PROPAFENONE HCL- propafenone hydrochloride tablet, film coated
Actavis Pharma, Inc.
- In the National Heart, Lung, and Blood Institute’s Cardiac Arrhythmia Suppression Trial (CAST), a long-term, multicenter, randomized, double-blind trial in subjects 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 subjects treated with encainide or flecainide (Class IC antiarrhythmics) compared with that seen in subjects 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 is indicated to:
- prolong the time to recurrence of paroxysmal atrial fibrillation/flutter (PAF) associated with disabling symptoms in patients without structural heart disease.
- prolong the time to recurrence of paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients without structural heart disease.
- treat documented ventricular arrhythmias, such as sustained ventricular tachycardia that, in the judgment of the physician, are life-threatening. Initiate treatment in the hospital.
- The use of propafenone hydrochloride tablets in patients with permanent atrial fibrillation (AF) or in patients exclusively with atrial flutter or PSVT has not been evaluated. Do not use propafenone hydrochloride tablets 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 use of propafenone hydrochloride tablets in patients with chronic atrial fibrillation has not been evaluated.
- Because of the proarrhythmic effects of propafenone hydrochloride, its use with lesser ventricular arrhythmias is not recommended, even if patients are symptomatic, and any use of the drug should be reserved for patients in whom, in the opinion of the physician, the potential benefits outweigh the risks.
- The effect of propafenone on mortality has not been determined [see Boxed Warning].
2 DOSAGE AND ADMINISTRATION
The dose of propafenone hydrochloride tablets must be individually titrated on the basis of response and tolerance. Initiate therapy with propafenone hydrochloride tablets 150 mg given every 8 hours (450 mg per day). Dosage may be increased at a minimum of 3 to 4 day intervals to 225 mg every 8 hours (675 mg per day). If additional therapeutic effect is needed, the dose of propafenone hydrochloride tablets may be increased to 300 mg every 8 hours (900 mg per day). The usefulness and safety of dosages exceeding 900 mg per day have not been established.
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.
As with other antiarrhythmic agents, in the elderly or in ventricular arrhythmia patients with marked previous myocardial damage, the dose of propafenone hydrochloride tablets should be increased more gradually during the initial phase of treatment.
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 with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions ( 5.4) and Drug Interactions ( 7.1)].
3 DOSAGE FORMS AND STRENGTHS
150 mg and 225 mg round, scored, film-coated tablets.
Propafenone hydrochloride is 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
- 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 tablets be evaluated electrocardiographically prior to and during therapy to determine whether the response to propafenone hydrochloride tablets 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 a U.S. uncontrolled, open-label, multicenter trial in subjects with symptomatic supraventricular tachycardia (SVT), 1.9% (9/474) of these subjects experienced ventricular tachycardia (VT) or ventricular fibrillation (VF) during the trial. However, in 4 of the 9 subjects, the ventricular tachycardia was of atrial origin. Six of the 9 subjects that developed ventricular arrhythmias did so within 14 days of onset of therapy. About 2.3% (11/474) of all subjects had a recurrence of SVT during the trial which could have been a change in the subjects’ 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, torsade de pointes, asystole, and death.
Overall in clinical trials with propafenone hydrochloride tablets (which included subjects treated for ventricular arrhythmias, atrial fibrillation/flutter, and PSVT), 4.7% of all subjects 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 subjects 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 subjects with less serious or benign arrhythmias, which include subjects 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 proarrhythmia is present throughout treatment.
In a trial of sustained-release propafenone, there were too few deaths to assess the long-term risk to patients. There were 5 deaths; 3 in the pooled group for propafenone sustained-release (0.8%), and 2 in the placebo group (1.6%). In the overall database of 8 trials of sustained-release propafenone and propafenone immediate-release, 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.
5.2 Unmasking Brugada Syndrome
Brugada Syndrome may be unmasked after exposure to propafenone hydrochloride. Perform an ECG after initiation of propafenone hydrochloride, and discontinue the drug if changes are suggestive of Brugada Syndrome [see Contraindications ( 4)].
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