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Colorectal Cancer: Avastin Safety Profile

Metastatic colorectal cancer (MCRC)
Avastin, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first‑ or second‑line treatment of patients with metastatic colorectal cancer.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line bevacizumab product-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Consistent safety profile demonstrated in 3 large Phase III trials


Safety evaluated in 2919 patients receiving Avastin in clinical trials across indications[1]


First-line Study 2107: Avastin plus 5-fluorouracil (5-FU)/leucovorin (LV)/irinotecan (IFL)[1]

Grade 3–4 adverse events in MCRC patients (≥2% higher incidence in the Avastin arm)[1]

National Cancer Institute Common Terminology Criteria (NCI-CTC) grade 3–4 events Patients (%)
Avastin + IFL (n=392) Placebo + IFL (n=396)
Asthenia 10 7
Abdominal pain 8 5
Pain 8 5
Hypertension 12 2
Deep vein thrombosis 9 5
Intra-abdominal thrombosis 3 1
Syncope 3 1
Diarrhea 34 25
Constipation 4 2
Leukopenia 37 31
Neutropenia* 21 14
     

*Central laboratories were collected on days 1 and 21 of each cycle. Neutrophil counts were available in 303 patients receiving placebo plus IFL and 276 patients receiving Avastin plus IFL.[1]

Second-line Avastin-naive Study E3200: Avastin plus 5-FU/LV/oxaliplatin (FOLFOX4)[1]

Grade 3–5 adverse events (≥2% higher incidence in the Avastin arm)[1]†

National Cancer Institute Common Terminology Criteria (NCI-CTC) grade 3–4 events Patients (%)
Avastin + IFL (n=392) Placebo + IFL (n=396)
Fatigue 19 13
Diarrhea 18 13
Sensory neuropathy 17 9
Nausea 12 5
Vomiting 11 4
Dehydration 10 5
Hypertension 9 2
Abdominal pain 8 5
Hemorrhage 5 1
Neurological disorder 5 3
Ileus 4 1
Headache 3 0
     

These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study.[1]

The TML study: Avastin plus fluoropyrimidine-based chemotherapy[4


No new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC.[4] 


TML=Treatment through Multiple Lines (first and second line).
§Chemotherapy combinations included either an irinotecan- or oxaliplatin-containing regimen.[1]

Important Safety Information & Indication

Indication

Metastatic colorectal cancer (MCRC)

Avastin, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first‑ or second‑line treatment of patients with metastatic colorectal cancer.

Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line bevacizumab product-containing regimen.

Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Serious adverse reactions (Warnings and Precautions)

  • Serious and sometimes fatal adverse reactions with increased incidence in the Avastin-treated arm vs chemotherapy arm included:
    • Gastrointestinal (GI) perforation ranged from 0.3% to 3% of patients across clinical studies
    • Non-GI fistulae (<1% to 1.8%, highest in patients with cervical cancer)
    • Arterial thromboembolic events (Grade ≥3, 5%, highest in patients with GBM)
    • The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients
    • Hemorrhage (Grade 3–5) ranged from 0.4% to 7% of patients across clinical studies
    • Renal injury and proteinuria
      • Grade 3–4 proteinuria ranged from 0.7% to 7% in clinical studies
      • Nephrotic syndrome (<1%)
  • Additional serious adverse reactions 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): Grade ≥3 left ventricular dysfunction (1%)
  • Infusion-related reactions with the first dose of Avastin occurred in <3% of patients, and severe reactions occurred in 0.4% of patients
  • Avoid use in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction
  • Inform females of reproductive potential of the risk of ovarian failure prior to initiating treatment with Avastin
  • An evaluation for the presence of varices is recommended within 6 months of initiation of Avastin in patients with HCC

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 not to breastfeed during treatment with Avastin and for 6 months following their last dose of treatment
  • Avastin may impair fertility

Most common adverse reactions

  • 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
    • 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 reactions

  • In first-line MCRC, the most common Grade 3–4 reactions in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%)
  • In second-line MCRC, the most common Grade 3–5 (nonhematologic) and 4–5 (hematologic) reactions in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were fatigue (19% vs 13%), diarrhea (18% vs 13%), sensory neuropathy (17% vs 9%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), hypertension (9% vs 2%), abdominal pain (8% vs 5%), hemorrhage (5% vs 1%), other neurological (5% vs 3%), ileus (4% vs 1%), and headache (3% vs 0%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study
  • When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC

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 for additional important safety information.

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