Flecainide acetate is a local anesthetic-type class Ic antiarrhythmic agent.1, 3, 4, 5, 6, 7, 146, 147
Flecainide acetate is used to suppress and prevent the recurrence of documented life-threatening ventricular arrhythmias (e.g., sustained ventricular tachycardia).1, 3, 4, 5, 24, 52, 53, 77, 89, 90, 91, 92, 110, 125, 161, 162, 166, 175, 176, 177, 178, 179 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), flecainide therapy should be reserved for the suppression and prevention of documented ventricular arrhythmias that, in the clinician's judgment, are considered life-threatening .1, 161, 162, 164, 176, 177, 178
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 premature ventricular complexes† [PVCs]), even when the patient is symptomatic, is not recommended.1, 162, 163, 164, 166, 170, 173, 174, 175, 176, 177, 178, 179, 186, 190, 211, 302 The findings of CAST involved a select patient population with recent myocardial infarction (MI), mild-to-moderate left ventricular dysfunction (e.g., mean baseline ejection fraction of 0.4), and asymptomatic or mildly symptomatic ventricular arrhythmias† (mean baseline PVCs 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 PVCs during the initial phase of the open trial.163, 170, 173, 177, 181, 183, 190, 211 It currently is not known whether the findings of CAST can be extrapolated to other patient populations with non-life-threatening ventricular arrhythmias (e.g., patients with arrhythmias in the absence of ventricular dysfunction, myocardial ischemia, or recent MI).1, 163, 164, 169, 170, 173, 181, 183, 187, 190, 191 CAST principally involved suppression and prevention of PVCs, with only about 10% of patients exhibiting more than a single run of tachycardia at baseline.164, 182, 183, 187, 190 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.164, 182, 183, 187 However, despite the limitations of the CAST findings, the manufacturer,1, 178 FDA,161, 176, 177 and other experts170, 186, 188 consider the potential risks of flecainide therapy substantial and currently do not recommend use of the drug in any patient with non-life-threatening ventricular arrhythmias in the absence of substantial evidence of safety and efficacy. The manufacturer states 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 non-life-threatening signs and symptoms.1 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.164, 173, 174, 181, 182, 183
Life-threatening Ventricular Arrhythmias
The optimum role of flecainide in the suppression and prevention of ventricular arrhythmias remains to be clearly determined.3, 4, 5, 30, 52, 53, 58, 59, 76, 77, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 136, 146, 147, 169, 174
In addition, it remains to be determined whether antiarrhythmic agents, including flecainide, have a beneficial effect on mortality or sudden death.1, 91, 92, 109, 163, 164, 167, 170, 171 Although flecainide has been effective in suppressing and preventing ventricular arrhythmias in carefully selected patients,1 further studies are needed to evaluate the long-term efficacy and safety and the relative role of the drug.3, 4, 5, 89, 136 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).5, 107, 108, 136, 146, 147, 164, 166, 182 In addition, because of flecainide's arrhythmogenic potential, some clinicians 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.136, 146 While it currently is not known whether the findings of the CAST study apply to class Ic antiarrhythmic agents other than flecainide and encainide (no longer commercially available in the US), some experts state that, in the absence of specific evidence of safety and efficacy, other class Ic drugs should be considered to share these risks.163, 164, 169, 170
There is relatively limited experience with the use of flecainide for suppression and prevention of recurrent life-threatening ventricular arrhythmias.24, 52, 53, 77, 89, 90, 91, 92, 110, 125 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.77, 92, 110 Younger patients24, 77, 89 and patients without coronary heart disease24, 53, 77, 89 and/or substantial ventricular dysfunction77, 89 appear to have a greater likelihood of responding to flecainide.24, 53, 77, 89 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.52, 53, 77, 89, 90, 91, 92, 136, 146
Limited information is available on the use of flecainide in conjunction with other antiarrhythmic agents for the management of severe refractory ventricular arrhythmias.77, 89, 92, 110, 111, 112, 122 (See Drug Interactions: Antiarrhythmic Agents.) In a limited number of patients, flecainide has been combined with amiodarone, with good results in selected patients;77, 92, 110, 112, 122 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.131, 136, 142 Combination antiarrhythmic therapy for severe refractory ventricular arrhythmias is generally empiric and must be individualized.108, 112
Controlled30, 58, 59, 76, 94, 96, 97, 101, 102, 103, 104, 105, 106, 180 and uncontrolled75, 93, 95, 98, 99, 100, 150 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 PVCs, including complex PVCs. In short-term clinical studies, flecainide therapy produced at least 80-90% suppression of PVCs in about 80-90% of patients;30, 58, 59, 76, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 106 in many patients, essentially complete suppression of uniform and multiform PVCs, complex PVCs, and/or nonsustained ventricular tachycardia may occur.30, 58, 59, 76, 94, 95, 97, 98, 99, 100, 101, 102, 103, 105, 106, 150 However, despite such documented evidence of efficacy in suppressing and preventing these arrhythmias, there currently is no evidence of beneficial effect on mortality,1, 91, 92, 109, 163, 164, 170, 171 and in at least one patient population (those with mild-to-moderate ventricular dysfunction and recent MI) with such arrhythmias, there was evidence of substantial risk (including mortality and nonfatal cardiac arrest) associated with flecainide or encainide therapy.1, 161, 162, 163, 164, 166, 169, 170, 173, 176, 178, 186 (See the opening discussion of Cautions.) Therefore, use of flecainide in nonlife-threatening ventricular arrhythmias currently is not recommended by the manufacturer,1, 178 FDA,161, 176, 177 and other experts.170, 186
Supraventricular Tachyarrhythmias
Flecainide is used for the prevention of paroxysmal supraventricular tachycardia (PSVT), including atrioventricular (AV) nodal reentrant tachycardia and AV reentrant tachycardia (e.g., Wolff-Parkinson-White syndrome); other symptomatic, disabling supraventricular tachycardias of unspecified mechanisms; and symptomatic, disabling paroxysmal atrial fibrillation/flutter (PAF) in patients without structural heart disease.1, 35, 110, 115, 140, 192, 193, 194, 197, 198, 199, 200, 201, 206, 300 Controlled1, 192, 193, 194, 197 and uncontrolled115, 140, 203 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;1, 115, 140, 192, 193, 194, 197, 198, 206 suppression of arrhythmias refractory to other antiarrhythmic agents also has occurred.113, 115 In some patients with atrial fibrillation or flutter associated with ventricular preexcitation and Wolff-Parkinson-White syndrome, flecainide may slow the ventricular rate35, 113, 115, 116, 141 or possibly restore and maintain normal sinus rhythm.113, 116, 141 Because of the risk of proarrhythmia, flecainide should not be used in patients with structural heart disease or ischemic heart disease.1, 300
Based on findings from the CAST study demonstrating substantial flecainide-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 (PAF, AV junctional tachycardias) in patients without structural heart disease.170, 181, 182, 186 However, some clinicians state that even these patients may be at risk of developing drug-induced arrhythmogenic effects (e.g., during exercise testing).182, 185 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.170, 188
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.300 Flecainide is one of several drugs that may be used for the ongoing management of PSVT (to prevent recurrences of these arrhythmias) in patients without structural or ischemic heart disease; because of the risk of adverse effects, however, use of flecainide generally is reserved for patients in whom other therapies are ineffective or contraindicated.300 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.1, 192, 193 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.1, 192, 193
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 in a median dosage of 300 mg daily (range: 100-600 mg daily in 2 divided doses) during the 8-week study period.1, 192, 194 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.1, 192, 194
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 PAF† and can reduce hospitalizations and emergency room visits in carefully selected patients who have mild or no heart disease.224, 228, 242, 243, 244, 301 Experts state that an initial conversion trial in a monitored setting is recommended before this approach is undertaken in an unmonitored setting outside of the hospital.301 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;229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241 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.224, 225, 226, 227, 228, 240, 242 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.227, 228, 242
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.224 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.224 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).224 The time to conversion to sinus rhythm following in-hospital treatment with flecainide or propafenone in these patients averaged 135 minutes (median: 120 minutes).224 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.224 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.224
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.224, 242 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.224 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).224 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.224 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.224, 242
Atrial Fibrillation and Flutter
Flecainide is considered a drug of choice for pharmacologic cardioversion of atrial fibrillation or atrial flutter†.301 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.301 (See Uses: Cardioversion of Atrial Fibrillation/Flutter, in Heparin 20:12.04.16.)
Limited data suggest that 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.123
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.207, 208, 209
Other Supraventricular Tachycardias
Flecainide may be used for the ongoing management of focal atrial tachycardia† or junctional tachycardia† in patients without structural or ischemic heart disease.300 Limited data suggest that flecainide may be effective in suppressing and preventing recurrent atrial tachycardia†.113, 120, 149
Flecainide acetate is administered orally.1 Flecainide also has been administered IV†, 3, 4, 5, 28, 29, 32, 34, 36, 62, 63, 64, 65, 66, 67, 68, 109, 113, 114, 115, 116, 117, 118, 119 but a parenteral dosage form of the drug is currently not commercially available in the US.300
Flecainide acetate is administered orally, usually in 2 equally divided doses daily at 12-hour intervals;1 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.1, 59, 89, 146, 150 The elimination half-life of flecainide suggests that once-daily oral dosing may be possible in some patients,58, 89 but once-daily dosing regimens of the drug have not been evaluated to date.89
Absorption of flecainide is not affected by food or antacids; however, milk may inhibit absorption in infants.1 Dosage reduction of flecainide acetate may be necessary when milk is removed from the diet in infants.1
Because of the risk of proarrhythmia, initiation of therapy in a hospital setting is recommended in patients with sustained ventricular tachycardia, regardless of their cardiac status.1, 89, 151 Some clinicians recommend that withdrawal of therapy should also occur in a hospital setting under continuous ECG monitoring.164, 172, 182
Extemporaneously Compounded Oral Solution
Extemporaneously compounded oral solutions of flecainide acetate have been prepared.247
Standardized concentrations for an extemporaneously compounded oral solution of flecainide have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Multidisciplinary expert panels were convened to determine recommended standard concentrations. 252Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 252 For additional information on S4S (including updates that may be available), see [Web].252
Concentration Standards |
|---|
10 mg/mL |
Dosage of flecainide acetate should be carefully adjusted according to individual patient response and tolerance.1, 3, 89 Clinical and ECG monitoring of cardiac function is recommended during therapy with the drug.1, 89 When feasible, plasma trough flecainide concentrations should be monitored; monitoring is required in patients with severe renal or hepatic impairment, and is recommended in other patients in whom elimination of the drug may be impaired (e.g., those with moderate renal impairment or congestive heart failure, or those receiving concomitant amiodarone therapy).1, 43 Dosage should be adjusted to maintain trough plasma flecainide concentrations at less than 0.7-1 mcg/mL since concentrations above this range have been associated with a higher rate of adverse cardiac effects,1, 59, 70, 78, 104 especially when the trough concentration exceeds 1 mcg/mL.1, 78 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)1, 76 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.1 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;1, 58, 90, 97, 98 however, efficacy of the drug at the lower dosage should be evaluated.1 If congestive heart failure, myocardial dysfunction, or renal or hepatic failure develops in patients receiving flecainide, dosage reduction may be necessary.1 Many clinicians recommend the use of low initial dosages in geriatric patients.136
Any use of flecainide in children should be supervised directly by a cardiologist experienced in the treatment of arrhythmias in this age group.1 (See Cautions: Pediatric Precautions.) In pediatric patients, flecainide should be initiated in a hospital setting with facilities available for cardiac rhythm monitoring.1 Because of the evolving nature of flecainide use in children, specialized references should be consulted for the most recent information.1 The manufacturer states that the initial flecainide acetate dosage in infants younger than 6 months of age is approximately 50 mg/m2 daily, divided into 2 or 3 equally spaced doses.1 For older children, an initial dosage of 100 mg/m2 daily may be given.1 The maximum dosage recommended by the manufacturer for pediatric patients is 200 mg/m2 daily, which should not be exceeded.1 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 or after any change in dosing, whether the dosage was increased for lack of effectiveness or for increased growth of the child.1 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.1 Small changes in dosage also may lead to disproportionate increases in plasma drug concentrations.1 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.1 The usual therapeutic concentration of flecainide in children is 200-500 ng/mL, although concentrations up to 800 ng/mL may be required for adequate control in some children.1
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;1 however, single oral loading doses (e.g., 200-300 mg) have been used for conversion of recent-onset atrial fibrillation to normal sinus rhythm† in selected patients (“pill-in-the-pocket” approach).224, 228, 233, 235, 236, 240, 241, 242, 243, 244, 301 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.1
