Advice for healthcare professionals:
the licence of ingenol mebutate gel has been suspended as a precautionary measure while the EMA continues to investigate an increased incidence of benign and malignant skin tumours in several clinical studies (see previous Drug Safety Update, October 2019)
stop prescribing ingenol mebutate gel and consider other treatment options for actinic keratosis as appropriate
existing unexpired stock of ingenol mebutate gel is being recalled from UK pharmacies and wholesalers (see Class 2 Medicines Recall)
advise patients who have been treated with ingenol mebutate gel to continue to be vigilant for new skin lesions within the treatment area and to seek medical advice immediately should any occur
report any suspected adverse drug reactions associated with medicines containing ingenol mebutate to the Yellow Card Scheme; reports can still be received for suspended medicines
Review of skin cancer risk
Ingenol mebutate gel (Picato▼) is indicated for the treatment of actinic keratosis in adults when the outer layer of the skin affected is not thickened or raised. It is used as a short course of 150 micrograms/gram gel on the face and scalp for 3 days, or 500 micrograms/gram gel on the trunk and extremities for 2 days.
The potential for ingenol mebutate gel to induce skin cancer was considered during the initial licence application and a 3-year safety study was initiated. In October 2019, we informed healthcare professionals via Drug Safety Update that an in-depth European review of ingenol mebutate gel had started to assess data from several sources showing an increased number of skin cancers with this medicine.
In January 2020, following final results from the 3-year safety study indicating a higher occurrence of skin cancer, the [European Medicines Agency (EMA)] recommended](https://www.ema.europa.eu/en/documents/referral/picato-article-20-referral-ema-suspends-picato-precaution-while-review-skin-cancer-risk-continues_en.pdf) suspending the marketing authorisation (licence) for ingenol mebutate gel as a precaution while the evidence was reviewed, noting that alternative treatments are available.
Several studies have found a higher incidence of skin tumours in the treatment area in patients who had used ingenol mebutate gel or a related ester, namely:
A higher incidence of squamous cell carcinoma with ingenol mebutate gel compared with imiquimod was found in the final results of the 3-year safety study in 484 patients (3.3% versus 0.4% of patients) that was agreed at the time of licensing;
A higher incidence of benign tumours (keratoacanthoma) compared with vehicle was seen in pooled 8-week trials with ingenol mebutate gel in 1262 patients (1.0% versus 0.1% of patients);
A higher incidence of tumours, including basal cell carcinoma, Bowen’s disease and squamous cell carcinoma, was seen compared with vehicle in four clinical trials with ingenol disoxate (an ester related to ingenol mebutate whose clinical development has been stopped) in 1234 patients (7.7% versus 2.9% of patients).
Post-marketing reports of skin tumours in patients treated with ingenol mebutate gel have also been received. Time to onset ranged from weeks to months.
Other studies have not shown an increased tumour incidence with ingenol mebutate gel and there is uncertainty over interpretation of some of the study data. Although a number of uncertainties remain and the data is still being reviewed, given the concerns regarding the possible risk of skin malignancy the EMA has recommended a precautionary EU-wide suspension of Picato. A letter was sent to healthcare professionals to inform them of these measures in January 2020.
Advice to give to patients
Since 2017, the patient information leaflet for Picato has included advice for patients to be vigilant for new lesions in their treatment area. Although the new EMA advice does not require patients to be recalled to discuss the risks, patients who have previously used Picato should be reminded of the need for continued vigilance and to immediately talk to their doctor if they notice any new scaly red patches, open sores, or elevated or warty growths in the treatment area.
Picato is authorised and supplied to allow for a 2 to 3 day treatment course and was recalled from pharmacies and wholesalers in the UK on 27 January 2020. As such, we do not consider it likely that patients will be currently using Picato at the time of publication of this article. However, patients who have been dispensed Picato but not yet used it, or patients who are in the middle of their treatment course, are advised to speak to their prescriber.
UK suspected adverse drug reactions
In the past year, around 34,000 packs of ingenol mebutate gel were dispensed in the UK. Since 2013 and up to January 2020, we have received reports of 10 cases of skin malignancies in the UK associated with ingenol mebutate gel, including cutaneous squamous cell carcinoma (including one metastatic case), atypical fibroxanthoma, neuroendocrine carcinoma of the skin, Bowen’s disease, and basosquamous carcinoma. These reports were received in both clinical trial and post-marketing settings.
Article citation: Drug Safety Update volume 13, issue 7: February 2020: 1.