Avastin Dosing and Administration1

Avastin dosing in approved indications1

Avastin dosing in approved indications
  • IV=intravenous.
  • q2w=every 2 weeks.
  • q3w=every 3 weeks.
  • *10 mg/kg IV dose evaluated in first-line metastatic renal cell carcinoma (mRCC) in combination with interferon alfa (IFN). IFN dose reduction or discontinuation was allowed per protocol. IFN was discontinued after 52 weeks or earlier.1,2
  • †15 mg/kg IV dose evaluated in first-line metastatic non-small cell lung cancer (NSCLC) in combination with paclitaxel/carboplatin (PC). Avastin plus PC was given for up to 6 cycles, after which Avastin was continued alone.
  • ‡ 10 mg/kg IV dose evaluated in second-line metastatic colorectal cancer (MCRC) in combination with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX).
  • §5 mg/kg IV dose evaluated in first-line MCRC in combination with 5-fluorouracil/leucovorin/irinotecan (IFL).

Treatment discontinuation and suspension1

  • Discontinue Avastin in patients with gastrointestinal (GI) perforations (GI perforations, fistula formation in the GI tract, intra-abdominal abscess), fistula formation involving an internal organ, wound dehiscence and wound healing complications requiring medical intervention, serious hemorrhage (i.e. requiring medical intervention), severe arterial thromboembolic event (ATE), nephrotic syndrome, hypertensive crisis, or hypertensive encephalopathy

  • In patients developing reversible posterior leukoencephalopathy syndrome (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. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known

  • Temporary suspension is recommended in patients with evidence of moderate to severe proteinuria and in patients with severe hypertension that is not controlled with medical management. The risk of continuation or temporary suspension of Avastin in patients with moderate to severe proteinuria is unknown. Avastin should be suspended for at least 4 weeks prior to elective surgery. Avastin should not be resumed until the surgical incision is fully healed

Duration of Avastin treatment

  • Study results were achieved when Avastin was continued until disease progression or unacceptable toxicity1-6

Avastin duration in approved indications1-4,6
Avastin duration per Phase III trial protocols
  • *10 mg/kg IV dose evaluated in first-line mRCC in combination with IFN. IFN dose reduction or discontinuation was allowed per protocol. IFN was discontinued after 52 weeks or earlier.1,2
  • †15 mg/kg IV dose evaluated in first-line metastatic NSCLC in combination with PC. Avastin plus PC was given for up to 6 cycles, after which Avastin was continued alone.
  • ‡ 10 mg/kg IV dose evaluated in second-line MCRC in combination with FOLFOX.
  • §5 mg/kg IV dose evaluated in first-line MCRC in combination with IFL.
FDA Approved prescribing information for the duration of Avastin treatment[1]
Per pivotal study protocols in mRCC, NSCLC, and MCRC1-4,6

  • Avastin administration was continued until disease progression or unacceptable toxicity

  • Dose reduction of Avastin was not allowed; in the event of unacceptable toxicity, Avastin was either discontinued or suspended

  • Avastin should be suspended at least 28 days prior to elective surgery and should not be resumed until the surgical incision is fully healed

    • The calculated half-life of Avastin (~20 days) should be considered when determining the interval between suspension and subsequent surgery

  • Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed

  • Avastin infusion should be interrupted in all patients with severe infusion reactions and appropriate medical therapy administered

  • Adequate information on rechallenge, including information on the most appropriate method of identifying patients who may safely be retreated with Avastin, is not available

Important treatment considerations—Women of childbearing potential1

Avastin may impair fertility. 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.

