Safety Alerts
Risk of potentiation of radiation toxicity associated with vemurafenib
19 May 2016
Audiences
Healthcare professional
Industry member
Product-type
Therapeutic Products
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Vemurafenib (Zelboraf®, Roche Singapore Pte Ltd) is a low molecular weight inhibitor of the BRAF serine-threonine kinase. It has been registered locally since February 2013 for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma.
The risk of potentiation of radiation toxicity, such as radiation recall and radiation sensitisation, has been known to be associated with the use of certain chemotherapeutic agents in combination with radiation therapy. Radiation recall is an uncommon and unpredictable phenomenon which is characterised by acute inflammatory reactions confined to the previously irradiated area. Radiation sensitisation refers to greater than expected severity of the reaction for local radiation injuries. This article highlights serious overseas cases of radiation recall and radiation sensitisation in patients who were treated with radiation before, during, or after treatment with vemurafenib and the international regulatory actions taken.
International regulatory actions
(a) UK MHRA
In November 2015, the UK MHRA issued a drug safety update highlighting the European Medicines Agency (EMA)’s review of serious global cases of radiation recall and radiation sensitisation associated with the use of vemurafenib in patients receiving radiation treatment.1 The EMA review concluded that vemurafenib is associated with the potentiation of radiation toxicity. As a result, the product labelling was subsequently strengthened to highlight this safety issue and a communication letter was issued to raise awareness of this risk among healthcare professionals.2
Cases of radiation recall and radiation sensitisation
In the review, a total of eight cases of radiation recall and 12 cases of radiation sensitisation have been reported globally, of which majority had received radiotherapy regimens greater than or equal to 2 gray/day.
The eight cases of radiation recall occurred in patients treated with vemurafenib following completion of radiotherapy. Of these, five were associated with cutaneous reactions such as erythema, hyperkeratosis, as well as eczematous, vesicular, or ulcerative lesions. Of the remaining three cases, two patients developed pneumonitis and one patient had cystitis. The time-to-onset of radiation recall after the initial dose for vemurafenib ranged from 7 to 21 days (mean 12 days) for cutaneous reactions, 24 days for pneumonitis, and one day for cystitis.
The cases of radiation sensitisation occurred in patients treated with radiation before, during, or after treatment with vemurafenib. Of the 12 cases, nine involved the skin, three involved the oesophagus (including two fatal cases of radiation oesophagitis), and one each involving liver (fatal case of radiation necrosis of the liver) and the rectum. Except for one case, all cases received vemurafenib either concomitantly with radiation or within three days after completion of radiotherapy. When reported, the time-to-onset of radiation sensitisation following initiation of radiation therapy or treatment with vemurafenib ranged from 3 to 27 days (mean 10 days).
(b) Health Canada
In December 2015, Health Canada also issued a communication to warn healthcare professionals of the risk of radiation sensitisation or radiation recall reactions with vemurafenib. This communication was in response to a safety review conducted by Health Canada on the 20 global cases of radiation toxicity involving vemurafenib. Health Canada concluded that vemurafenib is associated with the potentiation of radiation toxicity. Consequently, a warning concerning this serious risk was included in the product monograph for Zelboraf®.3
Local situation and HSA’s advisory
HSA has not received any local reports of radiation-related injuries associated with vemurafenib. The local package insert for Zelboraf® will be strengthened to warn of this risk.
Healthcare professionals are advised to take into consideration the above safety information when prescribing vemurafenib concomitantly or sequentially with radiation treatment.