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• • Efficacy in MCRC
  • Dose and Duration in MCRC
  • MCRC Resources
  • Safety Information
  • Prescribing Information

Avastin safety profile¹

Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions.

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

• Serious, and sometimes fatal, GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation, some fatal, in Avastin-treated patients range from 0.3% to 2.4% across clinical trials
• The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin
• Discontinue Avastin in patients with GI perforations (GI perforation, fistula formation in the GI tract, intra-abdominal abscess)

Surgery and wound healing complications (see Boxed WARNINGS in full Prescribing Information)

• The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
  • In a controlled clinical trial in MCRC patients who underwent surgery, the incidence of wound healing complications, including serious and fatal complications, was 15% vs 4% in patients who did not receive Avastin
• Avastin therapy should not be initiated for at least 28 days following major surgery. The surgical incision should be fully healed prior to initiation of Avastin
• The appropriate interval between discontinuation of Avastin and subsequent elective surgery required to reduce the risk of impaired wound healing/wound dehiscence has not been determined. The calculated half-life of Avastin (~20 days; range 11–50 days) should be taken into consideration. Suspend Avastin for at least 28 days prior to elective surgery
• Discontinue Avastin in patients with wound dehiscence and wound healing complications requiring medical intervention

Hemorrhage (see Boxed WARNINGS in full Prescribing Information)

• Avastin can result in 2 distinct patterns of bleeding: minor hemorrhage, most commonly grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events
• Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%
• Serious or fatal pulmonary hemorrhage occurred in 4 of 13 (31%) patients with squamous cell histology and 2 of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone
  • In clinical studies in non-small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic grade 2 CNS hemorrhage was documented in 1 of 83 Avastin-treated patients (rate 1.2%, 95% CI, 0.06%–5.93%)
  • Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; 2 patients had grade 3–4 hemorrhage
• Do not administer Avastin to patients with recent hemoptysis (≥1/2 tsp of red blood)
• Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Non-gastrointestinal (non-GI) fistula formation (Warnings and Precautions)

• Serious, and sometimes fatal, non-GI fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal, and bladder sites occurs at higher incidence in Avastin-treated patients compared to controls
• The incidence of non-GI perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy
• Discontinue Avastin in patients with fistula formation involving an internal organ

Arterial thromboembolic events (ATEs) (Warnings and Precautions)

• Serious, and sometimes fatal, ATEs, including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATEs, occurred at a higher incidence in patients receiving Avastin compared to the control arms
• Across indications, the incidence of grade ≥3 ATEs in the Avastin-containing arms was 2.4% compared to 0.7% in the control arms
• Among patients receiving Avastin in combination with chemotherapy, the risk of developing an ATE during therapy was increased in patients with a history of ATE or age greater than 65 years
• Permanently discontinue Avastin in patients who experience a severe ATE. The safety of resumption of Avastin therapy after resolution of an ATE has not been studied

Hypertension (Warnings and Precautions)

• The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies, the incidence of grade 3 or 4 hypertension ranged from 5% to 18%
• Blood pressure monitoring should be conducted every 2 to 3 weeks during treatment. Treat with antihypertensive therapy and monitor regularly
• Patients with Avastin-induced or -exacerbated hypertension who discontinue Avastin should continue to have their blood pressure monitored at regular intervals
• Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management

Reversible posterior leukoencephalopathy syndrome (RPLS) (Warnings and Precautions)

• RPLS has been reported in clinical trials at an incidence of <0.1%
• RPLS is a neurologic disorder that can present with headache, seizure, lethargy, confusion, blindness, and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary for diagnosis of RPLS
• The onset of symptoms has been reported to occur from 16 hours to 1 year after initiation of Avastin
• Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin in patients previously experiencing RPLS is unknown

Proteinuria/nephrotic syndrome (Warnings and Precautions)

• The incidence and severity of proteinuria are increased in patients receiving Avastin compared to controls
• Grade 3 and 4 proteinuria ranged from 0.7% to 7.4% across clinical trials
  • The overall incidence of proteinuria (all grades) was only adequately assessed in AVOREN, in which the incidence was 20%
  • In AVOREN, median onset of proteinuria was 5.6 months (range 15 days to 37 months) and median time to resolution was 6.1 months (95% CI, 2.8 months–11.3 months). Proteinuria did not resolve in 40% of patients after median follow-up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria
• Nephrotic syndrome occurred in <1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome
• In a published case series, kidney biopsy of 6 patients with proteinuria showed findings consistent with thrombotic microangiopathy
• Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with 2+ or greater urine dipstick reading should undergo further assessment, eg, a 24-hour urine collection
• Suspend Avastin administration for ≥2 grams of proteinuria/24 hours and resume when proteinuria is <2 g/24 hours
• Discontinue Avastin in patients with nephrotic syndrome. The safety of continued Avastin treatment in patients with moderate to severe proteinuria is unknown

Infusion reactions (Warnings and Precautions)

• In clinical studies, infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients
• Infusion reactions in clinical trials and in postmarketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, NCI-CTC grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis
• Avastin infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered

Pregnancy Category C (Use in Specific Populations)

• Prior to initiation of therapy, advise patients of the potential risk of Avastin to the developing fetus. Counsel patients who become pregnant about the possible risks, including hazard to the fetus and/or loss of pregnancy, of both continued treatment and prolonged exposure following discontinuation, keeping in mind the approximate half-life of Avastin (20 days; range 11–50 days). Patients should also be counseled to continue adequate contraception for at least 6 months following the last dose of Avastin

Nursing mothers (Use in Specific Populations)

• Women should be advised to discontinue nursing or Avastin, taking into account the half-life of the product, approximately 20 days (range 11–50 days), and the importance of Avastin to the mother

Impairment of fertility (Nonclinical Toxicology)

• Avastin may impair fertility

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 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.¹ 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.²

Grade 3–4 postsurgical complications in 2 randomized MCRC trials²

• *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.³

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.^1,3

Increased OS in patients ≥65 years (Study 2107)³

• ^†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 IV q2w plus FOLFOX4 maintained a safety profile consistent with Avastin 5 mg/kg IV q2w plus IFL in first-line treatment, while significantly extending OS.^1,4,5

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