The parenteral toxicity of Cyclofem.
The intraperitoneal median lethal dose of Cyclofem [Cyclo-Provera, C-P; depot-medroxyprogesterone acetate (Depo-Provera, DMPA)+estradiol cypionate (EC)] in mice was greater than 2500 mg/kg. The subcutaneous median lethal dose in mice and rats was greater than 1000 mg/kg. The suspension containing 50 mg/ml DMPA and 10 mg/ml EC used in all toxicology studies was not irritating to rabbit muscle. Chronic parenteral toxicity studies of Cyclofem were conducted in mice, rats and monkeys for 18, 22 and 24 months, respectively. Monthly doses were 2.5, 7.5 and 25 mg/kg Cyclofem in all species, 25 mg/kg DMPA and 25 mg/kg EC. Cyclofem was nontoxic but produced hormonal effects in all species. Decreased survival noted in the rodent studies was likely due to excessive EC dose. Mammary gland adenocarcinomas and pituitary adenomas were increased in the chronic rat study. Literature indicates the tumors were likely the result of the excessive hormone dose and were specific to rodents. In monkeys, Cyclofem was nontoxic, hormonally active, and noncarcinogenic at all doses including 50 times the human dose.
Drug Safety Research Unit, Upjohn Company, Kalamazoo, MI 49001.
K M
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Cookson
D000230:Adenocarcinoma / Q000139:chemically induced; D000818:Animals; D003277:Contraceptives, Oral, Combined / Q000008:administration & dosage / Q000633:toxicity; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008253:Macaca mulatta; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage* / Q000633:toxicity*; D051379:Mice; D008813:Mice, Inbred ICR; D010911:Pituitary Neoplasms / Q000139:chemically induced; D011817:Rabbits; D051381:Rats
D003277:Contraceptives, Oral, Combined; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D004958:Estradiol; C034528:CycloProvera; D017258:Medroxyprogesterone Acetate