FDA Adds Fertility, Osteonecrosis Risks to Bevacizumab Label

A warning about the risk of ovarian failure in premenopausal women has been added to the label for bevacizumab, along with new postmarketing data identifying osteonecrosis of the jaw as an "adverse reaction," the Food and Drug Administration announced on Oct. 4.

Information about the increased risk of venous thromboembolic events (VTEs) and bleeding associated with bevacizumab in patients receiving anticoagulation therapy after a first VTE event has also been added in the section on Clinical Trial Experience, the FDA said.

Bevacizumab – marketed as Avastin by Genentech, a member of the Roche group – is a vascular endothelial growth factor inhibitor approved for the treatment of several different cancers, as a single agent or in combination with other treatments. It was first approved in 2004; a controversial FDA move to withdraw an indication in metastatic breast cancer is pending.

The potential for ovarian failure associated with bevacizumab treatment in premenopausal women is new information. It has been added to the warnings and precautions section of the label and in a new "Females of Reproductive Potential" subsection.

The information includes the results of a study of that found new cases of ovarian failure in 34% of women with stage II and III colorectal cancer treated with bevacizumab plus mFOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy, compared with 2% of women on chemotherapy alone – a 14-fold increase in relative risk. After treatment was stopped, recovery of ovarian function was documented in 22% of the women with ovarian failure.

This section now states that the long-term effects of exposure to bevacizumab on fertility are unknown and that women of reproductive potential should be informed about the risk of ovarian failure before starting treatment.

The postmarketing experience section of the label now includes a statement about postmarketing reports of osteonecrosis of the jaw (ONJ) in patients treated with bevacizumab who have not been treated with bisphosphonates (ONJ has been reported in patients on bisphosphonates).

The statement says that the pathogenesis of ONJ is not clear and that "it is possible that the antiangiogenic properties of bevacizumab may result in bone tissue avascularization leading to ischemic changes in the microvasculature of the jaw, resulting in osteonecrosis."

The new information on VTEs summarizes the results of a randomized, prospective four-arm study of 1,401 patients with mCRC that evaluated the VTE incidence. Among those in the bevacizumab-containing arms, the incidence of a first VTE was 13.5%, compared with 9.6% among the patients in the chemotherapy-only arms.

The overall incidence of subsequent VTEs was also higher with bevacizumab in a subgroup analysis of patients that received anticoagulants after an initial VTE event: The subsequent VTE rate was 31.5% among those in the bevacizumab-containing arms, compared with 25.6% among those in the chemotherapy-only arms.

Among patients treated with anticoagulants, the overall incidence of bleeding was also higher in the bevacizumab-containing arms, compared with the chemotherapy-only arms: 27.4% vs. 20.9%, respectively.

The label already included a boxed warning about the increased risk of gastrointestinal perforations, surgery and wound healing complications, and hemorrhage associated with bevacizumab, an angiogenesis inhibitor designed to interfere with the growth of new blood vessels feeding tumors.

Serious adverse events associated with bevacizumab should be reported to the FDA’s MedWatch program at 800-332-1088.

A warning about the risk of ovarian failure in premenopausal women has been added to the label for bevacizumab, along with new postmarketing data identifying osteonecrosis of the jaw as an "adverse reaction," the Food and Drug Administration announced on Oct. 4.

Information about the increased risk of venous thromboembolic events (VTEs) and bleeding associated with bevacizumab in patients receiving anticoagulation therapy after a first VTE event has also been added in the section on Clinical Trial Experience, the FDA said.

Bevacizumab – marketed as Avastin by Genentech, a member of the Roche group – is a vascular endothelial growth factor inhibitor approved for the treatment of several different cancers, as a single agent or in combination with other treatments. It was first approved in 2004; a controversial FDA move to withdraw an indication in metastatic breast cancer is pending.

The potential for ovarian failure associated with bevacizumab treatment in premenopausal women is new information. It has been added to the warnings and precautions section of the label and in a new "Females of Reproductive Potential" subsection.

The information includes the results of a study of that found new cases of ovarian failure in 34% of women with stage II and III colorectal cancer treated with bevacizumab plus mFOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy, compared with 2% of women on chemotherapy alone – a 14-fold increase in relative risk. After treatment was stopped, recovery of ovarian function was documented in 22% of the women with ovarian failure.

This section now states that the long-term effects of exposure to bevacizumab on fertility are unknown and that women of reproductive potential should be informed about the risk of ovarian failure before starting treatment.

