The U.S. Food and Drug Administration (FDA) has recently announced that, following clinical trials, three new warnings of adverse effects should be added to the packaging for Bevacizumab, which is marketed by Genentech as Avastin. These involve increased risks of ovarian failure in pre-menopausal women; osteonecrosis of the jaw; and venous thromboembolytic events (VTEs) including pulmonary embolism.

Bevacizumab is an angiogenesis inhibitor that has been marketed as therapy for several types of metastatic solid tumour, including colon and non-small cell lung cancer, since 2004. It is a humanized monoclonal antibody that binds to, and thus inhibits, vascular endothelial growth factor A (VEGF-A). It was the first angiogenesis inhibitor to be licensed for use against cancer, and its mechanism of action is still novel; it is given by injection, most often in combination with chemotherapy drugs.

The increased risk of ovarian failure with bevacizumab was observed in a subset study that compared women taking this drug with the standard combination chemotherapy regimen mFOLFOX to those taking mFOLFOX alone. All patients had been diagnosed with stage II or state III colorectal cancer, which is not an indication for which bevacizumab has yet been licensed.

Ovarian failure, defined as amenorrhea lasting at least three months with abnormally high levels of follicle-stimulating hormone and a negative pregnancy test, was observed in 32/95 (34%) of women in the bevacizumab arm and 2/84 (2%) of women taking standard chemotherapy alone. Seven of those 32 women recovered ovarian function during the observation period. The FDA now advises that women of reproductive age should be warned of the risk of ovarian failure before starting treatment with bevacizumab.

The FDA's warning of the increased risk of venous thromboembolytic events (VTEs) arose from the results of two clinical trials. The larger of these was a randomized, four-arm trial of bevacizumab with chemotherapy compared to chemotherapy alone in patients with metastatic colorectal cancer. Prospective evaluation of VTE risk in this trial found that the risks of both a first such event and a second or subsequent event following treatment with anticoagulants were significantly raised in the two arms that included bevacizumab.

Patients treated with anticoagulants were also more likely to bleed if they had been receiving bevacizumab, although most cases of bleeding were mild. The increased risk of osteonecrosis of the jaw, a debilitating disease in which a bone or bones of the jaw become exposed through the gingival tissue, was added to the label as a result of post-marketing adverse event reports. This has often been observed in patients taking bisphosphonates but has now also been seen in those taking bevacizumab without bisphosphonates.

Full prescribing information for bevacizumab, including all warnings of adverse events and drug-drug interactions, is available from the FDA.

References

FDA

FDA Accessable Data