DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, the NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

Product Overview

17-hydroxyprogesterone caproate (17-OHPC) is a synthetic progestogen produced by acetylating 17α-hydroxyprogesterone, a naturally occurring metabolite of progesterone.¹ Progesterone plays a key role in preparing the endometrium for pregnancy and maintaining it throughout gestation.^2-3 Since 17-OHPC is believed to bind to the same receptors on cells that progesterone typically targets, it is expected to lower the risk of pregnancy loss or premature labour in pregnant women as well as aid in treating certain infertility and gynaecological disorders linked to progesterone deficiency.

In Malaysia, 17-OHPC products are approved to treat habitual and imminent abortion, infertility due to corpus luteum insufficiency, primary and secondary amenorrhoea.⁴ There are currently two 17-OHPC products, both in injectable forms, registered with the Drug Control Authority (DCA).⁵

 

Background of the Safety Issue

(I) History of 17-OHPC Product Withdrawal by the US FDA^6-7

1973 - The United States Food and Drug Administration (US FDA) raised concerns over insufficient evidence supporting 17-OHPC’s use for preventing habitual and threatened abortion, as well as its link to congenital heart defects in offspring.

2000 - The FDA withdrew approval of 17-OHPC products following a request by the manufacturer, as the products were no longer available on the market.

2011 - Makena, a 17-OHPC product, received accelerated FDA conditional approval based on preliminary trials demonstrating its efficacy in reducing preterm birth risks in women with a singleton pregnancy who have a history of preterm birth. The trial showed that the drug decreased deliveries occurring before 37 weeks of gestation. Makena was approved solely for reducing the risk of preterm birth in women with a singleton pregnancy who have a history of singleton spontaneous preterm birth and was not intended for use in women with multiple gestations or other risk factors for preterm birth.⁸

2023 - Subsequent confirmatory trials failed to verify their clinical benefits, leading to the FDA’s withdrawal of Makena and its generics.

 

(II) Recent 17-OHPC Product Suspension by the EMA  

In May 2024, the National Pharmaceutical Regulatory Agency (NPRA) received information from the European Medicines Agency (EMA) regarding a new recommendation to suspend marketing authorisations for products containing 17-OHPC in the European Union (EU).^2-3

The EMA Pharmacovigilance Risk Assessment Committee (PRAC) reviewed a large epidemiological study involving >18,000 mother-child pairs that examined cancer risk in individuals exposed to 17-OHPC in utero over 50 years since birth.^2,3,6 The findings suggested a potential increased cancer risk (adjusted hazard ratio 1.99 [95% CI 1.31, 3.02]), with 23 out of 234 exposed offspring diagnosed with cancer. Given the study’s low number of cancer cases and limitations, including insufficient information on cancer risk factors, the PRAC concluded that while there is a possible cancer risk for those exposed to 17-OHPC in utero, this risk cannot be confirmed.^2-3

During the review, the PRAC identified new studies indicating that 17-OHPC is not effective in preventing premature birth.^2-3 This included a multi-centre, international, double-blind randomised controlled trial of over 1,700 pregnant women with a history of preterm delivery, which found that 17-OHPC was no more effective than a placebo in preventing recurrent preterm births or complications in premature newborns.^2,3,9 Moreover, two published meta-analyses confirmed that 17-OHPC does not effectively prevent preterm birth.^2,3,10-11 For other approved obstetrical and gynaecological indications, the PRAC also found limited evidence of effectiveness.^2-3 Additionally, the PRAC sought expert input from obstetrics, gynaecology, fertility treatment, and patient representatives.

Considering the benefits of 17-OHPC do not outweigh its risks in any authorised use, in June 2024, the EMA has therefore suspended the marketing authorisations for these products, noting that alternative treatment options are available.^2-3 The decision does not affect the use of progesterone, which functions differently from 17-OHPC.

Within the existing literature, the mechanisms behind the increased cancer risk in offspring exposed to 17-OHPC during pregnancy are still unclear.³ However, it has been postulated that synthetic hormones, as seen with diethylstilbestrol (DES), can disrupt embryonic development and lead to adverse health outcomes.⁶ Evidence suggests that 17-OHPC crosses the placental barrier, and both the foetus and placenta can metabolise it. Like DES, early exposure to 17-OHPC may induce cellular, molecular, and epigenetic changes, potentially contributing to carcinogenesis later in life.

