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.

 

Overview

Progestogens, also known as gestagens, can be either natural or synthetic (referred to as progestins) compounds that bind to progesterone receptors and mimic effects of progesterone.¹ They are used to treat various gynaecological conditions, such as endometriosis, fibroids, prolonged or heavy periods, and menstrual cycle disorders.² Additionally, they are applied in hormone replacement therapy, including menopausal hormone therapy, as well as in obstetrics for conditions like luteal insufficiency-related sterility and recurrent abortions.

Meningiomas are typically slow-growing, non-cancerous tumours that can still exert pressure on nearby brain tissue, potentially necessitating surgical interventions.³ They account for nearly 40% of all primary central nervous system tumours. Potential risk factors for developing intracranial meningiomas include increasing age (with a sharp rise after 65), female sex, neurofibromatosis type 2, and exposure to ionising radiation. Prior evidence also links prolonged use of high-dose progestogens (i.e., cyproterone acetate, nomegestrol acetate, and chlormadinone acetate) to the increased risk of meningiomas. This association is biologically plausible, considering that progesterone receptors are present in over 60% of meningiomas.

 

Background of the Safety Issue

In 2020, the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) confirmed a cumulative dose-dependent association between cyproterone acetate and the risk of meningioma. While the risk is considered rare overall, it is most pronounced at doses of 25 mg per day and higher.^4-5

In 2022, the EMA confirmed that nomegestrol and chlormadinone are also associated with an increased risk of meningioma, particularly when used at high doses (3.75-5 mg for nomegestrol and 5-10 mg for chlormadinone) and over prolonged periods of use.⁶

In 2023, the French National Agency for the Safety of Medicines and Health Products (ANSM) recommended implementing risk minimisation measures for medrogestone and medroxyprogesterone acetate, similar to those adopted for chlormadinone and nomegestrol, due to newly identified comparable meningioma risks.^2,7,8 ANSM has also brought this safety concern to the attention of the EMA. Notably, the marketing of promegestone in France ceased since 2020.

These recommendations were based on a large French epidemiological study, which assessed the risk of meningioma associated with progestogens using data from the France National Health Data System (SNDS) covering the period from 2009 to 2018.^2,3,7,8 This study, published in March 2024, analysed data from over 18,000 women who underwent meningioma surgery compared to more than 90,000 controls.

The study results revealed that prolonged use (≥ one year) of three additional progestogens—medrogestone, medroxyprogesterone (injectable), and promegestone—is associated with an excess risk of meningioma.^2,3,7,8 Additionally, the study confirmed the previously known risks for cyproterone acetate, nomegestrol acetate, and chlormadinone acetate, which served as positive controls. The odds ratios for these progestogens are detailed below:

Type of Progestogens	Odds Ratio (OR), 95% confidence interval	Dosage form and Strength	Registered in Malaysia
Cyproterone acetate*	19.21 (16.61 – 22.22)	Not declared	√
Medroxyprogesterone acetate	5.55 (2.27 – 13.56)	Injectable:150 mg/ 3 ml	√
Nomegestrol*	4.93 (4.50 – 5.41)	Not declared	X
Chlormadinone*	3.87 (3.48 – 4.30)	Not declared	√
Medrogestone	3.49 (2.38 – 5.10)	Oral: 5 mg	X
Promegestone	2.39 (1.85 – 3.09)	Oral: 0.125 mg, 0.25 mg, 0.5 mg	X

 *Known risks of meningioma

 

Conversely, this study also reported:^2,3,7,8

• No increased risks of meningioma:
  • Oral /intravaginal/ percutaneous progesterone, dydrogesterone, and levonorgestrel intrauterine systems (IUD).
• Risks not known but cannot be excluded for the following:
  • Dienogest and hydroxyprogesterone: no conclusive findings for due to the small number of patients receiving these drugs.
  • Drospirenone and desogestrel: risks of meningioma could not be assessed due to methodological limitations and insufficient historical data in the database.

 

Local Product Registration Status and Adverse Drug Reaction (ADR) Reports^9-10

Referring to the progestogens examined in the French study discussed above, the NPRA has received a total of 772 ADR reports related to progestogen products locally registered with the Drug Control Authority (DCA). Till date, no local cases of meningioma have been received among the submitted reports.

Below is a summary of the locally registered progestogens that were studied. The table outlines the number of registered products, ADR reports, and the most frequently reported adverse events in Malaysia: 

