HSA announces a safety alert on 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) in Singapore. 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 in Singapore had been strengthened to include safety information on both risks.
Since HSA’s 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.
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. 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.
Other international drug regulatory agencies, namely, US Food and Drug Administration (FDA), European Medicines Agency (EMA), Health Canada, Australia Therapeutic Goods Administration (TGA), 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.
Based on the sales data in Singapore, 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 in Singapore, 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, HSA cannot rule out the possibility of under-reporting of these adverse events.
The local PIs of isotretinoin products in Singapore 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. 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, 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.
Please refer to the following website in HSA for details:
http://www.hsa.gov.sg/announcements/safety-alert/isotretinoin-and-risk-of-psychiatric-disorders-and-sexual-dysfunction
In Hong Kong, there are 11 registered pharmaceutical products containing isotretinoin. All products are prescription-only medicines. So far, the Department of Health (DH) has received 2 cases of adverse drug reaction related to isotretinoin, but these cases were not related to mental health or sexual function side effects. Related news was previously issued by MHRA, and was posted on the Drug Office website since 27 Oct 2017, with the latest update posted on 1 Nov 2023. Letters to inform local healthcare professionals were issued by the DH on 27 Oct 2017 and 27 Apr 2023.
Currently, the sales pack or package insert of locally registered isotretinoin-containing products should include warnings on suicide, suicidal attempts and sexual dysfunction including erectile dysfunction and decreased libido.
As previously reported, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/ Saturday, December 16, 2023
Issued at HKT 19:00
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