Important Avastin Safety Information

Treatment discontinuation and suspension

Permanently discontinue Avastin in patients with GI perforation (GI perforation, fistula formation in the GI tract, intra-abdominal abscess), fistula formation involving an internal organ, wound dehiscence requiring medical intervention, serious bleeding, severe ATE, nephrotic syndrome, hypertensive crisis, or hypertensive encephalopathy
In patients developing RPLS, discontinue Avastin and initiate treatment of hypertension if present. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae
Temporary suspension is recommended in patients with evidence of moderate to severe proteinuria, in patients with severe hypertension that is not controlled with medical management, and for at least several weeks prior to elective surgery. Avastin should not be resumed until the surgical incision is fully healed
Patients who become pregnant while on Avastin therapy should be counseled regarding possible risk to the fetus and/or loss of pregnancy

Gastrointestinal (GI) perforation (see Boxed WARNINGS in full Prescribing Information)

Avastin administration can result in the development of GI perforation, in some instances resulting in fatality
GI perforation, sometimes associated with intra-abdominal abscess, occurred throughout treatment with Avastin (i.e., was not correlated to duration of exposure)
Typical presentation was reported as abdominal pain associated with symptoms such as constipation and vomiting
GI perforation should be included in the differential diagnosis of patients presenting with abdominal pain

Wound healing complication (see Boxed WARNINGS in full Prescribing Information)

Avastin administration can result in the development of wound dehiscence, in some instances resulting in fatality
The appropriate interval between discontinuation of Avastin and subsequent surgery required to avoid the risk of impaired wound healing has not been determined. The calculated half-life of Avastin (~20 days) should be taken into consideration

Hemorrhage (see Boxed WARNINGS in full Prescribing Information)

Two distinct patterns of bleeding have occurred in patients receiving Avastin. The first is minor hemorrhage, most commonly grade 1 epistaxis. The second is serious, and in some cases fatal, hemorrhagic events
- Mild (grade 1) epistaxis occurred in 35% of patients receiving Avastin plus IFL in MCRC
The incidence of severe or fatal hemoptysis was 31% in NSCLC patients with squamous histology (Study AVF0757g) and 2.3% in patients with NSCLC excluding predominant squamous histology (Study E4599)
- In Study E4599, the rate of pulmonary hemorrhage requiring medical intervention for the Avastin plus PC arm was 2.3% (10 of 427, 7 fatalities) vs 0.5% (2 of 441, 1 fatality) for the PC alone arm
- Of the patients experiencing pulmonary hemorrhage requiring medical intervention, many had cavitation and/or necrosis of the tumor, either pre-existing or developing during Avastin therapy
- Generally, these serious hemorrhagic events presented as major or massive hemoptysis without a history of minor hemoptysis during Avastin therapy
Do not administer Avastin to patients with recent hemoptysis (≥1/2 tsp of red blood)

Non-Gastrointestinal (Non-GI) Fistula Formation

Non-GI fistula formation has been reported in patients treated with Avastin in controlled clinical studies (with an incidence of <0.3%) and in post-marketing experience, in some cases with fatal outcome
Fistula formation involving the following areas of the body other than the GI tract have been reported: tracheoesophageal, bronchopleural, biliary, vagina, and bladder
Events were reported throughout treatment with Avastin, with most events occurring within the first 6 months

Arterial thromboembolic events (ATEs)

A pooled analysis of 5 randomized, controlled trials (N=1745) showed that Avastin plus chemotherapy increased the overall incidence of ATEs vs chemotherapy alone (4.4% vs 1.9%). These events were fatal in some instances
- ATEs included cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and others
The increase was greater in patients age 65 years and older (8.5% vs 2.9%) than in those younger than 65 years (2.1% vs 1.4%)

Hypertension

Across clinical studies, the incidence of severe (grade 3–4) hypertension ranged from 8% to 18% in Avastin-treated patients
Standard oral antihypertensives were used in the management of grade 3 hypertension
Complications can include hypertensive encephalopathy (in some cases fatal) and CNS hemorrhage
Blood pressure monitoring should be conducted every 2 to 3 weeks during treatment (more frequently in patients who develop hypertension, which may persist following discontinuation)

Reversible posterior leukoencephalopathy syndrome (RPLS)

RPLS has been reported in clinical trials at an incidence of < 0.1% and in the postmarketing setting
The safety of reinitiating Avastin in patients with RPLS is unknown

Neutropenia and infection

Increased rates of severe neutropenia, febrile neutropenia, and infection with severe neutropenia (including some fatalities) have been observed in patients treated with myelosuppressive chemotherapy plus Avastin

Proteinuria/nephrotic syndrome

Across clinical studies, the incidence of severe (grade 3–4) proteinuria, characterized as >3.5 g/24 hours, ranged up to 3.0% in Avastin-treated patients
Patients with moderate to severe proteinuria should be monitored regularly until improvement and/or resolution is observed

Congestive heart failure (CHF)

CHF, defined as NCI-CTC grade 2–4 left ventricular dysfunction, was reported in 25 of 1459 (1.7%) patients receiving Avastin in clinical studies
The rate of CHF (defined as NCI-CTC grade 3–4) was 2.2% in patients with metastatic breast cancer who have not received chemotherapy for metastatic HER2-negative breast cancer
- Among patients receiving anthracyclines, the rate of CHF was 3.8% for Avastin-treated patients
The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied

Avastin (bevacizumab)