Propafenone Extended Release Capsule

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

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 torsades 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 capsules be evaluated electrocardiographically prior to and during therapy, to determine whether the response to propafenone hydrochloride extended-release 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 five deaths, three in the pooled propafenone hydrochloride extended-release capsules group (0.8%) and two in the placebo group (1.6%). In the overall propafenone hydrochloride extended-release capsules and propafenone hydrochloride immediate-release database of eight studies, the mortality rate was 2.5% per year on propafenone and 4% 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 four of the nine 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, 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% 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 study [see Boxed Warning: Mortality] suggests that an increased risk of proarrhythmia is present throughout treatment.

Unmasking Brugada Syndrome

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

Use with Drugs that Prolong the QT Interval and Antiarrhythmic Agents

The use of propafenone hydrochloride extended-release capsules 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 five half-lives prior to dosing with propafenone hydrochloride extended-release 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.

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 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 hydrochloride extended-release capsules with both a CYP2D6 inhibitor and a CYP3A4 inhibitor.

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 four (1%) patients receiving propafenone hydrochloride extended-release capsules (all doses), compared to one (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 hydrochloride 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.

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 hydrochloride extended-release capsules, sinus bradycardia (rate < 50 beats/min) was reported with the same frequency with propafenone hydrochloride extended-release capsules and placebo.

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.

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.

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 hydrochloride immediate-release tablets. In eight patients with moderate to severe liver disease administered propafenone hydrochloride immediate-release tablets, the mean half-life was approximately 9 hours. No studies have compared bioavailability of propafenone from propafenone hydrochloride extended-release 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)].

Use in Patients with Renal Dysfunction

Approximately 50% of propafenone metabolites are excreted in the urine following administration of propafenone hydrochloride immediate-release tablets. No studies have been performed to assess the percentage of metabolites eliminated in the urine following the administration of propafenone hydrochloride extended-release capsules.

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

Use in Patients with Myasthenia Gravis

Exacerbation of myasthenia gravis has been reported during propafenone therapy.

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.

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

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Propafenone hydrochloride extended-release capsules should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal Data

Teratogenic Effects

Propafenone has been shown to be embryotoxic (decreased survival) in rabbits and rats when given in oral maternally toxic doses of 150 mg/kg/day (about 3 times the maximum recommended human dose [MRHD] on a mg/m2 basis) and 600 mg/kg/day (about 6 times the MRHD on a mg/m2 basis), respectively. Although maternally tolerated doses (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m2 basis) produced no evidence of embryotoxicity in rats, post-implantation loss was elevated in all rabbit treatment groups (doses as low as 15 mg/kg/day, about 1/3 the MRHD on a mg/m2 basis).

Non-teratogenic Effects

In a study in which female rats received daily oral doses of propafenone from mid-gestation through weaning of their offspring, doses as low as 90 mg/kg/day (equivalent to the MRHD on a mg/m2 basis) produced increases in maternal deaths. Doses of 360 or more mg/kg/day (4 or more times the MRHD on a mg/m2 basis) resulted in reductions in neonatal survival, body weight gain and physiological development.

Labor and Delivery

It is not known whether the use of propafenone during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetrical intervention.

Nursing Mothers

Propafenone is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from propafenone, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

Geriatric Use

Of the total number of subjects in Phase 3 clinical studies of propafenone hydrochloride extended-release capsules 46% were 65 and over, while 16% were 75 and over. 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.

Propafenone hydrochloride extended-release capsules, USP are an antiarrhythmic drug supplied in extended-release capsules of 225 mg, 325 mg and 425 mg for oral administration.

Chemically, propafenone hydrochloride is 2′-[2-Hydroxy-3-(propylamino)propoxy]-3-phenylpropiophenone hydrochloride, with a molecular weight of 377.90. The molecular formula is C21H27NO3•HCl.

Propafenone hydrochloride has some structural similarities to beta-blocking agents. The structural formula of propafenone hydrochloride is given below:

Propafenone hydrochloride, USP occurs as white or almost white powder with a very bitter taste. It is slightly soluble in water (20°C), chloroform and ethanol. Propafenone hydrochloride extended-release capsules are filled with white to off-white pellets containing propafenone hydrochloride, USP and the following inactive ingredients: colloidal silicon dioxide, ethylcellulose, gelatin, hypromellose, magnesium stearate, red iron oxide, sodium lauryl sulfate and titanium dioxide. The 425 mg capsules also contain yellow iron oxide.

In addition, the imprinting ink contains ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.

Meets USP Dissolution Test 3.

Propafenone hydrochloride extended-release capsules have been evaluated in patients with a history of electrocardiographically documented recurrent episodes of symptomatic AF in two randomized, double-blind, placebo controlled trials.

RAFT: In one U.S. multicenter study (Propafenone Hydrochloride Extended-Release Capsules Atrial Fibrillation Trial, RAFT), three doses of propafenone hydrochloride extended-release 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 study 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 hydrochloride extended-release capsules administered for up to 39 weeks were 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 to placebo, as shown in Table 3.

Table 3: Analysis of Tachycardia-Free Period (Days) from Day 1 of Randomization

* 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.
	Propafenone Hydrochloride Extended-Release Capsules Dose			Placebo
Parameter	225 mg twice daily (N = 126) n (%)	325 mg twice daily (N = 135) n (%)	425 mg twice daily (N = 136) n (%)	(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 to 285	0 to 293	0 to 300	0 to 289
p-Value (Log-rank test)	0.014	< 0.0001	< 0.0001	--
Hazard Ratio compared to placebo	0.67	0.43	0.35	--
95% CI for Hazard Ratio	(0.49, 0.93)	(0.31, 0.61)	(0.24, 0.51)	--

There was a dose response for propafenone hydrochloride extended-release 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 hydrochloride extended-release capsules (225 mg twice daily, 325 mg twice daily, and 425 mg twice daily) were 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 hydrochloride extended-release capsules 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 hydrochloride extended-release 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 hydrochloride extended-release capsules.

No difference in the average heart rate during the first recurrence of symptomatic arrhythmia between propafenone hydrochloride extended-release capsules and placebo was observed.

ERAFT: In a European multicenter trial [(European Propafenone Hydrochloride Extended-Release Capsules Atrial Fibrillation Trial (ERAFT)], two doses of propafenone hydrochloride extended-release 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 one 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 hydrochloride extended-release capsules were 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 propafenone hydrochloride extended-release capsules doses were superior to placebo. The antiarrhythmic effect of propafenone extended-release 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 hydrochloride extended-release capsules. There was a slight increase in the incidence of centrally diagnosed asymptomatic AF or atrial flutter in each of the two propafenone hydrochloride extended-release capsules treatment groups compared to placebo.

See FDA-approved patient labeling (Patient Information).

Information for Patients

• Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription and supplement use. The health care provider should assess the patients’ medication history including all over-the-counter, prescription and herbal/natural preparations for those that may affect the pharmacodynamics or kinetics of propafenone hydrochloride extended-release capsules [see Warnings and Precautions (5.4)]. • Patients should also check with their health care providers prior to taking a new over-the-counter medicine. • If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, vomiting, or loss of appetite or thirst, these conditions should be immediately reported to their health care provider. • Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time.