The European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has concluded its review of retinoid medicines and has recommended updating the measures for pregnancy prevention and including a warning on the possible risk of neuropsychiatric disorders (such as depression, anxiety and mood changes). Retinoids include the active substances acitretin, adapalene, alitretinoin, bexarotene, isotretinoin, tazarotene and tretinoin. They are taken by mouth or applied as creams or gels to treat several conditions mainly affecting the skin, including severe acne and psoriasis. Some retinoids are also used to treat certain forms of cancer.
During its review, the PRAC assessed the available data including published literature and post-marketing reports of side effects, and also sought the views of patients and healthcare professionals in a dedicated stakeholder meeting and a successive written consultation. The PRAC recommendations are summarised below.
Regarding pregnancy prevention, the PRAC confirmed that all oral (taken by mouth) retinoids can have harmful effects on the unborn child and therefore must not be used during pregnancy. In addition, the oral retinoids acitretin, alitretinoin and isotretinoin must not be taken by women able to have children unless the conditions of a pregnancy prevention programme (PPP) are met. Although PPPs for these retinoids were already in place in some EU Member States, the PRAC has now updated and harmonised the PPP to ensure it is optimal to support the discussion between the doctor and the patient on the risks of these medicines, and that it is followed in practice. In particular, the new PPP includes assessing patients for the likelihood of becoming pregnant, requirements around pregnancy testing and the need for effective contraception before, during and after treatment, and ensuring that patients and prescribers go through an ‘acknowledgement form’ to confirm that appropriate advice has been given. Educational materials for doctors and a reminder card for patients will also be provided.
The companies that market acitretin, alitretinoin and isotretinoin will also conduct a study and a survey to assess the effectiveness of the updated measures, particularly to check how the PPP is implemented.
For the oral retinoids bexarotene and tretinoin a PPP was not considered necessary because these medicines, which are used to treat certain cancers, are used in a very different patient population under strict medical supervision and the current measures are considered appropriate for pregnancy prevention.
For topical (applied to the skin) retinoids, the data showed that the amount of active substance absorbed from the skin into the body is extremely low, and therefore these products are unlikely to cause harm to the unborn child. However, excessive use or skin lesions could possibly increase the absorption of retinoids. Therefore, as a precaution, the PRAC recommended that topical retinoids must also not be used during pregnancy and in women planning to have a baby.
The PRAC also reviewed the available data on the possible risk of neuropsychiatric disorders such as depression, anxiety and mood changes with retinoids. Although warnings about this possible risk were already included in the product information for some oral retinoids, the Committee reviewed the extent and nature of these warnings to ensure that they reflect the available evidence, and that they are applied consistently.
For oral retinoids, the PRAC noted the limitations of the available data, and considered that it could not be clearly established whether this risk was due to the use of these medicines. However, the PRAC recognised that patients with severe skin conditions may be more vulnerable to neuropsychiatric disorders due to the nature of the disease. The PRAC therefore recommended that the prescribing information for all oral retinoids should include a warning about this risk, including signs and symptoms patients and their families should be aware of (such as changes in mood or behaviour).
For topical retinoids, the available data, although extremely limited, suggest that these medicines do not carry a risk of psychiatric side effects and therefore no additional warnings need to be added to the prescribing information.
Please refer to the following website in EMA for details:
http://www.ema.europa.eu/../human_referral_prac_000061.jsp&mid=WC0b01ac05805c516f
In Hong Kong, there are 49 registered pharmaceutical products containing retinoids, including acitretin (2 products), adapalene (14), isotretinoin (11), tazarotene (3) and tretinoin (19). All products are prescription-only medicines. There is no registered pharmaceutical product containing alitretinoin or bexarotene. Related news was previously issued by EMA, and was posted on the Drug Office website on 9 Jul 2016. So far, the Department of Health (DH) has received 2 cases of adverse drug reaction (ADR) related to isotretinoin associated with miscarriage and ectopic pregnancy. DH has also received 3 cases of ADR related to tretinoin, but none of them was related to adverse effects in pregnancy and of neuropsychiatric disorders. DH has not received any case of ADR related to other retinoids.
In light of the above EMA’s announcement, letters to inform local healthcare professionals will be issued. As the PRAC recommendations will now be sent to the Committee for Medicinal Products for Human Use (CHMP) for further adoption, DH will remain vigilant on the development of the issue and safety update of the drugs issued by other overseas drug regulatory authorities.
Ends/Saturday, Feb 10, 2018
Issued at HKT 14:00
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