Flecainide Acetate 50 MG Oral Tablet

Details

Generic Name: FLECAINIDE ACETATE

Brand Name: Flecainide Acetate

Substance Name(s):
FLECAINIDE ACETATE

WARNINGS

Mortality. Flecainide was included in the National Heart Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multi center, randomized, double-blind study in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than six days, but less than two years previously. An excessive mortality or non-fatal cardiac arrest rate was seen in patients treated with flecainide compared with that seen in a carefully matched placebo-treated group. This rate was 16/315 (5.1%) for flecainide and 7/309 (2.3%) for the matched placebo. The average duration of treatment with flecainide in this study was 10 months. The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) is uncertain, but at present it is prudent to consider the risks of Class 1C agents (including flecainide), coupled with the lack of any evidence of improved survival, generally unacceptable in patients without life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs. Ventricular Proarrhythmic Effects in Patients with Atrial Fibrillation/Flutter. A review of the world literature revealed reports of 568 patients treated with oral flecainide for paroxysmal atrial fibrillation/flutter (PAF). Ventricular tachycardia was experienced in 0.4% (2/568) of these patients. Of 19 patients in the literature with chronic atrial fibrillation (CAF), 10.5% (2) experienced VT or VF. FLECAINIDE IS NOT RECOMMENDED FOR USE IN PATIENTS WITH CHRONIC ATRIAL FIBRILLATION. Case reports of ventricular proarrhythmic effects in patients treated with flecainide for atrial fibrillation/flutter have included increased PVCs, VT, ventricular fibrillation (VF), and death. As with other Class 1 agents, patients treated with flecainide for atrial flutter have been reported with 1:1 atrioventricular conduction due to slowing the atrial rate. A paradoxical increase in the ventricular rate also may occur in patients with atrial fibrillation who receive flecainide. Concomitant negative chronotropic therapy such as digoxin or beta-blockers may lower the risk of this complication. PROARRHYTHMIC EFFECTS Flecainide, like other antiarrhythmic agents, can cause new or worsened supraventricular or ventricular arrhythmias. Ventricular proarrhythmic effects range from an increase in frequency of PVCs to the development of more severe ventricular tachycardia, e.g., tachycardia that is more sustained or more resistant to conversion to sinus rhythm, with potentially fatal consequences. In studies of ventricular arrhythmia patients treated with flecainide, three-fourths of proarrhythmic events were new or worsened ventricular tachyarrhythmias, the remainder being increased frequency of PVCs or new supraventricular arrhythmias. In patients treated with flecainide for sustained ventricular tachycardia, 80% (51/64) of proarrhythmic events occurred within 14 days of the onset of therapy. In studies of 225 patients with supraventricular arrhythmia (108 with paroxysmal supraventricular tachycardia and 117 with paroxysmal atrial fibrillation), there were 9 (4%) proarrhythmic events, 8 of them in patients with paroxysmal atrial fibrillation. Of the 9, 7 (including the one in a PSVT patient) were exacerbations of supraventricular arrhythmias (longer duration, more rapid rate, harder to reverse) while 2 were ventricular arrhythmias, including one fatal case of VT/VF and one wide complex VT (the patient showed inducible VT, however, after withdrawal of flecainide), both in patients with paroxysmal atrial fibrillation and known coronary artery disease. It is uncertain if flecainide’s risk of proarrhythmia is exaggerated in patients with chronic atrial fibrillation (CAF), high ventricular rate and/or exercise. Wide complex tachycardia and ventricular fibrillation have been reported in two of 12 CAF patients undergoing maximal exercise tolerance testing. In patients with complex ventricular arrhythmias, it is often difficult to distinguish a spontaneous variation in the patient’s underlying rhythm disorder from drug-induced worsening, so that the following occurrence rates must be considered approximations. Their frequency appears to be related to dose and to the underlying cardiac disease. Among patients treated for sustained VT (who frequently also had CHF, a low ejection fraction, a history of myocardial infarction and/or an episode of cardiac arrest), the incidence of proarrhythmic events was 13% when dosage was initiated at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most patients. In early studies in patients with sustained VT utilizing a higher initial dose (400 mg/day) the incidence of proarrhythmic events was 26%; moreover, in about 10% of the patients treated proarrhythmic events resulted in death, despite prompt medical attention. With lower initial doses, the incidence of proarrhythmic events resulting in death decreased to 0.5% of these patients. Accordingly, it is extremely important to follow the recommended dosage schedule. (See DOSAGE AND ADMINISTRATION.) The relatively high frequency of proarrhythmic events in patients with sustained VT and serious underlying heart disease, and the need for careful titration and monitoring, requires that therapy of patients with sustained VT be started in the hospital. (See DOSAGE AND ADMINISTRATION.) HEART FAILURE Flecainide has a negative inotropic effect and