- Medicines and Healthcare products Regulatory Agency
- 18 April 2016
- Therapeutic area:
- Cancer and Dentistry
Dental examination and appropriate preventive dentistry should be considered before treatment, especially for patients also treated with an intravenous bisphosphonate.
Advice for healthcare professionals:
- Cases of osteonecrosis of the jaw (ONJ) have been reported in patients with cancer who have been treated with aflibercept (Zaltrap)
- Patients who have also previously or concomitantly received an intravenous bisphosphonate may be at particular risk
- Before starting treatment, consider whether a dental examination and any appropriate preventive dentistry are needed
- Avoid invasive dental procedures, where possible, in patients being treated with Zaltrap who have previously received, or are currently receiving, an intravenous bisphosphonate
- During treatment, advise patients to: maintain good oral hygiene; receive routine dental check-ups; and to report any oral symptoms such as dental mobility, pain, or swelling
- Suspected adverse reactions should be reported to us on a Yellow Card
Zaltrap is authorised in combination with irinotecan, 5-fluorouracil, and folinic acid (FOLFIRI) chemotherapy for treatment of adults with metastatic colorectal cancer that is resistant to, or has progressed after, treatment with an oxaliplatin-containing regimen. More than 22,000 patients worldwide to date are estimated to have received Zaltrap.
Cases of ONJ
There have been 8 post-marketing cases of ONJ reported worldwide up to 3 August 2015, 3 of which stated concomitant treatment with intravenous bisphosphonates and 5 previous invasive dental procedure or infection (all of which are known risk factors for ONJ).
A meta-analysis of 3 phase III cancer clinical trials (EFC10262/VELOUR1, EFC10261/VITAL2, EFC10547/VANILLA3) found that 3 of 1,333 patients assigned Zaltrap had ONJ, compared with 1 of 1,329 assigned placebo (relative risk for all-grade osteonecrosis 2.99 [95% CI 0.31–28.72]).
A further phase III cancer trial (EFC6546/VENICE4) identified a higher frequency of ONJ in patients treated with Zaltrap and docetaxel independent of bisphosphonate use (7 of 209 patients receiving Zaltrap, docetaxel, and bisphosphonates compared with 2 of 224 patients receiving placebo, doxetaxel, and bisphosphonates).
The mechanism by which Zaltrap may increase the risk of ONJ is not fully known. However, it is an antiangiogenic agent and might therefore interfere with, and decrease, new capillary growth during wound healing at sites of physical trauma such as after dental procedures.
ONJ is a known risk with other antiangiogenic agents, such as sunitinib or bevacizumab, which target endothelial growth factor pathways.
Overall, although there are many known risk factors for ONJ, there is sufficient evidence to suggest that Zaltrap may independently increase or contribute to this risk.
Aflibercept is also the active ingredient in Eylea intravitreal injection, which is authorised for treatment of macular degeneration. ONJ has not been identified as a risk for Eylea.
Letter sent to health professionals in March 2016
Article citation: Drug Safety Update Vol 9 issue 9 April 2016: 6
EFC10262/VELOUR study: aflibercept versus placebo in combination with irinotecan and 5-FU in the treatment of patients with metastatic colorectal cancer after failure of an oxaliplatin based regimen (VELOUR). ↩
Published: 18 April 2016