propafenone hydrochloride 325 mg Capsule, Extended Release, 60-count — NDC 16714-826-01 (Billing 16714-0826-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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 to 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).

12.2Pharmacodynamics Cardiac Electrophysiology Electrophysiology trials in patients with ventricular tachycardia have shown that propafenone prolongs atrioventricular conduction while having little or no effect on sinus node function. Both atrioventricular nodal conduction time (AH interval) and His-Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged.

In patients with Wolff-Parkinson-White syndrome, propafenone hydrochloride immediate-release tablets reduce conduction and increase the effective refractory period of the accessory pathway in both directions. Electrocardiograms : Propafenone prolongs the PR and QRS intervals. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval.

Table 1. Mean Change ± SD in 12-Lead Electrocardiogram Results (RAFT) Propafenone Hydrochloride Extended-Release Capsules Twice-Daily Dosing Placebo 225 mg 325 mg 425 mg N=126 N=135 N=136 N=126 PR (ms) 9±22 12±23 21±24 1±16 QRS (ms) 4±14 6±15 6±15 -2±12 Heart rate 5±24 7±23 2±22 8±27 QTc* (ms) 2±30 5±36 6±37 5±35 *Calculated using Bazett’s correction factor In RAFT [see Clinical Studies ( 14 )] , the distribution of the maximum changes in QTc compared to baseline over the study in each patient was similar in the propafenone hydrochloride extended-release capsules 225 mg twice daily, 325 mg twice daily, and 425 mg twice daily and placebo dose groups.

Similar results were seen in the ERAFT trial. Table 2. Number of Patients According to the Range of Maximum QTc change compared to baseline over the Trial in each dose group (RAFT Trial).

Range maximum QTc change Propafenone Hydrochloride Extended-release Capsules Placebo 225 mg Twice Daily 325 mg Twice Daily 425 mg Twice Daily N=119 N=129 N=123 N=100 n (%) n (%) n (%) n (%) >20% 1 (1) 6 (5) 3 (2) 5 (4) 10-20% 19 (16) 28 (22) 32 (26) 24 (20) 0≤10% 99 (83) 95 (74) 88 (72) 91 (76) Hemodynamics Trials in humans have shown that propafenone exerts a negative inotropi… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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 to 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).

12.3Pharmacokinetics Absorption/Bioavailability Maximal plasma levels of propafenone are reached between 3 to 8 hours following the administration of propafenone hydrochloride extended-release capsules. Propafenone is known to undergo extensive and saturable presystemic biotransformation which results in a dose and dosage form dependent absolute bioavailability; e.g., a 150 mg immediate-release tablet had an absolute bioavailability of 3.4%, while a 300 mg immediate-release tablet had an absolute bioavailability of 10.6%.

Absorption from a 300 mg solution dose was rapid, with an absolute bioavailability of 21.4%. At still larger doses, above those recommended, bioavailability of propafenone from immediate-release tablets increased still further. Relative bioavailability assessments have been performed between propafenone hydrochloride extended-release capsules and propafenone hydrochloride immediate-release tablets.

In extensive metabolizers, the bioavailability of propafenone from the SR formulation was less than that of the immediate-release formulation as the more gradual release of propafenone from the prolonged-release preparations resulted in an increase of overall first pass metabolism [see Metabolism] . As a result of the increased first pass effect, higher daily doses of propafenone were required from the extended-release formulation relative to the immediate-release formulation, to obtain similar exposure to propafenone.

The relative bioavailability of propafenone from the 325 mg twice daily regimens of propafenone hydrochloride extended-release capsules approximates that of propafenone hydrochloride immediate-release 150 mg 3 times daily regimen. Mean exposure to 5-hydroxypropafenone was about 20 to 25% higher after extended-release capsule administration than after immediate-release tablet administration. Food increased the exposure to propafenone 4-fold after single dose administration of 425 mg of propafenone hydrochloride extended-release capsules.

However, in the multiple dose Trial (425 mg dose twice daily), the difference between the fed and fasted state was not significant. Distribution Following intravenous administration of propafenone, plasma levels decline in a bi-phasic manner consistent with a 2 compartment pharmacokinetic model. The average distribution half-life corresponding to the first phase was about 5 minutes.

The volume of the central compartment was about 88 liters (1.1 L/kg) and the total volume of distribution about 252 liters. In serum, propafenone is greater than 95% bound to proteins within the concentration range of 0.5 to 2 mcg/mL. Metabolism There are two genetically determined patterns of propafenone metabolism.

