Propafenone Hydrochloride 300 mg Tablet, Coated, 100-count — NDC 51407-017-01 (Billing 51407-0017-01)

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, 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.)

12.2Pharmacodynamics Cardiac Electrophysiology Electrophysiology trials in subjects 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 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 2. Mean Changes in Electrocardiogram Intervals a Interval Total Daily Dose (mg) 337.5 mg 450 mg 675 mg 900 mg msec % msec % msec % msec % RR -14.5 -1.8 30.6 3.8 31.5 3.9 41.7

5.1PR 3.6 2.1 19.1 11.6 28.9 17.8 35.6

21.9QRS 5.6 6.4 5.5 6.1 7.7 8.4 15.6

17.3QTc 2.7 0.7 -7.5 -1.8 5.0 1.2 14.7 3.7 a Change and percent change based on mean baseline values for each treatment group. In any individual patient, the above ECG changes cannot be readily used to predict either efficacy or plasma concentration. Propafenone hydrochloride tablets cause a dose-related and concentration-related decrease in the rate of single and multiple PVCs and can suppress recurrence of ventricular tachycardia.

Based on the percent of patients attaining substantial (80% to 90%) suppression of ventricular ectopic activity, it appears that trough plasma levels of 0.2 to 1.5 mcg/mL can provide good suppression, with higher concentrations giving a greater rate of good response. When 600 mg/day propafenone was administered to subjects with paroxysmal atrial tachyarrhythmias, mean heart rate during arrhythmia decreased 14 beats per min and 37 beats per min for subjects with PAF and subjects with PSVT, respectively. Hemodynamics Trials in humans have shown that propafenone hydrochloride ex… [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, 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.)

12.3Pharmacokinetics Absorption/Bioavailability Propafenone hydrochloride is nearly completely absorbed after oral administration with peak plasma levels occurring approximately 3.5 hours after administration in most individuals. Propafenone exhibits extensive saturable presystemic biotransformation (first-pass effect) resulting in a dose-dependent and dosage-form-dependent absolute bioavailability; e.g., a 150-mg tablet had absolute bioavailability of 3.4%, while a 300-mg tablet had absolute bioavailability of 10.6%.

A 300-mg solution which was rapidly absorbed had absolute bioavailability of 21.4%. At still larger doses, above those recommended, bioavailability increases still further. Propafenone hydrochloride follows a nonlinear pharmacokinetic disposition presumably because of saturation of first-pass hepatic metabolism as the liver is exposed to higher concentrations of propafenone and shows a very high degree of inter-individual variability.

For example, for an increase in daily dose from 300 to 900 mg/day there is a 10-fold increase in steady-state plasma concentration. The top 25% of subjects given 337.5 mg/day, however, had a mean concentration of propafenone larger than the bottom 25%, and about equal to the second 25%, of subjects given a dose of 900 mg. Although food increased peak blood level and bioavailability in a single-dose trial, during multiple-dose administration of propafenone to healthy volunteers, food did not change bioavailability significantly.

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 2 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 2 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. There are significant differences in plasma concentrations of propafenone in slow and extensive metabolizers, the former achieving concentrations 1.5 to 2.0 times those of the extensive metabolizers at daily doses of 675 to 900 mg/day.

At low doses the differences are greater, with slow metabolizers attaining concentrations more than 5 times that of extensive metabolizers. Because the difference decreases at high doses and is mitigated by the lack of the active 5-hydroxy metabolite in the slow metabolizers, and because steady-state conditions are achieved after 4 to 5 days of dosing in all patients, the recommended dosing regimen is the same for all patients. The greater variability in blood levels requires that the drug be titrated carefully in patients with close attention paid to clinical and ECG evidence of toxicity [see Dosage and Administration ( 2 )] .

Stereochemistry: Propafenone hydrochloride tablets are a racemic mixture. The R- and S-enantiome… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology Electrophysiology trials in subjects 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 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 2. Mean Changes in Electrocardiogram Intervals a Interval Total Daily Dose (mg) 337.5 mg 450 mg 675 mg 900 mg msec % msec % msec % msec % RR -14.5 -1.8 30.6 3.8 31.5 3.9 41.7

5.1PR 3.6 2.1 19.1 11.6 28.9 17.8 35.6

21.9QRS 5.6 6.4 5.5 6.1 7.7 8.4 15.6

17.3QTc 2.7 0.7 -7.5 -1.8 5.0 1.2 14.7 3.7 a Change and percent change based on mean baseline values for each treatment group. In any individual patient, the above ECG changes cannot be readily used to predict either efficacy or plasma concentration. Propafenone hydrochloride tablets cause a dose-related and concentration-related decrease in the rate of single and multiple PVCs and can suppress recurrence of ventricular tachycardia.

Based on the percent of patients attaining substantial (80% to 90%) suppression of ventricular ectopic activity, it appears that trough plasma levels of 0.2 to 1.5 mcg/mL can provide good suppression, with higher concentrations giving a greater rate of good response. When 600 mg/day propafenone was administered to subjects with paroxysmal atrial tachyarrhythmias, mean heart rate during arrhythmia decreased 14 beats per min and 37 beats per min for subjects with PAF and subjects with PSVT, respectively. Hemodynamics Trials in humans have shown that propafenone hydrochloride exerts a negative inotropic effect on the myocardium.

Cardiac catheterization trials in subjects with moderately impaired ventricular function (mean CI =

2.61L/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 3.0 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.

14 CLINICAL STUDIES In 2 randomized, crossover, placebo-controlled, double-blind trials of 60 to 90 days’ duration in subjects with PAF or PSVT, propafenone reduced the rate of both arrhythmias, as shown in Table 3. Table 3. Reduction of Arrhythmias in Subjects with Paroxysmal Atrial Fibrillation/Flutter or Paroxysmal Supraventricular Tachycardia Trial 1 Trial 2 Propafenone Placebo Propafenone Placebo PAF Percent attack free Median time to first recurrence n = 30 53% >98 days n = 30 13% 8 days n = 9 67% 62 days n = 9 22% 5 days PSVT Percent attack free Median time to first recurrence n = 45 47% >98 days n = 45 16% 12 days n = 15 38% 31 days n = 15 7% 8 days The patient population in the above trials was 50% male with a mean age of 57.3 years.

Fifty percent of the subjects had a diagnosis of PAF and 50% had PSVT. Eighty percent of the subjects received 600 mg per day propafenone. No subject died in the above 2 trials.

In U.S. long-term safety trials, 474 subjects (mean age: 57.4 ± 14.5 years) with supraventricular arrhythmias [195 with PAF, 274 with PSVT, and 5 with both PAF and PSVT] were treated up to 5 years (mean: 14.4 months) with propafenone. Fourteen of the subjects died. When this mortality rate was compared with the rate in a similar patient population (n = 194 subjects; mean age: 43.0 ± 16.8 years) studied in an arrhythmia clinic, there was no age-adjusted difference in mortality.

This comparison was not, however, a randomized trial and the 95% confidence interval around the comparison was large, such that neither a significant adverse or favorable effect could be ruled out.

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 the 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 dominant lethal 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 the 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/m2 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 hydrochloride 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 hydrochloride 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).