propafenone HCl 225 MG 12HR Extended Release Oral Capsule

Generic Name: PROPAFENONE HYDROCHLORIDE
Brand Name: Propafenone Hydrochloride
  • Substance Name(s):
  • PROPAFENONE HYDROCHLORIDE

DRUG INTERACTIONS

7 Inhibitors of CYP2D6, 1A2, and 3A4 may increase propafenone levels which may lead to cardiac arrhythmias.

Simultaneous use with both a CYP3A4 and CYP2D6 inhibitor (or in patients with CYP2D6 deficiency) should be avoided.

( 7.1 ) • Propafenone may increase warfarin or digoxin levels.

( 7.2 , 7.3 ) • Concomitant use of lidocaine may increase central nervous system side effects.

( 7.3 ) • Orlistat may reduce propafenone concentrations.

Abrupt cessation of orlistat in patients stable on propafenone has resulted in convulsions, atrioventricular block, and circulatory failure.

( 7.4 ) • Concomitant use of lidocaine may increase central nervous system side effects.

( 7.6 ) 7.1 CYP2D6 and CYP3A4 Inhibitors Drugs that inhibit CYP2D6 (such as desipramine, paroxetine, ritonavir, sertraline) and CYP3A4 (such as ketoconazole, ritonavir, saquinavir, erythromycin, and grapefruit juice) can be expected to cause increased plasma levels of propafenone.

The combination of CYP3A4 inhibition and either CYP2D6 deficiency or CYP2D6 inhibition with administration of propafenone may increase the risk of adverse reactions, including proarrhythmia.

Therefore, simultaneous use of propafenone ER capsules with both a CYP2D6 inhibitor and a CYP3A4 inhibitor should be avoided [see WARNINGS and PRECAUTIONS ( 5.4 ), DOSAGE AND ADMINISTRATION ( 2 )].

Amiodarone Concomitant administration of propafenone and amiodarone can affect conduction and repolarization and is not recommended.

Cimetidine Concomitant administration of propafenone immediate release tablets and cimetidine in 12 healthy subjects resulted in a 20% increase in steady state plasma concentrations of propafenone.

Fluoxetine Concomitant administration of propafenone and fluoxetine in extensive metabolizers increased the S-propafenone C max and AUC by 39% and 50%, respectively, and the R-propafenone C max and AUC by 71% and 50%, respectively.

Quinidine Small doses of quinidine completely inhibit the CYP2D6 hydroxylation metabolic pathway, making all patients, in effect, slow metabolizers [see CLINICAL PHARMACOLOGY ( 12 .

3 )].

Concomitant administration of quinidine (50 mg 3 times daily) with 150-mg immediate release propafenone 3 times daily decreased the clearance of propafenone by 60% in extensive metabolizers, making them poor metabolizers.

Steady-state plasma concentrations increased by more than 2-fold for propafenone, and decreased 50% for 5-OH-propafenone.

A 100-mg dose of quinidine increased steady-state concentrations of propafenone 3-fold.

Avoid concomitant use of propafenone and quinidine.

Rifampin Concomitant administration of rifampin and propafenone in extensive metabolizers decreased the plasma concentrations of propafenone by 67% with a corresponding decrease of 5-OH-propafenone by 65%.

The concentrations of norpropafenone increased by 30%.

In poor metabolizers, there was a 50% decrease in propafenone plasma concentrations and an increase in the AUC and C max of norpropafenone by 74% and 20%, respectively.

Urinary excretion of propafenone and its metabolites decreased significantly.

Similar results were noted in elderly patients: Both the AUC and C max of propafenone decreased by 84%, with a corresponding decrease in AUC and C max of 5-OH-propafenone by 69% and 57%, respectively.

7.2 Digoxin Concomitant use of propafenone and digoxin increased steady-state serum digoxin exposure (AUC) in patients by 60% to 270%, and decreased the clearance of digoxin by 31% to 67%.

Monitor plasma digoxin levels of patients receiving propafenone and adjust digoxin dosage as needed.

