Kidney Cancer: Avastin Safety Profile

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

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

*Including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Discontinue for gastrointestinal perforation
  • Surgery and wound healing complications
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue in patients with wound healing complications requiring medical intervention
  • Hemorrhage
    • Severe or fatal hemorrhage have occurred
    • Do not administer Avastin to patients with serious hemorrhage or recent history of hemoptysis
    • Discontinue for Grade 3-4 hemorrhage

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

Adverse event Avastin + IFN (%) (n=337) Placebo + IFN (%) (n=304)
Decreased appetite 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 more frequency 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, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma.

Boxed WARNINGS

  • Gastrointestinal (GI) perforation
    • Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to patients treated with chemotherapy
    • The incidence of GI perforation ranged from 0.3% to 3% 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
    • Withhold Avastin for at least 28 days prior to elective surgery. Do not administer Avastin for at least 28 days after surgery and until the wound is fully healed
    • Discontinue 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. In clinical studies, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 0.4% to 7%
    • Do not administer Avastin to patients with serious hemorrhage or a recent history of hemoptysis (≥1/2 tsp of red blood)
    • Discontinue Avastin in patients who develop grade 3-4 hemorrhage

Additional serious adverse events

  • Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
    • Arterial thromboembolic events (grade ≥3, 5%, highest in patients with GBM)
    • Renal injury and proteinuria
      • Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
      • Nephrotic syndrome (<1%)
  • Additional serious adverse events with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Venous thromboembolism (grade ≥3, 11% seen in GOG-0240)
    • Hypertension (grade 3–4, 5%–18%)
    • Posterior reversible encephalopathy syndrome (PRES) (<0.5%)
    • Congestive heart failure (CHF) (1%)
  • Infusion reactions with the first dose of Avastin occurred in <3% of patients, 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 and for 6 months following their last dose of treatment
  • Avastin may impair fertility

Most common adverse events

  • Across studies, the most common adverse reactions observed in Avastin patients at a rate >10% 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% to 22% 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%, including hypertension and hypertensive crisis), and hemorrhage (3% vs 0.3%;, including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, hemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma)

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.