S 0169 LBL

This label may not be the latest approved by FDA.
For current labeling information, please visit https://www.fda.gov/drugsatfda
1.14.2.3 Final Labeling Text ------------------------DOSAGE AND ADMINISTRATION---------------------

• Do not administer as an IV push or bolus. (2.1)
HIGHLIGHTS OF PRESCRIBING INFORMATION • Do not initiate Avastin for 28 days following major surgery and until
These highlights do not include all the information needed to use surgical wound is fully healed. (2.1)
AVASTIN safely and effectively. See full prescribing information for
AVASTIN. Metastatic colorectal cancer (2.2)
• 5 mg/kg IV every 2 weeks with bolus-IFL
AVASTIN® (bevacizumab) • 10 mg/kg IV every 2 weeks with FOLFOX4
Solution for intravenous infusion Non−squamous non−small cell lung cancer (2.2)
Initial U.S. Approval: 2004 • 15 mg/kg IV every 3 weeks with carboplatin/paclitaxel
Metastatic breast cancer (2.2)
• 10 mg/kg IV every 2 weeks with paclitaxel
WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY
Glioblastoma (2.2)
AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE
• 10 mg/kg IV every 2 weeks
See full prescribing information for complete boxed warning.
• Gastrointestinal Perforation: Occurs in up to 2.4% of -----------------------DOSAGE FORMS AND STRENGTHS--------------------
Avastin-treated patients. Discontinue Avastin for gastrointestinal • 100 mg/4 mL, single use vial (3)
perforation. (5.1) • 400 mg/16 mL, single use vial (3)
• Surgery and Wound Healing Complications: Discontinue in
patients with wound dehiscence. Discontinue at least 28 days prior ---------------------------CONTRAINDICATIONS---------------------------------
to elective surgery. Do not initiate Avastin for at least 28 days None (4)
after surgery and until the surgical wound is fully healed. (5.2)
• Hemorrhage: Severe or fatal hemorrhage, hemoptysis, -----------------------WARNINGS AND PRECAUTIONS------------------------
gastrointestinal bleeding, CNS hemorrhage, and vaginal bleeding • Non-Gastrointestinal Fistula Formation: Discontinue Avastin if fistula
are increased in Avastin- treated patients. Do not administer formation occurs. (5.4)
Avastin to patients with serious hemorrhage or recent hemoptysis. • Arterial Thromboembolic Events (e.g., myocardial infarction, cerebral
(5.3) infarction): Discontinue Avastin for severe ATE. (5.5)
• Hypertension: Monitor blood pressure and treat hypertension.
Temporarily suspend Avastin if not medically controlled. Discontinue
-------------------------RECENT MAJOR CHANGES----------------------------- Avastin for hypertensive crisis or hypertensive encephalopathy. (5.6)
Indications and Usage, Glioblastoma (1.4) 5/2009 • Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
Dosage and Administration, Glioblastoma (2.2) 5/2009 Discontinue Avastin. (5.7)
Warnings and Precautions, Hemorrhage (5.3) 5/2009 • Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome.
Warnings and Precautions, Proteinuria (5.8) 11/2008 Temporarily suspend Avastin for moderate proteinuria. (5.8)
• Infusion Reactions: Stop for severe infusion reactions. (5.9)
---------------------------INDICATIONS AND USAGE----------------------------
Avastin is a vascular endothelial growth factor-specific angiogenesis ------------------------------ADVERSE REACTIONS------------------------------
inhibitor indicated for the treatment of: Most common adverse reactions incidence (>10% and at least twice the
control arm rate) are epistaxis, headache, hypertension, rhinitis, proteinuria,
• Metastatic colorectal cancer, with intravenous 5-fluorouracil–based
taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, and
chemotherapy for first- or second-line treatment. (1.1)
exfoliative dermatitis. (6.1)
• Non-squamous non-small cell lung cancer, with carboplatin and paclitaxel
for first line treatment of unresectable, locally advanced, recurrent or
To report SUSPECTED ADVERSE REACTIONS, contact Genentech,
metastatic disease. (1.2)
Inc. at 1-888-835-2555 or FDA at 1-800-FDA-1088 or
• Metastatic breast cancer, with paclitaxel for treatment of patients who have
www.fda.gov/medwatch.
not received chemotherapy for metastatic HER2-negative breast cancer.
(1.3) -----------------------------USE IN SPECIFIC POPULATIONS------------------
-Effectiveness based on improvement in progression-free survival. No • Pregnancy: Based on animal data, may cause fetal harm. (8.1)
data available demonstrating improvement in disease-related symptoms or • Nursing Mothers: Discontinue nursing or discontinue drug, taking into
survival with Avastin. account the importance of the drug to the mother. (8.3)
-Not indicated for disease progression following anthracycline and taxane
chemotherapy administered for metastatic disease. See 17 for PATIENT COUNSELING INFORMATION.
• Glioblastoma, as a single agent for patients with progressive disease
following prior therapy. (1.4) Revised: May 2009
-Effectiveness based on improvement in objective response rate. No data
available demonstrating improvement in disease-related symptoms or
survival with Avastin.
U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

1 of 22/Regional (Glioblastoma): avastin_new.doc
FULL PRESCRIBING INFORMATION: CONTENTS* 6.1 Clinical Trial Experience