7.3 Warfarin The concomitant administration of propafenone and warfarin increased warfarin plasma concentrations at steady state by 39% in healthy volunteers and prolonged the prothrombin time (PT) in patients taking warfarin.

Adjust the warfarin dose as needed by monitoring INR (international normalized ratio).

7.4 Orlistat Orlistat may limit the fraction of propafenone available for absorption.

In postmarketing reports, abrupt cessation of orlistat in patients stabilized on propafenone has resulted in severe adverse events including convulsions, atrioventricular block, and acute circulatory failure.

7.5 Beta-Antagonists Concomitant use of propafenone and propranolol in healthy subjects increased propranolol plasma concentrations at steady state by 113%.

In 4 patients, administration of metoprolol with propafenone increased the metoprolol plasma concentrations at steady state by 100% to 400%.

The pharmacokinetics of propafenone was not affected by the coadministration of either propranolol or metoprolol.

In clinical trials using propafenone immediate release tablets, patients who were receiving beta-blockers concurrently did not experience an increased incidence of side effects.

7.6 Lidocaine No significant effects on the pharmacokinetics of propafenone or lidocaine have been seen following their concomitant use in patients.

However, concomitant use of propafenone and lidocaine has been reported to increase the risks of central nervous system side effects of lidocaine.

OVERDOSAGE

10 The symptoms of overdosage may include hypotension, somnolence, bradycardia, intra-atrial and intra-ventricular conduction disturbances, and rarely, convulsions and high-grade ventricular arrhythmias.

Defibrillation, as well as infusion of dopamine and isoproterenol, has been effective in controlling abnormal rhythm and blood pressure.

Convulsions have been alleviated with intravenous diazepam.

General supportive measures such as mechanical respiratory assistance and external cardiac massage may be necessary.

The hemodialysis of propafenone in patients with an overdose is expected to be of limited value in the removal of propafenone as a result of both its high protein binding (greater than 95%) and large volume of distribution.

DESCRIPTION

11 Propafenone Hydrochloride Extended Release Capsule, USP is an antiarrhythmic drug supplied in extended-release capsules of 225mg, 325mg and 425 mg for oral administration.

Chemically, propafenone hydrochloride is 2’-[2-hydroxy-3-(propylamino)-propoxy]-3‑phenylpropiophenone hydrochloride, with a molecular weight of 377.92.

The molecular formula is C 21 H 27 NO 3 •HCl.

Propafenone HCl has some structural similarities to beta-blocking agents.

The structural formula of propafenone HCl is given below: 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 ER capsules are filled with granules containing the following inactive ingredients: ethylcellulose, lactose anhydrous, magnesium stearate and povidone.

Each capsule contains titanium dioxide and gelatin.

In addition the 325 mg capsule also contains FD&C Blue No.

1, D&C Yellow No.

10 and FD&C Red No.

40 and the 425 mg capsule contains FD&C Blue No.

1, FD&C Red No.

40 and FD&C Yellow No.

6.

The black ink consists of D&C Yellow No.10, iron oxide black, n-butyl alcohol, propylene glycol, FD&C Blue No.

2, FD&C Red No.

40, FD&C Blue No.

1 and shellac glaze~45% (20% esterfied) in ethanol.

Structure

CLINICAL STUDIES

14 Propafenone ER capsules have been evaluated in patients with a history of electrocardiographically documented recurrent episodes of symptomatic AF in 2 randomized, double-blind, placebo-controlled trials.

RAFT In one U.S.

multicenter trial (RAFT), 3 doses of propafenone ER capsules (225 mg twice daily, 325 mg twice daily and 425 mg twice daily) and placebo were compared in 523 patients with symptomatic, episodic AF.

The patient population in this trial was 59% male with a mean age of 63 years; 91% white and 6% black.

The patients had a median history of AF of 13 months and documented symptomatic AF within 12 months of trial entry.

Over 90% were NYHA Class I, and 21% had a prior electrical cardioversion.

At baseline, 24% were treated with calcium channel blockers, 37% with beta-blockers, and 38% with digoxin.

Symptomatic arrhythmias after randomization were documented by transtelephonic electrocardiogram and centrally read and adjudicated by a blinded adverse event committee.

