Preclinical safety studies with terfenadine.

Preclinical safety studies indicate that alpha-[4-(1,1-dimethylethyl) phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol (terfenadine, RMI 9918. Triludan, Teldane, resp.) is a relatively nontoxic drug in animals. Oral LD50 values were approximately 5000 mg/kg in mature mice and rats; intraperitoneal and intravenous values could not be established because of the low solubility of the compound. In chronic studies rats and mice tolerated 100 mg/kg/day in the diet for 1 1/2 to 2 years without adverse effects, while 150 mg/kg/day or more caused some degree of reduction of body weight gain without evidence of histopathologic or clinical changes. Dogs tolerated single daily oral doses of 30 mg/kg/day for up to 2 years without effect, whereas weight loss, emesis and CNS effects were observed in some dogs at 80 mg/kg/day. Daily doses of 300 mg/kg did not affect the fertility of male or female rats or cause any dominant lethal effects, but did cause maternal toxicity as shown by reduced implants and higher post-implantation losses; however, these effects did not occur at 150 mg/kg/day. Reduced weight gain and survival of 300 mg/kg offsprings and reduced weight gain of 150 mg/kg offspring occurred only when the mothers remained on drug until weaning indicating a direct toxic effect on the offspring rather than any developmental abnormalities caused by in utero exposure. Dosages of up to 300 mg/kg/day were not teratogenic in either rats or rabbits, but were often lethal to rabbits. No evidence of mutagenic or carcinogenic potential was observed. These findings indicate that terfenadine has a lower toxicity potential than other antihistamines.