 

Adverse Drug Reaction Reports¹²

There were only 5 adverse drug reaction reports with 7 adverse events received following 17-hydroxyprogesterone caproate use received by the NPRA. The adverse events reported were pruritus (2 reports), urticaria (2), erythema (1), pulmonary oedema (1), and inflammation (1). To date, no local cases suspected of any form of cancer or lack of efficacy have been reported.

 

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware of the emerging concerns over the overall benefit-risk balance of 17-OHPC-containing products:
  • With respect to safety:
    • Findings from a large epidemiological study suggest a possible increased risk of cancer in people exposed to 17-OHPC in the womb, but the risk cannot be confirmed due to study limitations and uncertainties.
    • No effective preventive measures for this risk have been identified.
  • With respect to efficacy:
    • New studies indicates that 17-OHPC does not effectively prevent preterm birth.
    • There is a lack of comprehensive data on its efficacy in other obstetric, gynaecological, and fertility applications.
• Report all suspected adverse events associated with 17-OHPC-containing products to the NPRA.

 

References:

1. Hu T, Tang C, Stern S, Yang L, Du T. 17α-Hydroxyprogesterone Caproate Inhibits Cytokine Production via Suppression of NF-κB Activation. Frontiers in pharmacology. 2022 Mar 7;13.Available from: https://doi.org/10.3389/fphar.2022.831315
2. ‌European Medicines Agency (EMA). Hydroxyprogesterone caproate-containing medicinal products - referral [Internet]. 2024 Jun 28 [cited 2024 Jul 1]. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/hydroxyprogesterone-caproate-containing-medicinal-products
3. ‌European Medicines Agency (EMA). Hydroxyprogesterone-containing medicinal products Article 31-referral - Public assessment report [Internet]. 2024 Jul 5 [cited 2024 Jul 8]. Available from: https://www.ema.europa.eu/en/documents/referral/hydroxyprogesterone-containing-medicinal-products-article-31-referral-public-assessment-report_en.pdf
4. National Pharmaceutical Regulatory Agency (NPRA). PROLUTON DEPOT 250MG INJ (1ML AMP) (hydroxyprogesterone hexanoate/caproate) [Package Insert]. QUEST3+ Product Search. 2024 May [cited 2024 May 21].Available from: https://www.npra.gov.my
5. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [cited 2024 May 21]. Available from: https://www.npra.gov.my
6. Murphy CC, Cirillo PM, Krigbaum NY, Cohn BA. In Utero exposure to 17α-hydroxyprogesterone caproate and risk of cancer in offspring. American Journal of Obstetrics and Gynecology. 2022 Jan;226(1). Available from: https://doi.org/10.1016/j.ajog.2021.10.035
7. Center for Drug Evaluation and Research. Makena (hydroxyprogesterone caproate injection) information [Internet]. FDA; [cited 2024 May 21]. Available from: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/makena-hydroxyprogesterone-caproate-injection-information
8. United States Food and Drug Administration (US FDA). MAKENA (hydroxyprogesterone caproate) injection [Package Insert]. Drugs@FDA. 2013 Aug [cited 2024 May 21]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021945s005lbl.pdf
9. Blackwell SC, Gyamfi-Bannerman C, Biggio JR, Chauhan SP, Hughes BL, Louis JM, et al. 17-OHPC to prevent recurrent preterm birth in Singleton gestations (Prolong Study): A Multicenter, International, Randomized Double-Blind trial. American Journal of Perinatology. 2019 Oct 25;37(02):127–36.Available from: https://doi.org/10.1055/s-0039-3400227
10. Stewart LA, Simmonds M, Duley L, Llewellyn A, Sharif S, Walker RA, et al. Evaluating progestogens for preventing Preterm Birth International Collaborative (EPPPIC): Meta-analysis of individual participant data from Randomised Controlled Trials. The Lancet. 2021 Mar;397(10280):1183–94. Available from: https://doi.org/10.1016/S0140-6736(21)00217-8
11. Care A, Nevitt SJ, Medley N, Donegan S, Good L, Hampson L, et al. Interventions to prevent spontaneous preterm birth in women with singleton pregnancy who are at high risk: Systematic review and network meta-analysis. BMJ. 2022 Feb 15. Available from: https://doi.org/10.1136/bmj-2021-064547
12. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 May 21]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Noor'ain Shamsuddin
Reviewed/Edited by: Choo Sim Mei, Lim Sze Gee, Norleen Mohamed Ali