Propafenone ER capsules administered for up to 39 weeks was shown to prolong significantly the time to the first recurrence of symptomatic atrial arrhythmia, predominantly AF, from Day 1 of randomization (primary efficacy variable) compared with placebo, as shown in Table 3.

Table 3: Analysis of Tachycardia-Free Period (Days) from Day 1 of Randomization Parameter Dose of Propafenone HCl ER Capsules 225 mg Twice Daily (N = 126) n(%) 325 mg Twice Daily (N = 135) n(%) 425 mg Twice Daily (N = 136) n(%) Placebo (N=126) n(%) Patients completing with terminating event* 66(52) 56(41) 41(30) 87(69) Comparison of tachycardia-free periods Kaplan-Meier Media 112 291 NA† 41 Range 0-285 0-293 0-300 0-289 p-Value (Log-rank test) 0.014 <0.0001 <0.0001 — Hazard Ratio compared with placebo 0.67 0.43 0.35 — 95% CI for Hazard Ratio (0.49, 0.93) (0.31, 0.61) (0.24, 0.51) — * Terminating events comprised 91% AF, 5% atrial flutter, and 4% PSVT.

† Not Applicable: Fewer than 50% of the patients had events.

The median time is not calculable.

There was a dose response for propafenone ER capsules for the tachycardia-free period as shown in the proportional hazard analysis and the Kaplan-Meier curves presented in Figure 1.

Figure 1: RAFT Kaplan-Meier Analysis for the Tachycardia-free period from Day 1 of Randomization: In additional analyses, propafenone ER capsules (225 mg twice daily, 325 mg twice daily, and 425 mg twice daily) was also shown to prolong time to the first recurrence of symptomatic AF from Day 5 (steady-state pharmacokinetics were attained).

The antiarrhythmic effect of propafenone HCl extended release was not influenced by age, gender, history of cardioversion, duration of AF, frequency of AF, or use of medication that lowers heart rate.

Similarly, the antiarrhythmic effect of propafenone ER capsules was not influenced by the individual use of calcium channel blockers, beta‑blockers, or digoxin.

Too few non-white patients were enrolled to assess the influence of race on effects of propafenone ER capsules.

No difference in the average heart rate during the first recurrence of symptomatic arrhythmia between proprafenone ER capsules and placebo was observed.

ERAFT In a European multicenter trial (European Rythmonorm SR Atrial Fibrillation Trial [ERAFT]), 2 doses of propafenone ER capsules (325 mg twice daily and 425 mg twice daily) and placebo were compared in 293 patients with documented electrocardiographic evidence of symptomatic paroxysmal AF.

The patient population in this trial was 61% male, 100% white with a mean age of 61 years.

Patients had a median duration of AF of 3.3 years, and 61% were taking medications that lowered heart rate.

At baseline, 15% of the patients were treated with calcium channel blockers (verapamil and diltiazem), 42% with beta-blockers, and 8% with digoxin.

During a qualifying period of up to 28 days, patients had to have 1 ECG-documented incident of symptomatic AF.

The double-blind treatment phase consisted of a 4-day loading period followed by a 91-day efficacy period.

Symptomatic arrhythmias were documented by electrocardiogram monitoring.

In ERAFT, propafenone ER capsules was shown to prolong the time to the first recurrence of symptomatic atrial arrhythmia from Day 5 of randomization (primary efficacy analysis).

The proportional hazard analysis revealed that both doses of propafenone ER capsules were superior to placebo.

The antiarrhythmic effect of propafenone ER was not influenced by age, gender, duration of AF, frequency of AF, or use of medication that lowers heart rate.

It was also not influenced by the individual use of calcium channel blockers, beta-blockers or digoxin.

Too few non-white patients were enrolled to assess the influence of race on the effects of propafenone ER capsules.

There was a slight increase in the incidence of centrally diagnosed asymptomatic AF or atrial flutter in each of the 2 treatment groups receiving Propafenone ER capsules compared with placebo.

figure 1

HOW SUPPLIED

16 /STORAGE AND HANDLING Propafenone Hydrochloride Extended Release Capsules, USP, 225 mg are available as hard gelatin capsules containing 225 mg of propafenone HCl.

