Selective Estrogen Receptor Modulator
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: Contraindicated
PREGNANCY SUMMARY
No reports describing the use of raloxifene in human pregnancy have been located, but the animal reproduction studies suggest risk. The indications for this drug suggest that human pregnancy experience is unlikely. Moreover, raloxifene is an estrogen antagonist in uterine tissue and estrogen is required to maintain pregnancy. Therefore, the drug is contraindicated in pregnancy. If a woman inadvertently becomes pregnant while taking raloxifene, she should be informed of the risk to her embryo and/or fetus.
FETAL RISK SUMMARY
Raloxifene is an estrogen agonist/antagonist that is in the benzothiophene class of selective estrogen receptor modulators. It is indicated for the treatment and prevention of osteoporosis in postmenopausal women, reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis, and reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer. Raloxifene produces estrogen-like effects on bone and lipid metabolism, while antagonizing the effects of estrogen on uterine and mammary tissue. The drug undergoes hepatic metabolism to apparently inactive metabolites. Plasma protein binding is 95% to albumin and α1-acid glycoprotein, and the elimination half-life after multiple doses is 32.5 hours (1).
Reproduction studies have been performed in rats and rabbits. In rats, doses that were ≥0.2 times the human dose based on BSA (HD) caused retarded fetal development and developmental abnormalities (wavy ribs and kidney cavitation). Doses 0.02–1.6 times the HD during gestation and lactation resulted in delayed and disrupted parturition, decreased neonatal survival, and altered physical development; sex- and age-specific reductions in growth and changes in pituitary hormone content; and decreased lymphoid compartment size in offspring. The highest dose disrupted parturition resulting in maternal and offspring death and morbidity. In rabbits, doses that were ≥0.04 times the HD caused abortions and a low rate of ventricular septal defects. At ≥4 times the HD, hydrocephaly was observed in fetuses (1).
In a study with female rats before mating, minor delays in development of offspring without affecting viability or growth were observed (2). Raloxifene produced estrous cycle disruption in this study. When female rats were given the drug for 5 days after mating, delayed or inhibited implantation, an effect consistent with anti-estrogen administration in rodents was noted (3,4). Although pups were born up to a week late, they were morphologically and developmentally normal. Raloxifene given to pregnant rats from postimplantation until a few days before term caused impaired fetal growth. A higher dose decreased fetal viability without an increase in malformations (5,6). None of these studies compared the doses with the human dose.
In a 21-month carcinogenicity study in female mice with doses that produced systemic exposures that were 0.3–34 times the exposure in postmenopausal women taking 60 mg/day, an increased incidence of ovarian tumors, benign and malignant, were observed. In male mice, doses that were 4.7–24 times the AUC in humans were associated with an increase in testicular and prostatic tumors. Raloxifene was not genotoxic in multiple assays (1).
In fertility studies, no pregnancies resulted when daily doses ≥0.8 times the HD were given to male and female rats. Daily doses up to 16 times the HD had no effect on sperm production or quality, or reproductive performance in male rats. However, in female rats, daily doses that were 0.02–1.6 times the HD disrupted estrous cycles and inhibited ovulation. Doses that were ≥0.02 times the HD given during the preimplantation period caused delayed and disrupted embryo implantation, resulting in prolonged gestation and reduced litter size. These reproductive and developmental effects are consistent with the estrogen receptor activity of the drug (1).
It is not known whether raloxifene crosses the human placenta. The molecular weight (about 474 for the free base) and the long elimination half-life suggest that the drug will cross to the embryo–fetus. However, the high plasma protein binding might limit the exposure.
BREASTFEEDING SUMMARY
No reports describing the use of raloxifene during human lactation have been located. However, such reports are unlikely because of the drug’s indications. The molecular weight (about 474 for the free base) and the long elimination half-life (32.5 hours) suggest that the drug will be excreted into breast milk, but the high plasma protein binding (95%) might limit the exposure. However, as with other weak bases, accumulation in the relatively acidic milk may occur. Raloxifene is an estrogen antagonist in breast tissue. We agree with the manufacturer that it is contraindicated during breastfeeding.
References
1.Product information. Evista. Eli Lilly, 2011.
2.Hoyt JA, Fisher LF, Buelke-Sam JL, Hoffman WP, Francis PC. The selective estrogen receptor modulator, raloxifene: reproductive assessments following premating exposure in female rats. Teratology 1996;53:103.
3.Clarke DO, Griffey KI, Buelke-Sam JL, Francis PC. The selective estrogen receptor modulator, raloxifene: reproductive assessments following preimplantation exposure in mated female rats. Teratology 1996;53:103–4.
4.Clarke DO, Griffey KI, Buelke-Sam J, Francis PC. The selective estrogen receptor modulator, raloxifene: reproductive assessments following preimplantation exposure in mated female rats. Reprod Toxicol 1998;12:247–59.
5.Buelke-Sam J, Bryant HU, Francis PC. The selective estrogen receptor modulator, raloxifene: an overview of nonclinical pharmacology and reproductive and developmental testing. Reprod Toxicol 1998;12:217–21.
6.Byrd RA, Francis PC. The selective estrogen receptor modulator raloxifene: segment II studies in rats and rabbits. Teratology 1996;53:104.