may cause or worsen CHF, particularly in patients with cardiomyopathy, preexisting severe heart failure (NYHA functional class III or IV) or low ejection fractions (less than 30%). In patients with supraventricular arrhythmias new or worsened CHF developed in 0.4% (1/225) of patients. In patients with sustained ventricular tachycardia, during a mean duration of 7.9 months of flecainide therapy, 6.3% (20/317) developed new CHF. In patients with sustained ventricular tachycardia and a history of CHF, during a mean duration of 5.4 months of flecainide therapy, 25.7% (78/304) developed worsened CHF. Exacerbation of preexisting CHF occurred more commonly in studies which included patients with class III or IV failure than in studies which excluded such patients. Flecainide should be used cautiously in patients who are known to have a history of CHF or myocardial dysfunction. The initial dosage in such patients should be no more than 100 mg bid (see DOSAGE AND ADMINISTRATION) and patients should be monitored carefully. Close attention must be given to maintenance of cardiac function, including optimization of digitalis, diuretic, or other therapy. In cases where CHF has developed or worsened during treatment with flecainide, the time of onset has ranged from a few hours to several months after starting therapy. Some patients who develop evidence of reduced myocardial function while on flecainide can continue on flecainide with adjustment of digitalis or diuretics, others may require dosage reduction or discontinuation of flecainide. When feasible, it is recommended that plasma flecainide levels be monitored. Attempts should be made to keep trough plasma levels below 0.7 to 1 mcg/mL. Effects on Cardiac Conduction Flecainide slows cardiac conduction in most patients to produce dose-related increases in PR, QRS, and QT intervals. PR interval increases on average about 25% (0.04 seconds) and as much as 118% in some patients. Approximately one-third of patients may develop new first-degree AV heart block (PR interval 0.20 seconds). The QRS complex increases on average about 25% (0.02 seconds) and as much as 150% in some patients. Many patients develop QRS complexes with a duration of 0.12 seconds or more. In one study, 4% of patients developed new bundle branch block while on flecainide. The degree of lengthening of PR and QRS intervals does not predict either efficacy or the development of cardiac adverse effects. In clinical trials, it was unusual for PR intervals to increase to 0.30 seconds or more, or for QRS intervals to increase to 0.18 seconds or more. Thus, caution should be used when such intervals occur, and dose reductions may be considered. The QT interval widens about 8%, but most of this widening (about 60% to 90%) is due to widening of the QRS duration. The JT interval (QT minus QRS) only widens about 4% on the average. Significant JT prolongation occurs in less than 2% of patients. There have been rare cases of Torsade de Pointes-type arrhythmia associated with flecainide therapy. Clinically significant conduction changes have been observed at these rates: sinus node dysfunction such as sinus pause, sinus arrest and symptomatic bradycardia (1.2%), second degree AV block (0.5%) and third-degree AV block (0.4%). An attempt should be made to manage the patient on the lowest effective dose in an effort to minimize these effects. (See DOSAGE AND ADMINISTRATION .) If second- or third-degree AV block, or right bundle branch block associated with a left hemiblock occur, flecainide therapy should be discontinued unless a temporary or implanted ventricular pacemaker is in place to ensure an adequate ventricular rate. Sick Sinus Syndrome (Bradycardia-Tachycardia Syndrome) Flecainide should be used only with extreme caution in patients with sick sinus syndrome because it may cause sinus bradycardia, sinus pause, or sinus arrest. Effects on Pacemaker Thresholds Flecainide is known to increase endocardial pacing thresholds and may suppress ventricular escape rhythms. These effects are reversible if flecainide is discontinued. It should be used with caution in patients with permanent pacemakers or temporary pacing electrodes and should not be administered to patients with existing poor thresholds or nonprogrammable pacemakers unless suitable pacing rescue is available. The pacing threshold in patients with pacemakers should be determined prior to instituting therapy with flecainide, again after one week of administration and at regular intervals thereafter. Generally, threshold changes are within the range of multiprogrammable pacemakers and, when these occur, a doubling of either voltage or pulse width is usually sufficient to regain capture. Electrolyte Disturbances Hypokalemia or hyperkalemia may alter the effects of Class I antiarrhythmic drugs. Preexisting hypokalemia or hyperkalemia should be corrected before administration of flecainide. Pediatric Use The safety and efficacy of flecainide in the fetus, infant, or child have not been established in double-blind, randomized, placebo-controlled trials. The proarrhythmic effects of flecainide as described previously, apply also to children. In pediatric patients with structural heart disease, flecainide has been associated with cardiac arrest and sudden death. Flecainide should be started in the hospital with rhythm monitoring. Any use of flecainide in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children.

