythmias, it is recommended that it be performed in a hospital setting under continuous ECG monitoring. It also has been suggested that the need for hospitalization and ECG monitoring be considered when withdrawing therapy with these drugs in patients with nonsustained arrhythmias.

Since flecainide, like other antiarrhythmic agents, can worsen existing arrhythmias or cause new arrhythmias in some patients, clinical and ECG evaluations are essential prior to and during flecainide therapy to monitor for the appearance of arrhythmias and to determine the need for continued therapy. To minimize the risk of arrhythmogenic effects, the recommended flecainide dosage schedule should be closely followed, plasma drug concentrations should be monitored and concentrations higher than 1 mcg/mL avoided, ECG monitoring should be carefully evaluated before each dosage adjustment, and, if possible, concomitant use of other antiarrhythmic agents should be avoided. If flecainide is suspected or determined to be causing an increased frequency of VPCs despite adequate dosage or to be causing an increased frequency of complex VPCs or new and/or more serious arrhythmias, alternative therapy should be substituted. There is some evidence that exercise (e.g., treadmill) testing may be useful for detecting arrhythmogenic potential in some patients (e.g., those with preexisting sustained or nonsustained ventricular tachycardia and/or ventricular dysfunction), but additional study and experience are necessary.

Because of the relatively high incidence of arrhythmogenic effects in patients with sustained ventricular tachycardia and serious underlying heart disease and the need for careful dosage titration and monitoring, flecainide therapy should be initiated in a hospital setting with ECG monitoring in patients with sustained ventricular tachycardia, regardless of their cardiac status. Initiation of flecainide therapy in a hospital setting should also be considered for other patients with underlying structural heart disease, particularly those with serious disease, and for patients transferring from therapy with another antiarrhythmic agent in whom discontinuance of the current antiarrhythmic agent is likely to result in life-threatening arrhythmias. In patients with less severe and/or stable ventricular arrhythmias (frequent VPCs, nonsustained ventricular tachycardia), flecainide therapy may be initiated in an ambulatory setting with careful clinical and ECG monitoring.

Because of flecainide's mild to moderate negative inotropic effect, as well as an increased risk of arrhythmogenic effects, the drug should be used with caution in patients with a history of congestive heart failure or myocardial dysfunction, particularly those with advanced failure or dysfunction. Initiation of flecainide therapy in a hospital setting is recommended for patients with symptomatic congestive heart failure, even in those without a history of sustained ventricular tachycardia, and should be considered for patients with substantial myocardial dysfunction in whom heart failure is compensated. Patients with a history of congestive heart failure or myocardial dysfunction who receive flecainide must be carefully monitored, and the recommended initial dosage in these patients should not be exceeded. When feasible, plasma flecainide concentrations should be monitored and dosage adjusted to maintain trough concentrations less than 0.7-1 mcg/mL. Particular attention should be given to maintenance of cardiac function, including optimum management with cardiac glycoside, diuretic, and/or other therapy. If progressive congestive heart failure occurs despite a reduction of flecainide dosage and/or despite optimum management with other drugs and/or therapy, flecainide should be discontinued.

If the PR interval increases to 300 ms or greater, QRS duration increases to 180 ms or greater, QTc interval increases substantially, and/or new bundle-branch block develops during flecainide therapy, caution is necessary and dosage reduction should be considered. To minimize effects on cardiac conduction, an attempt should be made to manage patients on the lowest possible effective dosage. If second- or third-degree AV block or bifascicular block (right bundle-branch block associated with left hemiblock) occurs during flecainide therapy, the drug should be discontinued unless a temporary or implanted artificial ventricular pacemaker is in place to ensure an adequate ventricular rate.

