Immunologic Agent (Immunomodulator)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No published reports describing the use of ustekinumab in human pregnancy have been located. Thirteen pregnancies (protocol deviations) were identified during clinical studies, but specific details of the outcomes are very limited. Although the animal data suggest low risk, the limited human pregnancy experience prevents a more complete assessment of the embryo–fetal risk.
FETAL RISK SUMMARY
Ustekinumab is a human immunoglobulin GIk (IgG1k) monoclonal antibody against the P40 subunit of the interleukin (IL)-12 and IL-23 cytokines. It is given as an SC injection that is repeated at 4 weeks and then every 12 weeks. There are no other agents in this subclass. Ustekinumab is indicated for the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Although the metabolism has not been fully characterized, the antibody is expected to be degraded into small peptides and amino acids similar to endogenous IgG. The mean half-life is about 15–46 days, but ranges are very long (1).
Reproduction studies were conducted in pregnant monkeys with doses up to 45 times the human dose based on body weight (HD) given either SC twice weekly or IV once weekly during organogenesis. No significant adverse developmental effects were observed. In a separate study, monkeys were given SC doses twice weekly up to 45 times the HD from the beginning of organogenesis to day 33 after delivery. In dams, there were no treatment-related effects on mortality, clinical signs, body weight, food consumption, hematology, or serum biochemistry. There were two neonatal deaths: one at 22.5 times the HD and one at 45 times the HD. No drug-related abnormalities were observed in the offspring from birth through 6 months of age in clinical signs, body weight, hematology, serum biochemistry, functional development before and after weaning, morphologic and immunologic development, and gross and histopathologic examinations (1).
Studies evaluating the carcinogenic or mutagenic potential of ustekinumab have not been conducted. However, in mice, inhibition of IL-12/IL-23p40 increased the risk of malignancy, but the relevance of these findings for malignancy risk in humans is unknown. The antibody did not cause toxicity or affect fertility parameters in male monkeys. An analogous antibody did not cause toxicity or affect fertility parameters in female mice that were given SC doses of the agent twice weekly beginning 15 days before cohabitation and continuing through gestational day 7 (1).
It is not known if ustekinumab crosses the human placenta before term. The molecular weight (range 148,079–149,690) is high, but IgG crosses the placenta late in pregnancy (see Immune Globulin Intravenous). Placental transfer of IgG was a function of dose, as well as gestational age. Moreover, the long half-life will place the protein at the maternal–fetal interface for prolonged periods. In unpublished data, ustekinumab crossed the placenta at the time of cesarean section (2).
During clinical studies, 30 pregnancies occurred (protocol deviations), 13 involved exposures in pregnant women and 17 were the result of paternal exposure (2). The drug was discontinued at the time of pregnancy diagnosis in all women. The outcome of the 13 cases were 2 live births with no defect or other adverse effect, 1 spontaneous abortion (SAB), 5 elective abortions (EABs) (all within 12 weeks of pregnancy), 3 ongoing pregnancies, and 2 unknown outcomes. The SAB occurred at 12 weeks’ in a 42-year-old woman. No information was available on the presence or absence of fetal abnormalities in the EABs (2).
BREASTFEEDING SUMMARY
No reports describing the use of ustekinumab during human lactation have been located. The molecular weight (range 148,079–149,690) is high, but immunoglobulins and other large proteins are excreted into colostrum during the first 48 hours after birth. Moreover, the long half-life (15–46 days) will assure that the antibody is in the maternal plasma for long periods. In addition, ustekinumab is excreted into the milk of lactating monkeys (1). These data suggest that the antibody will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown, but there may be an increased risk of infections and malignancies.
References
1.Product information. Stelara. Centocor Ortho Biotech, 2009.
2.Dermatologic and Ophthalmic Drugs Advisory Committee. Briefing document for ustekinumab (CNTO 1275). Available at http://www.fda.gov. Accessed May 4, 2010.