The capsule is a white opaque cap printed “par/209” in black ink and white opaque body printed “par/209” in black ink.

NDC 49884-113-02 Bottles of 60 capsules NDC 49884-113-09 Bottles of 90 capsules NDC 49884-113-01 Bottles of 100 capsules NDC 49884-113-05 Bottles of 500 capsules NDC 49884-113-10 Bottles of 1000 capsules Propafenone Hydrochloride Extended Release Capsules, USP, 325 mg are available as hard gelatin capsules containing 325 mg of propafenone HCl.

The capsule is an orange opaque cap printed “par/210” in black ink and white opaque body printed “par/210” in black ink.

NDC 49884-210-02 Bottles of 60 capsules NDC 49884-210-09 Bottles of 90 capsules NDC 49884-210-01 Bottles of 100 capsules NDC 49884-210-05 Bottles of 500 capsules NDC 49884-210-10 Bottles of 1000 capsules Propafenone Hydrochloride Extended Release Capsules, USP, 425 mg are available as hard gelatin capsules containing 425 mg of propafenone HCl.

The capsule is a red opaque cap printed “par/211” in black ink and white opaque body printed “par/211” in black ink.

NDC 49884-211-02 Bottles of 60 capsules NDC 49884-211-09 Bottles of 90 capsules NDC 49884-211-01 Bottles of 100 capsules NDC 49884-211-05 Bottles of 500 capsules NDC 49884-211-10 Bottles of 1000 capsules Storage: Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Dispense in a tight container as defined in the USP.

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects in Phase 3 clinical trials of propafenone ER capsules (propafenone hydrochloride) 46% were 65 and older, while 16% were 75 and older.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity of some older individuals at higher doses cannot be ruled out.

The effect of age on the pharmacokinetics and pharmacodynamics of propafenone has not been studied.

DOSAGE FORMS AND STRENGTHS

3 The 225 mg capsule is a white opaque cap and a white opaque body, imprinted with “par/209” on the cap and “par/209” on the body.

The 325 mg capsule is a orange opaque cap and a white opaque body, imprinted with “par/210” on the cap and “par/210” on the body.

The 425 mg capsule is a red opaque cap and a white opaque body, imprinted with “par/211” on the cap and “par/211” on the body.

Capsules: 225 mg, 325 mg, 425 mg.

( 3 )

MECHANISM OF ACTION

12.1 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).

INDICATIONS AND USAGE

1 Propafenone HCl Extended Release Capsules, USP 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 ER 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 ER 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 ].

Propafenone HCl Extended Release Capsules, USP is 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 ) Usage Considerations: • Use in patients with permanent atrial fibrillation or with atrial flutter or paroxysmal supraventricular tachycardia (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 ER capsules with drugs that increase the atrioventricular nodal refractory period.

( 1 ) • The effect of propafenone on mortality has not been determined.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of propafenone in pediatric patients have not been established.

PREGNANCY

8.1 Pregnancy R isk Summary In the absence of studies in pregnant women, available data from published case reports and several decades of postmarketing experience with use of propafenone in pregnancy have not identified any drug-associated risks of miscarriage, birth defects, or adverse maternal or fetal outcomes.

Untreated arrhythmias during pregnancy may pose a risk to the pregnant woman and fetus (see Clinical Considerations).

Propafenone and its metabolite, 5-OH-propafenone, cross the placenta in humans.

In animal studies, propafenone was not teratogenic.

At maternally toxic doses (ranging from 2 to 6 times the maximum recommended human dose [MRHD]), there was evidence of adverse developmental outcomes when administered to pregnant rabbits and rats during organogenesis or when administered to pregnant rats during mid-gestation through weaning of their offspring (see Data) .

The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

C linical Considerations Disease-associated maternal and/or embryo/fetal risk: The incidence of VT is increased and may be more symptomatic during pregnancy.

Ventricular arrhythmias most often occur in pregnant women with underlying cardiomyopathy, congenital heart disease, valvular heart disease, or mitral valve prolapse.

Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state.

Fetal/Neonatal Adverse Reactions: Propafenone and its metabolite have been shown to cross the placenta.

Adverse reactions such as fetal/neonatal arrhythmias have been associated with the use of other antiarrhythmic agents by pregnant women.

Fetal/neonatal monitoring for signs and symptoms of arrhythmia is recommended during and after treatment of pregnant women with propafenone.

L abor or Delivery: Risk of arrhythmias may increase during labor and delivery.

Patients treated with propafenone should be monitored continuously for arrhythmias during labor and delivery [ see WARNING AND PRECAUTIONS ( 5.1 )] .

Data Propafenone has been shown to cause embryo-fetal mortality in rabbits and rats when given orally during organogenesis at maternally toxic doses of 150 mg/kg/day (rabbit: maternal mortality, decreased body weight gain and food consumption at approximately 3 times the MRHD on a mg/m2 basis) and 600 mg/kg/day (rat: maternal decreased body weight gain and food consumption at approximately 6 times the MRHD on a mg/m2 basis).

In addition, a maternally toxic dose of 600 mg/kg/day (approximately 6 times the MRHD on a mg/m2 basis) also caused decreased fetal weights in rats.

Increased placental weights and delayed ossification occurred in rabbits at a dose of 30 mg/kg/day (less than the MRHD on a mg/m2 basis) in the absence of maternal toxicity.

No adverse developmental outcomes in the absence of maternal toxicity were seen following oral doses of 15 mg/kg/day to rabbits or up to 270 mg/kg/day to rats administered during organogenesis (equivalent to 0.3 times or approximately 3 times the MRHD on a mg/m2 basis, respectively).

In an oral study, female rats received propafenone up to 500 mg/kg/day from mid-gestation through weaning.

At 90 mg/kg/day (equivalent to the MRHD on a mg/m2 basis), there were no adverse developmental outcomes in the absence of maternal toxicity.

However, doses ≥180 mg/kg/day (2 or more times the MRHD on a mg/m2 basis) produced increases in maternal deaths and resulted in reductions in neonatal survival, body weight gain, and delayed development in the presence of maternal toxicity.

BOXED WARNING

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.

WARNING: MORTALITY See full prescribing information for complete boxed warning.

• An increased rate of death or reversed cardiac arrest rate was seen in patients treated with encainide or flecainide (Class IC antiarrhythmics) compared with that seen in patients assigned to placebo.

At present, it is prudent to consider any IC antiarrhythmic to have a significant risk of provoking proarrhythmic events 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.

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 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.

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 propafenone ER capsules 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 ER capsules (0.8%), and 2 in the placebo group (1.6%).

In the overall database of 8 trials propafenone ER capsules and immediate release propafenone, 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, 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 trial [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 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 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 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 with 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 congestive heart failure has been reported in 3.7% of patients with ventricular arrhythmia.

These events were more likely in subjects with pre-existing heart failure and coronary artery disease.

New onset of heart failure attributable to propafenone developed in less than 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 ), 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 less than 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 with 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 trials 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 trials 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 erythematosus (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.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION A dvise the patient to read the FDA-approved patient labeling (Patient Information).

Instruct patients to notify their healthcare providers of any change in over-the-counter, prescription, and supplement use.

Instruct patients to report symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, vomiting, or loss of appetite or thirst.

Instruct patients not to double the next dose if a dose is missed.

The next dose should be taken at the usual time.

DOSAGE AND ADMINISTRATION

2 Propafenone HCl Extended Release Capsules, USP can be taken with or without food.

Do not crush or further divide the contents of the capsule.

The dose of propafenone ER capsules must be individually titrated on the basis of response and tolerance.

Initiate therapy with propafenone ER 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 ER 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 ER capsules with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.

[SEE WARNINGS AND PRECAUTIONS ( 5.4 ), DRUG INTERACTIONS ( 7.1 )].

• Initiate therapy with 225 mg given every 12 hours.

( 2 ) • Dosage may be increased at a minimum of 5-day intervals to 325 mg every 12 hours and, if necessary, to 425 mg every 12 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 )