Avastin dosing in approved cancer types

Avastin is administered as a solution for intravenous (IV) infusion at the following doses and schedules [1]:

Tumor type Combination regimen Avastin dose Avastin schedule
MCRC IFL* (First-line Study 2107) 5 mg/kg IV Every 2 weeks
FOLFOX4 (Second-line Study E3200) 10 mg/kg IV Every 2 weeks
Fluoropyrimidine-based chemotherapy in patients who had progressed on a first-line Avastin-containing regimen (First- through second-line TML study§) 5 mg/kg IV Every 2 weeks
7.5 mg/kg IV Every 3 weeks
NSCLC|| PC 15 mg/kg IV Every 3 weeks
mRCC IFN 10 mg/kg IV Every 2 weeks
CC# Cisplatin/paclitaxel or topotecan/paclitaxel 15 mg/kg IV Every 3 weeks
psOC** Carboplatin and gemcitabine 15 mg/kg IV Every 3 weeks
Carboplatin and paclitaxel
15 mg/kg IV Every 3 weeks
prOC†† Paclitaxel (weekly) 10 mg/kg IV Every 2 weeks
PLD
Topotecan (weekly)
Topotecan (every 3 weeks) 15 mg/kg IV Every 3 weeks
rGBM‡‡ None (single agent) 10 mg/kg IV Every 2 weeks

*5 mg/kg IV dose evaluated in first-line MCRC in combination with 5-fluorouracil (5-FU)/leucovorin (LV)/irinotecan (IFL).
10 mg/kg IV dose evaluated in second-line, Avastin-naive MCRC patients in combination with 5-FU/LV/oxaliplatin (FOLFOX4).
[1,4]
5 mg/kg IV every 2 weeks and 7.5 mg/kg IV every 3 weeks doses evaluated, in combination with fluoropyrimidine and either irinotecan- or oxaliplatin-containing chemotherapy, in MCRC patients who had progressed on a first-line Avastin-containing regimen.
§TML=Treatment through Multiple Lines (first and second line).
||15 mg/kg IV dose evaluated in first-line locally advanced or metastatic non-squamous NSCLC in combination with paclitaxel/carboplatin (PC). Avastin plus PC was given for up to 6 cycles, after which Avastin was continued alone until disease progression or unacceptable toxicity.
10 mg/kg IV dose evaluated in mRCC in combination with interferon alfa (IFN). AVOREN protocol allowed for IFN dose escalation (attaining a dose of 9 million international units [MIU] within the first 2 weeks), reduction, or discontinuation. IFN was discontinued after 52 weeks or earlier.
[1,7]
#15 mg/kg IV dose evaluated in CC in combination with cisplatin/paclitaxel or topotecan/paclitaxel. Treatment was given until disease progression or unacceptable toxicity.
**15 mg/kg IV dose evaluated in psOC in combination with carboplatin and paclitaxel or carboplatin and gemcitabine.
††10 mg/kg IV dose evaluated in prOC in combination with weekly paclitaxel, PLD (pegylated liposomal doxorubicin), or weekly topotecan, and 15 mg/kg IV dose evaluated in combination with topotecan administered every 3 weeks. Treatment was given until disease progression or unacceptable toxicity.
‡‡10 mg/kg IV dose evaluated as a single agent for rGBM that has progressed following prior therapy.

Glioblastoma (GBM)
Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. 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.

Important treatment considerations—Women of childbearing potential

  • Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin
  • Long-term effects of Avastin exposure on fertility are unknown
  • Counsel patients 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 6 months following the last dose of Avastin 
  • Nursing mothers should be advised to discontinue nursing or Avastin, taking into account the half-life of the product and the importance of Avastin to the mother

Duration of Avastin treatment

The FDA-approved Prescribing Information addresses the duration of Avastin treatment [1]
Patients should continue treatment until disease progression or unacceptable toxicity. 

Important treatment considerations—Dose modifications

  • There are no recommended dose reductions 
  • 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 (ie, requiring medical intervention)
    • Severe arterial thromboembolic event (ATE)
    • Life-threatening (grade 4) venous thromboembolic events, including pulmonary embolism
    • Hypertensive crisis or hypertensive encephalopathy 
    • Posterior reversible encephalopathy syndrome (PRES)
    • 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, and severe infusion reactions 
  • The safety of resumption of Avastin therapy in patients that experienced PRES or ATE is unknown

Indications

Glioblastoma (GBM)
Avastin is indicated for the treatment of glioblastoma as a single agent for adult patients with progressive disease following prior therapy. 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 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.

