Antiparkinson Agent
PREGNANCY RECOMMENDATION: No Human Data—Animal Data Suggest Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of rasagiline in human pregnancy have been located. The animal reproduction data when rasagiline was used alone or in combination with levodopa/carbidopa suggest risk, but the absence of human pregnancy experience prevents an assessment of the embryo–fetal risk. However, monoamine oxidase (MAO) inhibitors are characterized by interactions with several drugs, including some agents used for general anesthesia, and tyramine-rich foods, beverages, dietary supplements, or amines from over-the-counter medications. These interactions can result in severe, sometimes fatal, hypertension. Because this toxicity would have severe consequences for a woman and her pregnancy, rasagiline is best avoided during gestation.
FETAL RISK SUMMARY
Rasagiline is an oral irreversible MAO type B (MAO-B) inhibitor. Inhibition of MAO-B lasts at least 1 week after the last dose. Rasagiline is indicated for treatment of the signs and symptoms of idiopathic Parkinson’s disease as initial monotherapy and as adjunctive therapy to levodopa. (See also Levodopa.) It is in the same class as selegiline. (See Selegiline.) The mean elimination half-life at steady state is 3 hours but there is no correlation between the half-life and pharmacologic effect as inhibition of MAO-B is irreversible. Plasma protein binding, primarily to albumin, is 88%–94%. Rasagiline undergoes nearly complete metabolism in the liver before excretion (1).
Reproduction studies with rasagiline, either alone or in combination with levodopa/carbidopa, have been conducted in rats and rabbits. Pregnant rats given daily doses from the beginning of organogenesis to day 20 postpartum that produced plasma concentrations 10 and 16 times the maximum recommended human dose (MRHD) based on AUC (MRHD-AUC) caused decreased offspring survival and body weight. The plasma concentration for the no-effect dose was not determined, but it was one-third the lowest dose causing fetal toxicity and was equal to the MRHD based on BSA (MRHD-BSA). In another study, pregnant rats were given the same doses as above combined with levodopa/carbidopa throughout organogenesis. An increased incidence of wavy ribs in fetuses was observed at a dose producing exposures that were 8 times the MRHD-AUC for rasagiline and equal to the MRHD-BSA for levodopa/carbidopa (1).
Pregnant rabbits given daily doses producing exposures that were about ≥7 times the MRHD-AUC throughout organogenesis in combination with levodopa/carbidopa had an increase in fetal death. There was an increase in cardiovascular defects when levodopa/carbidopa was given alone at daily doses that were equal to the MRHD-BSA. This teratogenicity occurred to a greater extent when rasagiline, at exposures that were 1–13 times the MRHD-AUC, was given in combination with levodopa/carbidopa (1).
Carcinogenicity studies were conducted for 2 years in mice and rats. In mice, there was an increase in lung tumors (combined adenomas/carcinomas). The no-effect dose was about 5 times the MRHD-AUC. In rats, there was no increase in tumors at any dose tested. The highest doses tested in male and female rats were about 33 and 260 times, respectively, the MRHD-AUC. Rasagiline was mutagenic and/or clastogenic in some assays but negative in others. No effect was observed on mating performance or fertility in male and female rats with doses producing exposures that were ≤30 times the MRHD-AUC.
It is not known if rasagiline crosses the human placenta. The molecular weight (about 267 for the mesylate salt), protein binding, and elimination half-life suggest that the drug will cross to the embryo–fetus.
BREASTFEEDING SUMMARY
No reports describing the use of rasagiline during human lactation have been located. The molecular weight (about 267 for the mesylate salt), protein binding (88%–94%), and elimination half-life (3 hours) suggest that the drug will be excreted into breast milk. Rasagiline inhibits prolactin and may inhibit milk secretion (1). Nevertheless, the potential for severe adverse effects in a nursing infant suggest that women taking rasagiline should not breastfeed.
Reference
1.Product information. Azilect. Teva Neuroscience, 2006.