6.2 Immunogenicity
WARNING: GASTROINTESTINAL PERFORATIONS, 6.3 Postmarketing Experience
SURGERY AND WOUND HEALING COMPLICATIONS, and 7 DRUG INTERACTIONS
HEMORRHAGE 8 USE IN SPECIFIC POPULATIONS
1 INDICATIONS AND USAGE 8.1 Pregnancy
1.1 Metastatic Colorectal Cancer 8.3 Nursing Mothers
1.2 Non-Squamous Non−Small Cell Lung Cancer 8.4 Pediatric Use
1.3 Metastatic Breast Cancer 8.5 Geriatric Use
1.4 Glioblastoma 10 OVERDOSAGE
2 DOSAGE AND ADMINISTRATION 11 DESCRIPTION
2.1 Administration 12 CLINICAL PHARMACOLOGY
2.2 Recommended Doses and Schedules 12.1 Mechanism of Action
2.3 Preparation for Administration 12.3 Pharmacokinetics
2.4 Dose Modifications 13 NONCLINICAL TOXICOLOGY
3 DOSAGE FORMS AND STRENGTHS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
4 CONTRAINDICATIONS 13.2 Animal Toxicology and/or Pharmacology
5 WARNINGS AND PRECAUTIONS 13.3 Reproductive and Developmental Toxicology
5.1 Gastrointestinal Perforations 14 CLINICAL STUDIES
5.2 Surgery and Wound Healing Complications 14.1 Metastatic Colorectal Cancer (mCRC)
5.3 Hemorrhage 14.2 Unresectable Non−Squamous Non−Small Cell Lung
5.4 Non-Gastrointestinal Fistula Formation Cancer (NSCLC)
5.5 Arterial Thromboembolic Events 14.3 Metastatic Breast Cancer (MBC)
5.6 Hypertension 14.4 Glioblastoma
5.7 Reversible Posterior Leukoencephalopathy Syndrome 16 HOW SUPPLIED/STORAGE AND HANDLING
(RPLS) 17 PATIENT COUNSELING INFORMATION
5.8 Proteinuria
5.9 Infusion Reactions * Sections or subsections omitted from the Full Prescribing Information are
6 ADVERSE REACTIONS not listed.

FULL PRESCRIBING INFORMATION
WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND

HEALING COMPLICATIONS, and HEMORRHAGE
Gastrointestinal Perforations
The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges
from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See
Dosage and Administration (2.4), Warnings and Precautions (5.1).]
Surgery and Wound Healing Complications
The incidence of wound healing and surgical complications, including serious and fatal
complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with
wound dehiscence. 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 at least 28 days prior to elective surgery. Do not initiate
Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See
Dosage and Administration (2.4), Warnings and Precautions (5.3).]
Hemorrhage
Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous
systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more
frequently in patients receiving Avastin. Do not administer Avastin to patients with serious
hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and
Precautions (5.4), and Adverse Reactions (6.1).]
1 INDICATIONS AND USAGE

1.1 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.
1.2 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.
1.3 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 MBC 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. [See Clinical Studies (14.3).]
Avastin is not indicated for patients with breast cancer that has progressed following anthracycline
and taxane chemotherapy administered for metastatic disease.
1.4 Glioblastoma
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. [See Clinical Studies (14.4).]

2 DOSAGE AND ADMINISTRATION

2.1 Administration
Do not administer as an intravenous push or bolus. Administer only as an intravenous (IV)
infusion.
• Do not initiate Avastin until at least 28 days following major surgery. Administer Avastin after
the surgical incision has fully healed.
• First infusion: Administer infusion over 90 minutes.
• Subsequent infusions: Administer second infusion over 60 minutes if first infusion is tolerated;
administer all subsequent infusions over 30 minutes if infusion over 60 minutes is tolerated.
2.2 Recommended Doses and Schedules
Patients should continue treatment until disease progression or unacceptable toxicity.
Metastatic Colorectal Cancer (mCRC)
The recommended doses are 5 mg/kg or 10 mg/kg every 2 weeks when used in combination with
intravenous 5-FU-based chemotherapy.
• Administer 5 mg/kg when used in combination with bolus-IFL.
• Administer 10 mg/kg when used in combination with FOLFOX4.
Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
The recommended dose is 15 mg/kg every 3 weeks.
Metastatic Breast Cancer (MBC)
T
Glioblastoma
2.3 Preparation for Administration
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for
particulate matter and discoloration prior to administration, whenever solution and container permit.
Withdraw necessary amount of Avastin 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.
DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION.
2.4 Dose Modifications
There are no recommended dose reductions.
Discontinue Avastin for:
• Gastrointestinal perforations (gastrointestinal perforations, fistula formation in the
gastrointestinal tract, intra-abdominal abscess), fistula formation involving an internal organ
[See Boxed Warning, Warnings and Precautions (5.1, 5.4).]
• Wound dehiscence and wound healing complications requiring medical intervention [See
Warnings and Precautions (5.2).]
• Serious hemorrhage (i.e., requiring medical intervention) [See Boxed Warning, Warnings and
Precautions (5.3).]
• Severe arterial thromboembolic events [See Warnings and Precautions (5.5).]
• Hypertensive crisis or hypertensive encephalopathy [See Warnings and Precautions (5.6).]
• Reversible posterior leukoencephalopathy syndrome (RPLS) [See Warnings and Precautions
(5.7).]
• Nephrotic syndrome [See Warnings and Precautions (5.8).]
Temporarily suspend Avastin for:

• At least 4 weeks prior to elective surgery [See Warnings and Precautions (5.2).]
• Severe hypertension not controlled with medical management [See Warnings and Precautions
(5.6).]
• Moderate to severe proteinuria pending further evaluation [See Warnings and Precautions
(5.8).]
• Severe infusion reactions [See Warnings and Precautions (5.9).]
3 DOSAGE FORMS AND STRENGTHS

100 mg per 4 mL single-use vial
400 mg per 16 mL single-use vial
4 CONTRAINDICATIONS
None.
5 WARNINGS AND PRECAUTIONS

