Immunologic Agent (Immunomodulator)/Antirheumatic Agent
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Although the animal data suggest low risk, the human pregnancy experience is too limited to assess the embryo–fetal risk. Several reviews have discussed the potential risk of abatacept in human pregnancy ( 1– 5). Some recommend discontinuing the drug 10–18 weeks before pregnancy because the drug has a long elimination half-life (2,4,5). It is not known if in utero exposure could result in autoimmune diseases in later life (6). Moreover, use in pregnancy is contraindicated if abatacept is combined with methotrexate or leflunomide. Until more data are available, the safest course is to avoid abatacept during gestation. If abatacept is used in pregnancy for the treatment of rheumatoid arthritis, health care professionals are encouraged to call the toll-free number (877-311-8972) for information about patient enrollment in the Organization of Teratology Information Specialists (OTIS) Rheumatoid Arthritis study.
FETAL RISK SUMMARY
Abatacept, a soluble fusion protein, is a selective costimulation modulator that inhibits T-lymphocyte activation, thereby decreasing T-cell proliferation and inhibiting the production of the cytokines tumor necrosis factor-α, interferon-γ, and interleukin-2. It is administered as an IV infusion. Abatacept is indicated, either as monotherapy or in combination with other agents, for the treatment of rheumatoid arthritis in patients with moderately to severely active rheumatoid arthritis that has not responded to other drug therapy. The elimination half-life after a single 10 mg/kg IV dose in a healthy subject was 16.7 days (range 12–23 days), whereas in rheumatoid arthritis patients after multiple 10 mg/kg IV infusions, it was 13.1 days (range 8–25 days) (6).
Reproduction studies have been conducted in mice, rats, and rabbits. In these species, daily doses (route not specified but assumed to be SC) were not teratogenic. The dose comparisons were about 29 times the maximum recommended human dose of 10 mg/kg dose based on AUC (MRHD). There were no adverse effects in the offspring when rats were treated every 3 days from early gestation and throughout lactation with doses up to 3 times the MRHD. However, at a dose 11 times the MRHD, alterations of immune function were observed in female pups and one female pup (of 10 male and 10 female pups evaluated) had inflammation of the thyroid (6).
In carcinogenicity studies, weekly SC doses of abatacept for about 2 years in mice were associated with increased incidences of malignant lymphomas and mammary gland tumors at doses ≤3 times the HD. However, the mice were infected with viruses known to cause these cancers in immunosuppressed mice. In cynomolgus monkeys, an IV dose given once weekly that was 9 times the HD was not associated with any significant adverse effects. No evidence of lymphomas or preneoplastic morphologic changes was observed despite the presence of a virus known to cause these lesions in immunosuppressed monkeys. Abatacept was not mutagenic and did not cause chromosomal aberrations, nor did it impair the fertility of male and female monkeys given doses every 3 days up to 11 times the HD (6).
Abatacept crosses the human placenta, despite its high molecular weight (about 92,000) (6). However, the amount reaching the embryo and/or fetus was not quantified.
Several reviews have discussed the potential risks of abatacept in pregnancy (1–5). As discussed in a 2012 review, eight patients became pregnant while receiving abatacept during clinical trials in rheumatoid arthritis, seven of whom were also receiving methotrexate and one was also receiving leflunomide (4). A spontaneous abortion (SAB) occurred during the 1st trimester in three (two had a prior history of SAB) and two had an elective abortion (EAB). The remaining three women were still pregnant. In another case, the wife of a man treated with abatacept became pregnant and gave birth to a healthy baby. In a phase II trial of abatacept in multiple sclerosis, two women became pregnant and a third women became pregnant by a abatacept-treated man. The outcomes of these pregnancies were a healthy baby, an EAB, and a SAB (4).
A 2013 case report described the outcome of a pregnancy exposed to abatacept in the 1st trimester (7). A 33-year-old woman with rheumatoid arthritis conceived while receiving abatacept (10 mg/kg every 4 weeks) and methotrexate (15 mg/week). The dose given in pregnancy occurred at 2.5 weeks’. Both drugs were stopped, but a daily 5 mg dose of an unspecified corticosteroid was allowed. At 40 weeks’, the woman gave birth vaginally to a healthy 3180-g infant (sex not specified) with Apgar scores of 10 and 10 at 5 and 10 minutes, respectively. The child was doing well at 3.5-year follow-up (7).
BREASTFEEDING SUMMARY
No reports describing the use of abatacept during human lactation have been located. Although the molecular weight is high (about 92,000), excretion into breast milk is a possibility, especially because of the long elimination half-life (13 days; range 8–25 days). However, the amount in milk and the systemic bioavailability are unknown as are the effects on a nursing infant, but the potential for adverse effects on an infant’s developing immune system should be considered.
References
1.Ostensen M, Lockshin M, Doria A, Valesini G, Meroni P, Gordon C, Brucato A, Tincani A. Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs. Rheumatology 2008;47(Suppl 3):iii28–31.
2.Ostensen M, Förger F. Management of RA medications in pregnant patients. Nat Rev Rheumatol 2009;5:382–90.
3.Makol A, Wright K, Amin S. Rheumatoid arthritis and pregnancy—safety considerations in pharmacological management. Drugs 2011;71:1973–87.
4.Pham T, Bachelez H, Barthelot JM, Blacher J, Claudepierre P, Constantin A, Fautrel B, Gaujoux-Viala C, Goeb V, Gossec L, Goupille P, Guillaume-Czitrom S, Hachulla E, Lequerre T, Marolleau JP, Martinez V, Masson C, Mouthon L, Puechal X, Richette P, Saraux A, Schaeverbeke T, Soubrier M, Viguier M, Vittecoq O, Wendling D, Mariette X, Sibilia J. Abatacept therapy and safety management. Joint Bone Spine 2012;72(Suppl 1):3–84.
5.Furst DE, Keystone EC, So AK, Braun J, Breedveld FC, Burmester GR, De Benedetti F, Dorner T, Emery P, Fleischmann R, Gibofsky A, Kalden JR, Kavanaugh A, Kirkham B, Mease P, Rubbert-Roth A, Sieper J, Singer NG, Smolen JS, VanRiel PLCM, Weisman MH, Winthrop KI. Updated consensus statement on biological agents in the treatment of rheumatic disease, 2012. Ann Rheum Dis 2013;72(Suppl 2):ii2–34.
6.Product information. Orencia. Bristol-Myers Squibb, 2011.
7.Ojeda-Uribe M, Afif N, Dahan E, Sparsa L, Haby C, Sibilia J, Ternant D, Ardizzone M. Exposure to abatacept or rituximab in the first trimester of pregnancy of three women with autoimmune diseases. Clin Rheumatol 2013;32:695–700.