Based on theoretical considerations, it is recommended that, when transferring patients from therapy with another antiarrhythmic agent to flecainide, at least 2-4 plasma half-lives of the agent being discontinued be allowed to elapse before therapy with flecainide is initiated at the usual dosage.1 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.1
Life-threatening Ventricular Arrhythmias
For the 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.1 Some clinicians suggest an initial dosage of 50 mg twice daily in these patients.3 Dosage may be increased in increments of 50 mg twice daily every 4 days until an effective response is attained.1 Most patients do not require dosages greater than 150 mg every 12 hours or 300 mg daily.1 The maximum recommended dosage of flecainide acetate in most patients with sustained ventricular tachycardia is 400 mg daily.1
Supraventricular Tachyarrhythmias
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.1, 192, 193, 200 Dosage may be increased in increments of 50 mg twice daily every 4 days until an effective response is attained.1 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).1 The maximum recommended dosage of flecainide in patients with paroxysmal supraventricular arrhythmias is 300 mg daily.1
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 (“pill-in-the-pocket” approach), 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.224
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.224, 242 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.224 Patients should not take more than a single oral dose of flecainide during a 24-hour period.224
Dosage in Renal and Hepatic Impairment
In patients with renal impairment, dosage of flecainide acetate must be carefully adjusted based on the degree of renal impairment.1, 70 The recommended initial oral dosage of flecainide acetate in patients with severe renal impairment (creatinine clearance of 35 mL/minute per 1.73 m2 or less) is 100 mg once daily (or 50 mg twice daily).1 In patients with less severe renal impairment, an initial dosage of 100 mg every 12 hours is recommended.1 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.1 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.1 Plasma trough flecainide concentrations should be monitored in patients with severe renal impairment and also may be useful in patients with moderate renal impairment.1
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.1 If flecainide is used in patients with hepatic impairment, plasma flecainide concentrations should be monitored closely to guide dosage, and dosage should be increased cautiously at intervals of longer than 4 days.1, 3
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).1, 161, 162, 163, 164, 170, 174, 175, 176, 177, 178, 181, 190, 191, 211 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 (MI), mild-to-moderate left ventricular dysfunction, and asymptomatic or mildly symptomatic ventricular arrhythmias (principally frequent premature ventricular complexes [PVCs]) who received flecainide was increased substantially.1, 161, 162, 163, 164, 174, 175, 176, 177, 178, 190, 191, 211
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 PVCs following recent MI (more than 6 days but less than 2 years previously) in patients with asymptomatic or mildly symptomatic ventricular arrhythmias.1, 161, 162, 163, 164, 178, 180, 181, 184, 190, 191, 211 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.161, 163, 174, 175, 176, 177, 181, 182, 190, 191 These findings were consistent across a variety of patient subgroups,161, 162, 163, 164, 178 and the degree of undesirable effects associated with flecainide or encainide was similar.162, 163, 178, 190 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,163, 190, 191 and the rate of death secondary to arrhythmia or cardiac arrest for these drugs was 3.6 times that observed with placebo.163, 190, 191 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 1989.162, 163, 164, 178, 179, 181, 190, 191 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 in patients being treated for life-threatening arrhythmias.1, 162, 164, 178, 190
The frequency of flecainide-induced adverse effects tends to decrease with time, and adverse effects tend to occur intermittently.124 Flecainide-induced adverse effects are often alleviated by dosage reduction,1, 78, 124 occasionally disappear despite continued treatment and without dosage reduction,124 and are usually reversible following discontinuance of the drug.76, 124 The risk of adverse effects, particularly adverse cardiac effects, may increase when trough plasma flecainide concentrations increase above 0.7-1 mcg/mL,1, 59, 70, 78, 104 especially when the trough concentration exceeds 1 mcg/mL.1, 78
The most common adverse effects of flecainide are dizziness1 and visual disturbances,1, 3, 4, 5, 30, 58, 59, 76, 77, 78, 94, 95, 96, 97, 98, 101, 102, 103, 104, 124, 150 which are dose related,1, 124 often occur concomitantly,124 and are also the most common adverse reactions requiring discontinuance of the drug.124 Adverse extracardiac effects requiring discontinuance of flecainide therapy occur in about 5-15% of patients.1, 102, 124 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.124
Dizziness (including dizziness, lightheadedness, faintness, unsteadiness, near syncope),1, 30, 58, 76, 77, 78, 94, 95, 96, 97, 98, 101, 102, 103, 104, 150 which is dose related1, 124 and often accompanied by visual disturbances,124 occurs in about 11-13% of patients receiving flecainide acetate dosages of 200-400 mg daily.1 Dizziness has required discontinuance of therapy in about 4-6% of patients.124 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.124
Headache,1, 30, 94, 95, 97, 98, 102, 103, 104 which appears to be dose related,1, 124 occurs in about 5-9% of patients receiving flecainide acetate dosages of 200-400 mg daily.1 Headache has required discontinuance of therapy in less than 1% of patients.124
Fatigue has occurred in about 3-8% of patients receiving flecainide1, 124 and required discontinuance in about 1% of patients.124 Tremor or nervousness1, 78, 94, 104, 124 has occurred in about 3-5% of patients1, 124 and required discontinuance in less than 1% of patients.124 Hypoesthesia and paresthesia,1, 23, 25, 30, 34, 36, 94, 124 which tend to occur in the perioral region23, 25, 34, 36, 94 or the extremities,124 occur in about 1-3% of patients receiving flecainide.1, 124 Other adverse nervous system effects occurring in about 1-3% of patients receiving the drug include paresis,1 ataxia,1, 124 vertigo,1, 150 syncope,1, 78 somnolence,1, 30, 124 tinnitus,1, 30, 78, 124, 150 anxiety,1, 124 insomnia,1, 124, 150 and depression.1 Twitching,1, 124 weakness,1, 95, 101, 124, 150 change in taste perception,1, 30 dry mouth,1, 104, 124 speech disorder,1 stupor,1 seizures,1 amnesia,1 confusion,1, 90, 94, 124 neuropathy,1 hallucinations,35 depersonalization,1 euphoria,1 morbid dreams,1, 124 and apathy1 have been reported in less than 1% of patients.1
Visual disturbances (including blurred vision, difficulty in focusing, spots before eyes),1, 30, 58, 59, 76, 77, 78, 95, 97, 98, 101, 102, 103, 104, 150 which are dose related1, 124 and often associated with dizziness,124 occur in about 5-20% of patients receiving flecainide acetate dosages of 200-400 mg daily1 and about 18-30% of patients receiving 400-600 mg daily.1, 124 Visual disturbances have required discontinuance of therapy in about 2-3% of patients.124 The most common visual disturbance is blurred vision on lateral gaze and/or turning the head to the side.124 Diplopia has occurred in about 1-3% of patients receiving flecainide, and photophobia,1 nystagmus,1 and ocular pain1, 98 or irritation1 have occurred in less than 1% of patients.1
Flecainide-induced visual disturbances tend to be mild to moderate in severity and transient; persistent disturbances often respond to dosage reduction.124 Visual disturbances occur intermittently,124 usually last only for a few seconds,124 and occur most often during the time of expected peak plasma concentrations following an individual dose.30, 96, 124 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.124
Like other antiarrhythmic agents,1, 27, 40, 41, 42 flecainide can worsen existing arrhythmias or cause new arrhythmias, and the arrhythmogenic potential is the most serious risk associated with the drug.1, 27, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 151, 159 Arrhythmogenic effects associated with flecainide range from an increased frequency of PVCs to the development of new and/or more severe and potentially fatal1, 27, 43, 44, 45, 91, 159 ventricular tachyarrhythmias.1, 27, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 151, 159 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),27, 43, 159 with the remainder consisting of increased frequency of PVCs or new or worsened supraventricular arrhythmias.1, 27 In some patients, principally those with factors predisposing them to the risk of arrhythmogenic effects,27, 43, 45, 91, 143 flecainide therapy has been associated with episodes of ventricular tachycardia or fibrillation that required prolonged27, 43, 45 or unusual resuscitative measures27 or that resulted in death despite resuscitative measures.1, 27, 43, 45, 78, 91, 143
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.1, 27, 151 Patients with atherosclerosis, cardiac disease, previous MI, 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.27, 136, 143, 151 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 PVCs.151 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.27, 40, 41, 42
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.1, 27, 159 In clinical studies, new or worsened arrhythmias occurred with an overall frequency of about 1-7%.1, 27, 151 In patients with sustained ventricular tachycardia who also often had heart failure, a low left ventricular ejection fraction, a history of MI, 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.1 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%,1 and arrhythmogenic effects resulted in death in about 10% of patients receiving the drug despite immediate medical attention.1, 151 With lower initial dosages in these patients, the incidence of arrhythmogenic effects resulting in death has decreased to about 0.5% of patients.1, 151 In patients with less severe arrhythmias (chronic PVCs, nonsustained ventricular tachycardia) receiving flecainide, the overall incidence of arrhythmogenic effects appears to be approximately 3-4%.27, 43, 151 It is not known whether the incidence of arrhythmogenic effects is increased in patients with chronic atrial fibrillation, high ventricular rate, and/or exercise.1 Wide complex tachycardia and ventricular fibrillation have been reported in about 17% of patients with chronic atrial fibrillation who were undergoing maximal exercise tolerance testing.1
In patients with supraventricular arrhythmias including paroxysmal atrial fibrillation (PAF), the incidence of arrhythmogenic effects during flecainide therapy was about 4%; proarrhythmic events resulted in one fatal case of ventricular tachycardia/ventricular fibrillation and one case of wide complex ventricular tachycardia.1
Flecainide-induced arrhythmogenic effects appear to be directly related to dosage and the rate of dosage escalation,1, 27, 136, 151 particularly in patients with sustained ventricular tachycardia.151 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.1, 27, 45, 50, 78 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.27, 143, 151 In patients with sustained ventricular tachycardia, 80% of the arrhythmogenic effects occur within 14 days of initiation of flecainide therapy.1 The exact role is not clear, but concomitant use of other antiarrhythmic agents may increase the risk of arrhythmogenic effects during flecainide therapy.1, 27, 43, 91, 126 When transferring patients from another antiarrhythmic drug to flecainide, a transition period is recommended to allow the effects of the previous antiarrhythmic to dissipate prior to initiating flecainide.1 (See Dosage and Administration: Dosage.) 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 in whom withdrawal of a previous antiarrhythmic agent is likely to produce life-threatening arrhythmia.1, 89, 151 (See Cautions: Precautions and Contraindications.)
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%).1, 19, 92, 102, 150 New or worsened congestive heart failure associated with flecainide has occurred in about 6% of patients with PVCs, non-sustained or sustained ventricular tachycardia.1 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.1 New or worsened congestive heart failure occurred in about 0.4% of patients with supraventricular arrhythmias.1
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).1 When congestive heart failure has developed or worsened, the onset has occurred within hours to several months after initiation of therapy;1 the risk appears to be greatest during the first 1-4 weeks of treatment.19, 151 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.1
Palpitation has occurred in about 6%,1 chest pain in about 5%,1 and edema in about 3%1 of patients receiving flecainide. Tachycardia and flushing have occurred in about 1-3% of patients,1 and bradycardia,1, 51 angina pectoris,1 hypertension,1 and hypotension1 have occurred in less than 1% of patients receiving the drug.1
Clinically important conduction disturbances occur infrequently during flecainide therapy1, 27, 151 in patients without preexisting conduction abnormalities;136, 151 however, the risk of adverse cardiac effects appears to increase as plasma flecainide concentrations increase above 0.7-1 mcg/mL.1, 70, 78 Sinus bradycardia,1 pause,1, 78 and arrest1 have occurred collectively in about 1.2% of patients. First-degree AV block occurs in about 30-40% of patients receiving flecainide.1, 27, 103 Second-degree AV block occurs in about 0.5% of patients and third-degree AV block in about 0.4% of patients.1 New bundle-branch block may develop rarely.1, 78, 92, 106, 150 Some patients with atrial flutter may develop 1:1 AV conduction with flecainide due to slowing of the atrial rate.1 Paradoxically, an increase in ventricular rate also may occur when flecainide is used in patients with atrial fibrillation.1 Discontinuance of the drug may be necessary in some patients unless a temporary or permanent artificial pacemaker is in place.1, 89, 151 (See Cautions: Precautions and Contraindications.) Syncope also has occurred rarely as a result of sinus node dysfunction.78, 151 Torsades de pointes-type arrhythmia associated with flecainide therapy also has been reported rarely.1
Flecainide-induced increases in PR and QRS intervals are usually not clinically important.1, 27, 103 The degree of lengthening of PR and QRS intervals does not allow prediction of therapeutic efficacy or the development of adverse cardiac effects,1 although some data suggest that absolute increases in PR and QRS intervals (at least 40 ms) may be associated with adverse cardiac effects.78 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.1, 27 (See Cautions: Precautions and Contraindications.) Rarely, substantial prolongation of QTc may occur and also require caution and dosage reduction.46, 50
Nausea1, 94, 95, 97, 98, 102, 103, 104 occurs in about 9-10% of patients receiving flecainide1, 124 and has required discontinuance of the drug in about 1% of patients.124 Dyspepsia,1, 124 anorexia,1 vomiting,1, 124 constipation,1, 76, 98, 124 and diarrhea1, 95, 124 have occurred in about 1-4% of patients1, 124 and flatulence in less than 1% of patients.1
Rash occurs in about 1-3% of patients receiving flecainide.1, 124 Urticaria,1 pruritus,1, 76 and exfoliative dermatitis1 have occurred in less than 1% of patients.1
