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Side Effects & Adverse Reactions
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 increased rate of death or reversed cardiac arrest rate (7.7%; 56/730) was seen in patients treated with encainide or flecainide (Class 1C antiarrhythmics) compared with that seen in patients assigned to placebo (3.0%; 22/725). The average duration of treatment with encainide or flecainide in this study was ten months.
The applicability of the CAST results to other populations (e.g., those without recent myocardial infarction) or other antiarrhythmic drugs is uncertain, but at present, it is prudent to consider any 1C antiarrhythmic to have a significant risk in patients with structural heart disease. Given the lack of any evidence that these drugs improve survival, antiarrhythmic agents should generally be avoided in patients with non-life-threatening ventricular arrhythmias, even if the patients are experiencing unpleasant, but not life-threatening, symptoms or signs.
Propafenone has caused new or worsened arrhythmias. Such proarrhythmic effects include sudden death and life-threatening ventricular arrhythmias such as ventricular fibrillation, ventricular tachycardia, asystole and Torsade de Pointes. It may also worsen premature ventricular contractions or supraventricular arrhythmias, and it may prolong the QT interval. It is therefore essential that each patient given propafenone ER capsules be evaluated electrocardiographically prior to and during therapy, to determine whether the response to propafenone ER capsules supports continued treatment. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret.
In a 474 patient U.S. uncontrolled, open label multicenter trial using the immediate release formulation in patients with symptomatic SVT, 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the study. However, in four of the nine patients, the ventricular tachycardia was of atrial origin. Six of the nine patients that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all patients had recurrence of SVT during the study which could have been a change in the patients’ arrhythmia behavior or could represent a proarrhythmic event. Case reports in patients treated with propafenone HCl for atrial fibrillation/flutter have included increased PVCs, VT, VF, Torsade de Pointes, asystole, and death.
In the RAFT study, there were five deaths, three in the pooled propafenone ER capsules group (0.8%) and two in the placebo group (1.6%). In the overall propafenone ER capsules and propafenone HCl immediate release database of eight studies, the mortality rate was 2.5% per year on propafenone HCl and 4% per year on placebo. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.
The use of propafenone ER capsules (propafenone hydrochloride) in conjunction with other drugs that prolong the QT interval has not been extensively studied and is not recommended. Such drugs may include many antiarrhythmics, some phenothiazines, cisapride, bepridil, tricyclic antidepressants and oral macrolides. Class Ia and III antiarrhythmic agents should be withheld for at least five half-lives prior to dosing with propafenone ER capsules. The use of propafenone with Class Ia and III antiarrhythmic agents (including quinidine and amiodarone) is not recommended. There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics.
Patients with bronchospastic disease should not, in general, receive propafenone or other agents with beta-adrenergic-blocking activity.
Propafenone exerts a negative inotropic activity on the myocardium as well as beta-blockade effects and may provoke overt congestive heart failure. In the U.S. trial (RAFT) in patients with symptomatic atrial fibrillation, congestive heart failure was reported in four (1%) patients receiving propafenone ER capsules (all doses), compared to one (0.8%) patient receiving placebo. Proarrhythmic effects are more likely to occur when propafenone is administered to patients with congestive heart failure (NYHA III and IV) or severe myocardial ischemia (see CONTRAINDICATIONS).
Propafenone causes dose-related first degree AV block. Average PR interval prolongation and increases in QRS duration are also dose-related.
Propafenone should not be given to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker (see CONTRAINDICATIONS).
In a U.S. trial (RAFT) in 523 patients with a history of symptomatic atrial fibrillation treated with propafenone ER capsules, electrocardiograms obtained in response to symptoms were associated with no patients having sinus rhythm with Mobitz Type I (Wenckenbach) second degree AV block, sinus rhythm with Mobitz Type II second degree AV block, or third degree AV block. Sinus bradycardia (rate <50 beats/min) was reported with the same frequency with propafenone ER capsules and placebo.
Propafenone may alter both pacing and sensing thresholds of artificial pacemakers. Pacemakers should be monitored and programmed accordingly during therapy.
Agranulocytosis (fever, chills, weakness, and neutropenia) has been reported in patients receiving propafenone. Generally, the agranulocytosis occurred within the first two months of propafenone therapy and upon discontinuation of therapy, the white count usually normalized by 14 days. Unexplained fever and/or decrease in white cell count, particularly during the initial three months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia. Patients should be instructed to report promptly the development of any signs of infection such as fever, sore throat, or chills.
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FDA Safety Alerts
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FDA Labeling Changes
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Propafenone Extended Release Capsules are indicated to prolong the time to recurrence of symptomatic atrial fibrillation in patients without structural heart disease.
The use of propafenone ER capsules in patients with permanent atrial fibrillation or in patients exclusively with atrial flutter or PSVT has not been evaluated. Propafenone ER capsules should not be used to control ventricular rate during atrial fibrillation.
The effect of propafenone ER capsules on mortality has not been determined (see black box WARNINGS).
There is currently no drug history available for this drug.
Propafenone hydrochloride is an antiarrhythmic drug supplied in extended-release capsules of 225 mg, 325 mg and 425 mg for oral administration.
The structural formula of propafenone HCl is given below:
Propafenone HCl has some structural similarities to beta-blocking agents. Propafenone HCl occurs as colorless crystals or white crystalline powder with a very bitter taste. It is slightly soluble in water (20ºC), chloroform and ethanol. Propafenone extended release are capsules filled with granules containing the following inactive ingredients: ethylcellulose, lactose anhydrous, magnesium stearate and povidone. The capsules consist of D&C Red #28, FD&C Blue #1, FD&C Red #40, FD&C Yellow #5, FD&C Yellow #6, gelatin and titanium dioxide. In addition the ink consists of D&C Yellow #10 aluminum lake, iron oxide black, n-butyl alcohol, propylene glycol, FD&C Blue #2 aluminum lake, FD&C Red #40 aluminum lake, FD&C Blue #1 aluminum lake and shellac glaze~45% (20% esterfied) in ethanol.