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

Isotretinoin, or 13-cis-retinoic acid, is a type of retinoids, which is a vitamin A derivative used to treat acne.^1-4 Isotretinoin is believed to improve acne through various mechanisms, which include decreasing sebaceous gland size and sebum production, normalising follicular keratinisation, suppressing the growth of Cutibacterium acnes, and decreasing dermal inflammation. It impacts all major aetiological factors implicated in acne, affecting cell-cycle progression, cellular differentiation, sebocyte survival and apoptosis, as well as hormones in the hypothalamo–pituitary axis.⁴ There is accumulating evidence that suggests the therapeutic, adverse, and teratogenic effects of isotretinoin may all be mediated by the upregulation of Forkhead box O (FoxO)-mediated gene transcription.

In Malaysia, isotretinoin is indicated for the treatment of severe forms of acne and acne that has failed to respond to standard therapies with systemic antibacterials and topical therapy.² There are currently eight (8) products containing isotretinoin registered in Malaysia, all of which are available in oral capsule forms.⁵ In 2020, the special conditional registration for all oral retinoids indicated for skin disease was updated, specifying that those products shall only be sold or supplied to, and prescribed by (i) dermatologists registered in the National Specialist Register, or (ii) dermatologists serving in any government health facilities.⁶

 

Background of the Safety Issue

In April 2023, the United Kingdom (UK)’s Medicines and Healthcare products Regulatory Agency (MHRA) introduced a number of new safety measures aimed at strengthening the safety of isotretinoin treatment, particularly concerning the risks of psychiatric disorders and sexual dysfunction.⁷ These measures were based on recommendations made by the Isotretinoin Expert Working Group (IEWG) formed in September 2019 by the Commission on Human Medicines (CHM), an independent body that advises ministers on the safety, efficacy, and quality of medicines in the UK.^4,7

The in-depth safety review by the IEWG of the CHM concluded that the currently available data is unable to definitively confirm that isotretinoin caused the psychiatric and sexual side effects.^4,7 However, given that the individual experiences of patients and families continue to raise concerns, the CHM has recommended new measures to further strengthen the current practice of isotretinoin treatment. Additionally, the CHM has established a new Implementation Advisory Expert Working Group, composed of experts and representatives of health care organisations, to aid in the implementation of these recommendations, which include:

1. Isotretinoin should not be used for the treatment of prepubertal acne and is not recommended in children younger than 12 years of age.
2. For patients younger than 18 years of age, two (2) prescribers have to jointly agree that the acne is severe enough to justify treatment with isotretinoin, and that other treatments have been sufficiently tried and found ineffective.
3. The product information and educational materials for isotretinoin will be updated with these new requirements and some new information, such as:

• • Reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of isotretinoin.
  • Patients, and where applicable their families, must be counselled about the risk of psychiatric side effects and sexual dysfunction prior to the initiation of treatment
  • Patients have to undergo an assessment of their mental health and sexual function prior to treatment and should be monitored throughout the treatment.

Psychiatric Disorders

Psychiatric adverse events, including depression, anxiety, and psychotic symptoms, have been reported in patients treated with isotretinoin.^4,7

Recent theories for the pathogenesis of depression suggest impairments of neurogenesis in the hippocampus (a brain region associated with mood disorders).⁴ Isotretinoin is hypothesised to induce depression through several mechanisms, including apoptosis of hippocampal cells via upregulation of FoxO1 leading to impaired hippocampal neurogenesis, alterations in the serotonergic signalling system, effects on the brain dopamine system, changes in biotin and homocysteine metabolism, as well as impact on the hypothalamo–pituitary axis. While data on the link between isotretinoin and psychosis are limited, a significant retinoic acid-inducible gene 1 (RAI-1) upregulation has been observed in the brains of patients with schizophrenia, bipolar disorder, or major depression.

Sexual dysfunction

Sexual dysfunction including erectile dysfunction, decreased libido, vulvovaginal dryness, difficulties achieving orgasm, and reduced sensation in the genital area have also been reported following isotretinoin use.⁴ Some cases have also reported persistent sexual dysfunction even after discontinuing isotretinoin.