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 Avastin-containing regimen.

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

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

Persistent, recurrent, or metastatic cervical cancer (CC)
Avastin in combination with paclitaxel and cisplatin or paclitaxel and topotecan is indicated for the treatment of persistent, recurrent, or metastatic carcinoma of the cervix.

Recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (rOC)
Avastin in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan is indicated for the treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens.
Avastin, either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine, followed by Avastin as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

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
    • Venous thromboembolism (grade 3–4, up to 10.6%) in patients with persistent, recurrent, or metastatic cervical cancer treated with Avastin
    • 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 
  • 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

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 GBM 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 GBM patients receiving Avastin alone or Avastin plus irinotecan,a 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 PRES (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

aAvastin is not approved for use in combination with irinotecan or any other combination regimens.

  • 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%). 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
  • 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 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 CC, grade 3 or 4 adverse reactions in Study GOG 240, occurring at a higher incidence (≥2%) in 218 patients receiving chemotherapy plus Avastin compared to 222 patients receiving chemotherapy alone, were abdominal pain (11.9% vs 9.9%), diarrhea (5.5% vs 2.7%), anal fistula (3.7% vs 0%), proctalgia (2.8% vs 0%), urinary tract infection (8.3% vs 6.3%), cellulitis (3.2% vs 0.5%), fatigue (14.2% vs 9.9%), hypertension (11.5% vs 0.5%), thrombosis (8.3% vs 2.7%), hypokalemia (7.3% vs 4.5%), hyponatremia (3.7% vs 1.4%), dehydration (4.1% vs 0.5%), neutropenia (7.8% vs 4.1%), lymphopenia (6.0% vs 3.2%), back pain (5.5% vs 3.2%), and pelvic pain (5.5% vs 1.4%). There were no grade 5 adverse reactions occurring at a higher incidence (≥2%) in patients receiving chemotherapy plus Avastin compared to patients receiving chemotherapy alone
  • In psOC, grade 3 or 4 adverse events in the OCEANS study occurring at a higher incidence (≥2%) in 247 patients receiving Avastin plus carboplatin and gemcitabine (chemotherapy) compared to 233 patients receiving placebo plus chemotherapy were thrombocytopenia (40.1% vs 33.9%), nausea (4.5% vs 1.3%), fatigue (6.5% vs 4.3%), headache (3.6% vs 0.9%), proteinuria (9.7% vs 0.4%), dyspnea (4.5% vs 1.7%), epistaxis (4.9% vs 0.4%), and hypertension (17.0% vs 0.9%). Grade ≥3 anemia (16.2% vs 18.9%) and decreased white blood cell count (1.6% vs 4.3%) occurred with a ≥2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. No grade 5 AE occurred with a ≥2% higher frequency in the Avastin plus chemotherapy arm compared to the placebo plus chemotherapy arm
  • In psOC, grade 3 or 4 adverse events in the GOG 213 study occurring at a higher incidence (≥2%) in 325 patients receiving Avastin plus carboplatin and paclitaxel (chemotherapy) compared to 332 patients receiving chemotherapy alone were hypertension (11.1% vs 0.6%), fatigue (7.7% vs 2.7%), febrile neutropenia (6.2% vs 2.7%), proteinuria (8% vs 0%), abdominal pain (5.8% vs 0.9%), hyponatremia (3.7% vs 0.9%), headache (3.1% vs 0.9%), and pain in extremity (3.4% vs 0%). No Grade ≥3 adverse events occurred with a ≥2% higher frequency in the chemotherapy alone arm compared to the Avastin plus chemotherapy arm. No grade 5 AE occurred with a ≥2% higher frequency in the Avastin plus chemotherapy arm compared to the chemotherapy alone arm
  • In prOC, grade 3–4 adverse events occurring at a higher incidence (≥2%) in 179 patients receiving Avastin plus chemotherapy compared to 181 patients receiving chemotherapy alone were hypertension (6.7% vs 1.1%) and palmar-plantar erythrodysaesthesia syndrome (4.5% vs 1.7%). There were no grade 5 events occurring at a higher incidence (≥2%) in patients receiving Avastin plus chemotherapy compared to patients receiving chemotherapy alone

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.