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
OC Carboplatin and 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 stage III or IV OC following initial surgical resection in combination with carboplatin and paclitaxel. Avastin plus carboplatin and paclitaxel was given for up to 6 cycles, after which Avastin was continued alone for a total of up to 22 cycles, or until disease progression or unacceptable toxicity.
††15 mg/kg IV dose evaluated in psOC in combination with carboplatin and paclitaxel for 6-8 cycles or carboplatin and gemcitabine for 6-10 cycles after which Avastin continued alone until disease progression.
‡‡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.

Recurrent Glioblastoma (GBM)
Avastin is indicated for the treatment of recurrent glioblastoma in adults.

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 the first dose of Avastin
  • Long-term effects of Avastin exposure on fertility are unknown
  • Patients should also use effective contraception during treatment and for 6 months following the last dose of Avastin
  • Nursing mothers should be advised to discontinue nursing during treatment and for 6 months following their last dose of treatment

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

No dose reductions for Avastin are recommended.

Dose Modifications for Adverse Reactions

Adverse Reaction

Severity

Dose Modification

Gastrointestinal Perforation and Fistulae

  • Gastrointestinal perforation, any grade
  • Tracheoesophageal fistula, any grade
  • Fistula, Grade 4
  • Fistula formation involving any internal organ

Discontinue Avastin

Wound Healing Complications

  • Wound healing complications requiring medical intervention
  • Necrotizing fasciitis

Discontinue Avastin

Hemorrhage

  • Grade 3 or 4

Discontinue Avastin

  • Recent history of hemoptysis of 1/2 teaspoon (2.5 mL) or more

Withhold Avastin

Thromboembolic Events

  • Arterial thromboembolism, severe

Discontinue Avastin

  • Venous thromboembolism, Grade 4

Discontinue Avastin

Hypertension

  • Hypertensive crisis
  • Hypertensive encephalopathy

Discontinue Avastin

  • Hypertension, severe

Withhold Avastin if not controlled with medical management; resume once controlled

Posterior Reversible Encephalopathy Syndrome (PRES)

Any

Discontinue Avastin

Renal Toxicity and Proteinuria

  • Nephrotic syndrome

Discontinue Avastin

  • Proteinuria greater than or equal to 2 grams per 24 hours in absence of nephrotic syndrome

Withhold Avastin until proteinuria less than 2 grams per 24 hours

Infusion Reaction

  • Severe infusion reaction

Discontinue Avastin

  • Clinically significant

Interrupt infusion; resume at a decreased rate of infusion after symptoms resolve

 

  • Mild, clinically insignificant

Decrease infusion rate

Congestive Heart Failure

Any

Discontinue Avastin

View dose and duration information by specific cancer type

Indications

Stage III or IV ovarian cancer (OC) after primary surgery
Avastin, in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, is indicated for the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer following initial surgical resection.

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, in combination with carboplatin and paclitaxel, or 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.

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

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

Recurrent Glioblastoma (GBM)
Avastin is indicated for the treatment of recurrent glioblastoma in adults.

First-line non-squamous non-small cell lung cancer (NSCLC)
Avastin, in combination with carboplatin and paclitaxel, is indicated for the first‑line treatment of patients with unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer.

Metastatic colorectal cancer (MCRC)
Avastin, in combination with intravenous 5‑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 Avastin-containing regimen.

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

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
  • 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

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 Stage III or IV OC after primary surgery, 608 patients received CP+Avastin→Avastin, 607 patients received CP+Avastin→PBO, and 602 patients received CP+PBO→PBO. Grade 3–4 adverse reactions occurring at a higher incidence (≥2%) in either of the Avastin arms vs the chemotherapy only arm were fatigue (CP+Avastin→Avastin, 9%; CP+Avastin→PBO, 6%; CP+PBO→PBO, 6%), hypertension (CP+Avastin→Avastin, 10%; CP+Avastin→PBO, 6%; CP+PBO→PBO, 2%), platelet count decreased (CP+Avastin→Avastin, 21%; CP+Avastin→PBO, 20%; CP+PBO→PBO, 15%), and white blood cell count decreased (CP+Avastin→Avastin, 51%; CP+Avastin→PBO, 53%; CP+PBO→PBO, 50%)
  • In psOC, grade 3 or 4 adverse reactions 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% vs 34%), nausea (4% vs 1.3%), fatigue (6% vs 4%), headache (4% vs 0.9%), proteinuria (10% vs 0.4%), dyspnea (4% vs 1.7%), epistaxis (5% vs 0.4%), and hypertension (17% vs 0.9%)
  • In psOC, grade 3 or 4 adverse reactions in the GOG-0213 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% vs 0.6%), fatigue (8% vs 3%), febrile neutropenia (6% vs 3%), proteinuria (8% vs 0%), abdominal pain (6% vs 0.9%), hyponatremia (4% vs 0.9%), headache (3% vs 0.9%), and pain in extremity (3.4% vs 0%)
  • In prOC, grade 3–4 adverse reactions in AURELIA 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%)
  • In CC, grade 3 or 4 adverse reactions in Study GOG-0240, occurring at a higher incidence (≥2%) in 218 patients receiving Avastin plus chemotherapy compared to 222 patients receiving chemotherapy alone, were abdominal pain (12% vs 10%), diarrhea (6% vs 3%), anal fistula (4% vs 0%), proctalgia (3% vs 0%), urinary tract infection (8% vs 6%), cellulitis (3% vs 0.5%), fatigue (14% vs 10%), hypertension (11% vs 0.5%), thrombosis (8% vs 3%), hypokalemia (7% vs 4%), hyponatremia (4% vs 1%), dehydration (4% vs 0.5%), neutropenia (8% vs 4%), lymphopenia (6% vs 3%), back pain (6% vs 3%), and pelvic pain (6% vs 1%)
  • 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)
  • In rGBM Study EORTC 26101, 22% of patients discontinued treatment in the Avastin with lomustine arm due to adverse reactions compared with 10% of patients in the lomustine arm. In patients receiving Avastin with lomustine, the adverse reaction profile was similar to that observed in other approved indications
  • 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 thromboembolism (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 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 MCRC5

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.