In a European worksharing procedure (WSP), Glucophage was approved as the first oral anti-diabetic medication to be used safely from conception to birth.
The approval was granted on the basis of Merck’s own safety cohort study CLUE1 and a large body of published evidence.
This approval addresses a significant unmet medical need as the prevalence of hyperglycemia during pregnancy is rising worldwide, currently at one in six births (21.1 million).2

DARMSTADT, Germany -- (BUSINESS WIRE) --

Merck, a leading science and technology company, today announced in a European worksharing procedure (WSP) an extension to the label for metformin products in the EU - Glucophage^® (metformin hydrochloride [HCL] immediate release), Glucophage XR^® (metformin HCL extended release) and Stagid^® (metformin embonate immediate release) - for use throughout pregnancy.

Maria Rivas, SVP and Chief Medical Officer at Merck said, “During pregnancy and when wanting to become pregnant, good glycemic control is of utmost importance, as insufficient glycemic control leads to a three times higher risk of pregnancy loss than in normoglycemic women. The estimated risk of malformation is doubled. Until now, pregnant women were required to use insulin to control their blood sugar during this period. The label extension now opens a tablet alternative to women who are not able or wanting to use daily injections.”

In a European worksharing procedure (WSP), the variation for label extension was approved based on results from Merck’s register-based cohort safety study, investigating the follow up of children from over ~4.000 pregnancies with metformin¹ for up to 11 years and extensive independent scientific publications, which all confirmed no increased risk of congenital abnormalities or feto/neonatal toxicity after exposure to metformin at the time of conception and throughout pregnancy.

Pregnancy and diabetes

The prevalence of type 2 diabetes is rising around the world.² In 2021, 21.1 million births worldwide (16.7%) were affected by hyperglycemia.² In Europe, 3-7% of all pregnant women develop gestational diabetes (GDM).^3,4 Furthermore, 1% of all pregnancies are in women with pre-existing type 2 diabetes.⁵ To date, these conditions had to be managed with insulin when drugs were needed. Regarding the periconceptional phase, insulin-resistant polycystic ovary syndrome (PCOS), which affects 5-20% of all reproductive-aged women^6,7, is associated with a 15-fold increase in infertility. The rate of early pregnancy loss is three times greater in PCOS pregnancies.

Metformin during pregnancy

The European Health authorities participating in the WSP weighed the benefit and risk of metformin use on both the mother and child. Their decision was informed by data investigating metformin in pre-gestational and gestational diabetes. Regarding the mother, metformin was comparable to insulin in reaching maternal blood sugar control and was better than insulin regarding pregnancy weight gain.^8,9,10 Metformin use during pregnancy was associated with a lower risk of pregnancy-induced hypertension and preeclampsia.^9,11,12 When used together with insulin for pregestational diabetes, metformin significantly lessened the amount of insulin required and lowered the risk of severe hypoglycemia.^13,14

As metformin crosses the placenta,^15,16,17 the safety of the unborn child had to be confirmed: Children exposed to metformin in utero may be born lighter than those exposed to insulin but are less in danger of a risky blood sugar dip directly after birth. So far, no long-term risks for the child later in life (e.g. on mental development and weight) have been confirmed.¹

Metformin alone may sometimes not be enough to control blood glucose. In these cases, it is recommended for doctors to use metformin in combination with insulin²¹ or change to insulin.

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References

1. Brand KMG, Saarelainen L, Sonajalg J, et al. Metformin in pregnancy and risk of adverse long-term outcomes: a register-based cohort study. BMJ Open Diab Res Care 2022;10:e002363
2. IDF Diabetes Atlas, Tenth Edition 2021
3. Behboudi-Gandevani S., Parajuli R., Vaismoradi M. A systematic review of the prevalence of gestational diabetes in Norway. [In Process] International Journal of Environmental Research and Public Health 2021 18:4 (1-12) Article Number 1423
4. Wierzba W., liwczyński A., Karnafel W., Bojar I., Pinkas J. Gestational diabetes mellitus/hyperglycaemia during pregnancy in Poland in the years 2010-2012 based on the data from the National Health Fund. Ginekologia polska 2017 88:5 (244-248)
5. Shub A., Lappas M.: Pregestational diabetes in pregnancy: Complications, management, surveillance, and mechanisms of disease—A review. Prenatal Diagnosis 2020 40:9 (1092-1098)
6. National Health Statistics Reports Number 86, May 20, 2015. https://www.cdc.gov/nchs/data/nhsr/nhsr086.pdf
7. McDonnell, Women’s Health 2017, Vol. 13(3) 89–97
8. Tarry-Adkins PLoS Med 2020, 17(5): e1003126
9. Guo, Journal of Diabetes Research 2019 Article Number 9804708
10. Butalia Diabetic Medicine 2017 34:1 (27-36)
11. Mateus Journal of Obstetrics and Gynecology 2020 222:1 Supplement (S691- S692)
12. Cluver BMJ 2021;374:n2103
13. Tarry-Adkins PLoS Med 2020, 17(5): e1003126
14. Feig The Lancet Diabetes and Endocrinology 2020 8:10 (834-844)
15. Charles Ther Drug Monit 28:67–72
16. de Oliveira Baraldi. Clin Pharmacokinet 2012;51:743-9
17. Ahmadimoghaddam Reprod Toxicol 2013;39:17-22
18. Lee: DIABETICMedicine 2020. DOI: 10.1111/dme.14250
19. Freinkel: Banting Lecture 1980: Of pregnancy and Progeny. Diabetes 1980: 1023- 35X
20. Latif British Journal of Diabetes and Vascular Disease 2013 13:4 (178-182)
21. Rowan New England Journal of Medicine 2008 358:19 (2003-2015)

About Glucophage^®

Glucophage^® (metformin hydrochloride) is a prescription-only medicine indicated for the treatment of type 2 diabetes mellitus, particularly when dietary management and exercise alone does not result in adequate glycaemic control. In adults, Glucophage^® may be used as monotherapy or in combination with other oral anti-diabetic agents or with insulin. In children from 10 years old and adolescents, Glucophage^® may be used as monotherapy or in combination with insulin. A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with Glucophage^® as first-line therapy after diet failure. The most commonly reported side effects with Glucophage^® are gastro-intestinal disturbances that may occur during treatment initiation and resolve spontaneously in most cases. The Glucophage^® product portfolio comprises: Glucophage^® IR (immediate release) and Glucophage^reg; XR (extended release) and Stagid^® (metformin embonate immediate release).

About Merck

Merck, a leading science and technology company, operates across healthcare, life science and electronics. Around 58,000 employees work to make a positive difference to millions of people’s lives every day by creating more joyful and sustainable ways to live. From advancing gene editing technologies and discovering unique ways to treat the most challenging diseases to enabling the intelligence of devices – the company is everywhere. In 2020, Merck generated sales of € 17.5 billion in 66 countries.

Scientific exploration and responsible entrepreneurship have been key to Merck’s technological and scientific advances. This is how Merck has thrived since its founding in 1668. The founding family remains the majority owner of the publicly listed company. Merck holds the global rights to the Merck name and brand. The only exceptions are the United States and Canada, where the business sectors of Merck operate as EMD Serono in healthcare, MilliporeSigma in life science, and EMD Electronics.

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