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.

 

This information is an update to the NPRA Safety Alerts published on 22 July 2024. Please click here for further information on the safety issue.

 

[Regulatory Updates] Cancellation of Product Registration and Product Recall

The National Pharmaceutical Regulatory Agency (NPRA) has completed a review of the potential cancer risk in offspring exposed in utero and the limited efficacy data related to the use of 17-hydroxyprogesterone caproate (17-OHPC) use. The Malaysian Adverse Drug Reactions Advisory Committee (MADRAC) concluded that the risk of 17-OHPC use outweighs its benefits.

On 3 October 2024, the Drug Control Authority (DCA) made the decision to cancel the registration of all products containing 17-OHPC in Malaysia with immediate effect. All stocks of 17-OHPC-containing products are being recalled up to the level of sub-distributors (wholesalers).

 

Product Overview

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 is currently one 17-OHPC product in injectable form registered with the DCA.⁵

 

Background of the Safety Issue (Please refer to the previous safety alert for full details)

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

17-OHPC products have been withdrawn from the market by the United States Food and Drug Administration (US FDA) following concerns over insufficient evidence supporting the use of 17-OHPC for preventing habitual and threatened abortion, as well as its link to congenital heart defects in offspring.

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

In May 2024, the 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

This recommendation was made following EMA’s review of 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, which suggested a potential increased cancer risk.^2,3,6 Additionally, the EMA identified new evidence showing that 17-OHPC does not effectively prevent preterm birth and found limited evidence of its effectiveness in other approved obstetrical and gynaecological indications.^2,3,7-9

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.

 

Adverse Drug Reaction Reports¹⁰

NPRA has received 5 adverse drug reaction reports with 7 adverse events following 17-hydroxyprogesterone caproate use. 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

• Be informed of the cancellation of registration and recall of products containing 17-OHPC in Malaysia. This decision was made as the overall benefit of the product no longer outweighs the risk and alternative treatment options are available.
• Immediately stop prescribing, dispensing, selling, or distributing 17-OHPC products. Consider appropriate alternatives for any indications.
• For patients already on 17-OHPC treatment: ensure patients are properly counselled and informed of the risk and treatment options available. Further follow-up and monitoring of offspring is necessary if they have received 17-OHPC during their first trimester.
• Be reminded that the outcome of this review does not impact the use of progesterone, which operates differently from 17-OHPC.
• 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 Oct 3]. 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. 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
8. 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
9. 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
10. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Jul 21]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Noor'ain Shamsuddin
Reviewed/Edited by: Choo Sim Mei, Dr Rema Panickar, Norleen Mohamed Ali