Medicines and Healthcare products Regulatory Agency (MHRA) announces that cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnsons syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with immune-stimulatory anti-cancer drugs, including atezolizumab.
SCARs are a heterogeneous group of delayed hypersensitivity reactions. These events mainly consist of acute generalised exanthematous pustulosis (AGEP), SJS, TEN, and drug reaction with eosinophilia and systemic symptoms (DRESS) and can be potentially life-threatening, and lead to severe, potentially chronic sequelae.
Immune-stimulatory anti-cancer drugs authorised in the United Kingdom include Tecentriq▼(atezolizumab), Bavencio▼ (avelumab), Libtayo▼ (cemiplimab), Imfinzi▼ (durvalumab), Yervoy (ipilimumab), Opdivo (nivolumab), and Keytruda (pembrolizumab).
SCARs were previously known to be potentially associated with the use of atezolizumab. Based on evidence from a recent analysis, SCARs are now considered to be an identified risk for atezolizumab. The product information, including the Patient Information Leaflet, has been updated to include information about these reactions. Although review of the cases worldwide found no reports of SCARs for patients on atezolizumab with a history of these reactions with another immune-stimulatory drug, healthcare professionals are advised to carefully consider the use of atezolizumab in patients who have had a severe or life-threatening SCAR following treatment with an immune-stimulatory anti-cancer drug.
A review of safety data for atezolizumab and risk of SCARs was recently completed in Europe. As of 31 Jul 2020, a cumulative analysis of the company’s safety database identified 99 cases of SCARs worldwide (97 of which were serious). Of the 99 cases, the majority (48%) were reported from clinical studies, with 30% from post-marketing settings. Approximately 23,654 clinical trial patients and 106,316 patients in post-marketing settings worldwide have been exposed to atezolizumab as of 17 May 2020. Of the 99 cases, 35 cases were identified as erythema multiforme, 25 cases as SJS, 12 cases as a toxic skin eruption, 8 cases as TEN, 7 cases as dermatitis bullous, 6 cases as dermatitis exfoliative generalised, 4 cases as DRESS, and 2 cases as skin necrosis.
Of the 99 cases of SCARs, 36 were confirmed by histopathology or specialist diagnosis. Of which, 5 cases were considered to be of likely causality and 20 cases were possibly temporally related to multiple suspect medications including atezolizumab. In the majority of cases (55 of 99), the outcome was reported as recovered, in 21 cases the patients were recovering, and in 14 cases the patients had not recovered. One elderly patient who received atezolizumab monotherapy died. Based on clinical trials and post-marketing data, the most frequently reported range of time to onset was within 1 month after the first dose of atezolizumab (37%; 38 cases). Where reported, atezolizumab treatment was withdrawn or interrupted in 58 cases and the dose was not changed in 16 cases. The incidence rates of SCARs, regardless of severity, from pooled atezolizumab monotherapy (n=3178) and combination therapy (n=4371) company-sponsored clinical studies was 0.7% and 0.6% respectively.
Other products used for cancers in the same class as atezolizumab, including cemiplimab, ipilimumab, nivolumab, and pembrolizumab list SCARs (including SJS and TEN) as a possible side effects in the Summary of Product Characteristics (SmPC) with an associated warning and precautions. Avelumab and durvalumab are known to cause other immune-mediated skin adverse reactions. As for the other immune-stimulatory anti-cancer drugs, patients should be monitored for the signs and symptoms of serious skin reactions and treatment withheld or discontinued according to the severity of the event as described in the SmPC for each product.
Since authorisation and up to 13 Jun 2021, in the United Kingdom, Yellow Cards reporting SJS, TEN or DRESS have been received for atezolizumab (n=2), ipilimumab (n=13), nivolumab (n=15), and pembrolizumab (n=9). In interpreting these data, caution should be exercised and comparisons not drawn between the medicines given different exposures and other factors unrelated to the inherent safety of the medicines that may affect the number of reports. Reporters are asked to submit Yellow Card reports even if they only have a suspicion that the medicine may have caused the adverse drug reaction.
Advice for healthcare professionals:
- SCARs, including cases of SJS and TEN, have been reported in patients treated with immune-stimulatory anti-cancer drugs including atezolizumab.
- Advise patients of the need to seek urgent medical assistance if severe skin reactions occur.
- Monitor patients for signs and symptoms of severe skin reactions and exclude other causes.
- If a SCAR is suspected, treatment should be withheld, and patients referred to a specialist for diagnosis and treatment.
- If SJS or TEN is confirmed, or for any grade 4 (life-threatening) SCAR, permanently discontinue treatment with the immune-stimulatory drug.
- Caution is recommended when considering the use of immune-stimulatory drugs associated with SCARs in patients with previous history of life-threatening SCAR with other immune-stimulatory anti-cancer drugs.
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/atezolizumab-tecentriqv-and-other-immune-stimulatory-anti-cancer-drugs-risk-of-severe-cutaneous-adverse-reactions-scars
In Hong Kong, there are registered pharmaceutical products containing atezolizumab (3 products), avelumab (1 product), durvalumab (2 products), ipilimumab (2 products), nivolumab (2 products) and pembrolizumab (1 product). All products are prescription-only medicines. There is no registered pharmaceutical product containing cemiplimab.
So far, the Department of Health (DH) has received adverse drug reaction related to atezolizumab (91 cases), avelumab (29 cases), durvalumab (27 cases), ipilimumab (33 cases; of which 1 case is related to erythema multiforme), nivolumab (87 cases; of which 1 case is related to erythema multiforme and 1 case is related to TEN) and pembrolizumab (107 cases; of which 1 case is related to DRESS and TEN, and 1 case is related to TEN).
The local product insert of the above registered pharmaceutical products containing ipilimumab, nivolumab and pembrolizumab include safety information about SJS and TEN. For registered products containing avelumab and durvalumab, the local product insert include other immune-mediated skin adverse reactions.
Related news on the risk of SCARS associated with the use of atezolizumab was previously issued by Singapore Health Sciences Authority, and was posted on the Drug Office website on 13 Nov 2020. Letters to inform local healthcare professionals were issued by the DH on the same day. In light of the above MHRA’s announcement, the matter will be discussed by the Registration Committee of the Pharmacy and Poisons Board.
Ends/Friday, Jun 18, 2021
Issued at HKT 16:00
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