Because its effects on sinus node function may be marked, flecainide should be used with particular caution in patients with preexisting sinus node dysfunction. Because of the possibility of inducing a syncopal episode, it is recommended that flecainide therapy be initiated in a hospital setting in patients with sinus node dysfunction, even in those without a history of sustained ventricular tachycardia. Flecainide should be used only with extreme caution, if at all, in patients with sick sinus syndrome (including bradycardia-tachycardia syndrome), since the drug may cause sinus bradycardia, pause, or arrest in such patients.

Flecainide can increase acute and chronic endocardial pacing thresholds and may suppress ventricular escape rhythms; these effects are reversible following discontinuance of the drug. Flecainide should be used with particular caution in patients with permanent artificial pacemakers or temporary pacing electrodes and should not be administered to patients with existing poor thresholds or nonprogrammable artificial pacemakers unless suitable pacing rescue is available. In patients with pacemakers, the pacing threshold should be determined before and 1 week after initiating therapy with the drug and at regular intervals thereafter. Flecainide-induced changes in pacing threshold are generally within the range of multiprogrammable pacemakers and, when such changes occur, doubling of voltage or pulse width is usually sufficient to regain capture.

Since hypokalemia or hyperkalemia may alter the effects of class I antiarrhythmic agents, the possibility of a potassium imbalance should be evaluated and, if present, corrected before administration of flecainide.

Since elimination of flecainide may be impaired, the drug should be used with caution and dosage adjusted carefully in patients with renal impairment, particularly severe impairment. Because the urinary excretion of flecainide can be markedly affected by extremes of urinary pH, the potential effects of dietary regimens (e.g., very alkaline pH in strict vegetarians), disease states or conditions (e.g., metabolic alkalosis or acidosis), or concomitant drugs that may affect urinary pH should be kept in mind. Since flecainide is extensively metabolized, probably in the liver, elimination may be markedly prolonged in patients with substantial hepatic impairment, and therefore the drug should not be used in such patients unless the potential benefits are considered to clearly outweigh the risks. If flecainide is used in patients with severe renal or hepatic impairment, periodic monitoring of plasma concentrations of the drug is necessary.

Flecainide therapy should be discontinued in patients who develop unexplained jaundice, signs of hepatic dysfunction, or a blood dyscrasia to rule out the drug as a possible cause.

Use of flecainide in chronic atrial fibrillation has not been studied and the drug is not recommended in patients with this arrhythmia. Flecainide should not be used in patients with recent myocardial infarction. In the absence of an artificial ventricular pacemaker, flecainide is contraindicated in patients with preexisting second- or third-degree AV block, bifascicular block (right bundle-branch block associated with left hemiblock), or trifascicular block. Flecainide is also contraindicated in patients with cardiogenic shock or known hypersensitivity to the drug.

Pediatric Precautions

Safety and efficacy of flecainide in infants or children have not been established. Limited data suggest that the drug may be useful in children for the management of refractory paroxysmal reentrant supraventricular tachycardias. The proarrhythmic effects of flecainide observed in adults also may occur in children. In pediatric patients with structural heart disease, flecainide has been associated with cardiac arrest and sudden death. Treatment with flecainide should be initiated in a hospital setting equipped with ECG monitoring. Pediatric use of flecainide should be supervised directly by a cardiologist experienced in the treatment of arrhythmias in children.

Mutagenicity and Carcinogenicity

No evidence of flecainide-induced mutagenicity was seen with in vitro microbial (Ames test) or mammalian (mouse lymphoma) test systems, or with in vivo cytogenetic tests in rats receiving dosages up to 180 mg/kg daily for 5 days.

