Flecainide Acetate 100 mg Tablet, 100-count — NDC 53746-642-01 (Billing 53746-0642-01)

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 exer… [Excerpted — this section continues on DailyMed.]

ADVERSE REACTIONS In post-myocardial infarction patients with asymptomatic PVCs and nonsustained ventricular tachycardia, flecainide therapy was found to be associated with a 5.1% rate of death and non-fatal cardiac arrest, compared with a 2.3% rate in a matched placebo group (see WARNINGS ). Adverse effects reported for flecainide, described in detail in the WARNINGS section, were new or worsened arrhythmias which occurred in 1% of 108 patients with PSVT and in 7% of 117 patients with PAF; and new or exacerbated ventricular arrhythmias which occurred in 7% of 1330 patients with PVCs, non-sustained or sustained VT.

In patients treated with flecainide for sustained VT, 80% (51/64) of proarrhythmic events occurred within 14 days of the onset of therapy. 198 patients with sustained VT experienced a 13% incidence of new or exacerbated ventricular arrhythmias when dosage was initiated at 200 mg/day with slow upward titration, and did not exceed 300 mg/day in most patients. In some patients, flecainide treatment has been associated with episodes of unresuscitatable VT or ventricular fibrillation (cardiac arrest) (see WARNINGS ).

New or worsened CHF occurred in 6.3% of 1046 patients with PVCs, non-sustained or sustained VT. Of 297 patients with sustained VT, 9.1% experienced new or worsened CHF. New or worsened CHF was reported in 0.4% of 225 patients with supraventricular arrhythmias.

There have also been instances of second- (0.5%) or third-degree (0.4%) AV block. Patients have developed sinus bradycardia, sinus pause, or sinus arrest, about 1.2% altogether (see WARNINGS ). The frequency of most of these serious adverse events probably increases with higher trough plasma levels, especially when these trough levels exceed 1 mcg/mL.

There have been rare reports of isolated elevations of serum alkaline phosphatase and isolated elevations of serum transaminase levels. These elevations have been asymptomatic and no cause and effect relationship with flecainide has been established. In foreign postmarketing surveillance studies, there have been rare reports of hepatic dysfunction including reports of cholestasis and hepatic failure, and extremely rare reports of blood dyscrasias.

Although no cause and effect relationship has been established, it is advisable to discontinue flecainide in patients who develop unexplained jaundice or signs of hepatic dysfunction or blood dyscrasias in order to eliminate flecainide as the possible causative agent. Incidence figures for other adverse effects in patients with ventricular arrhythmias are based on a multicenter efficacy study, utilizing starting doses of 200 mg/day with gradual upward titration to 400 mg/day. Patients were treated for an average of 4.7 months, with some receiving up to 22 months of therapy.

In this trial, 5.4% of patients discontinued due to non-cardiac adverse effects. Table 1 Most Common Non-Cardiac Adverse Effects in Ventricular Arrhythmia Patients Treated with Flecainide in the Multicenter Study Adverse Effect Incidence All 429 Patients at Any Dose Incidence by Dose During Upward Titration 200 mg/Day (N=426) 300 mg/Day (N=293) 400 mg/Day (N=100) Dizziness * 18.9% 11% 10.6% 13% Visual Disturbances † 15.9% 5.4% 12.3% 18% Dyspnea 10.3% 5.2% 7.5% 4% Headache 9.6% 4.5% 6.1% 9% Nausea 8.9% 4.9% 4.8% 6% Fatigue 7.7% 4.5% 4.4% 3% Palpitation 6.1% 3.5% 2.4% 7% Chest Pain 5.4% 3.1% 3.8% 1% Asthenia 4.9% 2.6% 2% 4% Tremor 4.7% 2.4% 3.4% 2% Constipation 4.4% 2.8% 2.1% 1% Edema 3.5% 1.9% 1.4% 2% Abdominal Pain 3.3% 1.9% 2.4% 1% * Dizziness includes reports of dizziness, lightheadedness, faintness, unsteadiness, near syncope, etc. † Visual disturbance includes reports of blurred vision, difficulty in focusing, spots before eyes, etc.

The following additional adverse experiences, possibly related to flecainide therapy and occurring in 1% to less than 3% of patients, have been reported in acute and chronic studies: Body as a Whole - malaise, fever; Cardiovascular - tachycardia, sinus pause… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS Drug Interactions Flecainide has been administered to patients receiving digitalis preparations or beta-adrenergic blocking agents without adverse effects. During administration of multiple oral doses of flecainide to healthy subjects stabilized on a maintenance dose of digoxin , a 13% to 19% increase in plasma digoxin levels occurred at six hours postdose. In a study involving healthy subjects receiving flecainide and propranolol concurrently, plasma flecainide levels were increased about 20% and propranolol levels were increased about 30% compared to control values.

In this formal interaction study, flecainide and propranolol were each found to have negative inotropic effects; when the drugs were administered together, the effects were additive. The effects of concomitant administration of flecainide and propranolol on the PR interval were less than additive. In flecainide clinical trials, patients who were receiving beta blockers concurrently did not experience an increased incidence of side effects.

Nevertheless, the possibility of additive negative inotropic effects of beta blockers and flecainide should be recognized. Flecainide is not extensively bound to plasma proteins. In vitro studies with several drugs which may be administered concomitantly showed that the extent of flecainide binding to human plasma proteins is either unchanged or only slightly less.

Consequently, interactions with other drugs which are highly protein bound (e.g., anticoagulants ) would not be expected. Flecainide has been used in a large number of patients receiving diuretics without apparent interaction. Limited data in patients receiving known enzyme inducers ( phenytoin, phenobarbital, carbamazepine ) indicate only a 30% increase in the rate of flecainide elimination.

In healthy subjects receiving cimetidine (1 gm daily) for one week, plasma flecainide levels increased by about 30% and half-life increased by about 10%. When amiodarone is added to flecainide therapy, plasma flecainide levels may increase two-fold or more in some patients, if flecainide dosage is not reduced (see DOSAGE AND ADMINISTRATION ). Drugs that inhibit cytochrome P450IID6, such as quinidine , might increase the plasma concentrations of flecainide in patients that are on chronic flecainide therapy; especially if these patients are extensive metabolizers.

There has been little experience with the co-administration of flecainide and either disopyramide or verapamil . Because both of these drugs have negative inotropic properties and the effects of co-administration with flecainide are unknown, neither disopyramide nor verapamil should be administered concurrently with flecainide unless, in the judgment of the physician, the benefits of this combination outweigh the risks. There has been too little experience with the co-administration of flecainide with nifedipine or diltiazem to recommend concomitant use.

Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies with flecainide in rats and mice at doses up to 60 mg/kg/day have not revealed any compound-related carcinogenic effects. Mutagenicity studies (Ames test, mouse lymphoma and in vivo cytogenetics) did not reveal any mutagenic effects. A rat reproduction study at doses up to 50 mg/kg/day (seven times the usual human dose) did not reveal any adverse effect on male or female fertility.

Pregnancy Pregnancy Category C. Flecainide has been shown to have teratogenic effects (club paws, sternebrae and vertebrae abnormalities, pale hearts with contracted ventricular septum) and an embryo-toxic effect (increased resorptions) in one breed of rabbit (New Zealand White) when given doses of 30 and 35 mg/kg/day, but not in another breed of rabbit (Dutch Belted) when given doses up to 30 mg/kg/day. No teratogenic effects were observed in rats and mice given doses up to 50 and 80 mg/kg/day, respectively; however, delayed sternebral and vertebral ossification was observed at the high dose in rats.

Because th… [Excerpted — this section continues on DailyMed.]