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MHRA medicines recall for Picato Gel (ingenol mebutate) manufactured by LEO Pharma

Zahra Nanji considers the withdrawal of Picato skin gel from the UK medicines market.

Posted on 12 November 2020

On 27 January 2020 The Medicines and Healthcare Regulatory Agency (MHRA) issued a class 2 medicines recall for Picato Gel (ingenol mebutate) manufactured by LEO Pharma.  

A class 2 recall means that the defect may cause mistreatment or harm to the patient, but it is not life-threatening or serious.

Picato is used for treating the skin condition actinic keratosis, a rough, scaly patch on your skin that can develop from exposure to the sun. 

The gel is used as a short course of 150 micrograms/gram on the face and scalp for three days, or 500 micrograms/gram on the trunk and extremities for two days. 

Picato was initially cleared for marketing in Europe in November 2012. The potential for ingenol mebutate to induce skin cancer was considered during the initial licence application and a three-year safety study was initiated. 

However, after data suggested the occurrence of a higher number of skin cancer cases, in September 2019 the European Medicines Agency (EMA) requested a safety review of the drug, using its Pharmacovigilance Risk Assessment Committee (PRAC). 

The following month, the UK regulator, the Medicines and Healthcare Regulatory Agency (MHRA), reported that the potential for Picato to induce skin cancer had been known during its initial licence application, but it had been reported that overall, the potential was considered to be low.

In January 2020 the EMA posted interim measures for use of Picato and reported that the final results of a three-year study in 484 patients showed:  

  • A higher incidence of squamous cell carcinoma with ingenol mebutate gel compared with imiquimod 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 an inactive substance was seen in pooled eight-week trials with ingenol mebutate gel in 1,262 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 an inactive substance in four clinical trials with ingenol disoxate (a compund related to ingenol mebutate whose clinical development has been stopped) in 1,234 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

The EMA not only noted a higher occurrence of skin cancers in areas treated with Picato than Imiquimod, but it also noted that Picato’s benefits were not maintained over time and that other treatment options were available.

LEO Laboratories Ltd, which trades as LEO Pharma and manufactures Picato, recalled the gel in January 2020, some eight years after its initial approval for use.

Between 2013 and February 2020 the MHRA received reports of 10 cases of skin malignancies in the UK associated with ingenol mebutate. These reports were received in both clinical trial and post-marketing settings.

Picato appears to be causing concerns worldwide: Health Canada conducted a safety review in July 2020 and concluded that there may be a link between its use and an increased risk of non-melanoma skin cancer. It also determined that the benefits of treatment with Picato do not outweigh the potential risk of skin cancer.

On 14 October 2020, Health Canada directed LEO Pharma to stop the sale of Picato and subsequently Leo Pharma initiated a recall from the Canadian market. The US FDA is also investigating the safety of Picato.

I find it very surprising that the initial concerns in 2012 and then clear evidence that Picato was causing significantly higher incidence of skin cancers did not lead to the product being recalled earlier and that it did not have a higher grade of recall.

Given that treatment is over a matter of days and that adverse effects are mostly reported over the course of weeks and months, it would have been obvious very early on that the suspicion of the risk of cancer raised when the initial licence was granted in 2012, were proven to be true. 
I find it difficult to understand why the trials were not therefore concluded much earlier or interim findings not posted sooner to ensure that patients were adequately warned of known risks or concerns or more importantly, not exposed to the risk. 

I consider much more focus needs to be put on patient focused information and safety.  That is not to say that treatments should not be used when they carry a risk, but that patients should be warned of risks as they emerge to allow them to make an informed decision when consenting to use of a treatment. 

It is important that if you are concerned about the safety of a medicine or medical device, that you report the concern about the safety of that product or of any suspected adverse drug reaction using the MHRA Yellow Card Scheme.


Zahra Nanji
Medical devices Medicines

Zahra Nanji

Zahra Nanji is an associate solicitor in the consumer law team.