5.1 Gastrointestinal Perforations
Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin
treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3
to 2.4% across clinical studies. [See Adverse Reactions (6.1).]
The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever.
Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of
cases occurred within the first 50 days of initiation of Avastin.
Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage
and Administration (2.4).]
5.2 Surgery and Wound Healing Complications
Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical
trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled
clinical trial, the incidence of wound healing complications, including serious and fatal
complications, in patients with mCRC who underwent surgery during the course of Avastin
treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions
(6.1).]
Avastin should not be initiated for at least 28 days following surgery and until the surgical wound
is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical
intervention.
The appropriate interval between the last dose of Avastin and elective surgery is unknown;
however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days
prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed
Warning, Dosage and Administration (2.4).]
5.3 Hemorrhage
Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly
Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal
hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage,
epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin
compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3
hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse
Reactions (6.1).]
Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell
histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving
Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.
In clinical studies in non−small cell lung cancer where patients with CNS metastases who
completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with
serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83
Avastin-treated patients (rate 1.2%, 95% CI 0.06%−5.93%).
Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two
patients had Grade 3−4 hemorrhage.
Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red
blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and
Administration (2.4).]
5.4 Non-Gastrointestinal Fistula Formation
Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal,
bronchopleural, biliary, vaginal and bladder sites occurs at a higher incidence in Avastin-treated
patients compared to controls. The incidence of non-gastrointestinal perforation was <0.3% in
clinical studies. Most events occurred within the first 6 months of Avastin therapy.
Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage
5.5 Arterial Thromboembolic Events
Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction,
transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a
higher incidence in patients receiving Avastin compared to those in the control arm. Across
indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to
0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the
risk of developing ATE during therapy was increased in patients with a history of arterial
thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]
The safety of resumption of Avastin therapy after resolution of an ATE has not been studied.
Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration
(2.4).]
5.6 Hypertension
The incidence of severe hypertension is increased in patients receiving Avastin as compared to
controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.
Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with
appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to monitor
blood pressure at regular intervals in patients with Avastin-induced or -exacerbated hypertension
after discontinuation of Avastin.
Temporarily suspend Avastin in patients with severe hypertension that is not controlled with
medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive
encephalopathy. [See Dosage and Administration (2.4).]
5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms
occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which
can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic
disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is
necessary to confirm the diagnosis of RPLS.
Discontinue Avastin in patients developing RPLS. 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. [See Dosage
5.8 Proteinuria
The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to
controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in
some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney
biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.
Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria
with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading
should undergo further assessment, e.g. a 24-hour urine collection.
Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when
proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Use
in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate
to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]
5.9 Infusion Reactions
Infusion reactions reported in the clinical trials and post-marketing experience include
hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen
desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical
studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe
reactions occurred in 0.2% of patients.
Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy.
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the
label:
• Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings
and Precautions (5.1).]
• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration
(2.4), Warnings and Precautions (5.2).]
• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions
(5.3).]
• Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and
Precautions (5.4).]
• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and
Precautions (5.5).]
• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]
• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4),
Warnings and Precautions (5.7).]
• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]
The most common adverse reactions observed in Avastin patients at a rate > 10% and at least
twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration,
dry skin, rectal hemorrhage, lacrimation disorder, and exfoliative dermatitis.
Across all studies, Avastin was discontinued in 8.4 to 20.3% of patients because of adverse
reactions.
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in practice.
The data below reflect exposure to Avastin in 2324 patients with mCRC, non-squamous NSCLC,
MBC, or glioblastoma in controlled (Studies 1, 2, 4, 5 and 6) or uncontrolled, single arm (Study 7)
trials treated at the recommended dose and schedule for a median of 8 to 11 doses of Avastin. [see
Clinical Studies (14).] The population was aged 21-88 years (median 59), 42.8% male and 82.4%
white. The population included 1089 first- and second-line mCRC patients who received a median
of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses
of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a
median of 8 doses of Avastin, and 163 glioblastoma patients who received a median of 9 doses of
Avastin.
Surgery and Wound Healing Complications
The incidence of post-operative wound healing and/or bleeding complications was increased in
patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy.
Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing
and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus-IFL plus Avastin
as compared to 4% (1/25) of patients who received bolus-IFL alone.
In Study 7, events of post-operative wound healing complications (craniotomy site wound
dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma:
3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See
Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]
Hemorrhage
The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL
plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events
were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic
events were more frequent in patients receiving bolus-IFL plus Avastin when compared to those
receiving bolus-IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor
gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and
Administration (2.4), Warnings and Precautions (5.3).]
Venous Thromboembolic Events
The incidence of Grade 3−4 venous thromboembolic events was higher in patients with mCRC or
NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone.
The risk of developing a second subsequent thromboembolic event in mCRC patients receiving
Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. In
Study 1, 53 patients (14%) on the bolus-IFL plus Avastin arm and 30 patients (8%) on the bolus-IFL
plus placebo arm received full dose warfarin following a venous thromboembolic event. Among
these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving
bolus-IFL plus Avastin and 3% (1/30) of patients receiving bolus-IFL alone.
The overall incidence of Grade 3−4 venous thromboembolic events in Study 1 was 15.1% in
patients receiving bolus-IFL plus Avastin and 13.6% in patients receiving bolus-IFL plus placebo.
In Study 1, the incidence of the following Grade 3−4 venous thromboembolic events was higher in
patients receiving bolus-IFL plus Avastin as compared to patients receiving bolus-IFL plus placebo:
deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs.
5 patients).
Neutropenia and Infection
The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin
plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4
neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients
receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in
NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients
receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs.
1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus
Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving
PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious
infections including pneumonia, febrile neutropenia, catheter infections and wound infections was

increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm
[29 patients (6.6%)].
In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated
glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving
Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.
Proteinuria
In Studies 1, 2 and 4, the incidence of Grade 3 and 4 proteinuria, characterized as
>3.5 gm/24 hours, ranged up to 3.0% in Avastin-treated patients. The highest incidence of
proteinuria was observed in a dose-ranging, placebo-controlled, randomized study of Avastin in
patients with metastatic renal cell carcinoma, an indication for which Avastin is not approved.
Among patients for whom 24-hour urine collections were obtained (approximately half of the
enrolled patients), four of 19 (21%) patients receiving Avastin at 10 mg/kg every two weeks, two of
14 (14%) patients receiving Avastin at 3 mg/kg every two weeks, and none of the 15 placebo
patients experienced Grade 3 proteinuria ( > 3.5 gm protein/24 hours). [See Warnings and
Precautions (5.9).]
Congestive Heart Failure
The incidence of Grade ≥ 3 left ventricular dysfunction was 1.2% in patients receiving Avastin
compared to 0.7% in the control arm across indications. In patients with MBC, the incidence of
Grade 3-4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm
(2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for
MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients
receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with
cardiac dysfunction has not been studied.
Metastatic Colorectal Cancer (mCRC)
The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled
trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was
administered at 5 mg/kg every 2 weeks.
All Grade 3−4 adverse events and selected Grade 1−2 adverse events (hypertension, proteinuria,
thromboembolic events) were collected in the entire study population. Severe and life-threatening
(Grade 3−4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving
bolus-IFL plus Avastin as compared to bolus-IFL plus placebo, are presented in Table 1.

Table 1
NCI-CTC Grade 3−4 Adverse Events in Study 1
(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)
Arm 1 Arm 2
IFL + Placebo IFL + Avastin
(n = 396) (n = 392)
NCI-CTC Grade 3-4 Events 295 (74%) 340 (87%)
Body as a Whole
Asthenia 28 (7%) 38 (10%)
Abdominal Pain 20 (5%) 32 (8%)
Pain 21 (5%) 30 (8%)
Cardiovascular
Hypertension 10 (2%) 46 (12%)
Deep Vein Thrombosis 19 (5%) 34 (9%)
Intra-Abdominal Thrombosis 5 (1%) 13 (3%)
Syncope 4 (1%) 11 (3%)
Digestive
Diarrhea 99 (25%) 133 (34%)
Constipation 9 (2%) 14 (4%)
Hemic/Lymphatic
Leukopenia 122 (31%) 145 (37%)
a
Neutropenia 41 (14%) 58 (21%)
a
Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are
available in 303 patients in Arm 1 and 276 in Arm 2.
Grade 1−4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving
bolus-IFL plus Avastin as compared to the bolus-IFL plus placebo arm are presented in Table 2.
Grade 1−4 adverse events were collected for the first approximately 100 patients in each of the three
treatment arms who were enrolled until enrollment in Arm 3 (5-FU/LV + Avastin) was discontinued.

Table 2
NCI-CTC Grade 1-4 Adverse Events in Study 1
(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)
Arm 1 Arm 2 Arm 3

IFL + Placebo IFL + Avastin 5-FU/LV + Avastin
(n = 98) (n = 102) (n = 109)
Body as a Whole
Pain 54 (55%) 62 (61%) 67 (62%)
Abdominal Pain 54 (55%) 62 (61%) 55 (50%)
Headache 19 (19%) 27 (26%) 30 (26%)
Cardiovascular
Hypertension 14 (14%) 23 (23%) 37 (34%)
Hypotension 7 (7%) 15 (15%) 8 (7%)
Deep Vein Thrombosis 3 (3%) 9 (9%) 6 (6%)
Digestive
Vomiting 46 (47%) 53 (52%) 51 (47%)
Anorexia 29 (30%) 44 (43%) 38 (35%)
Constipation 28 (29%) 41 (40%) 32 (29%)
Stomatitis 18 (18%) 33 (32%) 33 (30%)
Dyspepsia 15 (15%) 25 (24%) 19 (17%)
GI Hemorrhage 6 (6%) 25 (24%) 21 (19%)
Weight Loss 10 (10%) 15 (15%) 18 (16%)
Dry Mouth 2 (2%) 7 (7%) 4 (4%)
Colitis 1 (1%) 6 (6%) 1 (1%)
Hemic/Lymphatic
Thrombocytopenia 0 5 (5%) 5 (5%)
Nervous
Dizziness 20 (20%) 27 (26%) 21 (19%)
Respiratory
Upper Respiratory Infection 38 (39%) 48 (47%) 44 (40%)
Epistaxis 10 (10%) 36 (35%) 35 (32%)
Dyspnea 15 (15%) 26 (26%) 27 (25%)
Voice Alteration 2 (2%) 9 (9%) 6 (6%)
Skin/Appendages
Alopecia 25 (26%) 33 (32%) 6 (6%)
Skin Ulcer 1 (1%) 6 (6%) 7 (6%)

Table 2 (cont’d)
NCI-CTC Grade 1-4 Adverse Events in Study 1
(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)
Arm 1 Arm 2 Arm 3

IFL + Placebo IFL + Avastin 5-FU/LV + Avastin
(n = 98) (n = 102) (n = 109)
Special Senses
Taste Disorder 9 (9%) 14 (14%) 23 (21%)
Urogenital
Proteinuria 24 (24%) 37 (36%) 39 (36%)
Avastin in Combination with FOLFOX4 in Second-line mCRC

