Oral retinoid medicines▼: revised and simplified pregnancy prevention educational materials for healthcare professionals and women

New prescriber checklists, patient reminder cards, and pharmacy checklists are available to support the Pregnancy Prevention Programme in women taking acitretin, alitretinoin, and isotretinoin. Advice about the risk of neuropsychiatric reactions has been made consistent for all oral retinoid medicines.

Advice for healthcare professionals about teratogenicity:

  • following a detailed review, educational materials to support the Pregnancy Prevention Programme for the oral retinoid medicines acitretin, alitretinoin, and isotretinoin have been revised and simplified
  • due to a high risk of serious congenital malformations, these medicines must not be used in pregnancy, and any use in women and girls must be within the conditions of a Pregnancy Prevention Programme, which are consistent with those previously in place (see below)

Advice for healthcare professionals about neuropsychiatric reactions:

  • advice about a possible risk of neuropsychiatric reactions has been made consistent for oral retinoid medicines (acitretin, alitretinoin, bexarotene, isotretinoin, and tretinoin)

  • monitor any patients treated with an oral retinoid for signs of depression or suicidal ideation and refer for appropriate treatment, if necessary; particular care needs to be taken in patients with history of depression

  • advise patients taking an oral retinoid that they may experience changes in their mood or behaviour and that they should speak to their doctor if their mood is affected; they should be encouraged to let family and friends know they are taking an oral retinoid so they can look out for any change in mood

  • report any suspected adverse drug reactions to retinoid medicines to the Yellow Card Scheme

Background

Retinoid-containing medicinal products are available in oral and topical forms.

An EU in-depth review of all the available data on safety and efficacy for all retinoid medicines concluded that the balance between benefits and risks for retinoids remains favourable. The review recommended that educational materials for patients and healthcare professionals about pregnancy prevention measures should be simplified and made consistent and warnings about neuropsychiatric disorders harmonised across oral retinoid medicines (see EMA Public Assessment Report).

Review of the effectiveness of pregnancy prevention measures

Revised and simplified educational materials

Women and girls of childbearing potential taking oral retinoids to treat dermatological conditions must be supported by a Pregnancy Prevention Programme.

The retinoid medicines that have a Pregnancy Prevention Programme as a condition of the licence are oral isotretinoin (Roaccutane▼) for severe acne, oral acitretin (Neotigason▼) for severe psoriasis, and oral alitretinoin (Toctino▼) for chronic severe hand eczema. The regulatory requirement for a Pregnancy Prevention Programme has been in place for female patients taking these oral retinoids since 2005.

The requirements of the Pregnancy Prevention Programme have not changed.

Educational materials to support healthcare professionals and female patients using acitretin, alitretinoin, and isotretinoin have been simplified and are now consistent, irrespective of which brand of medicine a patient receives. The educational materials are:

  • prescriber checklist – to be used by the dermatologist, specialist dermatology nurse, or a prescribing GP with a special interest in dermatology to record the discussion of risks with the patient. A copy should be provided to the patient
  • patient card – to be given by the dermatologist, specialist dermatology nurses, or prescribing GP to reinforce the key safety messages around risks
  • pharmacist checklist – to be used as an aide memoire by pharmacists when dispensing oral retinoid medicines.

New educational materials are available in electronic format at https://www.medicines.org.uk/emc and hardcopy distribution is ongoing to dermatology clinical teams, including consultant dermatologists, and to hospital pharmacists. A letter for healthcare professionals to accompany the materials is also available.

Reminder of pregnancy testing requirements

The terms of the Pregnancy Prevention Programme include that female patients at risk of pregnancy should receive regular follow-up and pregnancy testing, depending on method of contraception and pregnancy risk. The regulatory advice for pregnancy testing requirements of oral retinoids is displayed in the table below. Ideally pregnancy testing should be done on the same day as the issuing and dispensing of the prescription. The dates and results of pregnancy tests should be documented in the medical notes.

