Plan B - Product Monograph Page 27 of 36
Acute Toxicity Studies: In single dose studies, the LD
50
for norgestrel was > 5000 mg/kg dosed
orally in rodents and dogs. Multiple dose studies in mice for 18 months had no effect. In rats,
other than exaggerated physiological effects expected with high doses of estrogens, there was
little evidence of drug toxicity. Findings included decreased pituitary weights, secretory changes
in the cervix and vagina, and endometrial hyperplastic changes. Growth rate and food
consumption were depressed among norgestrel-treated animals at high doses.
Chronic Toxicity Studies: Data from the first seven years of a ten-year repeat administration
study in Rhesus monkeys with d,l-norgestrel was collected to support clinical use as an oral
contraceptive. Sixty-four female Rhesus monkeys (16/group) were administered norgestrel 0
mg, 0.02 mg, 0.1 mg, and 0.5 mg/kg/day as a dietary admixture for 21 consecutive days followed
by seven days of a non-dosing period (28-day cycle). There were no norgestrel-related effects
on mortality, behaviour, mean body weights, endocrine function, or ophthalmoscopic exams. A
number of minor dose related changes were noted in hematocrit, Stypven Times, activated partial
thromboplastin times, fibrinogen concentrations, and urinary output of 17-
hydroxycorticosteroids. There were no findings in gross or histopathologic evaluations
indicative of toxicity, and microscopic examination of cervical smears did not reveal any
evidence of neoplasia. No mammary nodules were palpable at the end of the first, third, sixth,
and seventh years, none of the monkeys had palpable mammary nodules at the end of the sixth
and seventh years, and there was no effect on the number of palpable mammary nodules or the
month when the first mammary nodule was found over the course of seven years. The
conclusion of the U.S. FDA review of this study indicated that administration of norgestrel to
female monkeys for ten years caused essentially no untoward effects.
Carcinogenicity Studies: In CF-LP (MTV
+
) mice administered doses described as low (2-5
times clinical), mid (50-150 times clinical), and high (200-400 times clinical) for 80 weeks, there
was no effect on incidence of tumours in any tissues. In castrated C3HxRIII (MTV
+
) mice
administered 0.5 mg/kg d-norgestrel or 1 mg/kg dl-norgestrel in the diet, the incidence of
mammary tumours was slightly raised in the absence of any effect on latency. In the rat,
administration of norgestrel in the diet (doses not described) for 104 weeks had no effect on the
incidence of tumours.
Genotoxicity: Levonorgestrel revealed no potential for genotoxicity in a standard Ames
Salmonella/Microsome Mutagenicity Test.
Reproductive Toxicity: A large number of reproductive toxicity studies were performed by
repeat dose administration to evaluate the effects on mating fertility, fecundity, post-treatment
recovery of fertility, effects on the estrous cycle, claudogenic effects as well as classic Segment
I, II, and III reproductive studies. Of greatest possible relevance to emergency contraception are
the studies of recovery of fertility and birth defects. In a study in mice treated with up to 50x the
human contraceptive dose, no irreversible impairment of fertility was noted.
Segment II studies were given by repeat dose during organogenesis. At the levels required to
maintain pregnancy, virilizing effects were noted and were considerably greater than those of
progesterone. Two of 439 fetuses from dams treated at these levels of norgestrel were deformed;