Isotretinoin (Roaccutane▼): new safety measures to be introduced in the coming months, including additional oversight on initiation of treatment for patients under 18 years

The Isotretinoin Expert Working Group of the Commission on Human Medicines has made recommendations to strengthen the safety of isotretinoin treatment. Recommendations include new warnings, the need for consistent monitoring requirements for psychiatric side effects, the introduction of new monitoring requirements for sexual side effects, and additional oversight of the initiation of treatment for patients younger than 18 years.

From:
Medicines and Healthcare products Regulatory Agency
Published
26 April 2023
Therapeutic area:
Dermatology

Following this article, in October 2023 we published new advice to strengthen the safe use of isotretinoin through the introduction of additional oversight of the initiation of isotretinoin in patients under 18 years and through improved assessment and monitoring of mental health and sexual function issues.

The advice in this article is therefore superseded and all healthcare professionals should consult the October 2023 Drug Safety Update when referring patients and when prescribing or dispensing isotretinoin.

Summary

The Isotretinoin Expert Working Group of the Commission on Human Medicines has made recommendations to strengthen the safety of isotretinoin treatment. Recommendations include new warnings, the need for consistent monitoring requirements for psychiatric side effects, the introduction of new monitoring requirements for sexual side effects, and additional oversight of the initiation of treatment for patients younger than 18 years.

While processes to support the implementation of these recommendations across the healthcare system are being developed, prescribers of isotretinoin are reminded of the need to fully inform all patients of the potential benefits and risks associated with isotretinoin treatment and monitor patients closely for any side effects throughout treatment.

No new action from healthcare professionals is needed for now – further communications will be issued once these recommendations are being implemented.

Information on the safety review:

  • the Commission on Human Medicines (CHM) and its Isotretinoin Expert Working Group has recommended new measures to strengthen the safety of isotretinoin treatment – see report and summary report of the recommendations
  • recommendations include the addition of new warnings for the risk of sexual dysfunction, including the possibility of persistence after treatment discontinuation, and advice for healthcare professionals to ask patients about symptoms or signs of sexual dysfunction prior to starting treatment with isotretinoin and to monitor patients for the development of new sexual disorders during treatment
  • recommendations also include the development of consistent monitoring requirements for potential psychiatric and sexual side effects in all patients throughout treatment
  • the initiation of treatment in patients younger than 18 years will require 2 prescribers to agree a patient’s acne is severe and that there is no other effective treatment before initiation of isotretinoin therapy
  • the CHM has formed an Implementation Advisory Group, which is composed of experts and representatives of healthcare organisations, to advise on the implementation of these recommendations
  • no new action is needed from healthcare professionals for now, but we ask prescribers to fully discuss the risks with patients considering isotretinoin

Advice for healthcare professionals:

  • isotretinoin is indicated for severe forms of acne (such as nodular or conglobate acne or acne at risk of permanent scarring) resistant to adequate courses of standard therapy with systemic anti-bacterials and topical therapy
  • continue to follow strict precautions on prescribing isotretinoin, including the conditions of the isotretinoin Pregnancy Prevention Programme
  • fully inform patients about the potential risks in addition to the expected benefits before prescribing isotretinoin
  • assess an individual’s mental health before initiation of isotretinoin and monitor regularly for developing or worsening psychiatric disorders
  • tell patients to seek advice if they feel their mental health or sexual function is affected or is worsening – patients with a serious side effect should be told to stop their treatment and seek urgent medical advice
  • report suspected adverse drug reactions associated with isotretinoin on a Yellow Card

Advice to provide to patients and caregivers:

  • isotretinoin is effective for severe types of acne, especially if there is a risk of permanent scarring, but like every medicine it is associated with a risk of side effects
  • isotretinoin should only be used when other treatments for acne have not worked
  • not every patient has side effects, but you should know about the risks and what to do if they occur — read the leaflet that comes with your medicine to learn about the risks associated with isotretinoin
  • take time to think about the information from your doctor about the benefits and risks of isotretinoin, and decide if isotretinoin is the right treatment for you
  • report side effects associated with isotretinoin directly to the MHRA via the Yellow Card scheme

Isotretinoin indication and potential risks

Isotretinoin is a treatment for severe acne. It should only be prescribed to treat severe forms of acne that have not responded to other treatments, such as antibiotics and topical treatments (creams or gels). Isotretinoin capsules are also known by the brand names Roaccutane and Reticutan in the UK.

Isotretinoin has a number of important risks, including causing significant harm to an unborn baby if used during pregnancy. Blood testing is required for all patients on isotretinoin to monitor for abnormalities associated with hepatobiliary disorders and lipid metabolism.

Suspected psychiatric disorders and cases of sexual dysfunction have also been reported by patients on isotretinoin and these issues should be managed promptly (see section below).

Isotretinoin Expert Working Group Review

In September 2019, the Commission on Human Medicines (CHM) formed the Isotretinoin Expert Working Group (IEWG) to review the safety of isotretinoin, in particular concerns about suspected psychiatric and sexual side effects and whether, in some cases, these continue after use of isotretinoin has been stopped (see Drug Safety Update, August 2020).