No evidence of carcinogenesis was seen in mice and rats receiving oral flecainide acetate dosages up to 60 mg/kg daily (about 8 times the usual human dosage) for 18 and 24 months, respectively.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and mice using oral flecainide acetate dosages up to 50 and 80 mg/kg daily, respectively, have not revealed evidence of fetal malformation; however, delayed sternebral and vertebral ossification were observed in rats receiving the highest dosages. Club paws, sternebral and vertebral abnormalities, pale hearts with contracted ventricular septum, and increased fetal resorptions were observed in New Zealand white rabbits receiving oral dosages about 4 times the usual human dosage, but not in those receiving oral dosages about 3 times the usual human dosage; reproduction studies in Dutch Belted rabbits using the same dosages did not reveal evidence of teratogenicity or embryotoxicity. There are no adequate and controlled studies to date using oral flecainide acetate in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. It is not known whether use of the drug during labor or delivery could have any immediate or delayed adverse effects on the mother or fetus, affect the duration of labor, or increase the likelihood of forceps delivery or other obstetrical intervention.

Fertility

The effect of flecainide on fertility in humans is not known. In vitro, the drug inhibits sperm motility. Reproduction studies in male and female rats using oral flecainide acetate dosages up to 50 mg/kg daily (7 times the usual human dosage) have not revealed evidence of impaired fertility.

Lactation

Limited data suggest that flecainide acetate is distributed into milk in humans. In one study in several women receiving multiple doses of flecainide soon after delivery, milk flecainide concentration averaged 2.5 times (sometimes as high as 4 times) that of maternal plasma concentrations. It is estimated that less than 3 mg of the drug would be ingested by a nursing infant (receiving about 700 mL of milk) over a 24-hour period assuming a maternal plasma flecainide concentration of 1 mcg/mL, which is considered at the top of the therapeutic range. Because of the potential for serious adverse reactions to flecainide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Metabolism of flecainide is mediated by the cytochrome P-450 (CYP) isoenzyme 2D6, and concurrent use of flecainide with CYP2D6 inhibitors (e.g., clozapine, quinidine) could result in increased plasma flecainide concentrations. Caution should be exercised and dosage of flecainide should be reduced accordingly when the drug is used concurrently with CYP2D6 inhibitors. In particular, patients with the extensive-metabolizer phenotype receiving such concomitant therapy should be monitored closely. Dosage adjustment of the concurrent drug also may be necessary.

Limited data indicate that the rate of flecainide elimination is increased by 30% in patients receiving flecainide concurrently with inducers of CYP2D6 (e.g., carbamazepine, phenytoin, phenobarbital).

Protein-bound Drugs

Flecainide is not extensively bound to plasma proteins. The manufacturer states that concomitant use of flecainide with other drugs that are highly protein-bound (e.g., oral anticoagulants) is not expected to affect the plasma concentrations of either drug.

Antiarrhythmic Agents

There is limited information on the use of flecainide in conjunction with other antiarrhythmic agents for the management of severe refractory ventricular or supraventricular arrhythmias. Combination antiarrhythmic therapy for severe refractory arrhythmias is generally empiric and must be individualized. Since the cardiac effects of multiple antiarrhythmic agents may be additive, synergistic, or antagonistic and adverse effects may be additive, combination therapy must be used with particular caution and careful monitoring. Because concomitant administration may increase the risk of arrhythmogenic effects, it is generally recommended that concomitant use of flecainide with other antiarrhythmic agents be avoided if possible; however, combination therapy may be useful in carefully selected and managed patients with severe refractory arrhythmias.

Flecainide has been used in combination with amiodarone, with good results in selected patients, for the management of severe refractory ventricular arrhythmias or refractory atrial fibrillation. Combined therapy may allow the use of lower dosages of flecainide and/or amiodarone and thereby potentially reduce the risk of toxicity. Plasma flecainide concentrations adjusted for daily dosage increased by an average of 60% (range: 5-190%) when amiodarone therapy was initiated in a limited number of patients receiving flecainide. Although the mechanism(s) of this interaction is not known, it has been suggested that amiodarone may inhibit the hepatic metabolism and/or decrease the renal clearance of flecainide. Pending further accumulation of data, it is recommended that dosage of flecainide be reduced by 30-50% several days after initiation of amiodarone therapy; subsequently, the patient and plasma flecainide concentrations should be monitored closely and flecainide dosage adjusted as necessary.

