Propafenone Hydrochloride SR

PROPAFENONE HYDROCHLORIDE SR- propafenone hydrochloride capsule, extended release
Prasco Laboratories

WARNING: MORTALITY

In the National Heart, Lung, and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, randomized, double-blind trial in patients with asymptomatic non-life-threatening ventricular arrhythmias who had a myocardial infarction more than 6 days but less than 2 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 IC 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 trial was 10 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 IC antiarrhythmic to have a significant proarrhythmic 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.

1 INDICATIONS AND USAGE

Propafenone Hydrochloride extended-release (SR) capsules are indicated to prolong the time to recurrence of symptomatic atrial fibrillation (AF) in patients with episodic (most likely paroxysmal or persistent) AF who do not have structural heart disease.

Usage Considerations:

The use of Propafenone Hydrochloride extended-release (SR) capsules in patients with permanent AF or in patients exclusively with atrial flutter or paroxysmal supraventricular tachycardia (PSVT) has not been evaluated. Do not use Propafenone Hydrochloride extended-release (SR) capsules to control ventricular rate during AF.
Some patients with atrial flutter treated with propafenone have developed 1:1 conduction, producing an increase in ventricular rate. Concomitant treatment with drugs that increase the functional atrioventricular (AV) nodal refractory period is recommended.
The effect of propafenone on mortality has not been determined [see Boxed Warning].

2 DOSAGE AND ADMINISTRATION

Propafenone Hydrochloride extended-release (SR) capsules can be taken with or without food. Do not crush or further divide the contents of the capsule.

The dose of Propafenone Hydrochloride extended-release (SR) capsules must be individually titrated on the basis of response and tolerance. Initiate therapy with Propafenone Hydrochloride extended-release (SR) capsules 225 mg given every 12 hours. Dosage may be increased at a minimum of 5-day intervals to 325 mg given every 12 hours. If additional therapeutic effect is needed, the dose of Propafenone Hydrochloride extended-release (SR) capsules may be increased to 425 mg given every 12 hours.

In patients with hepatic impairment or those with significant widening of the QRS complex or second- or third-degree AV block, consider reducing the dose.

The combination of cytochrome P450 3A4 (CYP3A4) inhibition and either cytochrome P450 2D6 (CYP2D6) deficiency or CYP2D6 inhibition with the simultaneous administration of propafenone may significantly increase the concentration of propafenone and thereby increase the risk of proarrhythmia and other adverse events. Therefore, avoid simultaneous use of Propafenone Hydrochloride extended-release (SR) capsules with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions (5.4), Drug Interactions (7.1)].

3 DOSAGE FORMS AND STRENGTHS

Propafenone Hydrochloride extended-release (SR) capsules are supplied as white, opaque, hard gelatin capsules containing either 225 mg, 325 mg, or 425 mg of propafenone HCl. The 225-mg strength is imprinted in red with GS EUG followed by 225. The 325-mg strength is imprinted in red with GS F1Y followed by 325, and also has a single red band around ¾ of the circumference of the body. The 425-mg strength is imprinted in red with GS UY2 followed by 425, and also has 3 red bands around ¾ of the circumference of the body.

4 CONTRAINDICATIONS

Propafenone Hydrochloride extended-release (SR) capsules are contraindicated in the following circumstances:

Heart failure
Cardiogenic shock
Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation or conduction (e.g., sick sinus node syndrome, AV block) in the absence of an artificial pacemaker
Known Brugada Syndrome
Bradycardia
Marked hypotension
Bronchospastic disorders or severe obstructive pulmonary disease
Marked electrolyte imbalance

5 WARNINGS AND PRECAUTIONS

5.1 Proarrhythmic Effects

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 Hydrochloride extended-release (SR) capsules be evaluated electrocardiographically prior to and during therapy to determine whether the response to Propafenone Hydrochloride extended-release (SR) capsules supports continued treatment. Because propafenone prolongs the QRS interval in the electrocardiogram, changes in the QT interval are difficult to interpret [see Clinical Pharmacology (12.2)].

In the RYTHMOL SR Atrial Fibrillation Trial (RAFT) trial [see Clinical Studies (14)] , there were too few deaths to assess the long-term risk to patients. There were 5 deaths, 3 in the pooled group for Propafenone Hydrochloride extended-release (SR) capsules (0.8%), and 2 in the placebo group (1.6%). In the overall database of 8 trials of Propafenone Hydrochloride extended-release (SR) capsules and immediate-release propafenone hydrochloride, the mortality rate was 2.5% per year on propafenone and 4.0% per year on placebo. Concurrent use of propafenone with other antiarrhythmic agents has not been well studied.

In a U.S. uncontrolled, open-label, multicenter trial using the immediate-release formulation in patients with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these patients experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the trial. However, in 4 of the 9 patients, the ventricular tachycardia was of atrial origin. Six of the 9 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 trial which could have been a change in the patients’ arrhythmia behavior or could represent a proarrhythmic event. Case reports in patients treated with propafenone for atrial fibrillation/flutter have included increased premature ventricular contractions (PVCs), VT, VF, torsades de pointes, asystole, and death.

Overall in clinical trials with propafenone hydrochloride immediate-release (which included patients treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all patients had new or worsened ventricular arrhythmia possibly representing a proarrhythmic event (0.7% was an increase in PVCs; 4.0% a worsening or new appearance of VT or VF). Of the patients who had worsening of VT (4%), 92% had a history of VT and/or VT/VF, 71% had coronary artery disease, and 68% had a prior myocardial infarction. The incidence of proarrhythmia in patients with less serious or benign arrhythmias, which include patients with an increase in frequency of PVCs, was 1.6%. Although most proarrhythmic events occurred during the first week of therapy, late events also were seen and the CAST trial [see Boxed Warning: Mortality] suggests that an increased risk of proarrythmia is present throughout treatment.

5.2 Unmasking Brugada Syndrome

Brugada Syndrome may be unmasked after exposure to Propafenone Hydrochloride extended-release (SR) capsules. Perform an ECG after initiation of Propafenone Hydrochloride extended-release (SR) capsules and discontinue the drug if changes are suggestive of Brugada Syndrome [see Contraindications (4)].

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