Dyspnea has occurred in about 5-10% of patients receiving flecainide.1, 124 Malaise, fever, and increased sweating have occurred in about 1-3% of patients receiving the drug.1 Decreased libido,1 impotence,1, 98, 124 polyuria,1 urinary retention,1 arthralgia,1 myalgia,1 bronchospasm,1 and swelling of the lips, tongue, and mouth1 have been reported in less than 1% of patients.1
There have been rare reports of asymptomatic, isolated increases in serum alkaline phosphatase1, 59, 76 or aminotransferase1 concentrations in patients receiving long-term flecainide therapy;59, 76 however, a causal relationship to the drug has not been established.1 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.1 (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.153
Precautions and Contraindications
Findings from the CAST study indicate that use of flecainide and other class I antiarrhythmic agents (e.g., disopyramide, quinidine, procainamide) may be associated with substantial risk in certain patients with ventricular arrhythmias.1, 161, 162, 163, 164, 166, 170, 173, 174, 175, 176, 177, 178, 181 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.1, 161, 163, 170, 176, 177, 178, 181 (See Uses.) Use in less severe ventricular arrhythmias, even when symptomatic, currently is not recommended.1, 161, 163, 170, 176, 177, 178 In addition, it has been recommended that use of these drugs in patients with supraventricular arrhythmias be limited to those with symptomatic disabling arrhythmias.170 It is essential that patients not alter their antiarrhythmic therapy without first consulting their physician.162, 164, 172 The decision to discontinue therapy with flecainide must be made by the physician, and physicians have been advised by FDA and the manufacturers to contact their patients receiving the drug and determine whether alternative therapy is indicated, reserving therapy with flecainide only for arrhythmias considered life-threatening .1, 161, 164, 176, 177, 178 Some experts state that discontinuance of therapy in patients with symptomatic sustained ventricular arrhythmias that have been treated effectively for prolonged periods seems unwarranted and is potentially dangerous.164, 181, 182, 183, 187 However, if withdrawal of therapy with flecainide 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.164, 172, 182 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.172
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.1, 89 To minimize the risk of arrhythmogenic effects, the recommended flecainide dosage schedule should be closely followed,1, 27 plasma drug concentrations should be monitored and concentrations higher than 1 mcg/mL avoided,1, 27 ECG monitoring should be carefully evaluated before each dosage adjustment,27 and, if possible, concomitant use of other antiarrhythmic agents should be avoided.27, 43, 44 If flecainide is suspected or determined to be causing an increased frequency of PVCs despite adequate dosage or to be causing an increased frequency of complex PVCs or new and/or more serious arrhythmias, alternative therapy should be substituted.89, 136, 139, 159 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.159
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.1, 89, 151 Initiation of flecainide therapy in a hospital setting should also be considered for other patients with underlying structural heart disease,89, 151 particularly those with serious disease,89, 136, 151 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.1 In patients with less severe and/or stable ventricular arrhythmias (frequent PVCs, nonsustained ventricular tachycardia), flecainide therapy may be initiated in an ambulatory setting with careful clinical and ECG monitoring.89, 151
Because of flecainide's mild to moderate negative inotropic effect, as well as an increased risk of arrhythmogenic effects,1, 27 the drug should be used with caution in patients with a history of congestive heart failure or myocardial dysfunction,1, 89, 146, 151, 154 particularly those with advanced failure or dysfunction.1, 19, 27, 62, 63, 89, 91, 146, 151, 154 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.1 When feasible, plasma flecainide concentrations should be monitored and dosage adjusted to maintain trough concentrations less than 0.7-1 mcg/mL.1 Particular attention should be given to maintenance of cardiac function, including optimum management with cardiac glycoside, diuretic, and/or other therapy.1 If myocardial dysfunction occurs, the patient may be managed with a reduction in flecainide dosage, discontinuance of therapy, or an adjustment in other drug therapy (e.g., diuretics, digoxin).1, 154
If the PR interval increases to 300 ms or greater,1 QRS duration increases to 180 ms or greater,1 or QTc interval increases substantially46, 50, 89 during flecainide therapy, caution is necessary and dosage reduction should be considered.1, 89 To minimize effects on cardiac conduction, an attempt should be made to manage patients on the lowest possible effective dosage.1 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.1, 89
Because its effects on sinus node function may be marked, flecainide should be used with particular caution in patients with preexisting sinus node dysfunction.1, 31, 32, 33, 151 Flecainide should be used only with extreme caution, if at all,136 in patients with sick sinus syndrome (including bradycardia-tachycardia syndrome), since the drug may cause sinus bradycardia, pause, or arrest in such patients.1, 90, 151
Flecainide can increase acute and chronic endocardial pacing thresholds1, 32, 38, 39 and may suppress ventricular escape rhythms;1, 32, 38 these effects are reversible following discontinuance of the drug.1, 32, 38, 39 Flecainide should be used with particular caution in patients with permanent artificial pacemakers or temporary pacing electrodes1, 32, 38, 39 and should not be administered to patients with existing poor thresholds or nonprogrammable artificial pacemakers unless suitable pacing rescue is available.1 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.1 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.1, 32, 38
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.1
Since elimination of flecainide may be impaired, the drug should be used with caution and dosage adjusted carefully in patients with renal impairment,1, 70 particularly severe impairment.70 Because the urinary excretion of flecainide can be markedly affected by extremes of urinary pH,1, 80, 85 the potential effects of dietary regimens (e.g., very alkaline pH in strict vegetarians), disease states or conditions (e.g., renal tubular acidosis or metabolic alkalosis or acidosis), or concomitant drugs that may affect urinary pH should be kept in mind.1, 70, 80 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.1 If flecainide is used in patients with severe renal or hepatic impairment, periodic monitoring of plasma concentrations of the drug is necessary.1
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.1, 153
Use of flecainide in chronic atrial fibrillation is not recommended.1, 207, 208, 209 Flecainide should not be used in patients with recent MI.1 In the absence of a pacemaker,1, 89 flecainide is contraindicated in patients with preexisting second- or third-degree AV block1, 89 or bifascicular block (right bundle-branch block associated with left hemiblock).1, 89 Flecainide also is contraindicated in patients with cardiogenic shock or known hypersensitivity to the drug.1
The manufacturer states that safety and efficacy of flecainide in infants or children have not been established in randomized controlled studies.1 Limited data suggest that the drug may be useful in children for the management of refractory supraventricular tachycardias.127, 300 The proarrhythmic effects of flecainide observed in adults also may occur in children.1 In pediatric patients with structural heart disease, flecainide has been associated with cardiac arrest and sudden death.1 Because of these risks, flecainide generally is not a preferred antiarrhythmic drug in pediatric patients;300 if use is necessary, therapy should be initiated in a hospital setting equipped with ECG monitoring and supervised directly by a cardiologist experienced in the treatment of arrhythmias in children.1
Pregnancy, Fertility, and Lactation
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;1 however, delayed sternebral and vertebral ossification were observed in rats receiving the highest dosages.1 Club paws, sternebral and vertebral abnormalities, pale hearts with contracted ventricular septum, and increased fetal resorptions were observed in one breed of rabbits (New Zealand white rabbits) receiving dosages of 30 and 35 mg/kg daily; reproduction studies in Dutch Belted rabbits using similar dosages did not reveal evidence of teratogenicity or embryotoxicity.1 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.1 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.1
The effect of flecainide on fertility in humans is not known. In vitro, the drug inhibits sperm motility.129 Reproduction studies in male and female rats using flecainide acetate dosages up to 50 mg/kg daily (7 times the usual human dosage) have not revealed evidence of impaired fertility.1
Limited data suggest that flecainide is distributed into milk in humans.1 In one study in postpartum women receiving multiple doses of flecainide, milk flecainide concentration averaged 2.5 times (sometimes as high as 4 times) that of maternal plasma concentrations.1 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.1
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Metabolism of flecainide is mediated by the cytochrome P-450 (CYP) isoenzyme 2D6,1 and concurrent use of flecainide with CYP2D6 inhibitors (e.g., quinidine)246 could result in increased plasma flecainide concentrations.1
Limited data indicate that the rate of flecainide elimination is increased by 30% in patients receiving flecainide concurrently with enzyme inducers (e.g., carbamazepine, phenytoin, phenobarbital).1
Flecainide is not extensively bound to plasma proteins.1 Concomitant use of flecainide with other drugs that are highly protein-bound (e.g., oral anticoagulants) is not expected to result in an interaction.1
There is limited information on the use of flecainide in conjunction with other antiarrhythmic agents for the management of severe refractory ventricular77, 89, 92, 110, 111, 112, 122 or supraventricular†112 arrhythmias. Combination antiarrhythmic therapy for severe refractory arrhythmias is generally empiric and must be individualized.108, 112 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.108, 112, 131, 136 Because concomitant administration may increase the risk of arrhythmogenic effects,27, 43, 91, 126 it is generally recommended that concomitant use of flecainide with other antiarrhythmic agents be avoided, if possible;27, 43, 44 however, combination therapy may be useful in carefully selected and managed patients with severe refractory arrhythmias.77, 92, 108, 110, 111, 112, 122 When transitioning from another antiarrhythmic drug to flecainide, sufficient time should elapse (at least 2-4 half-lives of the discontinued antiarrhythmic agent) before initiating flecainide therapy.1 (See Dosage and Administration: Dosage.)
Flecainide has been used in combination with amiodarone, with good results in selected patients, for the management of severe refractory ventricular arrhythmias77, 92, 110, 111, 112, 122, 160 or refractory atrial fibrillation†.112 Combined therapy may allow the use of lower dosages of flecainide and/or amiodarone and thereby potentially reduce the risk of toxicity.108, 112, 142 Plasma flecainide concentrations adjusted for daily dosage increased156, 157 by an average of 60% (range: 5-190%) when amiodarone therapy was initiated in a limited number of patients receiving flecainide.1, 142 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.142 Pending further accumulation of data, it is recommended that dosage of flecainide be reduced by 30-50% several days after initiation of amiodarone therapy;1, 131, 142, 156, 157 subsequently, the patient and plasma flecainide concentrations should be monitored closely and flecainide dosage adjusted as necessary.1, 142
The effects of concomitant administration of flecainide and disopyramide have not been evaluated and experience with combined use of the drugs is limited.1 Because both drugs have negative inotropic effects, there appears to be little rationale for their combined use4, 89 and the manufacturer cautions that they not be used concomitantly unless the potential benefits are considered to outweigh the risks.1
Studies in healthy individuals indicate that plasma digoxin concentrations may be increased by an average of about 13-25% when flecainide and digoxin are administered concomitantly.1, 132, 133, 134 The increase in plasma digoxin concentration may occur within a few days of initiating flecainide therapy in patients receiving digoxin133, 134 and may result from a decrease in the volume of distribution of digoxin.132 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.133, 134 Flecainide has been administered concomitantly with cardiac glycosides without adverse effects.1 Additional studies to determine the potential importance of an interaction in patients with congestive heart failure are needed.133, 134 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,134 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.133, 134 Pending further accumulation of data, patients receiving flecainide and digoxin should be monitored for signs of digoxin toxicity.133, 134
Beta-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.1, 133 The mechanism(s) of this interaction is not known, but the elimination half-lives of both drugs are apparently unchanged.133 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.1, 133 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;1, 92, 111 however, if flecainide and a β-adrenergic blocking agent are administered concomitantly, the possibility of additive negative inotropic effects should be considered.1
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.1 Because verapamil also has a negative inotropic effect and decreases AV nodal conduction,1, 89 the manufacturer cautions that flecainide and verapamil not be used concomitantly unless the potential benefits are considered to outweigh the risk.1 The manufacturer also cautions that there is insufficient experience with concomitant administration of flecainide and diltiazem or nifedipine to recommend such combined use.1
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.80, 85 (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.70
Flecainide has been used concomitantly with diuretics in a large number of patients without any apparent drug interaction.1
Plasma flecainide concentrations and 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 for 1 week).1 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.135
Limited information is available on the acute toxicity of flecainide.3, 88, 155
The acute lethal dose of flecainide acetate in humans is not known.1, 88 The oral and IV LD50s of the drug in mice were 190 and 24 mg/kg, respectively.139 Following IV, intraperitoneal, or oral administration of single large doses of flecainide acetate (up to 500 mg/kg) in animals, vomiting, ataxia, dyspnea, seizures, and death were observed; death appeared to result from respiratory depression and arrest.3 Surviving animals recovered within several hours after administration of flecainide with no apparent residual effects.3
