Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database

Abstract

Objective To assess the safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation. Methods Safety reports of suspected adverse drug reactions were retrieved from VigiBase as of 31 December 2019, for a case-by-case assessment and disproportionality analysis using the reporting odds ratio (ROR). Results There were 94 safety reports: 50 (53.2%) on erenumab, 31 (33.0%) on galcanezumab, and 13 (13.8%) on fremanezumab. In five (5.3%) safety reports, drug exposure occurred prior to pregnancy, in 85 (90.4%) during pregnancy, in one (1.1%) during lactation, in one (1.1%) via paternal exposure, and in two (2.1%) the exposure time was unknown. Out of 94 safety reports, 51 (54.3%) consisted only of drug exposure, while 43 (45.7%) additionally reported 47 adverse drug reactions including maternal toxicities (n = 18), poor breastfeeding (n = 1), spontaneous abortion (n = 23), preterm birth/prematurity (n = 3), and birth defects (n = 2). There was no signal of disproportionate reporting for spontaneous abortion compared to the full database (reporting odds ratio 1.46, 95% confidence interval 0.97–2.20). When triptans were used as a comparator group, a signal of disproportionate reporting for spontaneous abortion was detected in association with erenumab, galcanezumab, and fremanezumab (reporting odds ratio 1.86, 95% confidence interval 1.12–3.13), which was not statistically significant after excluding confounded safety reports (reporting odds ratio 1.21, 95% confidence interval 0.67–2.21). Conclusions No specific maternal toxicities, patterns of major birth defects, or increased reporting of spontaneous abortion were found. However, because of the relatively limited number of adverse drug reactions reported and the lack of long-term safety data, continuous surveillance is required in pregnant and lactating women exposed to these drugs.

Pregnancy Loss Signal from Prostaglandin Eye Drop Use in Pregnancy: A Disproportionality Analysis Using Japanese and US Spontaneous Reporting Databases

“…However, these studies require a system to collect pregnant women and a sufficient number of cases to be conducted. Given the possibility that safety information for pregnant women can be obtained earlier by using spontaneous reports, some reports using the spontaneous reporting database have been reported [2][3][4][5][6]. Lareb, a pharmacovigilance center in the Netherlands, is also developing a toolkit for monitoring drug safety in pregnant women under the guidance of the World Health Organization, in which the use of a spontaneous reporting database is discussed [7].…”

Reply to the Letter to the Editor by Kessler Y et al. regarding the manuscript “Safety profile of erenumab, galcanezumab and fremanezumab in pregnancy and lactation: Analysis of the WHO pharmacovigilance database.”

“…Most malformations occur prior to the eighth week after conception because of an abnormal developmental process (3). Renal aplasia, which was reported in association with fremanezumab in one safety report included in our study (4), indicates that kidneys undergo no primary growth or development, and differs from renal agenesis whereby kidneys are absent because the first steps of development do not occur (5). Current literature suggests that the risk of birth defects from NSAIDs and aspirin use in the first trimester cannot be excluded but appears low based on conflicting findings affected by the inherent limitations of observational studies and small sample sizes (6,7).…”

Management of cluster headache and other trigeminal autonomic cephalalgias in pregnancy and breastfeeding

“…Therefore, after this period, due to poor transfer and low oral bioavailability, anti‐CGRP antibodies are unlikely to cause adverse effects in a full‐term healthy child. No safety issues have emerged for galcanzumab in lactation so far [57]. If clinically needed, galcanezumab could be considered in breastfeeding women after the first postpartum week.…”

“…Animal studies have not reported adverse reproductive toxic effects [56]. Human immunoglobulin (IgG) is known to cross the placental barrier, but no specific safety issues have so far emerged with use of anti‐GCRP antibodies in pregnancy [57]. As real‐life data are still limited, it is preferable to avoid the use of galcanezumab during pregnancy as a precautionary measure.…”