The effects of concomitant administration of flecainide and disopyramide have not been evaluated and experience with combined use of the drugs is limited. Because both drugs have negative inotropic effects, there appears to be little rationale for their combined use and the manufacturer cautions that they not be used concomitantly unless the potential benefits are considered to outweigh the risks.

Cardiac Glycosides

Studies in healthy individuals indicate that plasma digoxin concentrations may be increased by an average of about 15-25% when flecainide and digoxin are administered concomitantly. The increase in plasma digoxin concentration may occur within a few days of initiating flecainide therapy in patients receiving digoxin and may result from a decrease in the volume of distribution of digoxin. Although the PR interval was substantially prolonged in most healthy individuals during concomitant administration of flecainide and digoxin, it was not determined whether this resulted from an additive effect of the drugs or mainly from flecainide. Flecainide has been administered concomitantly with cardiac glycosides in patients with ventricular arrhythmias without unusual adverse effects. Additional studies to determine the potential importance of an interaction in patients with congestive heart failure are needed. Flecainide-induced increases in plasma digoxin concentration generally appear to be of a small magnitude and are unlikely to be clinically important in most cases; however, patients with AV nodal dysfunction, plasma digoxin concentrations in the upper end of the therapeutic range, and/or high plasma flecainide concentrations may be at increased risk of digoxin toxicity. Pending further accumulation of data, patients receiving flecainide and digoxin should be monitored for signs of digoxin toxicity.

β-Adrenergic Blocking Agents

In healthy individuals, plasma flecainide concentrations are increased by about 20% and plasma propranolol concentrations are increased by about 30% when the drugs are administered concomitantly compared with administration of each drug alone. The mechanism(s) of this interaction is not known, but the elimination half-lives of both drugs are apparently unchanged. The negative inotropic effects of flecainide and propranolol are additive in healthy individuals, but the increases in PR interval produced by the drugs are less than additive. Flecainide has been administered concomitantly with β-adrenergic blocking agents in patients with ventricular arrhythmias without unusual adverse effects or an increased incidence of adverse effects; however, if flecainide and a β-adrenergic blocking agent are administered concomitantly, the possibility of additive negative inotropic effects should be considered.

Calcium-Channel Blocking Agents

The effects of concomitant administration of flecainide and calcium-channel blocking agents have not been evaluated, and experience with combined use of the drugs is limited. Because verapamil also has a negative inotropic effect and decreases AV nodal conduction, the manufacturer cautions that flecainide and verapamil not be used concomitantly unless the potential benefits are considered to outweigh the risk. The manufacturer also cautions that there is insufficient experience with concomitant administration of flecainide and diltiazem or nifedipine to recommend such combined use.

Acidifying and Alkalinizing Agents

The urinary excretion and systemic elimination of flecainide may be substantially affected by extremes of urinary pH, with urinary excretion of the drug decreased and elimination half-life increased in the presence of very alkaline urine and vice versa in the presence of very acidic urine.(See Pharmacokinetics: Elimination.) When drugs that can markedly affect urinary acidity (e.g., ammonium chloride) or alkalinity (e.g., high-dose antacids, carbonic anhydrase inhibitors, sodium bicarbonate) are administered concomitantly with flecainide, the potential effect on elimination of the antiarrhythmic agent and need for appropriate flecainide dosage adjustment should be kept in mind.

Diuretics

Flecainide has been used concomitantly with diuretics in a large number of patients without any apparent drug interaction.

Cimetidine

Plasma flecainide concentrations and elimination half-life reportedly increased by approximately 30 and 10%, respectively, in a study in healthy individuals receiving flecainide in conjunction with cimetidine (1 g daily). Further study of this potential interaction is needed, but these data suggest that reduction of flecainide dosage might be necessary in patients receiving cimetidine concomitantly.

