ORLANDO – When individuals with multiple sclerosis who were treated with teriflunomide and were using contraception, but became pregnant and followed the clinical program by stopping treatment and flushing the drug out of their systems, they had healthy babies, according to the drug maker’s analysis of several phase II and III trials.
The authors, who presented their findings as a poster at the fifth Cooperative Meeting of the Consortium of Multiple Sclerosis Centers and the Americas Committee for Treatment and Research in Multiple Sclerosis, said that there’s need for more prospective data on pregnancy outcomes, and a registry is planned.
The Food and Drug Administration approved teriflunomide, a once-daily oral medication for treating relapsing forms of multiple sclerosis, last year. The drug is currently classified as "X" and is contraindicated in pregnant women and women of childbearing age. Animal studies have shown that teriflunomide is teratogenic and embryo lethal, the authors wrote, although there has been no evidence that it affected the genes or fertility.
For those who worry about using the drug in women, "This is reassuring that if you follow the guidelines, it’s not going be an issue for mommies and daddies for teratogenicity," said Dr. Robert P. Lisak, professor of neurology at Wayne State University, Detroit, and president-elect of the Consortium of Multiple Sclerosis Centers (CMSC).
Dr. Lisak, who was not involved in the analysis, but has been a part of one of the trials used in the analysis, said that his concern, as a practicing physician, is that women outside of clinical trials are not monitored as closely.
Women who are using the drug are advised to use contraception. Those who want to become pregnant are advised to discontinue treatment and undergo an elimination procedure with cholestyramine or activated charcoal until the drug’s plasma concentrations are less than 0.02 mcg/mL. Men should also stop treatment and undergo accelerated elimination.
Researchers summarized the results of nine phase II and III clinical trials in the MS clinical development program, which included pregnancy outcomes in female patients and partners of men who were exposed to teriflunomide.
The patients had received 7 mg or 14 mg teriflunomide, interferon-beta, placebo, or a combination of treatments. In all trials, reliable contraception was required, but pregnancies were reported.
From a total of more than 4,000 patients, there were 81 pregnancies, 63 of which occurred in women taking teriflunomide, and 18 in women who were on placebo or interferon-beta.
Of those 63, 20 were live births, 26 were induced abortions, 12 were miscarriages, and 5 pregnancies were ongoing when the data collection stopped on April 2013.
The live births in patients treated with teriflunomide resulted in healthy babies. Most of the women had discontinued the drug a few days to 11 weeks after becoming pregnant and underwent an accelerated elimination procedure after discontinuing treatment. Two refused to undergo the procedure. Seven became pregnant after completing the elimination procedure.
The rate of miscarriage in the teriflunomide group was 19%, which is within the range reported in the non–MS population (Eur. J. Obstet. Gynecol. Reprod. Biol. 2002;102:111-9), the authors wrote.
There were 20 pregnancies in partners of 17 men in the teriflunomide clinical trials. In 16, the father was exposed to the drug. There were 12 live births of healthy babies, 1 induced abortion, 1 miscarriage, and 2 ongoing pregnancies when data collection stopped.
Researchers said that planned teriflunomide pregnancy registries will provide more information, but data so far haven’t shown the teratogenic signal seen in the leflunomide registry.
Teriflunomide is the main active metabolite in rheumatoid arthritis drug leflunomide. Animal studies for leflunomide have shown embryo lethality and teratogenicity. But in small human studies, there was no significant difference in teratogenicity and spontaneous abortion rates, compared with the general population (Arthritis Rheum. 2010;62:1494-503; Arthritis Rheum. 2012;64:2085-94), the authors noted.
Teriflunomide also has been detected in human semen. Although there have been no animal studies, researchers said that the estimated female exposure via semen of men treated with the drug is expected to be 100 times lower than in those who actually take the drug with 14-mg dosing.
"Pregnancy outcomes among women who received teriflunomide, including rates of spontaneous abortion, and gestational age and weight at birth, are consistent with those for non–MS populations," the authors wrote. The treatment "is a therapeutic option for women of childbearing potential and for male patients with female partners of childbearing potential, when using reliable contraception."
Some of the authors were employees of Sanofi or had received research support from the company. The study was supported by Genzyme, a Sanofi company, which is marketed as teriflunomide (Aubagio).