Only Grade 3-5 non-hematologic and Grade 4−5 hematologic adverse events related to treatment
were collected in Study 2. The most frequent adverse events (selected Grade 3−5 non-hematologic
and Grade 4−5 hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287 patients
receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone 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 under-estimate the true adverse event rates due to the reporting
mechanisms used in Study 2.
Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC)
Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected in
Study 4. Grade 3−5 non-hematologic and Grade 4−5 hematologic adverse events (occurring at a
higher incidence (≥ 2%) in 427 patients receiving PC plus Avastin compared with 441 patients
receiving PC alone 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%), hypoatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs.
0%).
Metastatic Breast Cancer (MBC)
Only Grade 3−5 non-hematologic and Grade 4−5 hematologic adverse events were collected in
Study 5. Grade 3−4 adverse events occurring at a higher incidence (≥ 2%) in 363 patients receiving
paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory
neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without
neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%),
bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3%
vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation
(3% vs. 0.3%) and proteinuria (3% vs. 0%).
Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence
in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.
Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin.
Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal,
and pain/weakness/hypotension (2).
Avastin is not approved for use in combination with capecitabine or for use in second or third line
treatment of MBC. The data below are presented to provide information on the overall safety profile
of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in
which all adverse events were collected for all patients. All patients in Study 6 received prior
anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1−4 events
which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin
compared to the capecitabine alone arm are presented in Table 3.
Table 3
NCI-CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher
Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)
Capecitabine Capecitabine + Avastin

(n = 215) (n = 229)
Body as a Whole
Asthenia 102 (47%) 131 (57%)
Headache 28 (13%) 76 (33%)
Pain 53 (25%) 71 (31%)
Cardiovascular
Hypertension 5 (2%) 54 (24%)
Digestive
Stomatitis 41 (19%) 58 (25%)
Metabolic/Nutrition
Weight loss 9 (4%) 21 (9%)
Musculoskeletal
Myalgia 17 (8%) 32 (14%)
Respiratory
Dyspnea 39 (18%) 61 (27%)
Epistaxis 3 (1%) 36 (16%)
Skin/Appendages
Exfoliative 162 (75%) 193 (84%)
dermatitis
Urogenital
Albuminuria 16 (7%) 51 (22%)
Glioblastoma
All adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin
alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide.
Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan.
Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.
In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any
grade 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 on study were possibly
related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.
In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of
Avastin-related adverse events (Grade 1−4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS
hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic
event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%),
and RPLS (1%). The incidence of Grade 3−5 events in these 163 patients were bleeding/hemorrhage
(2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial
thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and
gastrointestinal perforation (2%).
6.2 Immunogenicity
As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of
antibody development in patients receiving Avastin has not been adequately determined because the
assay sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent
assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin,
primarily in combination with chemotherapy. High titer human anti-Avastin antibodies were not
detected.
Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.
Additionally, the observed incidence of antibody positivity in an assay may be influenced by several
factors, including sample handling, timing of sample collection, concomitant medications, and
underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the
incidence of antibodies to other products may be misleading.
6.3 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Avastin.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole: Polyserositis
Cardiovascular: Pulmonary hypertension, RPLS
Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration
Hemic and lymphatic: Pancytopenia
Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria)
Respiratory: Nasal septum perforation, dysphonia
7 DRUG INTERACTIONS
A drug interaction study was performed in which irinotecan was administered as part of the
FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of
bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.
In Study 4, based on limited data, there did not appear to be a difference in the mean exposure of
either carboplatin or paclitaxel when each was administered alone or in combination with Avastin.
However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower
paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients
receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at
Day 0.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C
There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated
with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in
teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations.
Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases

in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical
Toxicology (13.3).]
Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted
from the mother to the developing fetus, and has the potential to cause fetal harm when administered
to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis
in humans, bevacizumab should be used during pregnancy only if the potential benefit to the
pregnant woman justifies the potential risk to the fetus.
8.3 Nursing Mothers
It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human
milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant
circulation in substantial amounts. Because many drugs are secreted in human milk and because of
the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be
made whether to discontinue nursing or discontinue drug, taking into account the half-life of the
bevacizumab (approximately 20 days [range 11−50 days]) and the importance of the drug to the
mother. [See Clinical Pharmacology (12.3).]
8.4 Pediatric Use
The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not
been established.
Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to
26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure).
The incidence and severity of physeal dysplasia were dose-related and were partially reversible upon
cessation of treatment.
8.5 Geriatric Use
In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged
≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis,
hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation,
anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin
on overall survival was similar in elderly patients as compared to younger patients.
In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk
as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.
In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater
relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).]
In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the
overall adverse events profile was different in the elderly as compared with younger patients.
Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events
were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of
any severity that occurred at a higher incidence in the elderly as compared to younger patients, in
addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis,
increased cough, and voice alteration.
In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies,
there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall
incidence of arterial thromboembolic events was increased in all patients receiving Avastin with
chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the
increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5%
vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]

10 OVERDOSAGE
The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of
16 patients and with severe headache in three of 16 patients.
11 DESCRIPTION
Avastin (bevacizumab) is a recombinant humanized monoclonal IgG1 antibody that binds to and
inhibits the biologic activity of human vascular endothelial growth factor (VEGF) in in vitro and
in vivo assay systems. Bevacizumab contains human framework regions and the
complementarity-determining regions of a murine antibody that binds to VEGF. Avastin has an
approximate molecular weight of 149 kD. Bevacizumab is produced in a mammalian cell (Chinese
Hamster Ovary) expression system in a nutrient medium containing the antibiotic gentamicin.
Gentamicin is not detectable in the final product.
Avastin is a clear to slightly opalescent, colorless to pale brown, sterile, pH 6.2 solution for
intravenous infusion. Avastin is supplied in 100 mg and 400 mg preservative-free, single-use vials
to deliver 4 mL or 16 mL of Avastin (25 mg/mL). The 100 mg product is formulated in 240 mg
α,α-trehalose dihydrate, 23.2 mg sodium phosphate (monobasic, monohydrate), 4.8 mg sodium
phosphate (dibasic, anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 400 mg
product is formulated in 960 mg α,α-trehalose dihydrate, 92.8 mg sodium phosphate (monobasic,
monohydrate), 19.2 mg sodium phosphate (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water
for Injection, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR)
on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial
cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration
of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction
of microvascular growth and inhibition of metastatic disease progression.
12.3 Pharmacokinetics
The pharmacokinetic profile of bevacizumab was assessed using an assay that measures total
serum bevacizumab concentrations (i.e., the assay did not distinguish between free bevacizumab and
bevacizumab bound to VEGF ligand). Based on a population pharmacokinetic analysis of
491 patients who received 1 to 20 mg/kg of Avastin weekly, every 2 weeks, or every 3 weeks, the
estimated half-life of bevacizumab was approximately 20 days (range 11−50 days). The predicted
time to reach steady state was 100 days. The accumulation ratio following a dose of 10 mg/kg of
bevacizumab every 2 weeks was 2.8.
The clearance of bevacizumab varied by body weight, gender, and tumor burden. After correcting
for body weight, males had a higher bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a
larger V c (3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or above median
value of tumor surface area) had a higher bevacizumab clearance (0.249 L/day vs. 0.199 L/day) than
patients with tumor burdens below the median. In Study 1, there was no evidence of lesser efficacy
(hazard ratio for overall survival) in males or patients with higher tumor burden treated with Avastin
as compared to females and patients with low tumor burden. The relationship between bevacizumab
exposure and clinical outcomes has not been explored.