Pharmacokinetics

Absorption

Flecainide acetate is rapidly and almost completely absorbed from the GI tract following oral administration. The absolute bioavailability of the commercially available flecainide acetate tablets averages approximately 85-90%. The rate of absorption may be slightly decreased by the presence of food, but the extent of absorption is not affected. The rate and extent of absorption are not affected by concomitant ingestion of an aluminum hydroxide antacid. Flecainide does not undergo any substantial first-pass metabolism.

Peak plasma flecainide concentrations usually occur within 2-3 hours (range: 0.5-6 hours) after oral administration. Following oral administration of a single 200-mg dose of flecainide acetate in fasting, healthy adults, peak plasma flecainide concentrations of approximately 0.19-0.34 mcg/mL are attained. The pharmacokinetic profile of flecainide is apparently not substantially affected by dose or plasma concentrations at usual dosages, but does deviate somewhat from linearity. Within the usual dosage range, plasma concentrations of the drug are approximately proportional to dosage, with average concentrations increasing from direct proportionality by about 10-15% per 100-mg increment in dosage. Although plasma flecainide concentrations are relatively linearly related and approximately proportional to dosage, there is considerable interindividual and intraindividual variation in plasma concentrations attained with a given dosage. Following single oral doses, total plasma concentrations of flecainide metabolites (free and conjugated) are generally 1-2 times higher than those of unchanged flecainide; however, free plasma concentrations of the 2 major metabolites, m-O-dealkylated flecainide and the m-O-dealkylated lactam derivative, are very low (less than 0.05 mcg/mL), even after multiple dosing.(See Pharmacokinetics: Elimination.)

In patients with ventricular premature complexes (VPCs), flecainide-induced decreases in single and multiple VPCs are related to dosage and plasma concentrations of the drug. The dose-related increases in PR, QRS, and, to a lesser degree, QT intervals also appear to be related to plasma concentrations of the drug. Based on greater than 90% suppression of VPCs, plasma flecainide concentrations of approximately 0.2-1 mcg/mL (mean of about 0.5-0.6 mcg/mL) appear to be necessary for optimum therapeutic effect, with minimum therapeutic concentrations ranging from about 0.2-0.4 mcg/mL. Plasma flecainide concentrations necessary to suppress serious ventricular arrhythmias are not clearly established, but trough plasma concentrations of the drug in patients effectively treated for recurrent ventricular tachycardia have also ranged from about 0.2-1 mcg/mL. Trough plasma concentrations higher than 0.7-1 mcg/mL are associated with a minimal increase in efficacy, but the risk of adverse effects, particularly adverse cardiac effects, may be increased, especially when the trough concentration exceeds 1 mcg/mL. The risk of adverse cardiac effects (e.g., conduction defects, bradycardia) probably increases progressively as plasma flecainide concentrations increase above 0.7-1 mcg/mL. A relationship between plasma flecainide concentrations and arrhythmogenic effects has not been established, but some data suggest that arrhythmogenicity may be associated with plasma concentrations higher than 1 mcg/mL. In clinical studies of patients with ventricular tachycardia, reduction of flecainide dosage (i.e., use of a lower initial dosage with slow upward titration) appeared to be associated with a decreased frequency and severity of arrhythmogenic effects.

Distribution

Distribution of flecainide acetate into human body tissues and fluids has not been fully characterized. Following IV administration in rats, flecainide and/or its metabolites are distributed extensively into many tissues, including the heart, but only minimally into the CNS. Studies in animals also indicate that the drug and/or its metabolites are distributed into and may accumulate in pigmented ocular tissues; however, chronic toxicity studies in animals and clinical experience to date in humans have not revealed evidence of specific flecainide-induced ocular toxicity. Following IV administration in humans, flecainide is rapidly and apparently widely distributed. The apparent volume of distribution of the drug in healthy adults reportedly averages 5.5-8.7 L/kg (range: 5-13.4 L/kg) following a single IV dose and about 10 L/kg following a single oral dose.

