Chronic oral toxicity and oncogenicity studies of flecainide, an antiarrhythmic, in rats and mice.

Chronic oral toxicity and oncogenicity studies on flecainide acetate, an antiarrhythmic compound, were made in male and female rats and mice. The duration of compound administration was 18 months in mice and 24 months in rats, and dose levels for both species were 0, 60, 30, and 15 mg/kg/day. The treated rats had dose-related significant decreases in mean body weights at all dose levels while the treated mice had a small body weight reduction (non-significant) at the higher doses. The body weight effects could not be correlated with reduced food consumption. Chronic administration of flecainide did not produce chronic toxic changes in either species. Likewise, chronic compound administration did not adversely affect survival rates; in fact, the treated groups of rats had survival rates higher than those of the controls with the differences from controls being significant for the male rat groups. All of the tumors in all groups of animals (control and treated) were considered spontaneous in nature. The incidence of the various types of tumors in the treated groups of animals was not significantly increased when compared to the control groups, with one exception. Interstitial cell adenoma in the testes was the most common tumor of the male rats and the increased survival rate of the high dose male rats had a direct effect on the incidence of this tumor. Since the high dose male rats had much better survival than the controls (90% vs 56%), a higher incidence of interstitial cell adenomas would be expected (more rats live longer, more rats with a late developing spontaneous tumor). Comparison of the incidence of interstitial cell adenomas in male rats which survived the 2-year study revealed no significant difference between controls and treated animals. Also when the incidence of interstitial cell adenomas was statistically evaluated with a life table approach, there was no indication of increased tumorigenic risk in the treated groups as compared to the controls.