New Bevacizumab Label Includes Risk for Ovarian Failure

Zosia Chustecka

October 05, 2011

October 5, 2011 (UPDATED October 11, 2011) — Revised labeling for bevacizumab (Avastin) contains information on the risks for ovarian failure and osteonecrosis of the jaw. It also contains new details on the risk for venous thromboembolic events (VTEs).

The US Food and Drug Administration (FDA) announced on October 4 that the changes were made to the drug's package insert on September 30.

Ovarian Failure

The new label instructs clinicians to inform women of reproductive potential before they start treatment with bevacizumab that there is a risk for ovarian failure.

The data for this warning come from a subset of 179 women taking part in a study investigating bevacizumab in combination with a modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen for adjuvant stage II and stage III colorectal cancer, a use for which the drug is not approved (its indication for colorectal cancer is for metastatic disease).

In this study, new cases of ovarian failure were identified in 34% of women (32/95) being treated with bevacizumab plus chemotherapy and only in 2% of women (2/84) being treated with chemotherapy alone (relative risk, 14; 95% confidence interval, 4 - 53). After the discontinuation of bevacizumab treatment, recovery of ovarian function was demonstrated in 22% of these women.

Osteonecrosis of the Jaw

Osteonecrosis of the jaw is a known adverse effect of bisphosphonate therapy; the new label notes that it has also been reported in patients receiving bevacizumab, but not bisphosphonates, in the postmarketing setting.

The pathogenesis is unclear, but it is possible that the antiangiogenic properties of bevacizumab result in bone tissue vascularization, which could lead to ischemic changes in the microvasculature of the jaw and result in osteonecrosis, the label explains.

Patients Taking Anticoagulants

Increased risk for a VTE has already been reported with bevacizumab, but a new section of the label notes that patients who have experienced a VTE while taking bevacizumab and who are now being treated with anticoagulants continue to be at increased risk for further VTEs.

These data come from a study conducted in 1401 patients with metastatic colorectal cancer, an approved indication for the drug. The overall incidence of a first VTE was higher in patients being treated with bevacizumab plus chemotherapy vs those being treated with chemotherapy alone (13.5% vs 9.6%).

Among those in whom a first VTE developed, 116 were treated with anticoagulants (73 with bevacizumab plus chemotherapy and 43 with chemotherapy alone). In this subgroup of patients, the overall incidence of subsequent VTEs was higher in patients receiving bevacizumab (31.5% vs 25.6%); the overall incidence of bleeding was also higher (27.4% vs 20.9%).

Other Adverse Events

Other warnings in the prescribing information, including a complete boxed warning, describe risks for gastrointestinal perforations, surgical and wound-healing complications, and hemorrhage with use of bevacizumab. Gastrointestinal perforation occurs in up to 2.4% of patients treated with bevacizumab. The drug should be discontinued in patients in whom this complication develops.

Because bevacizumab has been associated with surgical and wound-healing complications, it should be discontinued at least 28 days before elective surgery. Bevacizumab should not be started for at least 28 days after surgery and until the surgical wound is fully healed, and it should be discontinued in patients in whom wound dehiscence develops.

Patients receiving bevacizumab are at increased risks for severe or fatal hemorrhage, hemoptysis, gastrointestinal tract bleeding, hemorrhage involving the central nervous system, and vaginal bleeding. The drug should not be given to patients with serious hemorrhage or recent hemoptysis.

Adverse reactions occurring in at least 10% of patients and at least twice as often as in control participants are nosebleeds, headache, hypertension, rhinitis, proteinuria, changes in taste, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Use in Specific Populations

Animal studies suggest that bevacizumab may cause fetal harm, and it is therefore pregnancy category C. Bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.

Nursing mothers should not breast-feed while taking bevacizumab. A decision should be made whether to discontinue breast-feeding or to discontinue the drug, considering the half-life of bevacizumab (approximately 20 days; range, 11 - 50 days) and the importance of the drug to the mother.

The safety, effectiveness, and pharmacokinetic profile of bevacizumab in pediatric patients have not been established. A pooled analysis suggests that geriatric patients treated with bevacizumab had an increase in arterial thromboembolic events greater than that seen in younger patients (8.5% vs 2.9% in those aged ≥ 65 years, compared with 2.1% vs 1.4% in those aged < 65 years).

More information on the revised labeling for bevacizumab is available on the FDA Web site.

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