Kidney Cancer: Avastin Safety Profile


The Avastin® (bevacizumab) side effect and toxicity profile in metastatic renal cell carcinoma (mRCC) was demonstrated in the Phase III AVOREN study. [1,7]

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 3.2%) in Avastin-treated patients compared to controls. Discontinue Avastin for 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 
    • Discontinue in patients with wound dehiscence. Discontinue at least 28 days prior to elective surgery. 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
    • Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed
  • Hemorrhage
    • Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, epistaxis, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

Phase III AVOREN study: Avastin plus interferon alfa (IFN) [1]

Selected grade 3–5 adverse events in mRCC patients (≥2% higher incidence in Avastin arm) [1]

Adverse event Avastin + IFN (%) (n=337) Placebo + IFN (%) (n=304)
Fatigue 13 8
Asthenia 10 7
Proteinuria 7 0
Hypertension 6 1
Hemorrhage 3 0.3

Adverse events (all grades) occurring at ≥5% higher incidence in the Avastin arm [1]

Adverse event Avastin + IFN (%) (n=337) Placebo + IFN (%) (n=304)
Anorexia 36 31
Fatigue 33 27
Hypertension 28 9
Epistaxis 27 4
Headache 24 16
Diarrhea 21 16
Weight decreased 20 15
Proteinuria 20 3
Myalgia 19 14
Back pain 12 6
Dysphonia 5 0
  • The following adverse events were reported at a 5-fold greater incidence in the IFN-α plus Avastin arm compared to IFN-α alone and not represented in the table above: gingival bleeding (13 patients vs 1 patient), rhinitis (9 vs 0), blurred vision (8 vs 0), gingivitis (8 vs 1), gastroesophageal reflux disease (8 vs 1), tinnitus (7 vs 1), tooth abscess (7 vs 0), mouth ulceration (6 vs 0), acne (5 vs 0), deafness (5 vs 0), gastritis (5 vs 0), gingival pain (5 vs 0), and pulmonary embolism (5 vs 1) [1]
  • Adverse events were consistent with those previously reported for Avastin [1,7]
  • Deaths due to adverse events were reported in 8 (2%) patients who received Avastin and in 7 (2%) of those who did not receive Avastin [7]
    • Among patients who received Avastin, 3 (<1%) deaths were possibly related to Avastin [7]
  • Flexible IFN dose modification allowed for IFN toxicity management in AVOREN [3,7]

Indications

Metastatic renal cell carcinoma (mRCC)
Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls
    • The incidences of GI perforation ranged from 0.3% to 3.2% across clinical studies
    • 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 and 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 healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, 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 0.4% to 6.9% 
    • 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 (ie, requiring medical intervention)

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included
    • GI fistulae (up to 2% in metastatic colorectal cancer and ovarian cancer patients)
    • Non-GI fistulae (<1% in trials across various indications; 1.8% in a cervical cancer trial) 
    • Arterial thromboembolic events (grade ≥3, 2.6%)
    • Proteinuria (nephrotic syndrome, <1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included 
    • GI-vaginal fistulae occurred in 8.3% of patients in a cervical cancer trial
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
  • Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients
  • Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Pregnancy warning

  • Based on the mechanism of action and animal studies, Avastin may cause fetal harm
  • Advise female patients that Avastin may cause fetal harm, and to inform their healthcare provider of a known or suspected pregnancy 
  • Advise females of reproductive potential to use effective contraception during treatment with Avastin and for 6 months after the last dose of Avastin
  • Advise nursing women that breastfeeding is not recommended during treatment with Avastin
  • Avastin may impair fertility

Most common adverse events

  • Across indications, 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
— Exfoliative dermatitis

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

Indication-specific adverse events

  • In mRCC, the most common grade 3–5 adverse events in AVOREN, occurring at a ≥2% higher incidence in Avastin-treated patients vs controls, were fatigue (13% vs 8%), asthenia (10% vs 7%), proteinuria (7% vs 0%), hypertension (6% vs 1%), and hemorrhage (3% vs 0.3%)

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch.
You may also report side effects to Genentech at (888) 835-2555.

Please see full Prescribing Information, including Boxed WARNINGS, for additional important safety information.