In general, overdosage of flecainide may be expected to produce effects that are extensions of pharmacologic effects, particularly those involving cardiac conduction and function.1, 88, 155 Animal studies and case reports in humans indicate that possible effects may include increases in PR, QRS, and QT intervals;1, 155, 158 conduction disturbances;1, 155 hypotension;1, 155 asystole; or cardiac arrest and death.1 In one adult who reportedly intentionally ingested 2.5 g of flecainide acetate, somnolence, tremor, and sweating resulted.88 Plasma flecainide concentrations 3 and 4.5 hours after ingestion of the drug were 1.9 and 3 mcg/mL, respectively, with an AV nodal escape rhythm and substantial prolongation of QRS and QT intervals occurring in association with the higher of these concentrations.88 The patient recovered following symptomatic and supportive treatment, as well as the use of charcoal hemoperfusion and forced diuresis to enhance elimination of the drug.88 Other ECG abnormalities associated with flecainide intoxication have included regular ventricular tachycardia with right bundle-branch block that progressed to polymorphous tachycardia (possibly torsades de pointes); substantial prolongation of the PR and JT intervals;155, 158 broadened P waves;158 and inverted T waves.158 Regular or polymorphous ventricular tachycardia may progress to ventricular fibrillation and sudden death.155
Treatment of flecainide overdosage generally involves symptomatic and supportive care,1, 88, 155, 158 with ECG, blood pressure, and respiratory monitoring.1, 88, 136, 155, 158 There is no specific antidote for flecainide intoxication.1
Supportive treatment may include IV administration of inotropic agents or cardiac stimulants (e.g., dopamine, dobutamine, isoproterenol), circulatory assistance (e.g., intra-aortic balloon counterpulsation), mechanically assisted respiration, and transvenous pacing.1, 155 Because of the long elimination half-life of flecainide and the possibility of markedly nonlinear pharmacokinetics at very high doses, treatment for an extended period of time may be necessary.1 Hemodialysis is not an effective means for enhancing elimination of flecainide.1, 70 Specific data are not available, but acidification of the urine may be potentially useful for enhancing elimination of flecainide,1, 85, 136, 139, 144 particularly if the urine is very alkaline;1, 85, 144 however, the potential effects of acidification on serum electrolyte concentrations (e.g., potassium) would have to be considered.136 The value of forced diuresis is not known.88, 155
Antiarrhythmic and Electrophysiologic Effects
Flecainide acetate is a local anesthetic-type antiarrhythmic agent.1, 3, 4, 5, 6, 7, 146, 147 Studies in animals have shown that flecainide is at least as effective6, 9, 10 and more potent on a weight basis than most currently available antiarrhythmic agents in preventing and/or suppressing experimentally induced arrhythmias.9, 11
The exact mechanism of antiarrhythmic action of flecainide has not been conclusively determined, but the drug is considered a class I (membrane-stabilizing) antiarrhythmic agent.1, 3, 4, 5, 6, 12, 13, 14 The principal effect of flecainide on cardiac tissue appears to be a concentration-dependent inhibition of the transmembrane influx of extracellular sodium ions via fast sodium channels, as indicated by a decrease in the maximal rate of depolarization of phase 0 of the action potential6, 11, 12, 13, 14, 15, 16, 17 and a shift of the membrane-responsiveness curve in the hyperpolarizing direction.11, 16 Like other class I antiarrhythmic agents, flecainide is believed to combine with fast sodium channels in their inactive state and thereby inhibit recovery after repolarization in a time- and voltage-dependent manner which is associated with subsequent dissociation of the drug from the sodium channels.12, 13, 17 Flecainide also appears to have a slight inhibitory effect on the transmembrane influx of extracellular calcium ions via slow calcium channels, but generally only at high drug concentrations.15, 18, 19 Flecainide has no vagomimetic,15 vagolytic,15 or β-adrenergic blocking6 activity and does not antagonize the positive inotropic effect of calcium on cardiac muscle.6, 15, 19
Flecainide exhibits electrophysiologic effects characteristic of class Ic antiarrhythmic agents.1, 3, 4, 5, 12, 13, 14, 20 The electrophysiologic characteristics of the subgroups of class I antiarrhythmic agents may be related to quantitative differences in their rates of attachment to and dissociation from transmembrane sodium channels, with class Ic agents exhibiting slow rates of attachment and dissociation.12, 13, 17 Flecainide decreases the amplitude and maximal rate of rise of the action potential in a concentration-dependent manner and has little or no effect on resting potential.6, 11, 15, 16, 17, 18 Like other class Ic antiarrhythmic agents, flecainide slows intracardiac conduction at low concentrations,1, 3, 4, 5, 12, 13, 14, 22, 23, 24, 25 has relatively small effects on refractoriness,3, 12, 13, 14, 22, 23, 24, 25, 26, 31 and generally has little effect on repolarization and action potential duration (APD).6, 11, 12, 13, 14, 15, 16, 17, 18, 21, 25 The drug produces a slight increase in APD in atrial6, 15, 21 and ventricular11, 15, 16, 17, 18, 25 muscle and a decrease in APD in Purkinje fibers.11, 15, 21 The electrophysiologic effects of flecainide generally appear to be comparable following multiple oral or single IV doses of the drug.3, 22, 24, 35, 36, 140
Effects on Cardiac Conduction and Refractoriness
Flecainide produces a dose-related decrease in intracardiac conduction throughout the heart, with the most marked effect on conduction within the His-Purkinje system.1, 3, 4, 5, 22, 23, 24, 25 The effect of the drug on intra-atrial and atrioventricular (AV) conduction is less pronounced than its effect on intraventricular conduction.1, 3, 22, 23, 24, 25 Flecainide may also prolong refractoriness in most parts of the heart,3, 22, 23, 24, 25, 26, 31 with the most marked effect on the ventricles;1, 3, 22, 23, 24, 25 however, the effects of the drug on refractoriness are less pronounced than its effects on intracardiac conduction.3, 22, 23, 24, 25, 77
The effects of flecainide on intracardiac conduction are manifested by dose-related increases1, 27 in PR, QRS, and, to a lesser degree, QT intervals.1, 3, 22, 23, 24, 25, 27, 30, 52, 53, 58, 59, 76, 89, 94, 102, 104 Increases in PR and QRS intervals average about 25% (40 and 20 ms, respectively)1, 3, 22, 27, 52, 58, 59, 76, 77, 89, 102 at dosages of 400 mg or more daily27, 52, 58, 59, 76, 77, 89, 102 but may be as large as approximately 118 and 150%, respectively, in some patients.1 About 30-40% of patients may develop first-degree AV block during flecainide therapy,1, 27, 103 and many patients develop a QRS interval of 120 ms or longer;1 however, PR intervals usually do not increase to 300 ms or longer and QRS intervals usually do not increase to 180 ms or longer.1 Flecainide generally increases QT interval by about 8%,1, 3, 22, 76, 102 but about 60-90% of this increase is secondary to the increase in QRS interval.1, 102 Consequently, the JT interval (QT minus QRS) increases by an average of about 4%.1, 26, 102 Substantial prolongation of the JT interval occurs in less than 2% of patients.1 The QT interval corrected for rate (QTc) may be unchanged3, 22, 25, 30, 53, 92, 98, 150 or slightly increased.3, 22, 23, 31, 52, 58, 59, 77, 89, 95, 101, 104, 109 AH and HV intervals are prolonged.3, 22, 23, 24, 25, 26, 31, 36, 52, 77, 92, 145 The atrial effective refractory period (ERP) may be unchanged or slightly increased,22, 23, 24, 26, 31, 36, 77, 145 and ventricular ERP may be increased by about 5-15%.23, 24, 25, 36, 52, 53, 77, 92 The AV nodal ERP may be unchanged23, 24, 31, 77, 145 or slightly increased.31
Flecainide generally has minimal effects on normal sinus node function.3, 20, 22, 23, 24, 26, 28, 29, 30, 32 Spontaneous sinus rate may be unchanged20, 23, 24, 28, 29 or decreased,26, 30 and corrected sinus node recovery time following pacing and spontaneous cycle lengths is somewhat increased.1, 24, 26, 31, 77 Sinoatrial conduction time may be slightly increased.26, 32 In contrast to its effects on normal sinus node function, flecainide may have a marked depressive effect on sinus node function in individuals with preexisting sinus node dysfunction;31, 32, 33 corrected sinus node recovery time and sinoatrial conduction time may be substantially increased in some individuals.31, 32, 33
Effects on Dual AV Nodal and Anomalous AV Pathways
The relatively selective effects of flecainide on retrograde pathways of dual AV nodal and anomalous AV conduction are responsible for the drug's ability to effectively terminate paroxysmal reentrant supraventricular tachycardias in many patients.23, 32, 34, 35, 36, 115, 140 In patients with dual AV pathways, flecainide decreases conduction, markedly increases refractoriness of the retrograde fast pathway, and increases or has little effect on refractoriness of the anterograde fast pathway or the anterograde and retrograde slow pathways;23, 32, 34, 36, 140 complete block of the retrograde fast pathway and, rarely, the anterograde fast pathway may result.23, 32, 34, 36 In patients with Wolff-Parkinson-White syndrome or concealed accessory AV pathways, flecainide decreases conduction and increases the refractoriness of anterograde and retrograde accessory pathways, with the effects more pronounced on the retrograde pathway.23, 32, 34, 35, 36, 140 In addition, the effects of flecainide may be greater on accessory pathways that have a long pretreatment refractory period.23, 32, 34, 140 Complete block of the retrograde pathway and, sometimes, the anterograde pathway may result.23, 32, 34, 35, 36, 140
Effects on Endocardial Pacing Threshold
Flecainide can increase acute and chronic endocardial pacing thresholds1, 32, 38, 39 and may suppress ventricular escape rhythms;1, 32, 38 these effects are reversible following discontinuance of the drug.1, 32, 38, 39 (See Cautions: Precautions and Contraindications.) Increases in endocardial pacing threshold as large as 200% have occurred.32, 38 Flecainide-induced increases in endocardial pacing threshold appear to be correlated with plasma concentrations of the drug.32, 38 Flecainide appears to have a greater effect on endocardial pacing threshold than most other class I antiarrhythmic agents.32, 38
Like other antiarrhythmic agents,1, 27, 40, 41, 42 flecainide can worsen existing arrhythmias or cause new arrhythmias.1, 27, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 91, 151, 159 (See Cautions: Arrhythmogenic Effects.) The arrhythmogenic effects of the drug may range from an increased frequency of premature ventricular complexes (PVCs) to the development of more severe and potentially fatal1, 27, 43, 44, 45, 91, 151, 159 ventricular tachyarrhythmias.1, 27, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 151 The exact mechanism(s) by which various antiarrhythmic agents, including flecainide, produce arrhythmogenic effects has not been fully determined,40, 41, 43, 51 but the arrhythmogenic potential of flecainide may be related to its effects on conduction44, 49 and possibly myocardial contractility.136
Flecainide generally exhibits minimal cardiovascular effects following oral3, 30, 53, 54, 55, 56, 57, 58, 59, 96, 98, 104 or IV19, 60, 61, 62, 63, 64, 65, 66, 67, 68, 109 administration. The cardiovascular effects of the drug appear to be more pronounced following IV than oral administration, but evaluations have been more extensive following IV administration.54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68
Flecainide exhibits a mild to moderate negative inotropic effect.1, 10, 18, 19, 60, 61, 62, 63, 64, 65, 66, 67, 68 The negative inotropic effect and other cardiovascular effects may be more pronounced and clinically important in patients with coronary heart disease,19, 57, 62, 63, 64, 65 acute myocardial infarction (MI),66, 67 congestive heart failure,1, 65, 68 or myocardial dysfunction.1, 19, 66 (See Cautions: Cardiovascular Effects.) The exact mechanism of flecainide's negative inotropic effect has not been determined, but it may be related in part to its effect on slow calcium channels.18, 19 The myocardial depressant effect of flecainide appears to be less than that of disopyramide, but further evaluation is needed.19, 121
Heart rate is usually unchanged following oral1, 30, 56, 57, 58, 76, 90, 95, 96, 98, 104, 150 or IV19, 62, 64, 65, 67, 68, 109 administration of flecainide, but slight increases may occur;54, 55, 60, 61, 63, 66, 121 occasionally, bradycardia1, 51 or tachycardia1 has been reported. Similarly, blood pressure is usually unchanged following oral30, 54, 55, 56, 57, 58, 77, 94, 96, 98, 104 or IV19, 62, 63, 65, 66, 67, 109 administration of the drug, but small increases in mean systolic and/or diastolic blood pressure have been observed.60, 66, 76, 154
Following IV administration of flecainide in patients with coronary heart disease,19, 62, 63, 64, 65 acute MI,66, 67, 121 congestive heart failure,65, 68 or myocardial dysfunction,19, 66 cardiac output19, 62, 63, 64, 65, 66, 67, 68, 121 and left ventricular ejection fraction19, 62, 63, 65 are generally decreased, pulmonary artery19, 63, 66, 67, 121 and/or wedge19, 62, 63, 65, 67, 68 pressures are generally increased, and systemic vascular resistance may be unchanged62, 67, 68 or increased.19, 63, 65, 66, 121 The negative inotropic and other cardiovascular effects of IV flecainide are generally transient, being most marked during and immediately following administration of the drug,19, 62, 63, 64, 65, 66, 67, 68 and are generally more pronounced in patients with preexisting ventricular dysfunction.19, 65, 66 Following chronic oral administration of flecainide, left ventricular ejection fraction generally appears to be unchanged or only slightly decreased,30, 57, 58, 59, 76, 154 although both increases and decreases have been observed in patients receiving usual dosages of the drug.1, 154 The drug can worsen or cause congestive heart failure,1, 19, 92, 102, 154 particularly in patients with a history of congestive heart failure and/or a preexisting ejection fraction of 30% or less.154 (See Cautions: Cardiovascular Effects.)
Flecainide exhibits a local anesthetic action that is more potent and sustained than that of procaine (no longer commercially available in the US) in vitro.6 In animals, flecainide also exhibits anticonvulsant activity at doses higher than those required for antiarrhythmic action.69
Flecainide acetate is rapidly and almost completely absorbed from the GI tract following oral administration.1, 70, 71, 72, 73 The absolute bioavailability of the commercially available flecainide acetate tablets averages approximately 85-90%.70 The rate of absorption may be slightly decreased by the presence of food,70 but the extent of absorption is not affected.1, 70, 72 The rate and extent of absorption are not affected by concomitant ingestion of an aluminum hydroxide antacid.70, 72 Flecainide does not undergo any substantial first-pass metabolism.1, 70, 71
Peak plasma flecainide concentrations usually occur within approximately 3 hours (range: 1-6 hours) after oral administration.1, 56, 70, 71, 72, 73 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.56, 72, 73 The pharmacokinetic profile of flecainide is apparently not substantially affected by dose or plasma concentrations at usual dosages,70 but does deviate somewhat from linearity.1 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.1 Although plasma flecainide concentrations are relatively linearly related70 and approximately proportional to dosage,1, 70 there is considerable interindividual and intraindividual variation in plasma concentrations attained with a given dosage.30, 58, 59, 75, 78, 80 Following single oral doses, total plasma concentrations of flecainide metabolites (free and conjugated) are generally 1-2 times higher than those of unchanged flecainide;70, 73 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.1, 70, 74 (See Pharmacokinetics: Elimination.)
