12 HR propafenone hydrochloride 225 MG Extended Release Oral Capsule [Rythmol]

INDICATIONS AND USAGE Propafenone Hydrochloride Tablets are 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. Usage Considerations: • 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 Tablets, 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 ] . Propafenone Hydrochloride Tablets are an antiarrhythmic 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. ( 1 ) • prolong the time to recurrence of paroxysmal supraventricular tachycardia (PSVT) associated with disabling symptoms in patients who do not have structural heart disease. ( 1 ) • treat documented life-threatening ventricular arrhythmias. ( 1 ) Usage Considerations: • Use in patients with permanent atrial fibrillation or with atrial flutter or PSVT has not been evaluated. Do not use to control ventricular rate during atrial fibrillation. ( 1 ) • In patients with atrial fibrillation and atrial flutter, use Propafenone Hydrochloride Tablets with drugs that increase the atrioventricular nodal refractory period. ( 1 ) • Because of proarrhythmic effects, use with lesser ventricular arrhythmias is not recommended, even if patients are symptomatic. ( 1 ) • The effect of propafenone on mortality has not been determined. ( 1 )

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 Tablets with both a CYP2D6 inhibitor and a CYP3A4 inhibitor [see Warnings and Precautions ( 5.4 ), Drug Interactions ( 7.1 )] . • Initiate therapy with 150 mg given every 8 hours. ( 2 ) • As needed, uptitrate in 3 to 4 days to 225 to 300 mg every 8 hours. ( 2 ) • Consider reducing the dose in patients with hepatic impairment, significant widening of the QRS complex, or second- or third-degree AV block. ( 2 )

WARNINGS AND PRECAUTIONS May cause new or worsened arrhythmias. Evaluate patients via ECG prior to and during therapy. (5.1) Propafenone hydrochloride may unmask Brugada or Brugada-like Syndrome. (4 , 5.2) Avoid use with other drugs that prolong the QT interval. (5.3) Avoid simultaneous use of propafenone with both a cytochrome P450 2D6 (CYP2D6) inhibitor and a 3A4 inhibitor (CYP3A4). (5.4) May provoke overt heart failure. (5.5) May cause dose-related first-degree AV block or other conduction disturbances. Only use in patients with conduction disorders who have pacemakers. (5.6) May affect artificial pacemakers. Monitor pacemaker function. (5.7) Agranulocytosis: Patients should report signs of infection. (5.8) May exacerbate myasthenia gravis. (5.11) 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 be evaluated electrocardiographically prior to and during therapy to determine whether the response to propafenone hydrochloride 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 (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 proarrythmia 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 sustained-release propafenone (0.8%), and 2 in the placebo group (1.6%). In the overall database of 8 trials of sustained-release propafenone 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. 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) ] . 5.3 Use with Drugs that Prolong the QT Interval and Antiarrhythmic Agents The use of propafenone hydrochloride in conjunction with other drugs that prolong the QT interval has not been extensively studied. Such drugs may include many antiarrhythmics, some phenothiazines, tricyclic antidepressants, and oral macrolides. Withhold Class IA and III antiarrhythmic agents for at least 5 half-lives prior to dosing with propafenone hydrochloride. Avoid the use of propafenone with Class IA and III antiarrhythmic agents (including quinidine and amiodarone). There is only limited experience with the concomitant use of Class IB or IC antiarrhythmics. 5.4 Drug Interactions: Simultaneous Use with Inhibitors of Cytochrome P450 Isoenzymes 2D6 and 3A4 Propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2 isoenzymes. Approximately 6% of Caucasians in the U.S. population are naturally deficient in CYP2D6 activity and other demographic groups are deficient to a somewhat lesser extent. Drugs that inhibit these CYP pathways (such as desipramine, paroxetine, ritonavir, sertraline for CYP2D6; ketoconazole, erythromycin, saquinavir, and grapefruit juice for CYP3A4; and amiodarone and tobacco smoke for CYP1A2) can be expected to cause increased plasma levels of propafenone. Increased exposure to propafenone may lead to cardiac arrhythmias and exaggerated beta-adrenergic blocking activity. Because of its metabolism, the combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition in users of propafenone is potentially hazardous. Therefore, avoid simultaneous use of propafenone hydrochloride with both a CYP2D6 inhibitor and a CYP3A4 inhibitor. 5.5 Use in Patients with a History of Heart Failure Propafenone exerts a negative inotropic activity on the myocardium as well as beta-blockade effects and may provoke overt heart failure. In clinical trial experience with propafenone hydrochloride, new or worsened congestive heart failure (CHF) has been reported in 3.7% of subjects with ventricular arrhythmia; of those 0.9% were considered probably or definitely related to propafenone hydrochloride. Of the subjects with CHF probably related to propafenone, 80% had pre-existing heart failure and 85% had coronary artery disease. CHF attributable to propafenone hydrochloride developed rarely (less than 0.2%) in subjects with ventricular arrhythmia who had no previous history of CHF. CHF occurred in 1.9% of subjects studied with PAF or PSVT. In a U.S. trial of sustained-release propafenone in subjects with symptomatic AF, heart failure was reported in 4 (1.0%) subjects receiving sustained-release propafenone (all doses) compared with 1 (0.8%) subject receiving placebo. 5.6 Conduction Disturbances Propafenone slows atrioventricular conduction and may also cause dose-related first-degree AV block. Average PR interval prolongation and increases in QRS duration are also dose-related. Do not give propafenone to patients with atrioventricular and intraventricular conduction defects in the absence of a pacemaker [see Contraindications (4) , Clinical Pharmacology (12.2) ] . The incidence of first-degree, second-degree, and third-degree AV block observed in 2,127 subjects with ventricular arrhythmia was 2.5%, 0.6%, and 0.2%, respectively. Development of second- or third-degree AV block requires a reduction in dosage or discontinuation of propafenone hydrochloride. Bundle branch block (1.2%) and intraventricular conduction delay (1.1%) have been reported in subjects receiving propafenone. Bradycardia has also been reported (1.5%). Experience in patients with sick sinus node syndrome is limited and these patients should not be treated with propafenone. In a U.S. trial in 523 subjects with a history of symptomatic AF treated with sustained-release propafenone, sinus bradycardia (rate less than 50 beats/min) was reported with the same frequency with sustained-release propafenone and placebo. 5.7 Effec

