AVASTIN

Full Prescribing Information
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Avastin® (bevacizumab) is the first U.S. Food and Drug Administration (FDA) approved therapy designed to inhibit angiogenesis, the process by which new blood vessels develop and carry vital nutrients to a tumor.

Avastin is approved, in combination with intravenous 5-fluorouracil-based (5-FU) chemotherapy, for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum; in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC); and for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Avastin is also approved, in combination with paclitaxel, for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer. The effectiveness of Avastin in metastatic breast cancer is based on an improvement in progression-free survival. Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Avastin in breast cancer.

Status The FDA approved Avastin in February 2004 for use in combination with intravenous 5-FU-based chemotherapy as a treatment for first-line metastatic colorectal cancer. In June 2006, the FDA approved Avastin in combination with intravenous 5-FU-based chemotherapy for patients with metastatic colorectal cancer who have been previously treated for their cancer (or second-line metastatic colorectal cancer). In October 2006, the FDA approved Avastin in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC.

The original Avastin FDA approval was based on data from a large, placebo controlled, randomized study demonstrating prolongation in the median survival of patients treated with Avastin plus the IFL (5-FU/Leucovorin/CPT-11) chemotherapy regimen by approximately five months, compared to patients treated with the IFL chemotherapy regimen alone (20.3 months versus 15.6 months). This is one of the largest improvements in survival ever reported in a randomized, Phase III study of patients with metastatic colorectal cancer.

The second approval was based on results of a randomized, controlled, multicenter Phase III trial (E3200) of 829 patients with advanced or metastatic colorectal cancer who had received previous treatment with irinotecan and 5-FU as initial therapy for metastatic disease or as adjuvant therapy. The study showed that patients who received Avastin plus the 5-FU-based chemotherapy regimen known as FOLFOX4 (oxaliplatin/5-FU/leucovorin) had a 25 percent reduction in the risk of death (based on a hazard ratio of 0.75), the primary endpoint, which is equivalent to a 33 percent improvement in overall survival, compared to patients who received FOLFOX4 alone. Median survival for patients receiving Avastin plus FOLFOX4 was 13.0 months, compared to 10.8 months for those receiving FOLFOX4 alone.

The third approval was based on results from E4599, a randomized, controlled, multicenter trial that enrolled 878 patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. The most common Grade 3-5 (severe) adverse events in Study E4599 seen in Avastin-treated patients, were neutropenia (low white blood cell count), fatigue, hypertension (high blood pressure), infection and hemorrhage. Results showed that patients receiving Avastin plus paclitaxel and carboplatin chemotherapies had a 25 percent improvement in overall survival, the trial's primary endpoint, compared to patients who received chemotherapy alone (based on a hazard ratio of 0.80). One-year survival was 51 percent in the Avastin arm versus 44 percent in the chemotherapy-alone arm. Median survival of patients treated with Avastin plus chemotherapy was 12.3 months, compared to 10.3 months for patients treated with chemotherapy alone.

The FDA granted accelerated approval for Avastin in combination with paclitaxel chemotherapy for the first-line treatment of advanced HER2-negative breast cancer in February 2008.

Safety Patients treated with targeted therapies, including Avastin, may experience side effects. In clinical trials, some patients treated with Avastin experienced serious side effects, including:

Gastrointestinal (GI) perforation: The incidences of GI perforation, some fatal, in Avastin-treated patients range from 0.3% to 2.4%. Discontinue Avastin in patients with GI perforation.

Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery or until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention.

Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade >3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (>1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (i.e., requiring medical intervention).

Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (<0.3%), arterial thromboembolic events (grade >3, 2.4%), hypertension (grade >3, 5%-18%), reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%), and proteinuria including nephrotic syndrome (<1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients. The most common grade 3-5 (nonhematologic) and 4-5 (hematologic) events that occurred at a higher incidence in the Avastin-treated arms included neutropenia, fatigue, hypertension, infection, hemorrhage, asthenia, abdominal pain, pain, deep vein thrombosis, intra-abdominal thrombosis, syncope, diarrhea, constipation, leukopenia, nausea, vomiting, dehydration, ileus, neuropathy-sensory, neurologic-other, headache, infection without neutropenia, proteinuria, and cerebrovascular ischemia. The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis.

Please see the Avastin full prescribing information including Boxed WARNINGS and additional important safety information.

Proposed Mechanism of Action Avastin is a therapeutic antibody that is believed to work by targeting and inhibiting the function of a natural protein called "vascular endothelial growth factor" (VEGF) that stimulates new blood vessel formation, a process known as angiogenesis. Researchers have shown in preclinical models that anti-VEGF agents like Avastin may work by causing the following changes to occur in the blood vessels supporting tumor growth (tumor vasculature):

* Regression of existing microvessels — helps arrest tumor growth and reduce tumor size
* "Normalization" of surviving mature vasculature — makes the tumor vasculature more conducive to effective anti-cancer therapy
* Inhibition of vessel growth and neovascularization (e.g., the sprouting of new micro-vasculature from existing vessels)

Colorectal Cancer According to the American Cancer Society, every ten minutes someone dies from colorectal cancer in the United States. Colorectal cancer is the third leading cause of cancer death in the U.S. and the third most frequently diagnosed cancer in both men and women in the U.S. The ACS estimates there will be 148,000 new cases of colorectal cancer diagnosed and nearly 50,000 colorectal cancer deaths in 2008. Colorectal cancer begins in either the colon or the rectum. The colon and rectum form part of the body's digestive system, which separates nutrients and waste from food and stores the latter until it can be passed out of the body. The colon has four sections: the ascending colon, the transverse colon, the descending colon and the sigmoid colon. Cancer can start in any portion of the colon or the rectum. About 95 percent of colorectal cancers are adenocarcinomas, which are cancers of the cells lining the inside of the colon and rectum.

Lung Cancer Lung cancer is one of the most common cancers, with newly diagnosed cases expected to exceed 215,000 in the U.S. this year. Lung cancer is the leading cause of cancer deaths, accounting for approximately 30 percent of all cancer deaths (more than breast, colon and liver cancers combined) expected to occur in the U.S. this year. In 2005, lung cancer killed an estimated 1.3 million people worldwide.

Breast Cancer According to the American Cancer Society, in 2008 an estimated 182,000 American women will be diagnosed with breast cancer. Currently, there are approximately 2.5 million breast cancer survivors in the United States.

Clinical Trials Based on data showing that VEGF may play a broad role in a range of cancers, a global development program for Avastin currently includes more than 450 clinical trials in more than 30 different tumor types, including early-stage cancers. It is also being studied in combination with other targeted therapy agents in the absence of chemotherapy.