In vitro, flecainide is approximately 40-50% bound to plasma proteins, mainly α1-acid glycoprotein (α1-AGP). At in vitro plasma flecainide concentrations of 0.015-10 mcg/mL, binding is independent of the plasma concentration of the drug. Following acute myocardial infarction, protein binding of flecainide may be increased to an average of approximately 60% for about 24 hours, but this effect is not likely to be clinically important in most circumstances.

It is not known whether flecainide crosses the placenta in humans, but the drug and/or its metabolites cross the placenta in rats. Limited data suggest that flecainide is distributed into milk in humans.

Elimination

Plasma concentrations of flecainide acetate appear to decline in a biphasic manner. Following a single IV dose in healthy adults, the half-life of flecainide in the initial distribution phase (t½α) is about 3-6 minutes and the half-life in the terminal elimination phase (t½β) has been reported to average 11-14 hours (range: 7-19 hours). Following single or multiple oral doses in healthy adults, the elimination half-life has averaged 11.5-16 hours (range: 7-25 hours), but the half-life tends to be slightly more prolonged following multiple rather than single doses. The elimination half-life of flecainide following multiple oral doses in patients with VPCs is slightly longer than in healthy individuals, averaging 19-22 hours (range: 12-30 hours). The elimination half-life tends to increase with age in patients with VPCs. Following a single oral dose in patients with congestive heart failure, the elimination half-life is also slightly longer than in healthy individuals but similar to that in patients with VPCs, averaging 19 hours (range: 14-26 hours).

The elimination half-life of flecainide is prolonged in patients with renal impairment, particularly in those with severe renal impairment. Following a single oral dose, the elimination half-life reportedly averaged 17 hours (range: 12-26 hours) and 26 hours (range: 9-58 hours) in patients with creatinine clearances of 4-41 and 0-2 mL/minute per m, respectively. The elimination half-lives of flecainide metabolites have not been determined to date, but their elimination appears to occur somewhat more slowly than that of unchanged flecainide and free plasma concentrations of m-O-dealkylated flecainide appear to persist in some patients with severe renal impairment. Extremes of urinary pH can markedly affect the elimination half-life of flecainide, prolonging it when very alkaline (pH 7.2-8.3) and reducing it when very acidic (pH 4.4-5.8).

Flecainide is extensively metabolized, probably in the liver, to 2 major metabolites and to at least 3 unidentified minor metabolites. In vitro metabolic studies indicate that the cytochrome P-450 (CYP) isoenzyme 2D6 is involved in the drug's metabolism. The 2 major metabolites, m-O-dealkylated flecainide and the m-O-dealkylated lactam derivative, are formed by preferential O-dealkylation at the meta position of the benzamide ring and by subsequent oxidation of the piperidine ring of m-O-dealkylated flecainide, respectively. Both metabolites undergo extensive conjugation at the m-O-dealkylated position with glucuronic or sulfuric acid. Studies in animals indicate that, on a weight basis, m-O-dealkylated flecainide has up to 20-50% of the antiarrhythmic and electrophysiologic activity of flecainide and the m-O-dealkylated lactam derivative has less than 10% of the electrophysiologic activity of flecainide. Because free plasma concentrations of the major metabolites are so low following multiple oral doses, it is unlikely that these metabolites would contribute to the therapeutic or toxic effects of the parent drug under most clinical circumstances; however, further studies are needed to evaluate their potential contribution, if any, in the presence of conditions that might affect their formation and/or elimination (e.g., severe hepatic or renal impairment). The minor metabolites remain to be identified, but some data suggest that they may result from amide hydrolysis. Some data also suggest that cigarette smoking may induce metabolism of flecainide.

