Toxicology of progestogens of implantable contraceptives for women.
There are currently four progestogens used in implantable contraceptives marketed or tested in clinical trials: levonorgestrel in Norplant and Jadelle, etonogestrel (3-keto-desogestrel) in Implanon, nestorone in Elcometrine, and nomegestrol acetate in Uniplant and Surplant. Each progestogen was evaluated for hormonal activity and for safety in a wide variety of tests in vitro and in animals prior to their use in women. All four progestogens underwent pre-clinical testing that generally followed the format for animal testing of steroidal contraceptives published by the World Health Organization and the US Food and Drug Administration (FDA). Most of the progestogens have been tested for genotoxicity in bacterial and mammalian cultured cells and in rodents. All were tested for toxicity in short- and long-term toxicology studies in rodents and dogs or monkeys, and all were tested for their effects on reproduction and fetal development. In most cases, the progestogens were tested for carcinogenicity in two rodent species, rats and mice. Early clinical trials in small numbers of women provided additional safety data prior to the exposure of large numbers of women in Phase 3 clinical trials. The published data and data submitted to the FDA demonstrate that the implantable progestogens have no significant or unusual toxicities and have a similar safety profile to the progestogens found in the approved oral contraceptives.
Jordan
Alexander
A
Division of Reproductive & Urologic Drug Products, Food and Drug Administration, Center for Drug Evaluation and Research, Rockville, MD, USA. jordan@cder.fda.gov
D000818:Animals; D015197:Carcinogenicity Tests; D003271:Contraceptive Agents, Female / Q000009:adverse effects / Q000737:chemistry / Q000633:toxicity*; D004343:Drug Implants; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects; D006801:Humans; D023421:Models, Animal; D009152:Mutagenicity Tests; D011247:Pregnancy; D018873:Pregnancy Rate; D045167:Progesterone Congeners / Q000009:adverse effects / Q000737:chemistry / Q000633:toxicity*
D003271:Contraceptive Agents, Female; D004343:Drug Implants; D045167:Progesterone Congeners