Oral retinoid medicine Pregnancy testing advice before therapy Pregnancy testing advice during therapy Pregnancy testing advice after therapy
       
Acitretin (Neotigason▼) Up to 3 days before the first dose is given Ideally monthly, according to risk of pregnancy* 1–3 monthly intervals for 3 years after stopping treatment
Alitretinoin (Toctino▼) Shortly before first prescription (preferably a few days) Ideally monthly, according to risk of pregnancy* 1 month after stopping treatment
Isotretinoin (Roaccutane▼) Shortly before first prescription (preferably a few days) Ideally monthly, according to risk of pregnancy* 1 month after stopping treatment

*The need for repeated medically supervised pregnancy tests every month should be determined according to local practice including consideration of the patient’s sexual activity, recent menstrual history (abnormal menses, missed periods or amenorrhea), and method of contraception.

Teratogenic risk with topical retinoids

Systemic exposure is thought to be negligible following application of topical retinoids (topical adapalene, alitretinoin, isotretinoin, tazarotene, and tretinoin) during pregnancy. However, since risk cannot be excluded, use of topical retinoids is contraindicated during pregnancy as a precaution. Women and girls should be advised not to use topical retinoids if they are planning a pregnancy and to use effective contraception to minimise the risk of accidental exposure in pregnancy if they are of childbearing potential.

Oral retinoids indicated for haematological malignancies

Oral tretinoin (Vesanoid) is authorised for promyelocytic leukaemia. Oral bexarotene (Targretin) is authorised for T-cell lymphoma. These two products do not have a Pregnancy Prevention Programme in light of their oncology indication and specialist care setting. However, they are extremely teratogenic and the Summaries of Product Characteristics for these medicines should be consulted for contraceptive and pregnancy testing requirements in female patients at risk of pregnancy.

Review of risk of neuropsychiatric disorders

Harmonised warnings and advice

Evidence for a possible link between isotretinoin and psychiatric disorders (for example, depression, suicidal behaviour) has been under review for many years. The MHRA has monitored reports closely and since 2015 advice has been present in the Patient Information Leaflet for isotretinoin that patients should discuss any history of mental illness with their doctor before taking isotretinoin.

Cases of newly diagnosed depression, worsening of existing depression, and anxiety have been reported with oral retinoids. The limitations of the available data did not allow the review to establish a clear causal association between risk of neuropsychiatric disorders and use of oral retinoids. However, patients with severe skin conditions may be more likely to develop neuropsychiatric disorders due to the nature of the disease. The review therefore concluded that the prescribing information for oral retinoids should include a warning to ensure patients are informed about the possible risk and what to do if symptoms occur (see EU Public Assessment Report).

Therefore, advice about monitoring for neuropsychiatric disorders has been made consistent for alitretinoin and isotretinoin products, and added to the product information for acitretin, tretinoin and bexarotene. Advice about monitoring for neuropsychiatric disorders All patients treated with an oral retinoid should be monitored for signs of depression or suicidal ideation and refer for appropriate treatment, if necessary. Particular care needs to be taken in patients with history of depression. Healthcare professionals should discuss with patients taking an oral retinoid that they may experience changes in their mood or behaviour and to talk to their doctor if their mood is affected. Patients should also be encouraged to let family and friends know they are taking an oral retinoid so they can look out for any change in mood.

Topical retinoids and neuropsychiatric disorders

For topical retinoids (adapalene, alitretinoin, isotretinoin, tazarotene, and tretinoin), the review concluded that data show systemic exposure is negligible following topical application and is unlikely to be associated with an increased risk of neuropsychiatric disorders (see EU Public Assessment Report).

Report suspected adverse drug reactions

Please continue to report any suspected adverse drug reactions (ADRs) associated with retinoid medicines to the MHRA through the Yellow Card Scheme. It is easiest and quickest to report ADRs online via the Yellow Cards website or via the Yellow Card app available from Apple App Store and Google Play Store.

See article in the January 2019 Drug Safety Update for how you can use the Yellow Card App to report ADRs linked to exposure of medicines in pregnancy.

Article citation: Drug Safety Update volume 12, issue 11: June 2019: 4.

Published 19 June 2019