13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No carcinogenicity or mutagenicity studies of bevacizumab have been conducted.
Bevacizumab may impair fertility. Female cynomolgus monkeys treated with 0.4 to 20 times the
recommended human dose of bevacizumab exhibited arrested follicular development or absent
corpora lutea as well as dose-related decreases in ovarian and uterine weights, endometrial
proliferation, and the number of menstrual cycles. Following a 4- or 12-week recovery period, there
was a trend suggestive of reversibility. After the 12-week recovery period, follicular maturation
arrest was no longer observed, but ovarian weights were still moderately decreased. Reduced
endometrial proliferation was no longer observed at the 12-week recovery time point; however,
decreased uterine weight, absent corpora lutea, and reduced number of menstrual cycles remained
evident.
13.2 Animal Toxicology and/or Pharmacology
In cynomolgus monkeys, when bevacizumab was administered at doses of 0.4 to 20 times the
weekly human exposure, anatomical pathology revealed several adverse effects on general growth
and skeletal development, fertility and wound healing capacity. Severe physeal dysplasia was
consistently reported in juvenile monkeys with open growth plates receiving 0.4 to 20 times the
human dose. The physeal dysplasia was characterized by a linear cessation of growth line and
chondrocyte hyperplasia which did not completely resolve after the 4 to 12 weeks recovery period
without drug exposure.
Rabbits dosed with bevacizumab exhibited reduced wound healing capacity. Using full-thickness
skin incision and partial thickness circular dermal wound models, bevacizumab dosing resulted in
reductions in wound tensile strength, decreased granulation and re-epithelialization, and delayed
time to wound closure.
13.3 Reproductive and Developmental Toxicology
Pregnant rabbits dosed with 1 to 12 times the human dose of bevacizumab every three days during
the period of organogenesis (gestation day 6-18) exhibited teratogenic effects, decreases in maternal
and fetal body weights, and increased number of fetal resorptions. Teratogenic effects included:
reduced or irregular ossification in the skull, jaw, spine, ribs, tibia and bones of the paws;
meningocele; fontanel, rib and hindlimb deformities; corneal opacity; and absent hindlimb
phalanges. There are no data available regarding the level of bevacizumab exposure in the offspring.
14 CLINICAL STUDIES
14.1 Metastatic Colorectal Cancer (mCRC)
Study 1
In this double-blind, active-controlled study, patients were randomized (1:1:1) to IV bolus-IFL
(irinotecan 125 mg/m2, 5-FU 500 mg/m2, and leucovorin (LV) 20 mg/m2 given once weekly for
4 weeks every 6 weeks) plus placebo (Arm 1), bolus-IFL plus Avastin (5 mg/kg every 2 weeks)
(Arm 2), or 5-FU/LV plus Avastin (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 was
discontinued, as pre-specified, when the toxicity of Avastin in combination with the bolus-IFL
regimen was deemed acceptable. The main outcome measure was overall survival (OS).
Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 40% were female, 79%
were Caucasian, 57% had an ECOG performance status of 0, 21% had a rectal primary and 28%
received prior adjuvant chemotherapy. In 56% of the patients, the dominant site of disease was
extra-abdominal, while the liver was the dominant site in 38% of patients.
The addition of Avastin resulted in an improvement in survival across subgroups defined by age
(< 65 yrs, ≥ 65 yrs) and gender. Results are presented in Table 4 and Figure 1.

Table 4
Study 1 Efficacy Results
IFL + Avastin
IFL + Placebo 5 mg/kg q 2 wks
Number of Patients 411 402
Overall Survivala
Median (months) 15.6 20.3
Hazard ratio 0.66
Progression-free Survivala
Hazard ratio 0.54
Overall Response Rateb

Rate (percent) 35% 45%
Duration of Response
a
p < 0.001 by stratified log rank test.
b
p < 0.01 by χ2 test.
Figure 1
Duration of Survival in Study 1
Error bars represent 95% confidence intervals.
Among the 110 patients enrolled in Arm 3, median OS was 18.3 months, median progression-free
survival (PFS) was 8.8 months, objective response rate (ORR) was 39%, and median duration of
response was 8.5 months.
Study 2
Study 2 was a randomized, open-label, active-controlled trial in patients who were previously
treated with irinotecan +/- 5-FU for initial therapy for metastatic disease or as adjuvant therapy.
Patients were randomized (1:1:1) to IV FOLFOX4 (Day 1: oxaliplatin 85 mg/m2 and LV 200 mg/m2
concurrently, then 5-FU 400 mg/m2 bolus followed by 600 mg/m2 continuously; Day 2: LV
200 mg/m2, then 5-FU 400 mg/m2 bolus followed by 600 mg/m2 continuously; repeated every

