Propafenone Hydrochloride (Page 6 of 8)

13.2 Animal 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/m2 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/m2 basis). There were no renal or hepatic changes at 90 mg/kg/day equivalent to the MRHD on a mg/m2 basis).

14 CLINICAL STUDIES

Propafenone hydrochloride extended-release 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 US multicenter trial (RAFT), 3 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 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 hydrochloride extended-release 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 to placebo, as shown in Table 3.

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

Dose of Propafenone Hydrochloride Extended-release Capsules Twice-Daily Dose

Parameter

225 mg

Twice Daily(N = 126)n (%)

325 mg

Twice Daily(N = 135)n (%)

425 mg

Twice Daily(N = 136)n (%)

Placebo

Twice Daily(N = 126)n (%)

Patients completing withterminating 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)

* 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 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

figure-1
(click image for full-size original)

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.

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 [(Propafenone Hydrochloride Extended-release Atrial Fibrillation Trial)], 2 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 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 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 2 propafenone hydrochloride extended-release treatment groups compared to placebo.

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