Important treatment considerations—Dose modifications1

Discontinue Avastin in patients with GI perforations (GI perforations, fistula formation in the GI tract, intra-abdominal abscess), fistula formation involving an internal organ, wound dehiscence and wound healing complications requiring medical intervention, serious hemorrhage (ie, requiring medical intervention), severe ATE, hypertensive crisis or hypertensive encephalopathy, RPLS (symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae), and nephrotic syndrome. Temporarily suspend Avastin for at least 4 weeks prior to elective surgery, severe hypertension not controlled with medical management, moderate to severe proteinuria pending further evaluation, and severe infusion reactions. The safety of resumption of Avastin therapy in patients that experienced RPLS, ATE, and moderate to severe proteinuria is unknown.

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

Preparation for administration1

  • Avastin should be diluted for infusion using aseptic technique

  • Withdraw the necessary amount of Avastin to obtain the required dose and dilute in a total volume of 100 mL of 0.9% Sodium Chloride Injection, USP

  • Discard any unused portion left in a vial, as the product contains no preservatives. Inspect visually for particulate matter and discoloration prior to administration

  • Diluted Avastin solutions for infusion may be stored at 2°C-8°C (36°F-46°F) for up to 8 hours

  • Avastin infusions should not be administered or mixed with dextrose solutions

Administration1

  • DO NOT ADMINISTER AS AN IV PUSH OR BOLUS

  • DO NOT INITIATE AVASTIN UNTIL AT LEAST 28 DAYS FOLLOWING SURGERY AND UNTIL THE SURGICAL WOUND IS FULLY HEALED

Infusion times1

Infusion times

  • 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

Indications

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

Glioblastoma (GBM)
Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.
The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Metastatic Breast Cancer (MBC)
Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in metastatic breast cancer is based on an improvement in progression free survival. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

Non–Squamous Non–Small Cell Lung Cancer (NSCLC)
Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Metastatic Colorectal Cancer (MCRC)
Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS and additional important safety information

  • 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 2.4% 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 dehiscence 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 1.2% to 4.6%. 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 and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

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

  • 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%)

  • In GBM, in Study AVF3708g, in patients receiving Avastin alone, the most frequently reported adverse events were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%), and diarrhea (21%). Of these, the incidence of grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%), and diarrhea (1%). Two deaths were possibly related to Avastin: 1 retroperitoneal hemorrhage and 1 neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan, the incidences of Avastin-related adverse events (grade 1–4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic events (8%), arterial thromboembolic events (6%), wound healing complications (6%), proteinuria (4%), GI perforation (2%), and RPLS (1%). The incidences of grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic events (7%), arterial thromboembolic events (3%), wound healing complications (3%), proteinuria (1%), and GI perforation (2%). Intracranial hemorrhage occurred in 8 of 163 patients; 2 patients had grade 3–4 hemorrhage

  • In MBC, grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E2100 increased by 20.5% in the Avastin plus paclitaxel vs paclitaxel groups. Grade 1–2 adverse events were not collected in Study E2100, and common adverse events of Avastin in combination with paclitaxel for metastatic breast cancer are not known. The most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E2100, which occurred at a higher absolute incidence (≥5%) in the Avastin plus paclitaxel vs paclitaxel groups, were sensory neuropathy (24% vs 18%), hypertension (16% vs 1%), and fatigue (11% vs 5%). The rate of CHF (defined as NCI-CTC grade 3–4) in the Avastin plus paclitaxel arm was 2.2% vs 0.3% in the control arm. Among patients receiving anthracyclines, the rate of CHF was 3.8% for Avastin-treated patients and 0.6% for patients receiving paclitaxel alone. Fatal adverse reactions occurred in 1.7% (6/363) of patients who received Avastin plus paclitaxel in Study E2100. Causes of death were GI perforation (2), myocardial infarction (2), and diarrhea/abdominal pain/weakness/hypotension (2)

  • In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%)

  • In first-line MCRC, the most common grade 3–4 events 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) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%)

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

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References
  1. Avastin Prescribing Information, Genentech, Inc. July 2009.
  2. Escudier B, Pluzanska A, Koralewski P, et al. Lancet. 2007;370:2103-2111.
  3. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550.
  4. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342.
  5. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544.
  6. Data on file. Genentech, Inc.