Retinoid-containing medicinal products

• Retinoid medicines, used mainly to treat conditions affecting the skin such as severe acne, are harmful to the unborn baby if taken during pregnancy.
• Oral (taken by mouth) retinoids 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 special pregnancy prevention programme are met.
• The pregnancy prevention programme for acitretin, alitretinoin and isotretinoin includes:
  • pregnancy tests before, during and after stopping treatment;
  • the need to use at least one effective method of contraception during and after treatment;
  • an 'acknowledgement form' to confirm that appropriate advice has been given to patients;
  • a 'patient reminder card' stating that the medicine must not be used during pregnancy, and including information about pregnancy testing and the need to use effective contraception.
• The above information will also be included in the package leaflet, and a boxed warning will be added to the outer packaging.
• Topical (applied to the skin) retinoids are less likely to cause harm to the unborn child. However, as a precaution, they must not be used during pregnancy and by women planning to have a baby.
• With oral retinoids, there may be a possible risk of disorders such as depression and anxiety. Warnings will be included in the package leaflet of oral retinoids, as well as signs and symptoms that patients and their families should look out for (such as changes in mood or behaviour).
• Patients who have any questions should speak to their doctor or pharmacist.

A review of available data on teratogenicity and neuropsychiatric disorders with retinoid medicines has concluded that there is the need to strengthen the recommendations for pregnancy prevention and to raise awareness about possible neuropsychiatric risks.

• Oral retinoids (acitretin, alitretinoin, bexarotene, isotretinoin and tretinoin) are highly teratogenic and must not be used during pregnancy.
• Acitretin, alitretinoin and isotretinoin must be used in accordance with the conditions of a pregnancy prevention programme (PPP) for all women of childbearing potential. These include:
  • an assessment of each woman's potential for becoming pregnant;
  • pregnancy tests before starting treatment, during treatment and after treatment;
  • the need for at least one effective method of contraception during and after treatment;
  • a 'risk acknowledgement form' for patients and prescribers to go through and confirm that appropriate advice has been given and understood.
• For bexarotene and oral tretinoin it is considered that, in the light of the target population and an oncological indication subject to specialist care in the hospital setting, the implementation of a PPP is not necessary.
• Updated educational material will be provided to guide the discussion about the risks of oral retinoids before prescribing acitretin, alitretinoin and isotretinoin to women of childbearing potential.
• For topical retinoids (adapalene, alitretinoin, isotretinoin, tazarotene and tretinoin), the available data show that systemic absorption is negligible following topical application and that these products are unlikely to cause fetal harm. However, as a precaution, topical retinoids are contraindicated in pregnant women and in women planning a pregnancy.
• Cases of depression, depression-aggravated anxiety and mood alterations have been reported rarely in patients taking oral retinoids. Evidence from published literature and individual case reports is conflicting, and many published studies have a number of limitations. On this basis, it has not been possible to identify a clear increase in the risk of neuropsychiatric disorders in people who take oral retinoids compared to those that do not.
• However, since severe skin disorders themselves increase the risk of psychiatric disorders, a warning about this possible risk is being included in the product information for oral retinoids.
• Patients taking oral retinoids should be advised that they may experience changes in their mood and/or behaviour and that they and their families should be alert to this, and speak to their doctor if this occurs.
• Patients treated with oral retinoids should be monitored for signs and symptoms of depression and referred for appropriate treatment, if necessary. Particular care should be taken in patients with history of depression.
• For topically applied retinoids (adapalene, alitretinoin, isotretinoin, tazarotene and tretinoin), systemic absorption is negligible, and unlikely to result in psychiatric disorders.

Retinoids are vitamin A derivatives that are available as capsules to be taken by mouth or as creams and gels to be applied to the skin. Retinoids taken by mouth are used to treat various forms of severe acne, severe hand eczema that does not respond to treatment with corticosteroids, severe forms of psoriasis and other skin conditions, and certain types of cancer. Retinoids applied to the skin are used to treat various skin conditions including mild to moderate acne.

The following retinoids have been authorised nationally in a number of Member States of the EU and are covered by this review: acitretin, adapalene, alitretinoin, isotretinoin, tazarotene and tretinoin. Alitretinoin has also been authorised centrally as Panretin for the treatment of skin lesions in AIDS patients with Kaposi's sarcoma (a type of skin cancer). Bexarotene has been authorised centrally as Targretin for the treatment of cutaneous T-cell lymphoma (CTCL, a rare cancer of the lymph tissue).

The review of retinoid medicines was initiated on 8 July 2016 at the request of the United Kingdom, under Article 31 of Directive 2001/83/EC.

The review was first carried out by the Pharmacovigilance Risk Assessment Committee (PRAC), the Committee responsible for the evaluation of safety issues for human medicines, which has made a set of recommendations. The PRAC recommendations were sent to the Committee for Medicinal Products for Human Use (CHMP), responsible for questions concerning medicines for human use, which adopted the Agency's opinion.

The CHMP opinion was forwarded to the European Commission, which issued a final legally binding decision applicable in all EU Member States on 21/06/2018.