2 weeks), FOLFOX4 plus Avastin (10 mg/kg every 2 weeks prior to FOLFOX4 on Day 1), or
Avastin monotherapy(10 mg/kg every 2 weeks). The main outcome measure was OS.
The Avastin monotherapy arm was closed to accrual after enrollment of 244 of the planned
290 patients following a planned interim analysis by the data monitoring committee based on
evidence of decreased survival compared to FOLFOX4 alone.
Of the 829 patients randomized to the three arms, the median age was 61 years, 40% were female,
87% were Caucasian, 49% had an ECOG performance status of 0, 26% received prior radiation
therapy, and 80% received prior adjuvant chemotherapy, 99% received prior irinotecan, with or
without 5-FU as therapy for metastatic disease, and 1% received prior irinotecan and 5-FU as
adjuvant therapy.
The addition of Avastin to FOLFOX4 resulted in significantly longer survival as compared to
FOLFOX4 alone (median OS 13.0 months vs. 10.8 months; hazard ratio 0.75 [95% CI 0.63, 0.89],
p = 0.001 stratified log rank test) with clinical benefit seen in subgroups defined by age (< 65 yrs,
≥ 65 yrs) and gender. PFS and ORR based on investigator assessment were higher in the Avastin
plus FOLFOX4 arm.
Study 3
The activity of Avastin in combination with bolus or infusional 5-FU/LV was evaluated in a
single arm study enrolling 339 patients with mCRC with disease progression following both
irinotecan- and oxaliplatin-containing chemotherapy regimens. Seventy-three percent of patients
received concurrent bolus 5-FU/LV. One objective partial response was verified in the first
100 evaluable patients for an overall response rate of 1% (95% CI 0−5.5%).
14.2 Unresectable Non–Squamous Non–Small Cell Lung Cancer (NSCLC)
Study 4
The safety and efficacy of Avastin as first-line treatment of patients with locally advanced,
metastatic, or recurrent non–squamous NSCLC was studied in a single, large, randomized,
active-controlled, open-label, multicenter study.
Chemotherapy-naïve patients with locally advanced, metastatic or recurrent non–squamous
NSCLC were randomized (1:1) to receive six 21-day cycles of paclitaxel 200 mg/m2 and carboplatin
AUC=6.0, by IV on day 1 (PC) or PC in combination with Avastin 15 mg/kg by IV on day 1 (PC
plus Avastin). After completion or upon discontinuation of chemotherapy, patients in the PC plus
Avastin arm continued to receive Avastin alone until disease progression or until unacceptable
toxicity. Patients with predominant squamous histology (mixed cell type tumors only), central
nervous system (CNS) metastasis, gross hemoptysis (≥1/2 tsp of red blood), unstable angina, or
receiving therapeutic anticoagulation were excluded. The main outcome measure was duration of
survival.
Of the 878 patients randomized, the median age was 63, 46% were female, 43% were ≥ age 65,
and 28% had ≥ 5% weight loss at study entry. Eleven percent had recurrent disease and of the 89%
with newly diagnosed NSCLC, 12% had Stage IIIB with malignant pleural effusion and 76% had
Stage IV disease.
The results are presented in Figure 2. OS was statistically significantly higher among patients
receiving PC plus Avastin compared with those receiving PC alone; median OS was 12.3 months vs.
10.3 months [hazard ratio 0.80 (repeated 95% CI 0.68, 0.94), final p- value 0.013, stratified log-rank
test]. Based on investigator assessment which was not independently verified, patients were
reported to have longer PFS with Avastin in combination with PC compared to PC alone.

Figure 2
Duration of Survival in Study 4
In an exploratory analyses across patient subgroups, the impact of Avastin on OS was less robust
in the following: women [HR = 0.99 (95% CI: 0.79, 1.25)], age ≥ 65 years [HR = 0.91 (95% CI:
0.72, 1.14)] and patients with ≥5% weight loss at study entry [HR = 0.96 (95% CI: 0.73, 1.26)].
14.3 Metastatic Breast Cancer (MBC)
Study 5
The efficacy and safety of Avastin as first-line treatment of patients with MBC was studied in a
single, open-label, randomized, multicenter study. Patients who had not received chemotherapy for
locally recurrent or MBC were randomized (1:1) to receive paclitaxel (90 mg/m2 IV once weekly for
3 out of 4 weeks) alone or in combination with Avastin (10 mg/kg IV infusion every 2 weeks).
Patients were treated until disease progression or unacceptable toxicity. In situations where
paclitaxel was discontinued or held, treatment with Avastin alone could be continued until disease
progression. Patients with breast cancer overexpressing HER2 were not eligible unless they had
received prior therapy with trastuzumab.
Prior hormonal therapy for the treatment of metastatic disease was allowed, as was prior adjuvant
chemotherapy or hormonal therapy. Adjuvant taxane therapy, if received, must have been
completed 12 or more months prior to study entry. Patients with central nervous system metastasis
were excluded. The main outcome measure of the study was PFS as assessed by independent
radiographic review. Secondary outcome measures were OS and ORR.
Of the 722 patients randomized, the median age was 55 years, 76% were white, 55% were
postmenopausal, and 64% were ER and/or PR positive. Patient characteristics were similar across
treatment arms. Thirty-six percent had received prior hormonal therapy for advanced disease, and
66% had received adjuvant chemotherapy, including 20% with prior taxane use and 50% with prior
anthracycline use. Efficacy results are summarized in Table 5.

