Pregnancy outcomes in the clinical development program of fingolimod in multiple sclerosis

Abstract

Objective: To report outcomes of pregnancies that occurred during the fingolimod clinical development program.Methods: Pregnancy outcomes from phase II, phase III, and phase IV clinical studies (with optional extensions) were reported by clinical trial investigators. Fingolimod exposure in utero was defined as fingolimod treatment at the time of conception or in the 6 weeks before conception.Results: As of October 31, 2011, 89 pregnancies were reported in completed or ongoing clinical studies, with 74 in fingolimod treatment arms. Of 66 pregnancies with in utero exposure to fingolimod, there were 28 live births, 9 spontaneous abortions, 24 elective abortions, 4 ongoing pregnancies, and 1 pregnancy with an unknown outcome (patient lost to follow-up). Two infants were born with malformations: 1 with congenital unilateral posteromedial bowing of the tibia and 1 with acrania. Elective abortions were performed for 1 case each of tetralogy of Fallot, spontaneous intrauterine death, and failure of fetal development. There were 5 cases (7.6%; 95% confidence interval 3%-17%) of abnormal fetal development in the 66 pregnancies that had in utero exposure to fingolimod. In all 5 cases, fetal exposure to the drug took place in the first trimester of pregnancy. Conclusions:The number of patients becoming pregnant during fingolimod therapy remains small and does not permit firm conclusions to be drawn about fetal safety of fingolimod in humans. Given the known risks of teratogenicity in animals and the present data, women of childbearing potential should use effective contraception during fingolimod therapy and for 2 months after discontinuation. Neurology ® 2014;82:674-680 GLOSSARY CI 5 confidence interval; MS 5 multiple sclerosis.Multiple sclerosis (MS) is predominant among women of reproductive age, in whom approximately 50% of all pregnancies are unplanned.1 Fingolimod (FTY720; Gilenya, Novartis Pharma AG, Basel, Switzerland) is a sphingosine 1-phosphate receptor modulator that has been approved as a once-daily oral therapy for relapsing MS. Two phase II studies, 3 large-scale phase III studies, and their ongoing extension studies have indicated that fingolimod has a manageable safety profile and is generally well tolerated at the approved dose of 0.5 mg. [2][3][4][5][6] As preclinical studies indicate a risk of fetal toxicity, 7 fingolimod clinical study protocols require a negative pregnancy test at enrollment and that women of childbearing potential use reliable contraception throughout the studies. We report the outcomes of pregnancies that occurred in the fingolimod clinical development program despite these measures.METHODS Standard protocol approvals, registrations, and patient consents. Pregnancy outcomes are reported from 9 clinical studies in patients with relapsing MS: the phase III FREEDOMS study 3

Management of women with multiple sclerosis through pregnancy and after childbirth

“…The S1P receptor is involved in vascular formation during embryogenesis. The Fingolimod Pregnancy Registry reported on 66 human exposure cases, and noted a 7.6% rate of abnormal fetal development [Karlsson et al 2014]. Fingolimod has a half-life of 6-9 days [Novartis Pharmaceuticals Corporation, 2015].…”

The Effects of Multiple Sclerosis and Disease Modifying Therapy on Pregnancy

“…Rat experiments have shown no effect on female fertility upon administration of fingolimod, but they exerted teratogenic effects, the most common being congenital heart defects [9]. The rate of spontaneous abortion in women using fingolimod is higher than that of the general population [25]. Fingolimod has been confirmed to be excreted in breast-milk in rats, and is not recommended during lactation [25].…”

“…The rate of spontaneous abortion in women using fingolimod is higher than that of the general population [25]. Fingolimod has been confirmed to be excreted in breast-milk in rats, and is not recommended during lactation [25]. Natalizumab Natalizumab (trade name Tysabri®) is a monoclonal antibody against a subunit of the integrin molecule, thereby limiting the migration of leukocytes in the CNS.…”

Familieplanlegging, graviditet og amming ved multippel sklerose

“…Fem av disse hadde unormal utvikling, inkludert et barn med akrani, som døde to dager etter fødselen. Tallene er for små til å kunne fastslå eller avkrefte at fingolimod gir økt forekomst av misdannelser (29), men de understreker viktigheten av at kvinner som bruker midlet bør anvende effektiv prevensjon (30). Siden en betydelig andel svangerskap ikke er planlagt, bør denne problemstillingen vektlegges og diskuteres med alle fertile kvinner ved valg av terapi.…”