RYTHMOL nonclinical toxicology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]
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 following 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 (5.13)]. 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 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 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).[1]
References
- ↑ "RYTHMOL (PROPAFENONE HYDROCHLORIDE) TABLET, FILM COATED [GLAXOSMITHKLINE LLC]". Retrieved 12 March 2014.