The postmarketing experience section of the label now includes a statement about postmarketing reports of osteonecrosis of the jaw (ONJ) in patients treated with bevacizumab who have not been treated with bisphosphonates (ONJ has been reported in patients on bisphosphonates).

The statement says that the pathogenesis of ONJ is not clear and that "it is possible that the antiangiogenic properties of bevacizumab may result in bone tissue avascularization leading to ischemic changes in the microvasculature of the jaw, resulting in osteonecrosis."

The new information on VTEs summarizes the results of a randomized, prospective four-arm study of 1,401 patients with mCRC that evaluated the VTE incidence. Among those in the bevacizumab-containing arms, the incidence of a first VTE was 13.5%, compared with 9.6% among the patients in the chemotherapy-only arms.

The overall incidence of subsequent VTEs was also higher with bevacizumab in a subgroup analysis of patients that received anticoagulants after an initial VTE event: The subsequent VTE rate was 31.5% among those in the bevacizumab-containing arms, compared with 25.6% among those in the chemotherapy-only arms.

Among patients treated with anticoagulants, the overall incidence of bleeding was also higher in the bevacizumab-containing arms, compared with the chemotherapy-only arms: 27.4% vs. 20.9%, respectively.

The label already included a boxed warning about the increased risk of gastrointestinal perforations, surgery and wound healing complications, and hemorrhage associated with bevacizumab, an angiogenesis inhibitor designed to interfere with the growth of new blood vessels feeding tumors.

Serious adverse events associated with bevacizumab should be reported to the FDA’s MedWatch program at 800-332-1088.

A warning about the risk of ovarian failure in premenopausal women has been added to the label for bevacizumab, along with new postmarketing data identifying osteonecrosis of the jaw as an "adverse reaction," the Food and Drug Administration announced on Oct. 4.

Information about the increased risk of venous thromboembolic events (VTEs) and bleeding associated with bevacizumab in patients receiving anticoagulation therapy after a first VTE event has also been added in the section on Clinical Trial Experience, the FDA said.

Bevacizumab – marketed as Avastin by Genentech, a member of the Roche group – is a vascular endothelial growth factor inhibitor approved for the treatment of several different cancers, as a single agent or in combination with other treatments. It was first approved in 2004; a controversial FDA move to withdraw an indication in metastatic breast cancer is pending.

The potential for ovarian failure associated with bevacizumab treatment in premenopausal women is new information. It has been added to the warnings and precautions section of the label and in a new "Females of Reproductive Potential" subsection.

The information includes the results of a study of that found new cases of ovarian failure in 34% of women with stage II and III colorectal cancer treated with bevacizumab plus mFOLFOX (5-fluorouracil, leucovorin, oxaliplatin) chemotherapy, compared with 2% of women on chemotherapy alone – a 14-fold increase in relative risk. After treatment was stopped, recovery of ovarian function was documented in 22% of the women with ovarian failure.

This section now states that the long-term effects of exposure to bevacizumab on fertility are unknown and that women of reproductive potential should be informed about the risk of ovarian failure before starting treatment.

The postmarketing experience section of the label now includes a statement about postmarketing reports of osteonecrosis of the jaw (ONJ) in patients treated with bevacizumab who have not been treated with bisphosphonates (ONJ has been reported in patients on bisphosphonates).

The statement says that the pathogenesis of ONJ is not clear and that "it is possible that the antiangiogenic properties of bevacizumab may result in bone tissue avascularization leading to ischemic changes in the microvasculature of the jaw, resulting in osteonecrosis."

The new information on VTEs summarizes the results of a randomized, prospective four-arm study of 1,401 patients with mCRC that evaluated the VTE incidence. Among those in the bevacizumab-containing arms, the incidence of a first VTE was 13.5%, compared with 9.6% among the patients in the chemotherapy-only arms.

The overall incidence of subsequent VTEs was also higher with bevacizumab in a subgroup analysis of patients that received anticoagulants after an initial VTE event: The subsequent VTE rate was 31.5% among those in the bevacizumab-containing arms, compared with 25.6% among those in the chemotherapy-only arms.

Among patients treated with anticoagulants, the overall incidence of bleeding was also higher in the bevacizumab-containing arms, compared with the chemotherapy-only arms: 27.4% vs. 20.9%, respectively.

The label already included a boxed warning about the increased risk of gastrointestinal perforations, surgery and wound healing complications, and hemorrhage associated with bevacizumab, an angiogenesis inhibitor designed to interfere with the growth of new blood vessels feeding tumors.

Serious adverse events associated with bevacizumab should be reported to the FDA’s MedWatch program at 800-332-1088.