Isotretinoin and risk of psychiatric disorders and sexual dysfunction

Isotretinoin is a systemic oral retinoid that has been registered in Singapore since 1990. Currently, there are four brands registered, namely Acnotin (Goldplus Universal Pte Ltd), Nimegen (Zyfas Pharma Pte Ltd), Oratane (Apex Pharma Marketing Pte Ltd) and Roaccutane® (Roche Singapore Pte Ltd). It is indicated for the treatment of severe forms of acne (nodulo-cystic forms) and acne which has failed to respond to other therapies. The use of isotretinoin in paediatric patients less than 12 years of age has not been studied. Careful consideration should be given to patients aged 12 to 17 years who are being treated for severe recalcitrant nodular acne, especially for those with known metabolic or structural bone disease.

Psychiatric disorders and sexual dysfunction have previously been reported with the use of isotretinoin. HSA had reviewed the evidence on these associations in 2018 and 2017, respectively, and concluded that a definitive causal relationship could not be established due to limitations in the available data then. Nevertheless, as the role of isotretinoin in the development of psychiatric and sexual adverse events could not be ruled out, the local package inserts (PI) of isotretinoin products had been strengthened to include safety information on both risks.

Since our last review, new information has emerged, including published literature and actions taken by international drug regulatory agencies. This led HSA to re-evaluate whether the existing safety measures should be further strengthened. Based on the current available information, HSA, in consultation with its Product Vigilance Advisory Committee (PVAC), has concluded that the benefit-risk profile of isotretinoin remains favourable for its approved indications and the current product labelling is sufficient to mitigate both safety concerns.

Published literature

1) Isotretinoin and risk of psychiatric disorders

The association between isotretinoin and the risk of psychiatric disorders, particularly depression, has been investigated in several studies, but the results have been inconsistent and conflicting.1 Moreover, some studies have suggested that the risk of psychiatric disorders may be confounded by factors such as one’s underlying acne condition, acne severity, and physical symptoms induced by the prescribed acne medications (e.g., headache).2,3 Patients with severe acne may be particularly vulnerable to experiencing mental health symptoms triggered by acne-related psychosocial stress, low self-esteem, or acne flare-ups, especially among those with limited coping and emotional resilience. A study conducted by Paljarvi et al. (2022) found that isotretinoin was associated with a lower incidence of adverse neuropsychiatric outcomes compared to oral antibiotics, which are typically prescribed for patients with moderate to severe acne.3 Additionally, there have been other published studies supporting an improvement in the quality of life or symptoms of anxiety and depression with isotretinoin treatment.4,5

2) Isotretinoin and sexual dysfunction

The available evidence on the potential association between isotretinoin and sexual dysfunction, such as erectile dysfunction and decreased libido, is limited to case reports.6 Mental health issues arising from the underlying acne condition may also confound the relationship between isotretinoin and sexual dysfunction.7 Furthermore, several studies have shown that adolescents, an age group that is prescribed isotretinoin, commonly experience sexual distress due to the complex interplay of physical, social, and emotional factors (e.g., low sexual esteem and anxiety) that are typical during this developmental stage.8

International situation

In 2019, the UK Medicines and Healthcare products Regulatory Agency’s (MHRA) advisory committee, the Commission on Human Medicines (CHM), endorsed an independent review by the Isotretinoin Expert Working Group (IEWG) to address concerns raised by patients, families, and other stakeholders regarding the potential adverse effects of isotretinoin on mental health and sexual function when used for acne treatment. The review aimed to evaluate the impact of these adverse effects on the balance of benefits and risks of isotretinoin treatment. The CHM's review findings were published in April 2023, and their recommendations included warnings on the potential risk of psychiatric and sexual disorders and the need of patient counselling in isotretinoin product labels, improvement in their assessment and monitoring, and additional oversight of treatment initiation for patients under 18 years old. 9 These new safety measures and supporting materials were implemented by the UK MHRA on 31 October 2023, and healthcare professionals were advised to integrate them into their clinical practice to strengthen the safe use of isotretinoin.10

Other international drug regulatory agencies[a] had also previously reviewed the risks of psychiatric disorders and sexual dysfunction with isotretinoin between 2016 to 2018, and most of them had not imposed safety measures beyond product information labelling to mitigate these risks. At present, no additional safety measures have been implemented by these agencies in response to the UK MHRA’s regulatory actions.

[a] US Food and Drug Administration (FDA), European Medicines Agency (EMA), Health Canada, Australia Therapeutic Goods Administration (TGA)

Local situation

Based on the local sales data, the estimated patient exposure to isotretinoin has remained relatively stable between January 2019 and June 2023, ranging from approximately 3,500 to 4,500 patient-years. Given its long history of use in the local market, there were few local reports of suspected psychiatric disorders and sexual dysfunction associated with isotretinoin. Of the 65 local adverse event reports received for isotretinoin between 1999 to 2023, three were related to psychiatric disorders (depression, psychotic disorder, and suicidal ideation), while one reported erectile dysfunction. These reports generally had limited information or were confounded by the patients’ medical history which precluded a meaningful causality assessment. However, we cannot rule out the possibility of under-reporting of these adverse events.

The local PIs of isotretinoin products currently already contain warnings on psychiatric disorders such as depression, anxiety, mood alterations, psychotic disorders and suicidal ideation. Sexual dysfunction, including erectile dysfunction and decreased libido, are also listed in the local PI as adverse events reported in the post-market setting. Patient educational materials for isotretinoin are available on publicly accessible platforms, including the Medication Information Leaflets (MILs) on HealthHub.11 These MILs provide a brief overview on the administration of isotretinoin and its potential adverse effects. They have highlighted the rare but serious adverse effect of mood changes including depression which require immediate medical advice.

HSA’s assessment and advisory

HSA, in consultation with its PVAC, has assessed that the benefit-risk profile of isotretinoin remains favourable and the warnings and safety information in the local PIs of isotretinoin products are sufficient to manage the risks of psychiatric disorders and sexual dysfunction. Nevertheless, it would be relevant to remind healthcare professionals who are prescribing isotretinoin of these potential risks and the relevant measures to be taken.

To allow for prompt detection and management of these adverse effects, healthcare professionals may wish to consider counselling and screening their patients for depressive symptoms or other psychiatric adverse effects when prescribing isotretinoin. They may also consider referring their patients to the relevant specialists for further assessment, if necessary. Healthcare professionals may refer to the available MILs on isotretinoin during medication counselling to facilitate the communication of isotretinoin use and its adverse effects to patients and/or their caregivers.

References

  1. BMJ Open 2019; 9: e021549
  2. JAMA Dermatol 2019; 155: 1162-1166
  3. Br J Dermatol 2022; 187: 64-72
  4. JAMA Dermatol 2020; 156: 1098-1106
  5. Acta Derm Venereol 2013; 93: 701-706
  6. Sex Med 2022; 10: 100543
  7. J Am Acad Dermatol 2019; 81: 163-172
  8. https://www.dermcoll.edu.au/wp-content/uploads/2023/11/ACD-Position-Statement-Isotretinoin-November-2023-Final-version.pdf
  9. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1153036/Isotretinoin-final-CHM-report-26April2023.pdf
  10. https://www.gov.uk/drug-safety-update/isotretinoin-roaccutanev-introduction-of-new-safety-measures-including-additional-oversight-of-the-initiation-of-treatment-for-patients-under-18-years-of-age
  11. https://www.healthhub.sg/a-z/medications/isotretinoin
Healthcare professional, Industry member, Therapeutic Products
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