In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life from 2 to 10 hours. These patients metabolize propafenone into two active metabolites: 5-hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone (norpropafenone) which is formed by both CYP3A4 and CYP1A2. In less than 10% of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed.

In these patients, the estimated propafenone elimination half-life ranges from 10 to 32 hours. Decreased ability to form the 5-hydroxy metabolite of propafenone is associated with a diminished ability to metabolize debrisoquine and a variety of other drugs such as encainide, metoprolol, and dextromethorphan whose metabolism is mediated by the CYP2D6 isozyme. In these patients, the N-depropylpropafenone metabolite occurs in quantities comparable to the levels occurring in extensive metabolizers.

As a consequence of the observed differences in metabolism, administration of propafenone hydrochloride extended-release capsules to slow and extensive metabolizers results in significant differences in plasma concentrations of propafenone, with slow metabolizers achieving concentrations about twice those of the extensive metabolizers… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology Electrophysiology trials in patients with ventricular tachycardia have shown that propafenone prolongs atrioventricular conduction while having little or no effect on sinus node function. Both atrioventricular nodal conduction time (AH interval) and His-Purkinje conduction time (HV interval) are prolonged. Propafenone has little or no effect on the atrial functional refractory period, but AV nodal functional and effective refractory periods are prolonged.

In patients with Wolff-Parkinson-White syndrome, propafenone hydrochloride immediate-release tablets reduce conduction and increase the effective refractory period of the accessory pathway in both directions. Electrocardiograms : Propafenone prolongs the PR and QRS intervals. Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval.

Table 1. Mean Change ± SD in 12-Lead Electrocardiogram Results (RAFT) Propafenone Hydrochloride Extended-Release Capsules Twice-Daily Dosing Placebo 225 mg 325 mg 425 mg N=126 N=135 N=136 N=126 PR (ms) 9±22 12±23 21±24 1±16 QRS (ms) 4±14 6±15 6±15 -2±12 Heart rate 5±24 7±23 2±22 8±27 QTc* (ms) 2±30 5±36 6±37 5±35 *Calculated using Bazett’s correction factor In RAFT [see Clinical Studies ( 14 )] , the distribution of the maximum changes in QTc compared to baseline over the study in each patient was similar in the propafenone hydrochloride extended-release capsules 225 mg twice daily, 325 mg twice daily, and 425 mg twice daily and placebo dose groups.

Similar results were seen in the ERAFT trial. Table 2. Number of Patients According to the Range of Maximum QTc change compared to baseline over the Trial in each dose group (RAFT Trial).

Range maximum QTc change Propafenone Hydrochloride Extended-release Capsules Placebo 225 mg Twice Daily 325 mg Twice Daily 425 mg Twice Daily N=119 N=129 N=123 N=100 n (%) n (%) n (%) n (%) >20% 1 (1) 6 (5) 3 (2) 5 (4) 10-20% 19 (16) 28 (22) 32 (26) 24 (20) 0≤10% 99 (83) 95 (74) 88 (72) 91 (76) Hemodynamics Trials in humans have shown that propafenone exerts a negative inotropic effect on the myocardium. Cardiac catheterization trials in patients with moderately impaired ventricular function (mean C.I.=2.61 L/min/m 2 ), utilizing intravenous propafenone infusions (loading dose of 2 mg/kg over 10 min+ followed by 2 mg/min for 30 min) that gave mean plasma concentrations of 3 mcg/mL (a dose that produces plasma levels of propafenone greater than recommended oral dosing), showed significant increases in pulmonary capillary wedge pressure, systemic and pulmonary vascular resistances and depression of cardiac output and cardiac index.

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to propafenone hydrochloride extended-release capsules 225 mg twice daily in 126 patients, to propafenone hydrochloride extended-release capsules 325 mg twice daily in 135 patients, to propafenone hydrochloride extended-release capsules 425 mg twice daily in 136 patients, and to placebo in 126 patients for up to 39 weeks (mean: 20 weeks) in a placebo-controlled trial (RAFT) conducted in the U.S.

The most commonly reported adverse events with propafenone (greater than 5% and greater than placebo), excluding those not reasonably associated with the use of the drug or because they were associated with the condition being treated, were dizziness, palpitations, chest pain, dyspnea, taste disturbance, nausea, fatigue, anxiety, constipation, upper respiratory tract infection, edema, and influenza. The frequency of discontinuation due to adverse events was 17%, and the rate was highest during the first 14 days of treatment.

