DRUG INTERACTIONS
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenicity studies were conducted in mice and rats with cabergoline given by gavage at doses up to 0.98 mg/kg/day and 0.32 mg/kg/day, respectively. These doses are 7 times and 4 times the maximum recommended human dose calculated on a body surface area basis using total mg/m2/week in rodents and mg/m2/week for a 50 kg human.
There was a slight increase in the incidence of cervical and uterine leiomyomas and uterine leiomyosarcomas in mice. In rats, there was a slight increase in malignant tumors of the cervix and uterus and interstitial cell adenomas. The occurrence of tumors in female rodents may be related to the prolonged suppression of prolactin secretion because prolactin is needed in rodents for the maintenance of the corpus luteum. In the absence of prolactin, the estrogen/progesterone ratio is increased, thereby increasing the risk for uterine tumors. In male rodents, the decrease in serum prolactin levels was associated with an increase in serum luteinizing hormone, which is thought to be a compensatory effect to maintain testicular steroid synthesis. Since these hormonal mechanisms are thought to be species-specific, the relevance of these tumors to humans is not known.
The mutagenic potential of cabergoline was evaluated and found to be negative in a battery of in vitro tests. These tests included the bacterial mutation (Ames) test with Salmonella typhimurium, the gene mutation assay with Schizosaccharomyces pombe P 1 and V79 Chinese hamster cells, DNA damage and repair in Saccharomyces cerevisiae D 4, and chromosomal aberrations in human lymphocytes. Cabergoline was also negative in the bone marrow micronucleus test in the mouse.
In female rats, a daily dose of 0.003 mg/kg for 2 weeks prior to mating and throughout the mating period inhibited conception. This dose represents approximately 1/28 the maximum recommended human dose calculated on a body surface area basis using total mg/m2/week in rats and mg/m2/week for a 50 kg human.
Pregnancy
Teratogenic Effects: Category B
Reproduction studies have been performed with cabergoline in mice, rats, and rabbits administered by gavage.
(Multiples of the maximum recommended human dose in this section are calculated on a body surface area basis using total mg/m2/week for animals and mg/m2/week for a 50 kg human.)
There were maternotoxic effects but no teratogenic effects in mice given cabergoline at doses up to 8 mg/kg/day (approximately 55 times the maximum recommended human dose) during the period of organogenesis.
A dose of 0.012 mg/kg/day (approximately 1/7 the maximum recommended human dose) during the period of organogenesis in rats caused an increase in post-implantation embryofetal losses. These losses could be due to the prolactin inhibitory properties of cabergoline in rats. At daily doses of 0.5 mg/kg/day (approximately 19 times the maximum recommended human dose) during the period of organogenesis in the rabbit, cabergoline caused maternotoxicity characterized by a loss of body weight and decreased food consumption. Doses of 4 mg/kg/day (approximately 150 times the maximum recommended human dose) during the period of organogenesis in the rabbit caused an increased occurrence of various malformations. However, in another study in rabbits, no treatment-related malformations or embryofetotoxicity were observed at doses up to 8 mg/kg/day (approximately 300 times the maximum recommended human dose).
In rats, doses higher than 0.003 mg/kg/day (approximately 1/28 the maximum recommended human dose) from 6 days before parturition and throughout the lactation period inhibited growth and caused death of offspring due to decreased milk secretion.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
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