The mechanism behind isotretinoin-induced sexual dysfunction remains theoretical and not fully understood.⁷ It may involve a reduction in testosterone levels and an impact on male hormone receptors, but further research is required for clarification.

The NPRA has previously issued a directive [Ruj. Kami: (6) dlm. BPFK/PPP/07/25 Jld. 3] to request product registration holders of all oral retinoid products to update the package insert and consumer medication information leaflet (RiMUP) to include information regarding the risk of neuropsychiatric disorders, and has issued a safety alert to communicate this risk.

 

Adverse Drug Reaction Reports⁸

To date, the NPRA had received a total of 54 reports concerning 113 adverse events suspected to be associated with isotretinoin-containing products. Among the received reports, one (1) report detailed events of depressed mood, anxiety symptoms, and stress, and another one (1) report noted vaginal irritation following isotretinoin use.

 

Advice for Health Care Providers

• Be aware that there have been reported cases of psychiatric disorders or sexual dysfunction following isotretinoin use.
• Prescribe isotretinoin only after other alternatives had been sufficiently tried and found to be unsuccessful.
• Assess patient’s mental health and sexual function before starting treatment and monitor regularly for signs of psychiatric symptoms or sexual dysfunction.
• Fully inform patients and their families on the potential risks of isotretinoin.
• Advise patients to request family members and friends to help monitor for potential psychiatric symptoms.
• Encourage an open dialogue with patients regarding their sexual health especially after taking isotretinoin.
• Educate patients to seek medical advice if they feel their mental health or sexual function is affected or is worsening.
• Be vigilant as there are reported cases of persistent sexual dysfunction even after the discontinuation of isotretinoin.
• Stopping isotretinoin treatment may not be sufficient to alleviate the psychiatric symptoms. A referral for psychiatric evaluation may be warranted.
• Report all suspected adverse events associated with isotretinoin-containing products to the NPRA.

 

References:

1. Blaner WS. Cellular metabolism and actions of 13-cis-retinoic acid. Journal of the American Academy of Dermatology. 2001;45(5). Available from: https://doi.org/10.1067/mjd.2001.113714
2. National Pharmaceutical Regulatory Agency (NPRA). ROACCUTANE (isotretinoin) [Package Insert]. QUEST3+ Product Search. 2023 Jul 11 [cited 2023 Jul 11]. Available from: http://www.npra.gov.my
3. Fallah H, Rademaker M. Isotretinoin in the management of acne vulgaris: practical prescribing [Internet]. Int J Dermatol. 2021 Apr;60 [cited 2023 Jul 24] (4):451-460. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/ijd.15089
4. Commission on Human Medicines. Report of The Commission On Human Medicines Isotretinoin Expert Working Group [Internet]. 2023 Apr 26 [cited 2023 Jul 24]. Available from: https://www.gov.uk/government/publications/report-of-the-commission-on-human-medicines-isotretinoin-expert-working-group
5. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2023 [cited 2023 Jul 11]. Available from: https://www.npra.gov.my
6. National Pharmaceutical Regulatory Agency (NPRA). Peraturan-Peraturan Kawalan Dadah Dan Kosmetik 1984. Arahan Pengarah Perkhidmatan Farmasi Bilangan 17 Tahun 2020: Direktif Berkenaan Pindaan Syarat Pendaftaran Khas Bagi Produk Yang Mengandungi Oral Retinoid Yang Diindikasikan Untuk Rawatan Penyakit Kulit [Internet]. 2023 [cited 2023 Jul 11]. Available from: https://www.npra.gov.my/easyarticles/images/users/1048/gambar/DIREKTIF17_2020.pdf
7. Medicines and Healthcare Products Regulatory Agency (MHRA). Isotretinoin (Roaccutane▼): new safety measures to be introduced in the coming months, including additional oversight on initiation of treatment for patients under 18 years [Internet]. Drug Safety Update. 2023 Apr 26 [cited 2023 Jul 11]. Available from: https://www.gov.uk/drug-safety-update/isotretinoin-roaccutanev-new-safety-measures-to-be-introduced-in-the-coming-months-including-additional-oversight-on-initiation-of-treatment-for-patients-under-18-years
8. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2023 [cited 2023 Jul 4]. 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