OVERDOSAGE

No specific antidote has been identified for the treatment of flecainide overdosage. Overdoses ranging up to 8000 mg have been survived, with peak plasma flecainide concentrations as high as 5.3 mcg/mL. Untoward effects in these cases included nausea and vomiting, convulsions, hypotension, bradycardia, syncope, extreme widening of the QRS complex, widening of the QT interval, widening of the PR interval, ventricular tachycardia, AV nodal block, asystole, bundle branch block, cardiac failure and cardiac arrest. The spectrum of events observed in fatal cases was much the same as that seen in the non-fatal cases. Death has resulted following ingestion of as little as 1000 mg; concomitant overdose of other drugs and/or alcohol in many instances undoubtedly contributed to the fatal outcome. Treatment of overdosage should be supportive and may include the following: removal of unabsorbed drug from the gastrointestinal tract, administration of inotropic agents or cardiac stimulants such as dopamine, dobutamine or isoproterenol; mechanically assisted respiration; circulatory assists such as intra-aortic balloon pumping; and transvenous pacing in the event of conduction block. Because of the long plasma half-life of flecainide (12 to 27 hours in patients receiving usual doses), and the possibility of markedly non-linear elimination kinetics at very high doses, these supportive treatments may need to be continued for extended periods of time. Hemodialysis is not an effective means of removing flecainide from the body. Since flecainide elimination is much slower when urine is very alkaline (pH 8 or higher), theoretically, acidification of urine to promote drug excretion may be beneficial in overdose cases with very alkaline urine. There is no evidence that acidification from normal urinary pH increases excretion.

DESCRIPTION

Flecainide acetate, USP is an antiarrhythmic drug available in tablets of 50, 100, or 150 mg for oral administration. Flecainide acetate, USP is benzamide, N-(2-piperidinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)-, monoacetate. The structural formula is given below. Molecular formula: C 17H 20F 6N 2O 3•C 2H 4O 2 Molecular weight: 474.40 Flecainide acetate, USP is a white crystalline substance with a pK a of 9.3. It has an aqueous solubility of 48.4 mg/mL at 37°C. Flecainide acetate tablets, USP also contain the following inactive ingredients: croscarmellose sodium, microcrystalline cellulose and magnesium stearate. Flecainide Acetate Structural Formula

HOW SUPPLIED

Flecainide acetate tablets, USP are available as follows: 50 mg White, round tablets debossed with “AN” above “641” on one side and plain on other side. Unit dose packages of 30 (5 x 6) NDC 60687-225-25 100 mg White, round tablets debossed with “AN” above “642” with a single-line bisect separating them on one side and plain on other side. Unit dose packages of 30 (5 x 6) NDC 68084-540-25 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. FOR YOUR PROTECTION: Do not use if blister is torn or broken. PACKAGING INFORMATION American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Amneal Pharmaceuticals as follows: (50 mg / 30 UD) NDC 60687-225-25 packaged from NDC 65162-641 (100 mg / 30 UD) NDC 68084-540-25 packaged from NDC 65162-642 Distributed by: American Health Packaging Columbus, OH 43217 8254021/0616OS

INDICATIONS AND USAGE

In patients without structural heart disease, flecainide is indicated for the prevention of paroxysmal supraventricular tachycardias (PSVT), including atrioventricular nodal reentrant tachycardia, atrioventricular reentrant tachycardia and other supraventricular tachycardias of unspecified mechanism associated with disabling symptoms paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms. Flecainide is also indicated for the prevention of documented ventricular arrhythmias, such as sustained ventricular tachycardia ( sustained VT), that in the judgment of the physician, are life-threatening. Use of flecainide for the treatment of sustained VT, like other antiarrhythmics, should be initiated in the hospital. The use of flecainide is not recommended in patients with less severe ventricular arrhythmias even if the patients are symptomatic. Because of the proarrhythmic effects of flecainide, its use should be reserved for patients in whom, in the opinion of the physician, the benefits of treatment outweigh the risks. Flecainide should not be used in patients with recent myocardial infarction. (See Boxed WARNINGS .) Use of flecainide in chronic atrial fibrillation has not been adequately studied and is not recommended. (See Boxed WARNINGS .) As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of flecainide favorably affects survival or the incidence of sudden death.