The IEWG considered the available information on psychiatric and sexual side effects suspected to be associated with isotretinoin. This included suspected side effects reported to the MHRA via the Yellow Card scheme, research into the risks and the biological mechanisms that may explain these events, from published studies about patients taking isotretinoin, and information on how isotretinoin safety is managed in other countries. A public call for information resulted in 659 responses with views from patients, families, and other stakeholders and more than 7 hours of direct presentations, which were considered carefully by the IEWG in making its recommendations.

The recommendations of the expert safety review are available in the Report of the Commission on Human Medicines Isotretinoin Expert Working Group and the plain-language summary of the recommendations.

Recommendations from the review

The IEWG considered all the available evidence, including information from patients and their families and concluded that gaps in the available evidence meant that it was not possible to say that isotretinoin definitively caused many of the short-term or longer-term psychiatric and sexual side effects. However, the individual experiences of patients and families continue to cause concern and the Group emphasised the need for patients to be informed about the risks before starting isotretinoin treatment, for there to be additional oversight of prescribing in young patients under 18, and for patients to be consistently monitored for side effects. Following the review and endorsement by the CHM, the MHRA will be introducing a number of measures to strengthen the safety of isotretinoin.

Isotretinoin should not be used for the treatment of prepubertal acne and is not recommended in children younger than 12 years of age. For patients younger than 18 years of age, there will also be a requirement for two prescribers to jointly agree that the acne is severe enough to justify treatment with isotretinoin and that other standard treatments have been sufficiently tried and were ineffective before isotretinoin is started. There will be further communication when this requirement is implemented.

The product information for isotretinoin medicines is being updated with these new requirements and to add new information and warnings regarding psychiatric and sexual disorders. This will include a warning that there have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of isotretinoin.

The product information will state that patients, and where applicable their families, must be counselled about the risk of psychiatric side effects and sexual dysfunction prior to prescription of isotretinoin. Patients should have an assessment of their mental health and sexual function prior to treatment and should be monitored during treatment for developing psychiatric or sexual disorders.

The CHM has established an Implementation Advisory Expert Working Group to:

  • advise on pathways and strategies to implement the recommendations
  • help develop communication and educational materials for patients to support and record informed prescribing decisions
  • advise on how to monitor compliance and effectiveness of these new measures
  • advise and make recommendations on future research and a registry

The Implementation Advisory Expert Working Group is composed of experts and representatives of the healthcare organisations who will be involved in the implementation of these recommendations.

Advice for healthcare professionals during implementation

While processes to support the implementation of these recommendations across the healthcare system are being developed, healthcare professionals should continue to follow the existing strict precautions on prescribing isotretinoin. This includes the need to counsel patients on the potential risks of isotretinoin.

Warnings for psychiatric disorders

Depression, anxiety, and psychotic symptoms have been reported in patients treated with isotretinoin, and there have been cases where patients on isotretinoin died by suicide. More information on the suspected adverse drug reactions reported are included in the CHM report.

Prescribers should discuss the risks of psychiatric disorders with patients and their caregivers fully before starting isotretinoin treatment. This should include a discussion on the importance of seeking medical attention if their mental health is affected. It is recommended that patients taking isotretinoin ask their family and friends to watch out for potential symptoms of psychiatric disorders. Updated materials for patients are being developed for people taking isotretinoin.

All patients taking isotretinoin should have an assessment of their mental health before starting treatment and be monitored regularly for signs of psychiatric symptoms by their prescriber and referred for appropriate treatment if necessary. Discontinuation of isotretinoin may not be effective in alleviating symptoms and therefore further psychiatric or psychological evaluation may be necessary.

Warnings for sexual dysfunction

Use of isotretinoin may be associated with sexual dysfunction. Reported suspected side effects include erectile dysfunction and decreased libido, vulvovaginal dryness, orgasm difficulties, and genital hypoaesthesia. More information on the suspected adverse drug reactions reported are included in the CHM report. There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of isotretinoin.

Patients should be asked about the presence of symptoms or signs of sexual dysfunction prior to starting treatment with isotretinoin, and be monitored for the development of new sexual disorders during treatment. The age and maturity of the patient should be considered in choosing the most appropriate counselling approach, including giving the option to discuss without parents or carers present where appropriate. Appropriate guidelines should be considered when providing advice about sexual health to young people.

Report any reactions on a Yellow Card

Isotretinoin is a black triangle medicine and all suspected adverse reactions, including any sexual and psychiatric adverse reactions, should be reported via the Yellow Card scheme. Reports can be made of suspected reactions experienced at any time, including historic adverse experiences with medicines.

Please include in the report as much detail as possible, particularly if a side effect continued or started after treatment was stopped. Information about medical history, any concomitant medication, onset timing, treatment dates, and product brand name should also be included.

Report to the Yellow Card scheme electronically using:

Article citation: Drug Safety Update volume 16, issue 9: April 2023: 1.

Published 26 April 2023
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