THU0173 Pregnancy Outcomes in the Tofacitinib RA Safety Database Through April 2014

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Its effect in pregnant women is of interest, as it has been shown to be foeticidal and teratogenic in both rats and rabbits at exposures 146 times and 13 times, respectively, the maximum recommended human dose. There are no adequate, well-controlled tofacitinib studies in pregnant women; per the RA clinical development programme protocols, all studies exclude pregnant subjects and require use of highly effective contraception by females with child-bearing potential, and study treatment discontinuation if a subject becomes pregnant. Objectives To understand potential effects of tofacitinib, pregnancies in the RA clinical development programme were reviewed. Methods Cases were identified from Pfizer's internal safety database up to 30 April 2014, from interventional (one study is ongoing; database not locked) and non-interventional studies, plus cases from post-marketing reporting. Cases were limited to females administered tofacitinib/placebo/blinded therapy at time of conception and/or foetal subjects exposed to tofacitinib/placebo/blinded therapy through maternal exposure. Potential duplicate cases were eliminated. Remaining cases were reviewed for pregnancy-related outcomes and abnormalities; categorised as healthy newborns, spontaneous abortion, medical termination, still-birth, pending or lost to follow-up. Results 35 cases were identified. In tofacitinib RA clinical studies of 6192 subjects with 16839 patient-years exposure, there were 32 cases of maternal exposure. Subject age ranged from 22 to 40 years. Of the 32 cases, 31 received tofacitinib; 13 received 5 mg BID, 17 received 10 mg BID, and 1 received 15 mg BID. 14 of the 31 cases were also taking methotrexate (MTX). 1 subject received placebo/MTX. Pregnancy outcomes with tofacitinib were: 16 healthy newborns (including 1 low birth weight and 1 pre-term birth), 7 spontaneous abortions, 4 medical terminations, 1 congenital malformation of pulmonary valve stenosis reported in a 32-year-old subject with diabetes and hypertension, 1 ongoing pregnancy and 3 lost to follow-up; the placebo-treated subject experienced a spontaneous abortion. The remaining 3 cases receiving tofacitinib were reported from other data sources: 2 from non-interventional studies, 1 from post-marketing reporting. Foetal subjects had maternal exposure to tofacitinib. Of the 3 cases, 1 had a spontaneous abortion; outcomes were still pending for the other 2 cases. Conclusions Most cases with reported outcomes had healthy newborns. Adverse outcomes including spontaneous abortion and congenital malformation were observed in RA subjects who became pregnant during tofacitinib therapy. Pregnancy outcomes in subjects receiving tofacitinib continue to be monitored through routine pharmacovigilance and via a post-approval safety study within the Organization of Teratology Information Specialists (OTIS) registry. Acknowledgements Previously presented (Marren A et al. Arthritis Rheum 2014; 66(11): S5840 abs 1908) and reproduced with permission from Arthritis and Rheumatism. All aspects of this work were funded by Pfizer Inc. Editorial support, under the guidance of the authors, was provided by Amanda Pedder, of Complete Medical Communications, and funded by Pfizer Inc. Disclosure of Interest A. Marren Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer Inc, Y. Chen Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer Inc, D. Frazier Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer, J. Geier Shareholder of: Shareholder of Pfizer Inc, Employee of: Employee of Pfizer