In patients with premature ventricular complexes (PVCs), flecainide-induced decreases in single and multiple PVCs are related to dosage and plasma concentrations of the drug.1, 58, 59, 70, 75, 76 The dose-related increases1, 27 in PR, QRS, and, to a lesser degree, QT intervals1, 3, 22, 23, 24, 25, 27, 30, 58, 59 also appear to be related to plasma concentrations of the drug.59 Based on greater than 90% suppression of PVCs, plasma flecainide concentrations of approximately 0.2-1 mcg/mL1, 30, 58, 59, 70, 75, 78 (mean of about 0.5-0.6 mcg/mL)59, 70 appear to be necessary for optimum therapeutic effect, with minimum therapeutic concentrations ranging from about 0.2-0.4 mcg/mL.58, 59, 70, 75, 78 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.1, 59, 77, 92, 189 The risk of adverse cardiac effects (e.g., conduction defects, bradycardia) increases as plasma flecainide concentrations increase above 0.7-1 mcg/mL, particularly when concentrations exceed 1 mcg/mL.1, 70, 78 A relationship between plasma flecainide concentrations and arrhythmogenic effects has not been established,1 but some data suggest that adverse cardiac effects may be associated with plasma concentrations higher than 1 mcg/mL.1, 27, 45, 50, 78 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.1, 151
Distribution of flecainide acetate into human body tissues and fluids has not been fully characterized.70 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.70 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.70, 76 Following IV administration in humans, flecainide is rapidly and apparently widely distributed.70, 71, 79 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 dose70, 72, 79 and about 10 L/kg following a single oral dose.70
In vitro, flecainide is approximately 40-50% bound to plasma proteins,1, 70, 81, 82, 83 mainly α1-acid glycoprotein (α1-AGP).83 At in vitro plasma flecainide concentrations of 0.015-10 mcg/mL, binding is independent of the plasma concentration of the drug.1, 70, 81 Following acute myocardial infarction, protein binding of flecainide may be increased to an average of approximately 60% for about 24 hours,82, 83 but this effect is not likely to be clinically important in most circumstances.5, 70
It is not known whether flecainide crosses the placenta in humans, but the drug and/or its metabolites cross the placenta in rats.70 A multiple-dose study conducted in mothers soon after delivery indicated that flecainide is distributed into human milk in concentrations as high as 4 times (with average concentrations about 2.5 times) corresponding plasma concentrations; assuming a high maternal plasma concentration of 1 mcg/mL,1 the calculated daily dose to a nursing infant (assuming about 700 mL of breast milk over 24 hours) would be less than 3 mg.1
Plasma concentrations of flecainide acetate appear to decline in a biphasic manner.70, 72, 79, 84 Following a single IV dose in healthy adults, the half-life of flecainide in the initial distribution phase (t½α) is about 3-6 minutes72, 84 and the half-life in the terminal elimination phase (t½β) has been reported to average 11-14 hours (range: 7-19 hours).70, 71, 72, 79 Following single or multiple oral doses in healthy adults, the elimination half-life has averaged 11.5-16 hours (range: 7-25 hours),56, 70, 72, 80 but the half-life tends to be slightly more prolonged following multiple rather than single doses.70, 72 The elimination half-life of flecainide following multiple oral doses in patients with PVCs is slightly longer than in healthy individuals, averaging 19-22 hours (range: 12-30 hours).1, 30, 58, 59, 75, 76 The elimination half-life tends to increase with age in patients with PVCs.70 Although data are limited in infants younger than 1 year of age, currently available data suggest that half-life of flecainide at birth may be as long as 29 hours, decreasing to 11-12 hours by 3 months of age, and to 6 hours by 1 year of age.1 In children 1-12 years of age, the half-life of flecainide is approximately 8 hours.1 In adolescents 12-15 years of age, the plasma elimination half-life is approximately 11-12 hours.1 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 PVCs, averaging 19 hours (range: 14-26 hours).56, 70 Steady-state plasma concentrations are reached in 3-5 days; once at steady state, no additional accumulation of drug is expected during chronic therapy.1 Over the usual therapeutic range, plasma concentrations of flecainide increase in an approximately dose-proportional manner.1
The elimination half-life of flecainide is prolonged in patients with renal impairment,1, 70 particularly in those with severe renal impairment.70 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 m2, respectively.70 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 flecainide70, 73 and free plasma concentrations of m-O -dealkylated flecainide appear to persist in some patients with severe renal impairment.70 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).1, 80, 85
Flecainide is extensively metabolized, probably in the liver, to 2 major metabolites and to at least 3 unidentified minor metabolites.1, 70, 73 In vitro metabolic studies indicate that the cytochrome P-450 (CYP) isoenzyme 2D6 is involved in the drug's metabolism.1, 246 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.70, 73 Both metabolites undergo extensive conjugation at the m-O -dealkylated position with glucuronic or sulfuric acid.70, 73 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 flecainide1, 70, 73, 76 and the m-O -dealkylated lactam derivative has less than 10% of the electrophysiologic activity of flecainide.86 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;70, 86 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).70, 86 The minor metabolites remain to be identified, but some data suggest that they may result from amide hydrolysis.73 Some data also suggest that cigarette smoking may induce metabolism of flecainide.87
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.1, 70, 73 Flecainide appears to be excreted in urine mainly by glomerular filtration, but some tubular secretion may also occur.70, 72, 85 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.73 In healthy individuals, about 30% (range: 10-50%) of a single oral dose is excreted in urine as unchanged drug,1, 70, 72, 73, 80 10-20% as m-O -dealkylated flecainide and its conjugates,70, 73, 74 10-15% as the m-O -dealkylated lactam derivative and its conjugates,70, 73 and 3% or less as 3 unidentified minor metabolites.1, 70, 73 The major metabolites of the drug are excreted in urine principally as conjugates.1, 73, 74
The fraction of flecainide excreted in urine as unchanged drug decreases with decreasing renal function1, 70 and is markedly reduced in patients with severe renal impairment.70 Following a single oral dose in patients with creatinine clearances of 4-41 and 0-2 mL/minute per m2, the fraction excreted in urine within 72 hours as unchanged drug averaged approximately 15% (range: 5-30%) and 1% (range: 0-3%), respectively.70 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.80, 85 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).80, 85
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);56, 70 renal clearance of the drug is about 25-40% of the total plasma clearance.70, 72 In healthy geriatric individuals, total apparent plasma clearance decreases following multiple oral doses, apparently as a result of decreased nonrenal clearance of the drug.137 Total apparent plasma clearance is decreased in patients with PVCs 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.70 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;56, 70 renal clearance is also decreased in these patients, but still accounts for about 25% of total plasma clearance.70 It appears that an increase in nonrenal clearance can, to some extent, compensate for decreased renal clearance in some patients.70 Renal clearance of flecainide is inversely related to urinary pH, increasing with decreasing urinary pH and vice versa.80, 85 Extremes of urinary pH may substantially affect renal clearance of the drug.80, 85 The manufacturer states that elimination of flecainide from plasma may be markedly prolonged in patients with substantial hepatic impairment.1
Only about 1% of an oral dose of flecainide is removed by hemodialysis as unchanged drug;1, 70 however, about 10% of a dose is removed by hemodialysis as m-O -dealkylated flecainide and its conjugates.70 It is not known if flecainide and/or its metabolites are removed by peritoneal dialysis.139 There is some evidence that flecainide may be removed by charcoal hemoperfusion.88
Flecainide acetate is a local anesthetic-type antiarrhythmic agent.1, 3, 4, 5, 6, 7, 146, 147 Flecainide is an amide-type local anesthetic6, 7, 8 and is structurally related to procainamide6, 7, 8 in that the drug is a benzamide derivative.1 The antiarrhythmic potency of flecainide is associated with the presence and positions of the trifluoroethoxy groups on the benzamide ring, which enhance lipophilicity, and with the presence of the nonsubstituted piperidylmethyl group in the amide side chain.6, 7, 8
Flecainide acetate occurs as a white to slightly off-white crystalline powder1 and has a solubility of 48.4 mg/mL in water1 and 300 mg/mL139 in alcohol at 37°C. The drug has a pKa of 9.3.1
Flecainide acetate tablets should be stored in tight, light-resistant containers at 20-25°C.1 However, USP states that the tablets can be stored in well-closed containers.210
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 50 mg* | ||
100 mg* | Flecainide Acetate Tablets | |||
150 mg* | Flecainide Acetate Tablets |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
1. West-Ward Pharmaceuticals. Flecainide acetate tablets prescribing information. Eatontown, NJ; 2016 Mar.
3. Holmes B, Heel RC. Flecainide: a preliminary review of its pharmacodynamic properties and therapeutic efficacy. Drugs . 1985; 29:1-33. [PubMed 3882390]
4. Nappi JM, Anderson JL. Flecainide: a new prototype antiarrhythmic agent. Pharmacotherapy . 1985; 5:209-21. [PubMed 3898035]
5. Smith GH. Flecainide: a new class Ic antidysrhythmic. Drug Intell Clin Pharm . 1985; 19:703-7. [PubMed 3902429]
6. Cowan JC, Vaughan Williams EM. Characterization of a new oral antiarrhythmic drug, flecainide (R818). Eur J Pharmacol . 1981; 73:333-42.
7. Hudak JM, Banitt EH, Schmid JR. Discovery and development of flecainide. Am J Cardiol . 1984; 53:17-20B.
8. Banitt EH, Coyne WE, Schmid JR et al. Antiarrhythmics. N -(aminoalkylene) trifluoroethoxybenzamides and N -(aminoalkylene) trifluoroethoxynaphthamides. J Med Chem . 1975; 18:1130-4. [PubMed 1177259]
9. Banitt EH, Bronn WR, Coyne WE et al. Antiarrhythmics. 2. Synthesis and antiarrhythmic activity of N -(piperidylalkyl) trifluoroethoxybenzamides. J Med Chem . 1977; 20:821-6. [PubMed 874956]
10. Verdouw PD, Deckers JW, Gordon JC. Antiarrhythmic and hemodynamic actions of flecainide acetate (R-818) in the ischemic porcine heart. J Cardiovasc Pharmacol . 1979; 1:473-86. [PubMed 94625]
11. Kvam DC, Banitt EH, Schmid JR. Antiarrhythmic and electrophysiologic actions of flecainide in animal models. Am J Cardiol . 1984; 53:22-5B.
12. Vaughan Williams EM. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol . 1984; 24:129-47. [PubMed 6144698]
13. Harrison DC. Antiarrhythmic drug classification: new science and practical applications. Am J Cardiol . 1985; 56:185-7. [PubMed 2409789]
14. Harrison DC. Current classification of antiarrhythmic drugs as a guide to their rational clinical use. Drugs . 1986; 31:93-5. [PubMed 3948737]
15. Singh BN, Nademanee K, Josephson MA et al. The electrophysiology and pharmacology of verapamil, flecainide, and amiodarone: correlations with clinical effects and antiarrhythmic actions. Ann NY Acad Sci . 1984; 432:210-35. [PubMed 6395762]
16. Borchard U, Boisten M. Effect of flecainide on action potentials and alternating current-induced arrhythmias in mammalian myocardium. J Cardiovasc Pharmacol . 1982; 4:205-12. [PubMed 6175802]
17. Campbell TJ. Kinetics of onset of rate-dependent effects of class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res . 1983; 17:344-52. [PubMed 6883410]
18. Schulze JJ, Knops J. Effects of flecainide on contractile force and electrophysiological parameters in cardiac muscle. Arzneimittelforschung . 1982; 32:1025-9. [PubMed 6890819]
19. Josephson MA, Ikeda N, Singh BN. Effects of flecainide on ventricular function: clinical and experimental correlations. Am J Cardiol . 1984; 53:95-100B.
20. Milne JR, Hellestrand KJ, Bexton RS et al. Class 1 antiarrhythmic agents—characteristic electrocardiographic differences when assessed by atrial and ventricular pacing. Eur Heart J . 1984; 5:99-107. [PubMed 6723689]
21. Ikeda N, Singh BN, Davis LD et al. Effects of flecainide on the electrophysiologic properties of isolated canine and rabbit myocardial fibers. J Am Coll Cardiol . 1985; 5(2 Part 1):303-10. [PubMed 3968315]
22. Estes NAM III, Garan H, Ruskin JN. Electrophysiologic properties of flecainide acetate. Am J Cardiol . 1984; 53:26-9B.
23. Hellestrand KJ, Bexton RS, Nathan AW et al. Acute electrophysiological effects of flecainide acetate on cardiac conduction and refractoriness in man. Br Heart J . 1982; 48:140-8. [PubMed 7093083]
24. Anderson JL, Lutz JR, Allison SB. Electrophysiologic and antiarrhythmic effects of oral flecainide in patients with inducible ventricular tachycardia. J Am Coll Cardiol . 1983; 2:105-14. [PubMed 6853905]
25. Olsson SB, Edvardsson N. Clinical electrophysiologic study of antiarrhythmic properties of flecainide: acute intraventricular delayed conduction and prolonged repolarization in regular paced and premature beats using intracardiac monophasic action potentials with programmed stimulation. Am Heart J . 1981; 102:864-71. [PubMed 7304394]
26. Seipel L, Abendroth RR, Breithardt G. Electrophysiological effects of flecainide (R818) in man. Circulation . 1981; 62(4 Part II):III-153.
27. Morganroth J, Horowitz LN. Flecainide: its proarrhythmic effect and expected changes on the surface electrocardiogram. Am J Cardiol . 1984; 53:89-94B.
28. Abitbol H, Califano JE, Abate C et al. Use of flecainide acetate in the treatment of premature ventricular contractions. Am Heart J . 1983; 105:227-30. [PubMed 6823803]
29. Somani P. Antiarrhythmic effects of flecainide. Clin Pharmacol Ther . 1980; 27:464-70. [PubMed 7357804]
30. Anderson JL, Stewart JR, Perry BA et al. Oral flecainide acetate for the treatment of ventricular arrhythmias. N Engl J Med . 1981; 305:473-7. [PubMed 7019711]
31. Vik-Mo H, Ohm OJ, Lund-Johansen P. Electrophysiologic effects of flecainide acetate in patients with sinus nodal dysfunction. Am J Cardiol . 1982; 50:1090-4. [PubMed 7137036]
32. Hellestrand KJ, Nathan AW, Bexton RS et al. Electrophysiologic effects of flecainide acetate on sinus node function, anomalous atrioventricular connections, and pacemaker thresholds. Am J Cardiol . 1984; 53:30-8B.
