ing oral dosing of propafenone HCl, were seen at lethal or near lethal dose levels and were not seen in rats treated either orally or intravenously [see Warnings and Precautions (5.11)]. Treatment of male rabbits for 10 weeks prior to mating at an oral dose of 120 mg/kg/day (about 2.4 times the MRHD on a mg/m2 basis) or an intravenous dose of 3.5 mg/kg/day (a spermatogenesis-impairing dose) did not result in evidence of impaired fertility. Nor was there evidence of impaired fertility when propafenone HCl was administered orally to male and female rats at dose levels up to 270 mg/kg/day (about 3 times the MRHD on a mg/m2 basis).
13.2 Animal Toxicology and/or Pharmacology
Renal and Hepatic Toxicity in Animals
Renal changes have been observed in the rat following 6 months of oral administration of propafenone HCl at doses of 180 and 360 mg/kg/day (about 2 and 4 times, respectively, the maximum recommended human daily dose [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 HCl 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
RYTHMOL SR has been eva luated 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 study (Rythmol SR Atrial Fibrillation Trial, RAFT), 3 doses of RYTHMOL SR (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. RYTHMOL SR 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 RYTHMOL SR Dose
Parameter 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 eventa 66 (52) 56 (41) 41 (30) 87 (69)
Comparison of tachycardia-free periods
Kaplan-Meier Media 112 291 NAb 41
Range 0 - 285 0 - 293 0 - 300 0 – 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) --
a Terminating events comprised 91% AF, 5% atrial flutter, and 4% PSVT.
b Not Applicab |
