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, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

Product Overview

Clomiphene falls under the selective oestrogen receptor modulator (SERM) class, used for the treatment of female and male infertility.^1-2 It binds to oestrogen receptors in the hypothalamus, exerting an anti-oestrogenic effect by inhibiting the regular oestrogenic negative feedback mechanism. This inhibition leads to an increase in the release of gonadotrophin-releasing hormone (GnRH), which consequently triggers the pituitary gland to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH), ultimately facilitating ovulation in women or inducing testosterone production and spermatogenesis in men.

In Malaysia, there are currently three (3) clomiphene-containing products registered with the Drug Control Authority (DCA).³ It is approved locally for the treatment of ovulatory failure in women desiring pregnancy.⁴

Background of the Safety Issue

In June 2023, the National Pharmaceutical Regulatory Agency (NPRA) learned from the France National Agency for the Safety of Medicines and Health Products (ANSM) regarding the association of clomiphene treatment with the risk of serious visual disturbances potentially leading to blindness.⁵ The France product information has been updated to include recommendations on the risk of serious visual disturbances (blindness) associated with clomiphene, and a direct healthcare professional communication (DHPC) letter has been issued to inform healthcare professionals about this risk.⁶

Clomiphene is known to be associated with visual disturbance such as blurred vision, reduced visual acuity, phosphenes (flash in the visual field), and scintillating scotomas (spots in the visual field).^5-7 Recent safety data from international pharmacovigilance reports and scientific literature have raised concerns about new visual adverse effects associated with the use of clomiphene.^5-6 These adverse effects, including optic neuritis, ischaemic optic neuropathy, central retinal vein occlusion, retinal detachment, and vitreous detachment, in rare cases, have led to reversible or irreversible, partial or complete blindness, even after discontinuation of clomiphene, especially when increasing the dosage or duration of treatment.^5-7

Although the mechanism behind clomiphene-associated serious visual disturbances is not fully understood, several postulations have been proposed.^1,8 In addition to inducing the generation of thrombogenic oestradiol, which increases blood viscosity and coagulability, clomiphene may also cause ovarian hyperstimulation syndrome.^1,8,9 As a consequence of excess production of ovarian hormones and vasoactive substances, there is a depletion of  intravascular volume, resulting in haemoconcentration with a tendency towards blood coagulation. Such conditions may potentially make an individual more susceptible to serious visual disorders like ischaemic optic neuropathy, central retinal vein occlusion, or retinal detachment that are vascular-related disorders.

According to the literature, cases of serious visual disturbances leading to blindness have shown varied time-to-onset, occurring approximately from days to months after clomiphene ingestion.^1,7,9 While no precise risk factors have been identified, a few cases have reported a duration of use or a dosage exceeding the recommendations.^5-6

Adverse Drug Reaction Reports

To date, the NPRA has received 14 reports with 23 adverse events suspected to be related to clomiphene-containing products.¹⁰ As of now, no local reports of blindness linked to clomiphene have been received. However, one (1) event each of blurred vision, visual impairment, and photophobia was reported. Additionally, one (1) literature case report has documented visual disturbances associated with an abrupt increase in the clomiphene dose.¹¹

Advice for Healthcare Professionals

• While NPRA is still reviewing this safety issue, be aware that there have been post-marketing reports of blindness associated with clomiphene use, especially with increased dosage or duration of therapy.
• Given the seriousness and potential risk of permanent blindness, before starting treatment with clomiphene, ensure to:
  • Check if the patient has a history of visual problems previously diagnosed as related to clomiphene use;
  • Perform an ophthalmic examination and conduct regular examinations after starting clomiphene;
  • Counsel patients on the visual risks associated with clomiphene and emphasise the importance of compliance with the prescribed dose and treatment duration.
  • Advise patients to stop taking clomiphene immediately and seek urgent medical attention if they experience any visual disturbances during therapy.
• If visual disturbances are suspected, a comprehensive ophthalmological examination is necessary. If no other cause of visual disturbance is identified, consider discontinue clomiphene and switch to alternative treatment.
• Report all adverse events suspected to be related to the use of clomiphene to NPRA.

References:

1. Alizadeh Y, Moravvej Z, Khakpour Y, Azaripour E, Akbari M, Soltani-Moghadam R. Presumed clomiphene-induced optic neuropathy: A case report. Int J Reprod Biomed. 2021 Jun 23;19(5):471-476. Available from: https://doi.org/10.18502/ijrm.v19i5.9257
2. Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L Jr. A pharmacological review of selective oestrogen receptor modulators. Hum Reprod Update. 2000 May-Jun;6(3):212-24.available from: https://doi.org/10.1093/humupd/6.3.212
3. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2023 [cited 2023 Jul 5]. Available from: https://quest3plus.bpfk.gov.my/pmo2/index.php
4. National Pharmaceutical Regulatory Agency (NPRA). OVA-MIT (clomiphene) [Package Insert]. QUEST3+ Product Search. 2022 Jun [cited 2023 Jul 25]. Available from: http://www.npra.gov.my
5. France National Agency for the Safety of Medicines and Health Products (ANSM). CLOMID (clomiphene citrate): treatment should be discontinued if vision is impaired. [Internet]. 2023 Jun 27 [cited 2023 Jul 20]. Available from: https://ansm.sante.fr/actualites/clomid-citrate-de-clomifene-le-traitement-doit-etre-arrete-en-cas-dalteration-de-la-vision
6. France National Agency for the Safety of Medicines and Health Products (ANSM). Clomid 50mg, tablet: risk of serious visual disturbances (blindness). [Internet]. 2023 Jun 27 [cited 2023 Jul 20]. Available from: https://ansm.sante.fr/informations-de-securite/clomid-50-mg-comprime-risque-de-troubles-visuels-graves-cecite
7. Russom M, Pradeep B, Zeregabr M, Fessehatzion K, Araya N. Blindness and retinal disorder associated with clomifene citrate: Cases series assessment. Clin Med Invest. 2017;2(3):1-4. Available from: http://dx.doi.org/10.15761/CMI.1000133 
8. Lee VY, Liu DT, Li CL, Hoi-Fan, Lam DS. Central retinal vein occlusion associated with clomiphene-induced ovulation. Fertil Steril. 2008 Nov;90(5):2011.e11-2. Available from: https://doi.org/10.1016/j.fertnstert.2008.01.056
9. Lokaj AS, Rama B. Bilateral retinal detachment secondary to clomiphene citrate. Open Journal of Ophthalmology. 2018 Jan 8;8(1):31-5. Available from: https://doi.org/10.4236/ojoph.2018.81005
10. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2023 [cited 2023 Jul 6]. Available from: https://www.npra.gov.my (access restricted)
11. Ang CS. Visual disturbances with clomiphene. Med J Malaysia [Internet]. 2002 Jun [cited 2023 Jul 6];57(2):215-7. Available from: https://pubmed.ncbi.nlm.nih.gov/24326655/#full-view-affiliation-1

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