33. Hellestrand KJ, Nathan AW, Bexton RS et al. Response of an abnormal sinus node to intravenous flecainide acetate. PACE . 1984; 7(3 Part 1):436-9. [PubMed 6204297]
34. Hellestrand KJ, Nathan AW, Bexton RS et al. Cardiac electrophysiologic effects of flecainide acetate for paroxysmal reentrant junctional tachycardias. Am J Cardiol . 1983; 51:770-6. [PubMed 6829436]
35. Neuss H, Buss J, Schlepper M et al. Effects of flecainide on electrophysiological properties of accessory pathways in the Wolff-Parkinson-White syndrome. Eur Heart J . 1983; 4:347-53. [PubMed 6617681]
36. Bexton RS, Hellestrand KJ, Nathan AW et al. A comparison of the antiarrhythmic effects on AV junctional re-entrant tachycardia of oral and intravenous flecainide acetate. Eur Heart J . 1983; 4:92-102. [PubMed 6852073]
37. Bexton RS, Hellestrand KJ, Nathan AW et al. Retrograde gap in fast pathway conduction accentuated by the class I antiarrhythmic agent, flecainide. PACE . 1983; 6:1273-7. [PubMed 6196737]
38. Hellestrand KJ, Burnett PJ, Milne JR et al. Effect of the antiarrhythmic agent flecainide acetate on acute and chronic pacing thresholds. PACE . 1983; 6(5 Part 1):892-9. [PubMed 6195608]
39. Walker PR, Papouchado M, James MA et al. Pacing failure due to flecainide acetate. PACE . 1985; 8:900-2. [PubMed 2415944]
40. Velebit V, Podrid P, Lown B et al. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation . 1982; 65:886-94. [PubMed 6176355]
41. Torres V, Flowers D, Somberg JC. The arrhythmogenicity of antiarrhythmic agents. Am Heart J . 1985; 109(5 Part 1):1090-7. [PubMed 3993517]
42. Rae AP, Greenspan AM, Spielman SR et al. Antiarrhythmic drug efficacy for ventricular tachyarrhythmias associated with coronary artery disease as assessed by electrophysiologic studies. Am J Cardiol . 1985; 55:1494-9. [PubMed 3890509]
43. Nathan AW, Hellestrand KJ, Bexton RS et al. Proarrhythmic effects of the new antiarrhythmic agent flecainide acetate. Am Heart J . 1984; 107:222-8. [PubMed 6695656]
44. Nathan AW, Hellestrand KJ, Bexton RS et al. The proarrhythmic effects of flecainide. Drugs . 1985; 29(Suppl 4):45-53. [PubMed 4006779]
45. Spivack C, Gottlieb S, Miura DS et al. Flecainide toxicity. Am J Cardiol . 1984; 53:329-30. [PubMed 6695731]
46. Wehr M, Noll B, Krappe J. Flecainide-induced aggravation of ventricular arrhythmias. Am J Cardiol . 1985; 55:1643-4. [PubMed 4003313]
47. Sellers TD, DiMarco JP. Sinusoidal ventricular tachycardia associated with flecainide acetate. Chest . 1984; 85:647-9. [PubMed 6201323]
48. Hohnloser S, Zeiher A, Hust MH et al. Flecainide-induced aggravation of ventricular tachycardia. Clin Cardiol . 1983; 6:130-5. [PubMed 6851274]
49. Muhiddin K, Nathan AW, Hellestrand KJ et al. Ventricular tachycardia associated with flecainide. Lancet . 1982; 2:1220-1. [PubMed 6128526]
50. Lui HK, Lee G, Dietrich P et al. Flecainide-induced QT prolongation and ventricular tachycardia. Am Heart J . 1982; 103(4 Part 1):567-9. [PubMed 7064795]
51. Podrid PJ. Aggravation of ventricular arrhythmia: a drug-induced complication. Drugs . 1985; 29(Suppl 4):33-44. [PubMed 3924550]
52. Platia EV, Estes NAM, Heine DL et al. Flecainide: electrophysiologic and antiarrhythmic properties in refractory ventricular tachycardia. Am J Cardiol . 1985; 55:956-62. [PubMed 3984883]
53. Oetgen WJ, Tibbits PA, Abt MEO et al. Clinical and electrophysiologic assessment of oral flecainide acetate for recurrent ventricular tachycardia: evidence for exacerbation of electrical instability. Am J Cardiol . 1983; 52:746-50. [PubMed 6624666]
54. Hodges M, Hoback J, Graham E et al. Cardiac function after oral dosing with flecainide acetate. Clin Pharmacol Ther . 1981; 29:251.
55. Tanenbaum R, Wilen M, Franciosa JA. Effects of flecainide on hemodynamics and functional capacity in heart failure. Circulation . 1982; 66(4 Part II):II-68.
56. Franciosa JA, Wilen M, Weeks CE et al. Pharmacokinetics and hemodynamic effects of flecainide in patients with chronic low output heart failure. J Am Coll Cardiol . 1983; 1:699.
57. Lui HK, Lee G, Stobbe D et al. Effect of flecainide on left ventricular function. Clin Res . 1983; 31:13A.
58. Hodges M, Haugland JM, Granrud G et al. Suppression of ventricular ectopic depolarizations by flecainide acetate, a new antiarrhythmic agent. Circulation . 1982; 65:879-85. [PubMed 7074749]
59. Duff HJ, Roden DM, Maffucci RJ et al. Suppression of resistant ventricular arrhythmias by twice daily dosing with flecainide. Am J Cardiol . 1981; 48:1133-40. [PubMed 7304461]
60. Muhiddin KA, Shaw E, Blackett A et al. The effect of a new antiarrhythmic agent, flecainide acetate, on systolic time intervals. Eur J Clin Pharmacol . 1983; 25:13-8. [PubMed 6617715]
61. Muhiddin KA, Turner P, Blackett A. Effect of flecainide on cardiac output. Clin Pharmacol Ther . 1985; 37:260-3. [PubMed 3971650]
62. Legrand V, Vandormael M, Collignon P et al. Hemodynamic effects of a new antiarrhythmic agent flecainide (R-818), in coronary heart disease. Am J Cardiol . 1983; 51:422-6. [PubMed 6823856]
63. Josephson MA, Kaul S, Hopkins J et al. Hemodynamic effects on intravenous flecainide relative to the level of ventricular function in patients with coronary artery disease. Am Heart J . 1985; 109:41-5. [PubMed 3966331]
64. Serruys PW, Vanhaleweyk G, Van den Brand M et al. The haemodynamic effect of intravenous flecainide acetate in patients with coronary artery disease. Br J Clin Pharmacol . 1983; 16:51-9. [PubMed 6882622]
65. Legrand V, Materne P, Vandormael M et al. Comparative haemodynamic effects of intravenous flecainide in patients with and without heart failure and with and without beta-blocker therapy. Eur Heart J . 1985; 6:664-71. [PubMed 4054136]
66. Jackson N, Verma SP, Frais MA et al. Hemodynamic dose-response effects of flecainide in acute myocardial infarction with and without left ventricular decompensation. Clin Pharmacol Ther . 1985; 37:619-24. [PubMed 3891187]
67. Cohen AA, Daru V, Covelli G et al. Hemodynamic effects of intravenous flecainide in acute noncomplicated myocardial infarction. Am Heart J . 1985; 110:1193-6. [PubMed 4072876]
68. Dunselman PHJM, Kingma JH, van Wijk LM et al. Haemodynamic and antiarrhythmic effects of intravenous flecainide acetate in chronic congestive heart failure. Drugs . 1985; 29(Suppl 4):58-64. [PubMed 4006780]
69. von Philipsborn G, Gries J, Hofmann HP et al. Pharmacological studies on propafenone and its main metabolite 5-hydroxypropafenone. Arzneimittelforschung . 1984; 34:1489-97. [PubMed 6543124]
70. Conard GJ, Ober RE. Metabolism of flecainide. Am J Cardiol . 1984; 53:41-51B.
71. Conard GJ, Carlson GL, Frost JW et al. Human plasma pharmacokinetics of flecainide acetate (R-818), a new antiarrhythmic, following oral and intravenous doses. Clin Pharmacol Ther . 1979; 25:218.
72. Tjandramaga TB, Verbesselt R, Van Hecken A et al. I.V. and oral-flecainide kinetics: absolute bio-availability, effects of food, antacid (aluminum hydroxide) and multiple oral doses. Eur Heart J . 1984; 5(Suppl B):135. [PubMed 6373273]
73. McQuinn RL, Quarfoth GJ, Johnson JD et al. Biotransformation and elimination of14C-flecainide acetate in humans. Drug Metab Dispos . 1984; 12:414-20. [PubMed 6148206]
74. Chang SF, Welscher TM, Miller AM et al. High-performance liquid chromatographic method for the quantitation of a meta-O -dealkylated metabolite of flecainide acetate, a new antiarrhythmic. J Chromatogr . 1985; 343:119-27. [PubMed 4066846]
75. Conard GJ, Cronheim GE, Klempt HW. Relationship between plasma concentrations and suppression of ventricular extrasystoles by flecainide acetate (R-818), a new antiarrhythmic, in patients. Arzneimittelforschung . 1982; 32:155-9. [PubMed 7199921]
76. Woosley RL, Siddoway LA, Duff HJ et al. Flecainide dose-response relations in stable ventricular arrhythmias. Am J Cardiol . 1984; 53:59-65B.
77. Anderson JL. Experience with electrophysiologically guided therapy of ventricular tachycardia with flecainide: summary of long-term follow-up. Am J Cardiol . 1984; 53:79-86B.
78. Salerno DM, Granrud G, Sharkey P et al. Pharmacodynamics and side effects of flecainide acetate. Clin Pharmacol Ther . 1986; 40:101-7. [PubMed 3720173]
79. Conard GJ, Carlson GL, Frost JW et al. Plasma concentrations of flecainide acetate, a new antiarrhythmic agent, in humans. Clin Ther . 1984; 6:643-52. [PubMed 6478470]
80. Johnston A, Warrington S, Turner P. Flecainide pharmacokinetics in healthy volunteers: the influence of urinary pH. Br J Clin Pharmacol . 1985; 20:333-8. [PubMed 4074602]
81. Johnston A, Muhiddin KA, Hamer J. Serum protein binding of flecainide. Br J Clin Pharmacol . 1982; 13:606P.
82. Johnston A, Caplin JL, Hamer J et al. The serum protein binding of disopyramide and flecainide following acute myocardial infarction. Br J Clin Pharmacol . 1983; 15:601P.
83. Caplin JL, Johnston A, Hamer J et al. The acute changes in serum binding of disopyramide and flecainide after myocardial infarction. Eur J Clin Pharmacol . 1985; 28:253-5. [PubMed 4007029]
84. Wang T, Siddoway LA, Bergstrand RH et al. Treatment of ventricular arrhythmia with individualized intravenous flecainide dosing regimens. Circulation . 1983; 68(4 Part II):III-416.
85. Muhiddin KA, Johnston A, Turner P. The influence of urinary pH on flecainide excretion and its serum pharmacokinetics. Br J Clin Pharmacol . 1984; 17:447-51. [PubMed 6326790]
86. Guehler J, Gornick CC, Tobler HG et al. Electrophysiologic effects of flecainide acetate and its major metabolites in the canine heart. Am J Cardiol . 1985; 55:807-12. [PubMed 3919554]
87. Mottonen LR, Holtzman JL, Harrison LI et al. Effects of smoking on the clearance of flecainide acetate. Clin Pharmacol Ther . 1984; 35:260.
88. Fach WA, Mai BV, Preusler W et al. Flecainid-intoxikation. (German; with English abstract; translation provided by Riker Laboratories.) Inn Med Aktuel . 1984; 11:27-31.
89. Anderson JL, Stewart JR, Crevey BJ. A proposal for the clinical use of flecainide. Am J Cardiol . 1984; 53:112-9B.
90. Flowers D, O'Gallagher D, Torres V et al. Flecainide: long-term treatment using a reduced dosing schedule. Am J Cardiol . 1985; 55:79-83. [PubMed 3966401]
91. Reid PR, Griffith LSC, Platia EV et al. Evaluation of flecainide acetate in the management of patients at high risk of sudden cardiac death. Am J Cardiol . 1984; 53:108-11B.
92. Lal R, Chapman PD, Naccarrelli GV et al. Short- and long-term experience with flecainide acetate in the management of refractory life-threatening ventricular arrhythmias. J Am Coll Cardiol . 1985; 6:772-9. [PubMed 3928725]
93. Granrud G, Salerno D, Hodges M et al. Long term flecainide is effective and well tolerated. Circulation . 1982; 66(4 Part II):II-69. [PubMed 7116593]
94. Duran D, Platia EV, Griffith LSC et al. Suppression of complex ventricular arrhythmias by oral flecainide. Clin Pharmacol Ther . 1982; 32:554-61. [PubMed 7127996]
95. Vanhaleweyk G, Balakumaran K, Lubsen J et al. Oral flecainide for suppression of ventricular arrhythmias. Cardiology . 1984; 71:30-9. [PubMed 6722846]
96. Muhiddin KA, Turner P, Hellestrand K et al. Evaluation of the efficacy of flecainide acetate in the treatment of ventricular premature contractions. Postgrad Med J . 1985; 61:489-96. [PubMed 2409543]
97. Vanhaleweyk G, Balakumaran K, Lubsen J et al. Flecainide: one-year efficacy in patients with chronic ventricular arrhythmias. Eur Heart J . 1984; 5:814-23. [PubMed 6499854]
98. Meinertz T, Zehender MK, Geibel A et al. Long-term antiarrhythmic therapy with flecainide. Am J Cardiol . 1984; 54:91-6. [PubMed 6741844]
99. Webb CR, Morganroth J, Spielman SR et al. Use of flecainide for ventricular tachycardia in patients with left ventricular dysfunction. J Am Coll Cardiol . 1985; 5:482.
100. Lee G, Lui HK, Stobbe D et al. Efficacy of flecainide in patients with serious ventricular dysrhythmias unresponsive to conventional oral antiarrhythmic agents. Clin Res . 1983; 31:199A.
101. Salerno DM, Hodges M, Granrud G et al. Comparison of flecainide with quinidine for suppression of chronic stable ventricular ectopic depolarizations: a double-blind randomized study in ambulatory outpatients. Ann Intern Med . 1983; 98:455-60. [PubMed 6340575]
102. Flecainide-Quinidine Research Group. Flecainide versus quinidine for treatment of chronic ventricular arrhythmias: a multicenter clinical trial. Circulation . 1983; 67:1117-23. [PubMed 6339110]
103. Hodges M, Salerno DM, Granrud G et al. Flecainide versus quinidine: results of a multicenter trial. Am J Cardiol . 1984; 53:66-71B.
