Immunologic Agent (Immunomodulator)
PREGNANCY RECOMMENDATION: Contraindicated
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
One report cited a clinical trial that involved 43 pregnancies (1). Although no details of the exposures were provided, the report stated that there was no increased risk of spontaneous abortions, lower birth weights, lower gestational ages, or congenital malformations. The animal reproduction data suggest risk, including embryo malformations and fetal death. The manufacturer classifies the drug as contraindicated in pregnancy. If a woman conceives while taking this drug, or a woman a childbearing potential stops the drug, the 11-day procedure for accelerated elimination of teriflunomide is recommended because it takes on average 8 months, but possibly as long as 2 years, to reach plasma concentrations (<0.02 mg/mL) that are considered minimal risk (see package insert for procedure) (2). If exposure does occur in pregnancy, physicians are encouraged to enroll their patient in the manufacturer’s pregnancy registry, or women can enroll themselves, by calling 1-800-745-4447, option 2.
FETAL RISK SUMMARY
Teriflunomide, an oral immunomodulator with anti-inflammatory properties, inhibits a mitochondrial enzyme involved in de novo pyrimidine synthesis. It is the principal active metabolite of leflunomide and is responsible for leflunomide’s activity (see also Leflunomide). Teriflunomide is indicated for the treatment of patients with relapsing forms of multiple sclerosis. The drug is mainly distributed in plasma. It is metabolized to inactive metabolites. Plasma protein binding is high (>99%), and the dose-dependent elimination half-life is very long (18–19 days). The drug has been detected in human semen (2).
Reproduction studies with teriflunomide have been conducted in rats and rabbits. In rats given oral doses during organogenesis that were not maternal toxic, high incidences of fetal defects, mainly craniofacial, and axial and appendicular skeletal defects, as well as embryo–fetal death were observed. The no-effect maternal plasma exposure for embryo–fetal developmental toxicity was less than that in humans at the maximum recommended human dose (MRHD). When nonmaternal toxic doses were administered during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of limb defects and postnatal death were observed in the offspring. The no-effect maternal plasma exposure for prenatal and postnatal developmental toxicity in rats was less than that in humans at the MRHD. In rabbits given oral doses that caused minimal maternal toxicity, high incidences of defects (similar to those seen in rats) and embryo–fetal death, were observed. The maternal plasma exposure at the no-effect dose for prenatal and postnatal developmental toxicity in rabbits was less than that in humans at the MRHD (2).
No evidence of carcinogenicity was observed in mice and rats in lifetime studies. Both positive and negative results for mutagenic and clastogenic effects were noted in various assays. In studies with male rats, no adverse effect on fertility was noted, but a dose-related decrease in epididymal sperm count did occur. In female rats, oral doses before and during mating resulted in embryolethality, reduced fetal body weight, and malformations at all doses tested (2).
It is not known if teriflunomide crosses the human placenta. The molecular weight (about 270) and very long elimination half-life suggest that the drug will cross to the embryo–fetus, but the high plasma protein binding might limit the exposure.
A 2013 reference cited data from a clinical trial database that involved 43 pregnancies exposed to teriflunomide (1). Although no information was provided on the dose, timing of the exposures, or specific data on outcomes, the citation stated that no increased risk of spontaneous abortions, lower birth weights, lower gestational ages, or congenital malformations were observed (1).
No reports describing the use of teriflunomide during human lactation have been located. The molecular weight (about 270) and very long elimination half-life (about 18–19 days) suggest that the drug will be excreted into breast milk, but the high plasma protein binding (>99%) might limit the amount excreted. Because of the severe toxicity that has occurred in adults taking the drug (e.g., severe hepatotoxicity, bone marrow depression, immunosuppression), the drug is best not used in women who are nursing an infant.
1.Kieseier B, Benamor M, Benzerdjeb H, Stuve O. Pregnancy outcomes from the teriflunomide clinical development programme: retrospective analysis of the teriflunomide clinical trial database. Multi Scler 2012;18 (Suppl 4):P737. As cited by Lu E, Wang BW, Guimond C, Synnes A, Sadovnick AD, Dahlgren L, Traboulsee A, Tremlett H. Safety of disease-modifying drugs for multiple sclerosis in pregnancy: current challenges and future considerations for effective pharmacovigilance. Expert Rev Neurother 2013;13:251–61.
2.Product information. Aubagio. Genzyme, 2012.