Cardiac-related adverse events occurring in greater than or equal to 2% of the patients in any of the RAFT propafenone extended-release treatment groups and more common with propafenone than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, included the following: angina pectoris, atrial flutter, AV block first-degree, bradycardia, congestive cardiac failure, cardiac murmur, edema, dyspnea, rales, wheezing, and cardioactive drug level above therapeutic. Propafenone prolongs the PR and QRS intervals in patients with atrial and ventricular arrhythmias.

Prolongation of the QRS interval makes it difficult to interpret the effect of propafenone on the QT interval [see Clinical Pharmacology ( 12.2 )] . Non-cardiac related adverse events occurring in greater than or equal to 2% of the patients in any of the RAFT propafenone extended-release treatment groups and more common with propafenone than with placebo, excluding those that are common in the population and those not plausibly related to drug therapy, included the following: blurred vision, constipation, diarrhea, dry mouth, flatulence, nausea, vomiting, fatigue, weakness, upper respiratory tract infection, blood alkaline phosphatase increased, hematuria, muscle weakness, dizziness (excluding vertigo), headache, taste disturbance, tremor, somnolence, anxiety, depression, ecchymosis.

No clinically important differences in incidence of adverse reactions were noted by age or gender. Too few non-Caucasian patients were enrolled to assess adverse events according to race. Adverse events occurring in 2% or more of the patients in any of the ERAFT [see Clinical Studies ( 14 )] propafenone extended-release treatment groups and not listed above include the following: bundle branch block left, bundle branch block right, conduction disorders, sinus bradycardia, and hypotension.

Other adverse events reported with propafenone clinical trials not already listed elsewhere in the prescribing information include the following adverse events by body and preferred term. Blood and Lymphatic System Anemia, lymphadenopathy, spleen disorder, thrombocytopenia. Cardiac Unstable angina, atrial hypertrophy, cardiac arrest, coronary artery disease, extrasystoles, myocardial infarction, nodal arrhythmia, palpitations, pericarditis, sinoatrial block, sinus arrest, sinus arrhythmia, supraventricular extrasystoles, ventricular extrasystoles, ventricular hypertrophy.

Ear and Labyrinth Hearing impaired, tinnitus, vertigo. Eye Eye hemorrhage, eye inflammation, eyelid ptosis, miosis, retinal disorder, visual acuity reduced. Gastrointestinal Abdominal distension, abdominal pain, duodenitis, dyspepsia, dysphagi… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, approximately twice MRHD on a mg/m 2 basis) and rats (up to 270 mg/kg/day, approximately 3 times the MRHD on a mg/m 2 basis) provided no evidence of a carcinogenic potential for propafenone. Propafenone was not mutagenic in the Ames (salmonella) test and the in vivo mouse dominantlethal test. Propafenone was not clastogenic in the human lymphocyte chromosome aberration assay in vitro, the rat and Chinese hamster micronucleus tests, and other in vivo tests for chromosomal aberrations in rat bone marrow and Chinese hamster bone marrow and spermatogonia.

Propafenone, administered intravenously, has been shown to decrease spermatogenesis at lethal doses in rabbits (≥3.5 mg/kg/day) or at near-lethal dose levels in monkeys and dogs (≤5 mg/kg/day); doses were less than the MRHD on a mg/m 2 basis. These effects were reversible and did not impair fertility in rabbits at an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose). Effects on spermatogenesis were not found when propafenone was administered to rats either orally or intravenously up to 360 mg/kg/day or 6 mg/kg/day, respectively, or in dogs at oral doses up to 240 mg/kg/day (up to approximately 4 or 9 times the MRHD on a mg/m 2 basis in rats and dogs, respectively).

Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (approximately 2 times the MRHD on a mg/m 2 basis) did not result in evidence of impaired fertility. Nor was there evidence of impaired fertility when propafenone was administered orally to male and female rats at dose levels up to 270 mg/kg/day (approximately 3 times the MRHD on a mg/m 2 basis) for 10 weeks (males) or 2 weeks (females) prior to mating through mating.

13.2Animal Toxicology and/or Pharmacology Renal changes have been observed in the rat following 6 months of oral administration of propafenone at doses of 180 and 360 mg/kg/day (about 2 and 4 times, respectively, the MRHD on a mg/m 2 basis). Both inflammatory and non-inflammatory changes in the renal tubules, with accompanying interstitial nephritis, were observed. These changes were reversible, as they were not found in rats allowed to recover for 6 weeks.

Fatty degenerative changes of the liver were found in rats following longer durations of administration of propafenone at a dose of 270 mg/kg/day (about 3 times the MRHD on a mg/m 2 basis). There were no renal or hepatic changes at 90 mg/kg/day equivalent to the MRHD on a mg/m 2 basis).