No.	Type of Progestogens	Dosage form	No. of registered products	No. of ADR report	No. of adverse event	Top 3 adverse events
1	Cyproterone acetate	Oral	4	40	75	Vomiting (7), Nausea (6),  Dizziness (3)
2	Medroxyprogesterone acetate	Injection and oral	7	239	539	Pruritus (69), Rash (47), Urticaria (44)
3	Chlormadinone	Oral	1	-	-	-
4	Progesterone	Oral, Intravaginal, Percutaneous (vaginal gel, injection)	7	6	12	Drug ineffective (2), Nausea (2)
5	Dydrogesterone	Oral	5	53	97	Pruritus (13), Rash (11), Urticaria (9)
6	Levonorgestrel	IUD, Oral	13	129	224	Urticaria (19), Headache (12), Pruritus (12)
7	Dienogest	Oral	5	78	129	Menorrhagia (6), Intermenstrual bleeding (5), Menstruation irregular (5)
8	Hydroxyprogesterone	Injection	2	3	6	Pruritus (2), Urticaria (2), Inflammation (1)
9	Drospirenone	Oral	7	136	202	Abnormal withdrawal bleeding (12), Metrorrhagia (10), Amenorrhoea (10)
10	Desogestrel	Oral	11	88	149	Rash (14), Pruritus (14), Deep vein thrombosis (10)

 Note: At the time of review, no products containing nomegestrol, medrogestone, or promegestone were registered with the DCA in Malaysia.

 

Advice for Healthcare Professionals

• While the NPRA is still reviewing this status issue, be aware of the potential risk of meningioma when initiating any progestogens:
  • Cyproterone acetate and chlormadinone are known risk factors for meningioma, particularly with cumulative high doses.
  • A recent French epidemiological study identified an excess risk of meningioma with prolonged use (≥ 1 year) of medroxyprogesterone acetate (injectable).
• Be attentive to any previous progestogen use when prescribing new progestogens. Avoid using progestogens with reported risks of meningioma in patients with a history of meningioma or existing meningioma.
  • In exceptional cases, progestin treatment may be considered after a thorough evaluation in a multidisciplinary consultation, weighing the individual benefit-risk ratio and the availability of alternatives.
• Always prescribe progestogen at the minimum effective dose and for the shortest duration necessary.
• Educate patients to contact their doctor immediately if they experience a change in vision (seeing double or blurriness), hearing loss or ringing in the ears, loss of smell, headaches that worsen with time, memory loss, seizures, or weakness in their arms or legs.
• Vigilantly monitor high-risk patients for signs and symptoms of meningiomas in line with clinical practice. Consider a brain Magnetic Resonance Imaging (MRI) if meningioma is suspected.
• If a meningioma is diagnosed, consider discontinuing treatment with these progestogens permanently.
• Report all suspected adverse events associated with progestogens-containing products to the NPRA.

 

References:

1. Edwards M, Can AS. Progestins. [Updated 2024 Jan 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK563211/
2. France National Agency for the Safety of Medicines and Health Products (ANSM). News – Progestins and meningioma: no increase in risk with levonorgestrel IUDs but confirmation of the risk for 3 new substances [Internet]. 2023 Jul 21 [Cited 2024 Apr 19]. Available from: https://ansm.sante.fr/actualites/progestatifs-et-meningiome-pas-daugmentation-du-risque-avec-les-diu-au-levonorgestrel-mais-confirmation-du-risque-pour-3-nouvelles-substances
3. Roland N, Neumann A, Hoisnard L, Duranteau L, Froelich S, Zureik M et al. Use of progestogens and the risk of intracranial meningioma: national case-control study. 2024 Mar 27;384:e078078. Available from: https://doi.org/10.1136/bmj-2023-078078
4. United Kingdom Medicines and Healthcare Products Regulatory Agency. Drug safety update – Cyproterone acetate: new advice to minimize risk of meningioma [Internet]. 2020 June 29 [Cited 2024 Apr 19]. Available from: https://www.gov.uk/drug-safety-update/cyproterone-acetate-new-advice-to-minimise-risk-of-meningioma
5. European Medicines Agency. Restrictions in use of cyproterone due to meningioma risk. [Internet]. 2020 Mar 27 [Cited 2024 Apr 19]. Available from: https://www.ema.europa.eu/en/medicines/human/referrals/cyproterone-containing-medicinal-products
6. European Medicines Agency. New measures to minimise risk of meningioma with medicines containing nomegestrol or chlormadinone [Internet]. 2022 Sep 2 [Cited 2024 Apr 19]. Available from: https://www.ema.europa.eu/en/news/new-measures-minimise-risk-meningioma-medicines-containing-nomegestrol-or-chlormadinone
7. France National Agency for the Safety of Medicines and Health Products (ANSM). News – Colprone, Depo Provera and Surgestone: first recommendations to limit the risk of meningioma [Internet]. 2023 Jul 21 [Cited 2024 Apr 19]. Available from: https://ansm.sante.fr/actualites/colprone-depo-provera-et-surgestone-premieres-recommandations-pour-limiter-le-risque-de-meningiome
8. France National Agency for the Safety of Medicines and Health Products (ANSM). News – Progestins and risk of meningioma: recommendations to limit this risk [Internet]. 2023 Dec 18 [Cited 2024 Apr 19]. Available from: https://ansm.sante.fr/actualites/progestatifs-et-risque-de-meningiome-recommandations-pour-limiter-ce-risque
9. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2024 [Cited 2024 Aug 1]. Available from: https://www.npra.gov.my
10. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2024 [cited 2024 Apr 19]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wang Khee Ing

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