104. Kjekshus J, Bathen J, Orning OM et al. A double-blind, crossover comparison of flecainide acetate and disopyramide phosphate in the treatment of ventricular premature complexes. Am J Cardiol . 1984; 53:72-8B.
105. Klempt HW, Nayebagha A, Fabry E. Antiarrhythmic efficacy of mexiletine, propafenone and flecainide in ventricular premature beats: a comparative study in patients after myocardial infarction. (German; with English abstract.) Z Kardiol . 1982; 71:340-9.
106. Dubner SJ, Elencwajg BD, Palma S et al. Efficacy of flecainide in the management of ventricular arrhythmias: comparative study with amiodarone. Am Heart J . 1985; 109:523-8. [PubMed 3883728]
107. Anon. Flecainide: a new antiarrhythmic drug. Med Lett Drugs Ther . 1986; 28:19-20. [PubMed 3951388]
108. Zipes DP. A consideration of antiarrhythmic therapy. Circulation . 1985; 72:949-56. [PubMed 3930087]
109. Stroobandt R, Andries E, van Mieghiem W et al. Efficacy and tolerance of intravenous flecainide in patients with chronic high frequency ventricular arrhythmias. Eur Heart J . 1984; 5:876-82. [PubMed 6397356]
110. Slama R, LeClerq JF. The clinical use of oral flecainide. Drugs . 1985; 29(Suppl 4):28-9. [PubMed 4006778]
111. Stern H, Scheininger M, Theisen F et al. Antiarrhythmic therapy with flecainide in combination and comparison with propranolol. Drugs . 1985; 29(Suppl 4):77-85. [PubMed 4006784]
112. Coumel P, Chouty F, Slama R. Logic and empiricism in the selection of antiarrhythmic agents: the role of drug combinations. Drugs . 1985; 29(Suppl 4):68-76. [PubMed 4006782]
113. Orning OM. The use of tocainide, encainide, lorcainide and flecainide for supraventricular arrhythmias. Eur Heart J . 1984; 5(Suppl B):81-6. [PubMed 6437821]
114. Camm AJ, Hellestrand KJ, Nathan AW et al. Clinical usefulness of flecainide acetate in the treatment of paroxysmal supraventricular arrhythmias. Drugs . 1985; 29(Suppl 4):7-13. [PubMed 4006783]
115. Neuss H. Long term use of flecainide in patients with supraventricular tachycardia. Drugs . 1985; 29(Suppl 4):21-5. [PubMed 4006776]
116. Kappenberger LJ, Fromer MA, Shenasa M et al. Evaluation of flecainide acetate in rapid atrial fibrillation complicating Wolff-Parkinson-White syndrome. Clin Cardiol . 1985; 8:321-6. [PubMed 4006340]
117. Goy JJ, Grbic M, Hurni M et al. Conversion of supraventricular arrhythmias to sinus rhythm using flecainide. Eur Heart J . 1985; 6:518-24. [PubMed 4043101]
118. Goy JJ, Maendly R, Grbic M et al. Cardioversion with flecainide in patients with atrial fibrillation of recent onset. Eur J Clin Pharmacol . 1985; 27:737-8. [PubMed 3987780]
119. Rae BG, Ilsley CDJ, Ablett MB. Flecainide acetate in resistant atrial fibrillation. N Z Med J . 1985; 98:402. [PubMed 3857526]
120. Creamer JE, Nathan AW, Camm AJ. Successful treatment of atrial tachycardias with flecainide acetate. Br Heart J . 1985; 53:164-6. [PubMed 3966957]
121. Frais MA, Silke B, Verma SP et al. Comparative effects of intravenous disopyramide and flecainide in acute myocardial infarction. Br J Clin Pharmacol . 1985; 20:522P.
122. Frank R, Fontaine G, Tonet JL et al. Treatment of severe chronic ventricular arrhythmias by flecainide combined with amiodarone. Eur Heart J . 1984; 5(Suppl 1):181. [PubMed 6241892]
123. Agarwal AK, Lochan RG, Beard D et al. Efficacy of flecainide in the control of ventricular response during exercise in established atrial fibrillation in digitalised patients: its comparison with beta blockade. Br Heart J . 1985; 54:611.
124. Gentzkow GD, Sullivan JY. Extracardiac adverse effects of flecainide. Am J Cardiol . 1984; 53:101-5B.
125. Livelli FD Jr, Ferrick KJ, Bigger JT Jr et al. Mixed response to flecainide acetate. J Am Coll Cardiol . 1984; 3:583.
126. Griffith L, Platia E, Ord S et al. Persistent ventricular tachycardia/fibrillation: a possible adverse interaction between flecainide and class I anti-arrhythmic drugs. J Am Coll Cardiol . 1984; 3:583.
127. Ward DE, Jones S, Shinebourne EA. Use of flecainide acetate for refractory junctional tachycardias in children with the Wolff-Parkinson-White syndrome. Am J Cardiol . 1986; 57:787-90. [PubMed 3962866]
128. Case MT, Sibinski LJ, Steffen GR. Chronic oral toxicity and oncogenicity studies of flecainide, an antiarrhythmic, in rats and mice. Toxicol Appl Pharmacol . 1984; 73:232-42. [PubMed 6710523]
129. Penhall RK, Hong CY, Muhiddin KA. The effect of flecainide on human sperm motility. Br J Clin Pharmacol . 1982; 14:147P.
130. Gosselin RE, Smith RP, Hodge HC. Clinical toxicology of commercial products. 5th ed. Baltimore: The Williams & Wilkins Co; 1984:I10.
131. Wyeth Laboratories Inc. Cordarone® (amiodarone HCl) prescribing information. Philadelphia, PA; 1987 Jan.
132. Tjandramaga TB, Verbesselt R, Van Hecken A et al. Oral digoxin pharmacokinetics during multiple-dose flecainide treatment. Arch Int Pharmacodyn Ther . 1982; 260:302-3. [PubMed 7165437]
133. Lewis GP, Holtzman JL. Interaction of flecainide with digoxin and propranolol. Am J Cardiol . 1984; 53:52-7B.
134. Weeks CE, Conard GJ, Kvam DC et al. The effect of flecainide acetate, a new antiarrhythmic, on plasma digoxin levels. J Clin Pharmacol . 1986; 26:27-31. [PubMed 3950050]
135. Tjandramaga TB, Verbesselt R, Van Hecken A et al. Oral flecainide elimination kinetics: effects of cimetidine. Circulation . 1983; 68(4 Part II):III-416.
136. Reviewers' comments (personal observations).
137. McQuinn RL, Weeks CE, Kvam DC et al. Pharmacokinetics of flecainide in elderly subjects. Clin Pharmacol Ther . 1986; 39:210.
138. Crozier I, Ikram H. Flecainide acetate in atrial fibrillation. N Z Med J . 1985; 98:506. [PubMed 3859778]
139. Zweber MB (Riker Laboratories, Inc; St. Paul, MN): Personal communication.
140. Kim SS, Lal R, Ruffy R. Treatment of paroxysmal reentrant supraventricular tachycardia with flecainide acetate. Am J Cardiol . 1986; 58:80-5. [PubMed 3728336]
141. Ruffy R, Sears M. Wolff-Parkinson-White syndrome. JAMA . 1985; 145:533-6.
142. Shea P, Lal R, Kim SS et al. Flecainide and amiodarone interaction. J Am Coll Cardiol . 1986; 7:1127-30. [PubMed 3958371]
143. Anderson JL. Proarrhythmic effects of antiarrhythmic drug therapy. In: Smith WM, ed. Forum on the management of arrhythmias: the role of flecainide. Auckland, New Zealand: ADIS Press Limited; 1985:41-50.
144. Riker Laboratories Australia Pty Ltd. Tambocor® tablets and injection prescribing information. Thornleigh, Australia; 1985 Oct.
145. Webb CR, Morganroth J, Senior S et al. Flecainide: steady state electrophysiologic effects in patients with remote myocardial infarction and inducible sustained ventricular arrhythmia. J Am Coll Cardiol . 1986; 8:214-20. [PubMed 3711519]
146. Roden DM, Woosley RL. Flecainide. N Engl J Med . 1986; 315:36-41. [PubMed 3520324]
147. Somberg JC, Tepper D. Flecainide: a new antiarrhythmic agent. Am Heart J . 1986; 112:808-13. [PubMed 3094352]
148. Borgeat A, Goy JJ, Maendly R et al. Flecainide versus quinidine for conversion of atrial fibrillation to sinus rhythm. Am J Cardiol . 1986; 58:496-8. [PubMed 3529911]
149. Kunze KP, Kuck KH, Schluter M et al. Effect of encainide and flecainide on chronic ectopic atrial tachycardia. J Am Coll Cardiol . 1986; 7:1121-6. [PubMed 3082957]
150. Lal R, Chapman PD, Naccarelli GV et al. Flecainide in the treatment of nonsustained ventricular tachycardia. Ann Intern Med . 1986; 105:493-8. [PubMed 3752754]
151. Morganroth J, Anderson JL, Gentzkow GD. Classification by type of ventricular arrhythmia predicts frequency of adverse cardiac events from flecainide. J Am Coll Cardiol . 1986; 8:607-15. [PubMed 3745706]
152. Nitsch J, Kohler U, Neyses L et al. Inhibition of flecainide absorption by activated charcoal. Am J Cardiol . 1987; 60:753. [PubMed 3116835]
153. Samlowski WE, Frame RN, Logue GL. Flecainide-induced immune neutropenia: documentation of a hapten-mediated mechanism of cell destruction. Arch Intern Med . 1987; 147:383-4. [PubMed 2434046]
154. de Paola AAV, Horowitz LN, Morganroth J et al. Influence of left ventricular dysfunction on flecainide therapy. J Am Coll Cardiol . 1987; 9:163-8. [PubMed 3098817]
155. Winkelmann BR, Leinberger H. Life-threatening flecainide toxicity: a pharmacodynamic approach. Ann Intern Med . 1987; 106:807-14. [PubMed 3107447]
156. Fontaine G, Frank R, Tonet JL. Association amiodarone-flécainide dans le traitement des troubles du rythme ventriculaires graves. Arch Mal Coeur . 1984; 77:1421. [PubMed 6439167]
157. Leclercq JF, Coumel P. Association amiodarone-flécainide dans le traitement des troubles du rythme ventriculaires graves. Arch Mal Coeur . 1984; 77:1421-2. [PubMed 6439167]
158. Crijns HJGM, Kingma JH, Viersma JW et al. Transient giant inverted T waves during flecainide intoxication. Am Heart J . 1987; 113:214-5. [PubMed 3099561]
159. Anastasiou-Nana MI, Anderson JL, Stewart JR et al. Occurrence of exercise-induced and spontaneous wide complex tachycardia during therapy with flecainide for complex ventricular arrhythmias, a probable proarrhythmic effect. Am Heart J . 1987; 113:1071-7. [PubMed 3107362]
160. Leclercq JF, Coumel P. La flécainide: un nouvel antiarythmique. Arch Mal Coeur . 1983; 76:1218-29. [PubMed 6418100]
161. Food and Drug Administration. Enkaid and Tambocor use in non-life-threatening arrhythmias halted. FDA Talk Paper . 1989 Apr 25.
162. Department of Health and Human Services. Background statement regarding encainide, flecainide, and moricizine. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute; 1989 Apr.
163. The Cardiac Arrhythmia Suppression Trial (CAST) investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med . 1989; 321:406-12. [PubMed 2473403]
164. Ruskin JN. The Cardiac Arrhythmia Suppression Trial (CAST). N Engl J Med . 1989; 321:386-8. [PubMed 2501683]
166. Food and Drug Administration. FDA Cardio-renal Advisory Committee will review CAST study. FDC Rep . 1989(Aug 14):3-4.