Following oral administration, flecainide and its metabolites are excreted almost completely in urine; only small amounts of the drug and/or its metabolites are excreted in feces. Flecainide appears to be excreted in urine mainly by glomerular filtration, but some tubular secretion may also occur. It is not known whether the fraction of an oral dose excreted in feces represents unabsorbed drug, or drug and/or metabolites excreted via biliary elimination; because the fraction is so small, flecainide does not appear to undergo extensive biliary elimination, unless substantial enterohepatic circulation occurs. Following a single oral dose of flecainide in healthy individuals, about 80-90% of the dose is excreted in urine and about 5% in feces within 6 days; most excretion occurs within 24 hours, and excretion is almost complete within 72 hours. In healthy individuals, about 30% (range: 10-50%) of a single oral dose is excreted in urine as unchanged drug, 10-20% as m-O-dealkylated flecainide and its conjugates, 10-15% as the m-O-dealkylated lactam derivative and its conjugates, and 3% or less as 3 unidentified minor metabolites. The major metabolites of the drug are excreted in urine principally as conjugates.

The fraction of flecainide excreted in urine as unchanged drug decreases with decreasing renal function and is markedly reduced in patients with severe renal impairment. Following a single oral dose in patients with creatinine clearances of 4-41 and 0-2 mL/minute per m, the fraction excreted in urine within 72 hours as unchanged drug averaged approximately 15% (range: 5-30%) and 1% (range: 0-3%), respectively. The fraction of flecainide excreted in urine as unchanged drug is also inversely related to urinary pH, increasing with decreasing urinary pH and vice versa. Although usual variations in urinary pH would generally be expected to have minimal effects, extremes of urinary pH may substantially affect the fraction of unchanged flecainide excreted in urine, approximately doubling it when very acidic (pH 4.4-5.8) and decreasing it by half when very alkaline (pH 7.2-8.3).

Following oral administration in healthy individuals, total apparent plasma clearance of flecainide averages approximately 10 mL/minute per kg (range: 4-20 mL/minute per kg); renal clearance of the drug is about 25-40% of the total plasma clearance. In healthy geriatric individuals, total apparent plasma clearance decreases following multiple oral doses, apparently as a result of decreased nonrenal clearance of the drug. Total apparent plasma clearance is decreased in patients with VPCs compared with healthy individuals, averaging 6.2 mL/minute per kg (range: 3.1-12.6 mL/minute per kg) in a small group of patients. Total apparent plasma clearance of flecainide is somewhat decreased in patients with congestive heart failure compared with healthy individuals, averaging 8.1 mL/minute per kg (range: 3.1-13.4 mL/minute per kg) in a small group of patients; renal clearance is also decreased in these patients, but still accounts for about 25% of total plasma clearance. Total apparent plasma and renal clearances of the drug are also decreased in patients with reduced renal function. In patients with creatinine clearances of 4-41 and 0-2 mL/minute per m, total apparent plasma clearance averaged 6.7 mL/minute per kg (range: 2.2-13.9 mL/minute per kg) and 5.1 mL/minute per kg (range: 1.5-10 mL/minute per kg), respectively; renal clearance was about 17 and 1.3% of the total apparent plasma clearance, respectively. In patients with renal impairment, total apparent plasma and renal clearances of flecainide are correlated with urinary creatinine clearance, but the latter does not reliably allow estimation of total plasma clearance in an individual patient. It appears that an increase in nonrenal clearance can, to some extent, compensate for decreased renal clearance in some patients. Renal clearance of flecainide is inversely related to urinary pH, increasing with decreasing urinary pH and vice versa. Extremes of urinary pH may substantially affect renal clearance of the drug. The manufacturer states that elimination of flecainide from plasma may be markedly prolonged in patients with substantial hepatic impairment.

Only about 1% of an oral dose of flecainide is removed by hemodialysis as unchanged drug; however, about 10% of a dose is removed by hemodialysis as m-O-dealkylated flecainide and its conjugates. It is not known if flecainide and/or its metabolites are removed by peritoneal dialysis. There is some evidence that flecainide may be removed by charcoal hemoperfusion.

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