CONTRAINDICATIONS Propafenone hydrochloride extended-release 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 • Heart failure ( 4 ) • Cardiogenic shock ( 4 ) • Sinoatrial, atrioventricular, and intraventricular disorders of impulse generation and/or conduction in the absence of pacemaker ( 4 ) • Known Brugada Syndrome ( 4 ) • Bradycardia ( 4 ) • Marked hypotension ( 4 ) • Bronchospastic disorders and severe obstructive pulmonary disease ( 4 ) • Marked electrolyte imbalance ( 4 )

Mechanism of Action Propafenone is a Class 1C antiarrhythmic drug with local anesthetic effects and a direct stabilizing action on myocardial membranes. The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and, to a lesser extent, myocardial fibers, propafenone reduces the fast-inward current carried by sodium ions. Diastolic excitability threshold is increased and effective refractory period prolonged. Propafenone reduces spontaneous automaticity and depresses triggered activity. Studies in anesthetized dogs and isolated organ preparations show that propafenone has beta-sympatholytic activity at about 1 / 50 the potency of propranolol. Clinical studies employing isoproterenol challenge and exercise testing after single doses of propafenone indicate a beta-adrenergic blocking potency (per mg) about 1 / 40 that of propranolol in man. In clinical trials with the immediate-release formulation, resting heart rate decreases of about 8% were noted at the higher end of the therapeutic plasma concentration range. At very high concentrations in vitro , propafenone can inhibit the slow inward current carried by calcium, but this calcium antagonist effect probably does not contribute to antiarrhythmic efficacy. Moreover, propafenone inhibits a variety of cardiac potassium currents in in vitro studies (i.e., the transient outward, the delayed rectifier, and the inward rectifier current). Propafenone has local anesthetic activity approximately equal to procaine. Compared with propafenone, the main metabolite, 5-hydroxypropafenone, has similar sodium and calcium channel activity, but about 10 times less beta-blocking activity (N-depropylpropafenone has weaker sodium channel activity but equivalent affinity for beta-receptors).