Friday, 18 December 2015

ClinicSpeak: pregnancy and dimethyl fumarate

Will DMF usurp GA as the drug of choice for woman MSers wanting to fall pregnant? #ClinicSpeak #MSBlog

"DMTs and pregnancy are a big differentiator. Woman with MS outnumber men by ~3 to 1 and as MS is a disease of young adulthood pregnancy is the big issue. I spend a lot of clinic time counselling my patients about pregnancy and the issue of DMTs and pregnancy tops the list of issues. The problem is that most of the advice we give regarding DMTs in pregnancy is not covered by hard evidence. In addition, the advice given varies from one neurologist to the next. Would it be possible to get some consensus on this? The good news is that the MS Trust and the ABN are putting together an initiative to formulate some consensus guidelines on this specific issue; i.e. advice we give MSers about DMTs and pregnancy. Hopefully we will have a draft document out sometime in the New Year for comment."

"The paper below is timely. It summarises the current data on DMF (Tecfidera) and pregnancy. As you can see there is no obvious signal on DMF being teratogenic (causing fetal abnormalities) nor an abortifacient (increasing the spontaneous abortion rate). We don't really expect DMF to be teratogenic as it is rapidly metabolised into monomethyl fumarate (MMF) and as fumarate is metabolite (molecule that is part of normal human metabolism) is unlikely to be teratogenic. The one caveat to this statement is that when we use DMF as a DMT we are using it in so called pharmacological doses and not physiological doses therefore we need to remain vigilant to potential problems. If the DMF data holds up DMF will almost certainly usurp glatiramer acetate's (GA) position as the drug of choice for women wanting to fall pregnant, whilst remaining on a DMT. Please note the use of GA in pregnancy is not covered by the EMA's or FDA's label, but is what we do in clinical practice based on its mode of action and GA-pregnancy data collected via registers. Please note GA has been around for over 20 years and DMF is one of the new kids on the block. At present we have more data supporting GAs use in pregnancy compared to DMF; this will change over time. "

INTRODUCTION: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an oral agent for the treatment of relapsing forms of multiple sclerosis (MS). No formal studies of DMF were conducted in pregnant women, although pregnancies have occurred during clinical trials and in the postmarketing setting.

METHODS: Preclinical developmental and reproductive toxicology studies were performed with DMF in rats and rabbits. As of March 26, 2014, the DMF clinical development program included a total of 4132 subjects consisting of 2898 patients with MS, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers. Subjects were required to use reliable contraception and immediately discontinue treatment in the event of pregnancy.

RESULTS: Animal studies showed no evidence of impaired fertility or teratogenicity with DMF. Overall as of June 30, 2014, 63 pregnancies were reported in clinical trials. Outcomes are known for 39 of 42 subjects receiving DMF and include 26 live births (67%), three spontaneous abortions (8%), and 10 elective terminations (26%); follow-up is ongoing in 2 cases and one patient was lost to follow-up. The incidence of spontaneous abortion in subjects exposed to DMF was consistent with the expected rate of early pregnancy loss in the general population (12-22%). A total of 135 pregnancies were reported in the postmarketing setting (spontaneous and solicited reports). Outcomes are known for 30 cases and include 10 live births, 13 spontaneous abortions, and 5 elective terminations; follow-up is ongoing in 103 cases and 2 patients have been lost to follow-up.

CONCLUSION: Although data are limited and all known exposures have occurred in the first trimester, no increased risk of foetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to DMF has been observed.

CoI: multiple

1 comment:

  1. Prof G, based on this evidence, if one of your patients became pregnant while on Tecfidera, would you encourage her to continue taking it? I also remember an article a few months back where you mentioned that Tecfidera is ok while breastfeeding. Would you tell your patients to continue with it?


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