Flecainide Acetate

Mortality Flecainide acetate was included in the National Heart Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, 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 acetate compared with that seen in patients assigned to a carefully matched placebo-treated group. This rate was 16/315 (5.1%) for flecainide acetate and 7/309 (2.3%) for the matched placebo. The average duration of treatment with flecainide acetate in this study was ten 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 IC agents (including flecainide acetate), 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 Pro-arrhythmic Effects in Patients with Atrial Fibrillation/Flutter A review of the world literature revealed reports of 568 patients treated with oral flecainide acetate 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 I agents, patients treated with flecainide acetate 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 acetate. Concomitant negative chronotropic therapy such as digoxin or beta-blockers may lower the risk of this complication.

WARNINGS Mortality Flecainide acetate was included in the National Heart Lung and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, 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 acetate compared with that seen in patients assigned to a carefully matched placebo-treated group. This rate was 16/315 (5.1%) for flecainide acetate and 7/309 (2.3%) for the matched placebo. The average duration of treatment with flecainide acetate in this study was ten 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 IC agents (including flecainide acetate), 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 Pro-arrhythmic Effects in Patients with Atrial Fibrillation/Flutter A review of the world literature revealed reports of 568 patients treated with oral flecainide acetate 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 I agents, patients treated with flecainide acetate 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 acetate. Concomitant negative chronotropic therapy such as digoxin or beta-blockers may lower the risk of this complication.

ADVERSE REACTIONS In post-myocardial infarction patients with asymptomatic PVCs and non-sustained 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 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 Dizziness includes reports of dizziness, lightheadedness, faintness, unsteadiness, near syncope, etc. 18.9% 11.0% 10.6% 13.0% Visual Disturbances Visual disturbance includes reports of blurred vision, difficulty in focusing, spots before eyes, etc. 15.9% 5.4% 12.3% 18.0% Dyspnea 10.3% 5.2% 7.5% 4.0% Headache 9.6% 4.5% 6.1% 9.0% Nausea 8.9% 4.9% 4.8% 6.0% Fatigue 7.7% 4.5% 4.4% 3.0% Palpitation 6.1% 3.5% 2.4% 7.0% Chest Pain 5.4% 3.1% 3.8% 1.0% Asthenia 4.9% 2.6% 2.0% 4.0% Tremor 4.7% 2.4% 3.4% 2.0% Constipation 4.4% 2.8% 2.1% 1.0% Edema 3.5% 1.9% 1.4% 2.0% Abdominal Pain 3.3% 1.9% 2.4% 1.0% 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 or arrest; Gastrointestinal: vomiting, diarrhea, dyspepsia, anorexia; Skin: rash; Visual: diplopia; Nervous System: hypoesthesia, paresthesia, paresis, ataxia, flushing, increased sweating, vertigo, syncope, somnolence, tinnitus; Psychiatric: anxiety, insomnia, depression. The following additional adverse experiences, possibly related to flecainide, have been reported in less than 1% of patients: Body as a Whole: swollen lips, tongue and mouth; arthralgia, bronchospasm, myalgia; Cardiovascular: angina pectoris, second-degree and third-degree AV block, bradycardia, hypertension, hypotension; Gastrointestinal: flatulence; Urinary System: polyuria, urinary retention; Hematologic: leukopenia, granulocytopenia, thrombocytopenia; Skin: urticaria, exfoliative dermatitis, pruritus, alopecia; Visual: eye pain or irritation, photophobia, nystagmus; Nervous System: twitching, weakness, change in taste, dry mouth, convulsions, impotence, speech disorder, stupor, neuropathy; Respiratory: pneumonitis/pulmonary infiltration possibly due to chronic flecainide treatment; Psychiatric: amnesia, confusion, decreased libido, depersonalization, euphoria, morbid dreams, apathy. For patients with supraventricular arrhythmias, the most commonly reported noncardiac adverse experiences remain consistent with those known for patients treated with flecainide for ventricular arrhythmias. Dizziness is possibly more frequent in PAF patients. To report SUSPECTED ADVERSE REACTIONS, contact Beximco Pharmaceuticals USA Inc. at 877-372-6093 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

<table width="100%"><caption>Table 1: Most Common Non-Cardiac Effects in Ventricular Arrhythmia Patients Treated with Flecainide in the Multicenter Study</caption><col width="25%"/><col width="22%"/><col width="18%"/><col width="18%"/><col width="18%"/><tbody><tr><td rowspan="2" styleCode="Botrule Lrule Rrule Toprule" valign="top"><paragraph>Adverse Effect</paragraph></td><td rowspan="2" align="center" styleCode="Botrule Rrule Toprule" valign="top"><paragraph>Incidence All 429 Patients at Any Dose</paragraph></td><td colspan="3" align="center" styleCode="Botrule Rrule Toprule" valign="top"><paragraph>Incidence by Dose During Upward Titration</paragraph></td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule" valign="top"><paragraph>200 mg/Day (N=426)</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>300 mg/Day (N=293)</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>400 mg/Day (N=100)</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Dizziness <footnote ID="_Ref406500564">Dizziness includes reports of dizziness, lightheadedness, faintness, unsteadiness, near syncope, etc.</footnote></paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>18.9%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>11.0%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>10.6%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>13.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Visual Disturbances <footnote ID="_Ref406500577">Visual disturbance includes reports of blurred vision, difficulty in focusing, spots before eyes, etc.</footnote></paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>15.9%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>5.4%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>12.3%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>18.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Dyspnea</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>10.3%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>5.2%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>7.5%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>4.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>9.6%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>4.5%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>6.1%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>9.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>8.9%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>4.9%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>4.8%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>6.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Fatigue</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>7.7%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>4.5%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>4.4%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>3.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Palpitation</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>6.1%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>3.5%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>2.4%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>7.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Chest Pain</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>5.4%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>3.1%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>3.8%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>1.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Asthenia</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>4.9%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>2.6%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>2.0%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>4.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Tremor</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>4.7%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>2.4%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>3.4%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>2.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>4.4%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>2.8%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>2.1%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>1.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Edema</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>3.5%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>1.9%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>1.4%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>2.0%</paragraph></td></tr><tr><td styleCode="Botrule Lrule Rrule" valign="top"><paragraph>Abdominal Pain</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>3.3%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>1.9%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>2.4%</paragraph></td><td align="center" styleCode="Botrule Rrule" valign="top"><paragraph>1.0%</paragraph></td></tr></tbody></table>