Table 5
Avastin Efficacy Results from Study 5
Avastin + Paclitaxel
Paclitaxel Alone HR
Efficacy Parameter (n=368) (n=354) p-value (95% CI)
Progression-free Survival 11.3 5.8 0.48
[median, months (95% CI)] (10.5, 13.3) (5.4, 8.2) <0.0001 (0.39, 0.61)
Overall Survival 26.5 24.8 0.87
[median, months (95% CI)] (23.7, 29.2) (21.4, 27.4) 0.14 (0.72, 1.05)
Partial Response Rate (PR) 1
48.9% 2
22.2% <0.001 ⎯
1
Includes only patients with measurable disease.
2
The difference in partial response rates is 26.7% with a 95% CI (18.4%, 35.0%).
The addition of Avastin to paclitaxel resulted in an improvement in PFS with no significant

improvement in OS. Partial response rates in patients with measurable disease were higher with
Avastin plus paclitaxel. No complete responses were observed.
Thirty-four percent of the patients had incomplete follow-up for disease progression; therefore an
exploratory analysis using similar imputation between arms was performed, which yielded a hazard
ratio of 0.57.
Study 6
The efficacy and safety of Avastin as second- and third-line treatment of patients with MBC was
studied in a single open-label randomized study. Patients who had received prior anthracycline and
taxane therapy in the adjuvant setting or for their MBC were randomized (1:1) to receive
capecitabine alone or in combination with Avastin. Of the 462 enrolled patients, the median age was
51 years, 81% were white, and 50% were ER positive. Patient characteristics were similar across the
treatment arms.
The study failed to demonstrate a statistically significant effect on PFS or OS. The median PFS
was 4.2 months in the capecitabine arm and 4.9 months in the capecitabine plus Avastin arm
(log-rank p-value = 0.86, hazard ratio 0.98). The median OS was 14.5 months in the capecitabine
arm and 15.1 months in the capecitabine plus Avastin arm (hazard ratio of 1.08).
14.4 Glioblastoma
Study 7
The efficacy and safety of Avastin was evaluated in Study 7, an open-label, multicenter,
randomized, non-comparative study of patients with previously treated glioblastoma. Patients
received Avastin (10 mg/kg IV) alone or Avastin plus irinotecan every 2 weeks until disease
progression or until unacceptable toxicity. All patients received prior radiotherapy (completed at
least 8 weeks prior to receiving Avastin) and temozolomide. Patients with active brain hemorrhage
were excluded.
Of the 85 patients randomized to the Avastin arm, the median age was 54 years, 32% were
female, 81% were in first relapse, Karnofsky performance status was 90−100 for 45% and 70−80 for
55%.
The efficacy of Avastin was demonstrated using response assessment based on both WHO
radiographic criteria and by stable or decreasing corticosteroid use, which occurred in 25.9% (95%
CI 17.0%, 36.1%) of the patients. Median duration of response was 4.2 months (95% CI 3.0, 5.7).
Radiologic assessment was based on MRI imaging (using T1 and T2/FLAIR). MRI does not
necessarily distinguish between tumor, edema, and radiation necrosis.

Study 8
Study 8, was a single-arm, single institution trial with 56 patients with glioblastoma. All patients
had documented disease progression after receiving temozolomide and radiation therapy. Patients
received Avastin 10 mg/kg IV every 2 weeks until disease progression or unacceptable toxicity.
The median age was 54, 54% were male, 98% Caucasian, and 68% had a Karnofsky Performance
Status of 90−100.
The efficacy of Avastin was supported by an objective response rate of 19.6% (95% CI 10.9%,
31.3%) using the same response criteria as in Study 7. Median duration of response was 3.9 months
(95% CI 2.4, 17.4).
16 HOW SUPPLIED/STORAGE AND HANDLING

Avastin vials [100 mg (NDC 50242-060-01) and 400 mg (NDC 50242-061-01)] are stable at
2−8°C (36−46°F). Avastin vials should be protected from light. Do not freeze or shake.
Diluted Avastin solutions may be stored at 2−8°C (36−46°F) for up to 8 hours. Store in the
original carton until time of use. No incompatibilities between Avastin and polyvinylchloride or
polyolefin bags have been observed.
17 PATIENT COUNSELING INFORMATION

Advise patients:
• To undergo routine blood pressure monitoring and to contact their health care provider if blood
pressure is elevated.
• To immediately contact their health care provider for unusual bleeding, high fever, rigors,
sudden onset of worsening neurological function, or persistent or severe abdominal pain, severe
constipation, or vomiting.
• Of increased risk of wound healing complications during and following Avastin.
• Of increased risk of an arterial thromboembolic event.
• Of the potential risk to the fetus during and following Avastin and the need to continue adequate
contraception for at least 6 months following last dose of Avastin.
Manufactured by: 745531X

Genentech, Inc. LV0017
1 DNA Way 483570X
South San Francisco, CA Initial U.S.Approval: February 2004
94080-4990 Code Revision Date: May 2009
© 2009 Genentech, Inc


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This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda

1.14.2.3 Final Labeling Text ------------------------DOSAGE AND ADMINISTRATION---------------------

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

FULL PRESCRIBING INFORMATION: CONTENTS* 6.1 Clinical Trial Experience

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

FULL PRESCRIBING INFORMATION

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND

1 INDICATIONS AND USAGE

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

2 DOSAGE AND ADMINISTRATION

Temporarily suspend Avastin for:

3 DOSAGE FORMS AND STRENGTHS

5 WARNINGS AND PRECAUTIONS

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

Arm 1 Arm 2 Arm 3

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

Arm 1 Arm 2 Arm 3

Avastin in Combination with FOLFOX4 in Second-line mCRC

Capecitabine Capecitabine + Avastin

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

Overall Response Rateb

Error bars represent 95% confidence intervals.

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

The addition of Avastin to paclitaxel resulted in an improvement in PFS with no significant

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

Manufactured by: 745531X

U.S. BL 125085/169 Amendment: Bevacizumab⎯Genentech, Inc.

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