Changes in Bevacizumab Package Insert
Monday, October 03, 2011
Changes made to the bevacizumab package insert on September 30, 2011, include the following:
- a new warning subsection describing the increased risk of ovarian failure in premenopausal patients receiving bevacizumab and chemotherapy and recommendation that females of reproductive potential be informed of the increased risk of ovarian failure prior to starting treatment with bevacizumab,
- identification of osteonecrosis of the jaw as an adverse reaction of bevacizumab, and
- new information regarding the risks of venous thromboembolic events and bleeding in patients receiving anti-coagulation therapy after first VTE event while receiving bevacizumab.
Subsection (5.10) is added to the Warnings and Precautions, new information included in the Adverse Reactions (6.1) section and a new subsection (8.6 Female of Reproductive Potential) added to the Use in Specific population section of the bevacizumab package insert to convey the following information:
The incidence of new cases of ovarian failure, defined as amenorrhea lasting 3 or more months, FSH level ≥30 mIU/mL and a negative serum β-HCG pregnancy test, was prospectively evaluated in a subset study of 179 women receiving mFOLFOX alone (N= 84) or mFOLFOX with Avastin (N=95) for adjuvant stage II and III colorectal cancer, a use for which Avastin is not approved. New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function was demonstrated in 22% (7/32) of these women. Recovery of ovarian function is defined as resumption of menses and an FSH level < 30 mIU/mL at any visit in the post-treatment period. Long term effects of Avastin exposure on fertility are unknown.
Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin.
Osteonecrosis of the Jaw
There has been an addition of osteonecrosis of the jaw to the postmarketing experience subsection of the Adverse Reactions (6.0) section of the bevacizumab package insert.
Musculoskeletal: Osteonecrosis of the jaw
Osteonecrosis of the jaw (ONJ) was reported in patients receiving bevacizumab but not bisphosphonates in the postmarketing setting. The pathogenesis of the osteonecrosis is unclear. 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.
Venous Thromboembolic and Bleeding Events for Patients Receiving Anti-Coagulation
An information update was added to the Clinical Trial Experience section, Venous Thromboembolic Events: risk of venous thromboembolic events and bleeding in patients receiving anti-coagulation therapy after first VTE event while receiving bevacizumab.
Venous Thromboembolic Events (VTE)
A randomized, 4-arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%).
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interaction, contraindications is available at:
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by phone at 1-800-FDA-1088, by facsimile 1-800-FDA-0178m by mail using the Form 3500 at http://www.fda.gov/medwatch/index.html