WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • May cause new or worsened arrhythmias.

Evaluate patients via ECG prior to and during therapy.

( 5.1) • Propafenone HCl Extended Release may unmask Brugada or Brugada-like Syndrome.

Evaluate patients via ECG after initiation of therapy.

(4, 5.2).

• Avoid use with other antiarrhythmic agents or other drugs that prolong the QT interval.

( 5.3) • Avoid simultaneous use of propafenone with both a cytochrome P450 2D6 inhibitor and a 3A4 inhibitor.

( 5.2) • May provoke overt heart failure.

( 5.5) • May cause dose-related first degree AV block or other conduction disturbances.

Should not be given to patients with conduction defects in absence of a pacemaker.

( 5.6) • May affect artificial pacemakers.

Pacemakers should be monitored during therapy.

( 5.7) • Agranulocytosis: Patients should report signs of infection.

( 5.8) • Administer cautiously to patients with impaired hepatic and renal function.

( 5.9, 5.10) • Exacerbation of myasthenia gravis has been reported.

( 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 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 [see CLINICAL PHARMACOLOGY (12.2)].

In the RAFT study [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 propafenone ER capsules group (0.8%) and 2 in the placebo group (1.6%).

In the overall propafenone ER capsules and propafenone immediate release database of 8 studies, 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 study.

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 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 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 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 pro-arrhythmia 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 study [see BOXED WARNING: MORTALITY] suggests that an increased risk of proarrhythmia is present throughout treatment.

5.2 Unmasking Brugada Syndrome Brugada Syndrome may be unmasked after exposure to propafenone ER capsules.

Perform an ECG after initiation of propafenone 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 ER capsules (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 ER capsules.

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 U se 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 to a somewhat lesser extent in other demographic groups.

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 ER capsules 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 the U.S.

trial (RAFT) in patients with symptomatic AF, heart failure was reported in 4 (1.0%) patients receiving propafenone ER capsules (all doses), compared to 1 (0.8%) patient receiving placebo.

Proarrhythmic effects more likely occur when propafenone is administered to patients with heart failure (NYHA III and IV) or severe myocardial ischemia [see CONTRAINDICATIONS (4)].

In clinical trial experience with propafenone immediate release, new or worsened heart failure has been reported in 3.7% of patients with ventricular arrhythmia.

These events were more likely in subjects with preexisting heart failure and coronary artery disease.

New onset of heart failure attributable to propafenone developed in <0.2% of patients with ventricular arrhythmia and in 1.9% of patients with paroxysmal AF or PSVT.

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) and CLINICAL PHARMACOLOGY (12.2)].

In a U.S.

trial (RAFT) in 523 patients with a history of symptomatic AF treated with propafenone ER capsules, sinus bradycardia (rate <50 beats/min) was reported with the same frequency with propafenone ER capsules and placebo.

5.7 Effects on Pacemaker Threshold Propafenone may alter both pacing and sensing thresholds of implanted pacemakers and defibrillators.

During and after therapy, monitor and re-program these devices accordingly.

5.8 Agranulocytosis Agranulocytosis has been reported in patients receiving propafenone.

Generally, the agranulocytosis occurred within the first 2 months of propafenone therapy and upon discontinuation of therapy, the white count usually normalized by 14 days.

Unexplained fever or decrease in white cell count, particularly during the initial 3 months of therapy, warrant consideration of possible agranulocytosis or granulocytopenia.

Instruct patients to report promptly any signs of infection such as fever, sore throat, or chills.

5.9 Use in Patients with Hepatic Dysfunction Propafenone is highly metabolized by the liver.

Severe liver dysfunction increases the bioavailability of propafenone to approximately 70% compared to 3 to 40% in patients with normal liver function when given propafenone immediate release tablets.

In 8 patients with moderate to severe liver disease administered propafenone immediate release tablets, the mean half-life was approximately 9 hours.

No studies have compared bioavailability of propafenone from propafenone ER capsules in patients with normal and impaired hepatic function.

Increased bioavailability of propafenone in these patients may result in excessive accumulation.

Carefully monitor patients with impaired hepatic function for excessive pharmacological effects [see OVERDOSAGE (10)] 5.10 Use in Patients with Renal Dysfunction Approximately 50% of propafenone metabolites are excreted in the urine following administration of propafenone immediate release tablets.

No studies have been performed to assess the percentage of metabolites eliminated in the urine following the administration of propafenone ER capsules.

In patients with impaired renal function, monitor for signs of overdosage [ see OVERDOSAGE(10)].

5.11 Use in Patients with Myasthenia Gravis Exacerbation of myasthenia gravis has been reported during propafenone therapy.

5.12 Elevated ANA Titers Positive ANA titers have been reported in patients receiving propafenone.

They have been reversible upon cessation of treatment and may disappear even in the face of continued propafenone therapy.

These laboratory findings were usually not associated with clinical symptoms, but there is one published case of drug-induced lupus erythematosis (positive rechallenge); it resolved completely upon discontinuation of therapy.

Carefully evaluate patients who develop an abnormal ANA test and if persistent or worsening elevation of ANA titers is detected, consider discontinuing therapy.

Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs and rabbits after high dose intravenous administration of propafenone.

Evaluation of the effects of short-term propafenone HCl administration on spermatogenesis in 11 normal subjects suggested that propafenone HCl produced a reversible, short-term drop (within normal range) in sperm count.

5.13 Impaired Spermatogenesis Reversible disorders of spermatogenesis have been demonstrated in monkeys, dogs and rabbits after high dose intravenous administration of propafenone.

Evaluation of the effects of short-term propafenone HCl administration on spermatogenesis in 11 normal subjects suggested that propafenone HCl produced a reversible, short-term drop (within normal range) in sperm count.