ilar to propafenone in vitro. In man after administration of RYTHMOL SR, the 5-hydroxypropafenone metabolite is usually present in concentrations less than 40% of propafenone. The norpropafenone metabolite is usually present in concentrations less than 10% of propafenone.
Inter-Subject Variability
With propafenone, there is a considerable degree of inter-subject variability in pharmacokinetics which is due in large part to the first pass hepatic effect and non-linear pharmacokinetics in extensive metabolizers. A higher degree of inter-subject variability in pharmacokinetic parameters of propafenone was observed following both single and multiple dose administration of RYTHMOL SR capsules. Inter-subject variability appears to be substantially less in the poor metabolizer group than in the extensive metabolizer group, suggesting that a large portion of the variability is intrinsic to CYP2D6 polymorphism rather than to the formulation.
Stereochemistry
RYTHMOL is a racemic mixture. The R- and S-enantiomers of propafenone display stereoselective disposition characteristics. In vitro and in vivo studies have shown that the R-isomer of propafenone is cleared faster than the S-isomer via the 5-hydroxylation pathway (CYP2D6). This results in a higher ratio of S-propafenone to R-propafenone at steady state. Both enantiomers have equivalent potency to block sodium channels; however, the S-enantiomer is a more potent β-antagonist than the R-enantiomer. Following administration of RYTHMOL immediate release tablets or RYTHMOL SR capsules, the S/R ratio for the area under the plasma concentration-time curve was about 1.7. The S/R ratios of propafenone obtained after administration of 225, 325 and 425 mg RYTHMOL SR are independent of dose. In addition, no difference in the average values of the S/R ratios is evident between genotypes or over time.
Special Populations
Hepatic Impairment
Decreased liver function increases the bioavailability of propafenone. Absolute bioavailability assessments have not been determined for the RYTHMOL SR capsule formulation. Absolute bioavailability of RYTHMOL immediate-release tablets is inversely related to indocyanine green clearance, reaching 60-70% at clearances of 7 mL/min and below. Protein binding decreases to about 88% in patients with severe hepatic dysfunction. The clearance of propafenone is reduced and the elimination half-life increased in patients with significant hepatic dysfunction [see Warnings and Precautions (5.8)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Lifetime maximally tolerated oral dose studies in mice (up to 360 mg/kg/day, about twice the maximum recommended human oral daily dose [MRHD] on a mg/m2 basis) and rats (up to 270 mg/kg/day, about 3 times the MRHD on a mg/m2 basis) provided no evidence of a carcinogenic potential for propafenone HCl.
Propafenone HCl tested negative for mutagenicity in the Ames (salmonella) test and in the in vivo mouse dominant lethal test. It tested negative for clastogenicity in the human lymphocyte chromosome aberration assay in vitro and in 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 HCl, administered intravenously to rabbits, dogs, and monkeys, has been shown to decrease spermatogenesis. These effects were reversible, were not found follow |