167. Greene HL, Richardson DW, Barker AH et al. Classification of deaths after myocardial infarction as arrhythmic or nonarrhythmic (the Cardiac Arrhythmia Pilot Study). Am J Cardiol . 1989; 63:1-6. [PubMed 2462341]
168. Greene HL, Richardson DW, Hallstrom AP et al. Congestive heart failure after acute myocardial infarction in patients receiving antiarrhythmic agents for ventricular premature complexes (Cardiac Arrhythmia Pilot Study). Am J Cardiol . 1989; 63:393-8. [PubMed 2464919]
169. Vlay SC. Lessons from the past and reflections on the Cardiac Arrhythmia Suppression trial. Am J Cardiol . 1990; 65:112-3. [PubMed 1688480]
170. Pratt CM, Brater DC, Harrell FE Jr et al. Clinical and regulatory implications of the Cardiac Arrhythmia Suppression Trial. Am J Cardiol . 1990; 65:103-5. [PubMed 1688479]
171. Morganroth J, Bigger JT Jr, Anderson JL. Treatment of ventricular arrhythmias by United States cardiologists: a survey before the Cardiac Arrhythmia Suppression Trial results were available. Am J Cardiol . 1990; 65:40-8. [PubMed 1688481]
172. Thomas GS. Death following withdrawal of encainide. N Engl J Med . 1989; 321:393-4. [PubMed 2501684]
173. Garratt C, Ward DE, Camm AJ. Lessons from the cardiac arrhythmia suppression trial. BMJ . 1989; 299:805-6. [PubMed 2510839]
174. Coyle JD, Schaal SF. An interim perspective on the removal of encainide and flecainide from the Cardiac Arrhythmia Suppression Trial. DICP . 1989; 23:478-9. [PubMed 2500783]
175. Anon. Drugs for cardiac arrhythmias: new warning. Med Lett Drugs Ther . 1989; 31:48. [PubMed 2497313]
176. Nightingale SL. Flecainide and encainide not to be used in non-life-threatening arrhythmias. JAMA . 1989; 261:3368. [PubMed 2498536]
177. Anon. Restrictions on use of flecainide, encainide. FDA Drug Bull . 1989; 16.
178. Eagleton G. Dear doctor letter regarding appropriate uses of Tambocor®. St. Paul, MN: 3M Riker; 1989 May.
179. Anon. Dear pharmacist letter regarding appropriate uses of Tambocor®. St. Paul, MN: 3M Riker; 1989 May.
180. The Cardiac Arrhythmia Pilot Study (CAPS) Investigators. Effects of encainide, flecainide, imipramine and moricizine on ventricular arrhythmias during the year after acute myocardial infarction: the CAPS. Am J Cardiol . 1988; 61:501-9. [PubMed 2894169]
181. Anon. Flecainide and CAST. Lancet . 1989; 2:481-2. [PubMed 2570188]
182. Reviewers' comments (personal observations); 1990 Jan.
183. Ward D, Garratt C, Camm AJ. Cardiac arrhythmia suppression trial and flecainide. Lancet . 1989; 1:1267-8. [PubMed 2566810]
184. Pratt CM, Podrid P, Greatrix B et al. Efficacy and safety of moricizine in patients with congestive heart failure: a summary of the experience in the United States. Am Heart J . 1990; 119:1-7. [PubMed 1688682]
185. Falk RH. Flecainide-induced ventricular tachycardia and fibrillation in patients treated for atrial fibrillation. Ann Intern Med . 1989; 111:107-11. [PubMed 2500880]
186. Jones K, Wood SM. Indications for flecainide. Lancet . 1989; 1:1383. [PubMed 2567388]
187. Robson RH. Indications for flecainide. Lancet . 1989; 2:113.
188. Bigger JT Jr. Indications for flecainide. Lancet . 1989; 2:113-4.
189. Ray J. Flecainide: what are we measuring? Ther Drug Monit . 1990; 12:416. Letter.
190. Echt DS, Liebson PR, Mitchell LB et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the Cardiac Arrhythmia Suppression Trial. N Engl J Med . 1991; 324:781-8. [PubMed 1900101]
191. Anon. CAST deaths revealed. Lancet . 1991; 337:969.
192. Tambocor® (flecainide acetate): its role in the treatment of supraventricular arrhythmias. St. Paul, MN: 1991.
193. Henthorn RW, Waldo AL, Anderson JL et al. Flecainide acetate prevents recurrence of symptomatic paroxysmal supraventricular tachycardia. Circulation . 1991; 83:119-25. [PubMed 1898640]
194. Anderson JL, Gilbert EM, Alpert BL et al. Prevention of symptomatic recurrences of paroxysmal atrial fibrillation in patients initially tolerating antiarrythmic therapy: a multicenter, double-blind, crossover study of flecainide and placebo with transtelephonic monitoring. Circulation . 1989; 80:1557-70. [PubMed 2513143]
195. Pritchett ELC, Wilkinson WE. Mortality in patients treated with flecainide and encainide for supraventricular arrhythmias. Am J Cardio . 1991; 67:976-80.
196. Cockrell JL, Scheinman MM, Titus C et al. Safety and efficacy of oral flecainide therapy in patients with atrioventricular re-entrant tachycardia. Ann Intern Med . 1991; 114:189-94. [PubMed 1898629]
197. Pietersen AH, Hellemann H. Usefulness of flecainide for prevention of paroxysmal atrial fibrillation and flutter. Am J Cardiol . 1991; 67:713-7. [PubMed 1900978]
198. Benditt DG, Dunnigan A, Buetikofer J et al. Flecainide acetate for long-term prevention of paroxysmal supraventricular tachyarrhythmias. Circulation . 1991; 83:345-9. [PubMed 1898643]
199. van Wijk LM, den Heijer P, Crijns HJ et al. Flecainide versus quinidine in the prevention of paroxysms of atrial fibrillation. J Cardiovasc Pharmacol . 1989; 13:32-6. [PubMed 2468933]
200. Pritchett ELC, DaTorre SD, Platt ML et al. Flecainide acetate treatment of paroxysmal supraventricular tachycardia and paroxysmal atrial fibrillation: dose-response studies. J Am Coll Cardiol . 1991; 17:297-303. [PubMed 1899432]
201. Hughes MM, Trohman RG, Simmons TW et al. Flecainide therapy in patients treated for supraventricular tachycardia with near normal left ventricular function. Am Heart J . 1992; 123:408. [PubMed 1736577]
202. Suttorp MJ, Kingma JH, Lie-A-Huen L et al. Intravenous flecainide versus verapamil for acute conversion of paroxysmal atrial fibrillation or flutter to sinus rhythm. Am J Cardiol . 1989; 63:693-6. [PubMed 2493733]
203. Berns E, Rinkenberger RL, Jeang MK et al. Efficacy and safety of flecainide acetate for atrial tachycardia or fibrillation. Am J Cardiol . 1987; 59:1337-41. [PubMed 3109229]
204. Crozier IG, Ikram H, Kenealy M et al. Flecainide acetate for conversion of acute supraventricular tachycardia to sinus rhythm. Am J Cardiol . 197; 59:607-9.
205. Goy JJ, Kaufmann U, Kappenberger L et al. Restortation [sic] of sinus rhythm with flecainide in patients with atrial fibrillation. Am J Cardiol . 1988; 62(Suppl):38-40D.
206. Anon. Flecainide for supraventricular tachyarrhythmias. Med Lett Drugs Ther . 1992; 34:71-2. [PubMed 1630411]
207. Reviewers' comments (personal observations): 1992 Nov.
208. Flaker GC, Blackshear JL, McBride R et al. Antiarrhythmic drug therapy and cardiac mortality in atrial fibrillation. J Am Coll Cardiol . 1992; 20:527-32. [PubMed 1512329]
209. Coplen SE, Antman EM, Berlin JA et al. Efficacy and safety of quinidine therapy for maintenance of sinus rhythm after cardioversion: a meta-analysis of randomized control trials. Circulation . 1990; 82:1106-16. [PubMed 2144796]
210. The United States pharmacopeia, 23rd rev, and the national formulary, 18th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1995(Suppl 1):2462-3.
211. Epstein AE, Hallstrom AP, Rogers WJ et al. mortality following ventricular arrhythmia suppression by encainide, flecainide, and moricizine after myocardial infarction: the original design concept of the Cardiac Arrhythmia Suppression Trial (CAST). JAMA . 1993; 270:2451-5. [PubMed 8230622]
212. Searle. Norpace® and Norpace® CR (disopyramide phosphate) capsules prescribing information. In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996 (Suppl A):A141.
213. Berlex. Quinaglute Dura-tabs (quinidine gluconate) tablets prescribing information (dated 1994 Dec). In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:649-651.
214. Perdue Frederick. Cardioquin® (quinidine polygalacturonate) tablets prescribing information (dated 1995 Aug). In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996 (Suppl A):A57-A59.
215. Parke-Davis. Procan®SR (procainamide hydrochloride) extended-release tablets prescribing information (dated 1994 Sep). In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:1926-8.
216. Astra Merck. Tonocard® (tocainide hydrochloride) tablets information (dated 1994 Aug). In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:531-4.
217. Boehringer Ingelheim. Mexitil® (mexiletine hydrochloride) capsules prescribing information (dated 1993 Oct). In: Physicians' desk reference. 50th ed. Montvale, NJ: Medical Economics Company Inc; 1996:678-81.
219. Lui CY, Franchina JJ. Verapamil and multifocal atrial tachycardia. Ann Intern Med . 1988; 108:485-6.
220. Scher DL, Arsura EL. Multifocal atrial tachycardia: mechanisms, clinical correlates, and treatment. Am Heart J . 1989; 118:574-80. [PubMed 2570520]
221. Arsura EL, Scher DL. Verapamil and multifocal atrial tachycardia. Ann Intern Med . 1988; 108:486. [PubMed 3341685]
222. Levine JH, Michael JR, Guarnieri T. Verapamil for multifocal atrial tachycardia. N Engl J Med. 1985; 312:1126-7. Reply.
223. Arsura E, Lefkin AS, Scher DL et al. A randomized, double-blind, placebo-controlled study of verapamil and metoprolol in treatment of multifocal atrial tachycardia. Am J Med . 1988; 85:519-24. [PubMed 3052051]
224. Alboni P, Botto GL, Baldi Net al. Outpatient treatment of recent-onset atrial fibrillation with the “pill-in-the-pocket” approach. N Engl J Med . 2004; 351:2384-91. [PubMed 15575054]
225. Gronefeld GC, Hohnloser SH. The “pill-in-the-pocket” approach to atrial fibrillation. N Engl J Med . 2005; 352:1150. [PubMed 15784671]
226. Konety SH, Olshansky B. The “pill-in-the-pocket” approach to atrial fibrillation. N Engl J Med . 2005; 352:1150. [PubMed 15789457]
227. Wittkowsky AK. The “pill-in-the-pocket” approach to atrial fibrillation. N Engl J Med . 2005; 352:1150-1. [PubMed 15789456]
228. Alboni P, Botto GI, Baldi N. The “pill-in-the-pocket” approach to atrial fibrillation. N Engl J Med . 2005; 352:1151.
229. Botto GL, Capucci A, Bonini W et al. Conversion of recent onset atrial fibrillation to sinus rhythm using a single oral loading dose of propafenone: comparison of two regimens. Int J Cardiol . 1997; 58:55-61. [PubMed 9021428]
230. Boriani G, Biffi M, Capucci A et al. Oral propafenone to convert recent-onset atrial fibrillation in patients with and without underlying heart disease. A randomized, controlled trial. Ann Intern Med . 1997; 126:621-5. [PubMed 9103129]
231. Azpitarte J, Alvarez M, Baun O et al. Value of single oral loading dose of propafenone in converting recent-onset atrial fibrillation. Results of a randomized, double-blind, controlled study. Eur Heart J . 1997; 18:1649-54. [PubMed 9347277]
232. Boriani G, Biffi M, Capucci A et al. Oral loading with propafenone: a placebo-controlled study in elderly and nonelderly patients with recent onset atrial fibrillation. Pacing Clin Electrophysiol . 1998; 21(11 Pt 2):2465-9. [PubMed 9825368]
233. Boriani G, Biffi M, Capucci A et al. Conversion of recent-onset atrial fibrillation to sinus rhythm: effects of different drug protocols. Pacing Clin Electrophysiol . 1998; 21(11 Pt 2):2470-4. [PubMed 9825369]
234. Capucci A, Villani GQ, Aschieri D et al. Safety of oral propafenone in the conversion of recent onset atrial fibrillation to sinus rhythm: a prospective parallel placebo-controlled multicentre study. Int J Cardiol . 1999; 68:187-96. [PubMed 10189007]
235. Alboni P, Tomasi C, Menozzi C et al. Efficacy and safety of out-of-hospital self-administered single-dose oral drug treatment in the management of infrequent, well-tolerated paroxysmal supraventricular tachycardia. J Am Coll Cardiol . 2001; 37:548-53. [PubMed 11216977]
236. Capucci A, Lenzi T, Boriani G et al. Effectiveness of loading oral flecainide for converting recent-onset atrial fibrillation to sinus rhythm in patients without organic heart disease or with only systemic hypertension. Am J Cardiol . 1992; 70:69-72. [PubMed 1615873]
237. Blanc JJ, Voinov C, Maarek M. Comparison of oral loading dose of propafenone and amiodarone for converting recent-onset atrial fibrillation. PARSIFAL Study Group. Am J Cardiol . 1999; 84:1029-32. [PubMed 10569658]
238. Khan IA. Single oral loading dose of propafenone for pharmacological cardioversion of recent-onset atrial fibrillation. J Am Coll Cardiol . 2001; 37:542-7. [PubMed 11216976]
239. Boriani G, Martignani C, Biffi M et al. Oral loading with propafenone for conversion of recent-onset atrial fibrillation: a review on in-hospital treatment. Drugs . 2002; 62:415-23. [PubMed 11827557]
240. Khan IA. Oral loading single dose flecainide for pharmacological cardioversion of recent-onset atrial fibrillation. Int J Cardiol . 2003; 87:121-8. [PubMed 12559528]
241. Deneer VH, Borgh MB, Kingma JH et al.Oral antiarrhythmic drugs in converting recent onset atrial fibrillation. Pharm World Sci . 2004; 26:66-78. [PubMed 15085940]
242. Reviewers' comments (personal observations).
243. Van Gelder IC, Brugemann J, Crijns HJGM. Pharmacological management of arrhythmias in the elderly. Drugs Aging . 1997; 11:96-110. [PubMed 9259173]
244. Jung F, DiMarco JP. Treatment strategies for atrial fibrillation. Am J Med . 1998; 104:272-86. [PubMed 9552091]
246. Novartis Pharmaceuticals. Clozaril® (clozapine) prescribing information. East Hanover, NJ; 2005 May.
247. Casiraghi A, Centin G, Selmin F et al. Critical Aspects in the Preparation of Extemporaneous Flecainide Acetate Oral Solution for Paediatrics. Pharmaceutics. 2021 Nov 19;13(11):1963. doi: 10.3390/pharmaceutics13111963. PMID: 34834378; PMCID: PMC8618881.
252. ASHP. Standardize 4 Safety: compounded oral liquid standards. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]
300. Page RL, Joglar JA, Caldwell MA et al. 2015 ACC/AHA/HRS Guideline for the Management of Adult Patients With Supraventricular Tachycardia: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol . 2016; 67:e27-e115.
301. January CT, Wann LS, Alpert JS et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol . 2014; 64:e1-76. [PubMed 24685669]
302. Al-Khatib SM, Stevenson WG, Ackerman MJ et al. 2017 AHA/ACC/HRS Guideline for Management of Patients With Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation . 2017; [PubMed 29084733]