A well-established, consistent safety profile

Selected important safety information1

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

  • 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

Bleeding and surgical considerations

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. Avastin should be suspended at least several weeks prior to elective surgery and should not be resumed until the surgical incision is fully healed. The half-life of Avastin (~20 days; range 11–50 days) should be considered when determining this interval. Avastin should be permanently discontinued in patients with wound dehiscence requiring medical intervention.1

Avastin therapy should not be initiated for at least 28 days following major surgery, and the surgical incision should be fully healed prior to initiation of Avastin. In a pooled analysis of 2 randomized MCRC trials, there was a low incidence of wound healing complications when Avastin was administered 28 to 60 days after primary cancer surgery.22

Grade 3–4 postsurgical complications in 2 randomized MCRC trials22

  • *All complications occurred when surgery was performed within 60 days of the last Avastin dose. Within that 60-day period, there was no definite relationship between the timing of surgery and the development of complications.
Low-dose aspirin and the risk of bleeding

Low-dose aspirin (≤325 mg/d) is a standard therapy for primary and secondary prophylaxis of ATEs in high-risk patients. Although it is associated with an increased risk of bleeding, the use of low-dose aspirin has been permitted in Avastin trials. In a pooled analysis of 3 randomized MCRC trials, low-dose aspirin was not associated with an increased risk of bleeding in patients receiving Avastin.5

Arterial thromboembolic events (ATEs)

Results from an exploratory pooled analysis

An exploratory pooled analysis of 5 randomized, controlled trials (N=1745) showed that Avastin plus chemotherapy increased the incidence of ATEs vs chemotherapy alone (4.4% vs 1.9%). The increase was greater in patients ≥65 years (8.5% vs 2.9%) than in those younger than 65 years (2.1% vs 1.4%).1

Weighing the risk of ATEs

In the pivotal Phase III MCRC trial, the survival benefit of Avastin was seen in all subgroups tested, including elderly patients. In the Avastin group, the overall risk of death was reduced by 34% in all patients (HR=0.66) and by 39% in patients ≥65 years (HR=0.61). Avastin should be permanently discontinued in patients who experience a severe ATE during treatment.1,5

Increased overall survival in patients ≥65 years (Study 2107)5

  • *Difference statistically significant.

Positive benefit-risk ratio in both first- and second-line treatment

The safety of Avastin has been demonstrated in multiple randomized, controlled trials in combination with FOLFOX4, IFL, and IV 5-FU/LV. In second-line MCRC, Avastin 10 mg/kg q2w plus FOLFOX4 maintained a safety profile consistent with Avastin 5 mg/kg q2w plus IFL in first-line treatment, while significantly extending overall survival1,2,4

Avastin plus IFL (first-line MCRC)1
Selected grade 3–4 adverse events

  • †Difference statistically significant (P<0.01).
  • ‡Central laboratories were collected on days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients receiving placebo plus IFL and 276 patients receiving Avastin plus IFL.
Avastin plus FOLFOX4 (second-line MCRC)1
Selected grade 3–5 adverse events

References
  1. Avastin Prescribing Information. Genentech, Inc. March 2008.
  1. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342.
  1. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544.
  1. Data on file. Genentech, Inc.
  1. Scappaticci FA, Fehrenbacher L, Cartwright T, et al. J Surg Oncol. 2005;91:173-180.

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