BOXED WARNING

DOSAGE AND ADMINISTRATION

For patients with sustained VT, no matter what their cardiac status, flecainide, like other antiarrhythmics, should be initiated in hospital with rhythm monitoring. Flecainide has a long half-life (12 to 27 hours in patients). Steady-state plasma levels, in patients with normal renal and hepatic function, may not be achieved until the patient has received 3 to 5 days of therapy at a given dose. Therefore, increases in dosage should be made no more frequently than once every four days, since during the first 2 to 3 days of therapy the optimal effect of a given dose may not be achieved. For patients with PSVT and patients with PAF the recommended starting dose is 50 mg every 12 hours. Flecainide acetate, USP doses may be increased in increments of 50 mg bid every four days until efficacy is achieved. For PAF patients, a substantial increase in efficacy without a substantial increase in discontinuations for adverse experiences may be achieved by increasing the flecainide acetate, USP dose from 50 to 100 mg bid. The maximum recommended dose for patients with paroxysmal supraventricular arrhythmias is 300 mg/day. For sustained VT the recommended starting dose is 100 mg every 12 hours. This dose may be increased in increments of 50 mg bid every four days until efficacy is achieved. Most patients with sustained VT do not require more than 150 mg every 12 hours (300 mg/day), and the maximum dose recommended is 400 mg/day. In patients with sustained VT, use of higher initial doses and more rapid dosage adjustments have resulted in an increased incidence of proarrhythmic events and CHF, particularly during the first few days of dosing (see WARNINGS ). Therefore, a loading dose is not recommended. Intravenous lidocaine has been used occasionally with flecainide while awaiting the therapeutic effect of flecainide. No adverse drug interactions were apparent. However, no formal studies have been performed to demonstrate the usefulness of this regimen. An occasional patient not adequately controlled by (or intolerant to) a dose given at 12-hour intervals may be dosed at eight-hour intervals. Once adequate control of the arrhythmia has been achieved, it may be possible in some patients to reduce the dose as necessary to minimize side effects or effects on conduction. In such patients, efficacy at the lower dose should be evaluated. Flecainide should be used cautiously in patients with a history of CHF or myocardial dysfunction (see WARNINGS ). Any use of flecainide in children should be directly supervised by a cardiologist skilled in the treatment of arrhythmias in children. Because of the evolving nature of information in this area, specialized literature should be consulted. Under six months of age, the initial starting dose of flecainide acetate, USP in children is approximately 50 mg/M 2 body surface area daily, divided into two or three equally spaced doses. Over six months of age, the initial starting dose may be increased to 100 mg/M 2 per day. The maximum recommended dose is 200 mg/M 2 per day. This dose should not be exceeded. In some children on higher doses, despite previously low plasma levels, the level has increased rapidly to far above therapeutic values while taking the same dose. Small changes in dose may also lead to disproportionate increases in plasma levels. Plasma trough (less than one hour pre-dose) flecainide levels and electrocardiograms should be obtained at presumed steady state (after at least five doses) either after initiation or change in flecainide dose, whether the dose was increased for lack of effectiveness, or increased growth of the patient. For the first year on therapy, whenever the patient is seen for reasons of clinical follow-up, it is suggested that a 12-lead electrocardiogram and plasma trough flecainide level are obtained. The usual therapeutic level of flecainide in children is 200 to 500 ng/mL. In some cases, levels as high as 800 ng/mL may be required for control. In patients with severe renal impairment (creatinine clearance of 35 mL/min/1.73 square meters or less), the initial dosage should be 100 mg once daily (or 50 mg bid); when used in such patients, frequent plasma level monitoring is required to guide dosage adjustments (see Plasma Level Monitoring ). In patients with less severe renal disease, the initial dosage should be 100 mg every 12 hours; plasma level monitoring may also be useful in these patients during dosage adjustment. In both groups of patients, dosage increases should be made very cautiously when plasma levels have plateaued (after more than four days), observing the patient closely for signs of adverse cardiac effects or other toxicity. It should be borne in mind that in these patients it may take longer than four days before a new steady-state plasma level is reached following a dosage change. Based on theoretical considerations, rather than experimental data, the following suggestion is made: when transferring patients from another antiarrhythmic drug to flecainide allow at least two to four plasma half-lives to elapse for the drug being discontinued before starting flecainide at the usual dosage. In patients where withdrawal of a previous antiarrhythmic agent is likely to produce life-threatening arrhythmias, the physician should consider hospitalizing the patient. When flecainide is given in the presence of amiodarone, reduce the usual flecainide dose by 50% and monitor the patient closely for adverse effects. Plasma level monitoring is strongly recommended to guide dosage with such combination therapy (see below). Plasma Level Monitoring The large majority of patients successfully treated with flecainide were found to have trough plasma levels between 0.2 and 1 mcg/mL. The probability of adverse experiences, especially cardiac, may increase with higher trough plasma levels, especially when these exceed 1 mcg/mL. Periodic monitoring of trough plasma levels may be useful in patient management. Plasma level monitoring is required in patients with severe renal failure or severe hepatic disease, since elimination of flecainide from plasma may be markedly slower. Monitoring of plasma levels is strongly recommended in patients on concurrent amiodarone therapy and may also be helpful in patients with CHF and in patients with moderate renal disease.