• Metastatic renal cell carcinoma with interferon alfa (1.5)
`------------------------DOSAGE AND ADMINISTRATION---------------------
`• Do not administer as an IV push or bolus. (2.1)
`
`
`• Do not initiate Avastin for 28 days following major surgery and until
`surgical wound is fully healed. (2.1)
`
`
`
`Metastatic colorectal cancer (2.2)
`
`• 5 mg/kg IV every 2 weeks with bolus-IFL
`
`
`• 10 mg/kg IV every 2 weeks with FOLFOX4
`
`Non−squamous non−small cell lung cancer (2.2)
`
`• 15 mg/kg IV every 3 weeks with carboplatin/paclitaxel
`
`Metastatic breast cancer (2.2)
`
`• 10 mg/kg IV every 2 weeks with paclitaxel
`
`
`
`Glioblastoma (2.2)
`
`
`• 10 mg/kg IV every 2 weeks
`
`
`Metastatic renal cell carcinoma (mRCC) (2.2)
`
`• 10 mg/kg IV every 2 weeks with interferon alfa
`
`-----------------------DOSAGE FORMS AND STRENGTHS--------------------
`• 100 mg/4 mL, single use vial (3)
`• 400 mg/16 mL, single use vial (3)
`---------------------------CONTRAINDICATIONS---------------------------------
`None (4)
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`• Non-Gastrointestinal Fistula Formation: Discontinue Avastin if fistula
`formation occurs. (5.4)
`• Arterial Thromboembolic Events (e.g., myocardial infarction, cerebral
`
`infarction): Discontinue Avastin for severe ATE. (5.5)
`
`• Hypertension: Monitor blood pressure and treat hypertension.
`
`Temporarily suspend Avastin if not medically controlled. Discontinue
`Avastin for hypertensive crisis or hypertensive encephalopathy. (5.6)
`
`• Reversible Posterior Leukoencephalopathy Syndrome (RPLS):
`
`Discontinue Avastin. (5.7)
`
`• Proteinuria: Monitor urine protein. Discontinue for nephrotic syndrome.
`
`
`Temporarily suspend Avastin for moderate proteinuria. (5.8)
`
`
`Infusion Reactions: Stop for severe infusion reactions. (5.9)
`•
`------------------------------ADVERSE REACTIONS------------------------------
`Most common adverse reactions incidence (>10% and at least twice the
`
`control arm rate) are epistaxis, headache, hypertension, rhinitis, proteinuria,
`
`taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain
`
`and exfoliative dermatitis. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Genentech,
`
`Inc. at 1-888-835-2555 or FDA at 1-800-FDA-1088 or
`
`www.fda.gov/medwatch.
`
`-----------------------------USE IN SPECIFIC POPULATIONS------------------
`
`• Pregnancy: Based on animal data, may cause fetal harm. (8.1)
`
`
`• Nursing Mothers: Discontinue nursing or discontinue drug, taking into
`account the importance of the drug to the mother. (8.3)
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: July 2009
`
`
`
`
`
` 1.14.2.3 Final Labeling Text
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`AVASTIN safely and effectively. See full prescribing information for
`AVASTIN.
`
`AVASTIN® (bevacizumab)
`Solution for intravenous infusion
`
`Initial U.S. Approval: 2004
`
`
`
`
`WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY
`
`
`AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE
`See full prescribing information for complete boxed warning.
`
`
`• Gastrointestinal Perforation: Occurs in up to 2.4% of
`
`
`Avastin-treated patients. Discontinue Avastin for gastrointestinal
`perforation. (5.1)
`
`• Surgery and Wound Healing Complications: Discontinue in
`patients with wound dehiscence. 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. (5.2)
`
`• Hemorrhage: Severe or fatal hemorrhage, hemoptysis,
`gastrointestinal bleeding, CNS hemorrhage, and vaginal bleeding
`are increased in Avastin- treated patients. Do not administer
`
`
`Avastin to patients with serious hemorrhage or recent hemoptysis.
`
`(5.3)
`
`
`
`-------------------------RECENT MAJOR CHANGES----------------------------­
`Indications and Usage, Glioblastoma (1.4)
`5/2009
`
`
`Indications and Usage, Renal Cell Carcinoma (1.5)
`7/2009
`
`Dosage and Administration, Glioblastoma (2.2)
`5/2009
`
`Dosage and Administration, Renal Cell Carcinoma (2.2)
`7/2009
`
`Warnings and Precautions, Hemorrhage (5.3)
`5/2009
`
`Warnings and Precautions, Proteinuria (5.8)
`7/2009
`
`---------------------------INDICATIONS AND USAGE----------------------------
`Avastin is a vascular endothelial growth factor-specific angiogenesis
`
`inhibitor indicated for the treatment of:
`
`• Metastatic colorectal cancer, with intravenous 5-fluorouracil–based
`chemotherapy for first- or second-line treatment. (1.1)
`
`• Non-squamous non-small cell lung cancer, with carboplatin and paclitaxel
`for first line treatment of unresectable, locally advanced, recurrent or
`metastatic disease. (1.2)
`• Metastatic breast cancer, with paclitaxel for treatment of patients who have
`not received chemotherapy for metastatic HER2-negative breast cancer.
`(1.3)
`
`-Effectiveness based on improvement in progression-free survival. No
`
`
`data available demonstrating improvement in disease-related symptoms or
`
`
`survival with Avastin.
`
`-Not indicated for disease progression following anthracycline and taxane
`
`
`
`chemotherapy administered for metastatic disease.
`
`
`• Glioblastoma, as a single agent for patients with progressive disease
`following prior therapy. (1.4)
`-Effectiveness based on improvement in objective response rate. No data
`available demonstrating improvement in disease-related symptoms or
`survival with Avastin.
`
`
`
`
`
`
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`
`002012
`
`AVENTIS EXHIBIT 2019
`Mylan v. Aventis, IPR2016-00712
`
`

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

`
`
`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 (5.2), and Adverse Reactions
`(6.1).]
` 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 (5.3), 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).]
`
`
`
`1
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`2
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`3
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`
`
`
`

`
`
`1.5 Metastatic Renal Cell Carcinoma (mRCC)
`
`Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with
`
`interferon alfa.
`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 in combination with carboplatin and
`paclitaxel.
`
` Metastatic Breast Cancer (MBC)
`The recommended dose is 10 mg/kg every 2 weeks in combination with paclitaxel.
`
`
`Glioblastoma
`The recommended dose is 10 mg/kg every 2 weeks.
`
`
`Metastatic Renal Cell Carcinoma (mRCC)
`The recommended dose is 10 mg/kg every 2 weeks in combination with interferon alfa.
`
`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).]
`
`
`
`•
`•
`
`
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`45
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`46
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`47
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`48
`
`49
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`50
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`51
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`
`90
`
`91
`
`

`
`
`• 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
`
`92
`
`93
`
`94
`
`95
`
`
`96
`
`
`97
`
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`
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`
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`
`
`106
`
`
`107
`
`
`
`
`4 CONTRAINDICATIONS
`108
`
`109
` None.
`110
`
`
`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
`133
`
`134
` Warning, Dosage and Administration (2.4).]
`
`5.3 Hemorrhage
`135
`
`Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly
`
`136
`
`137
` Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal
`hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage,
`138
`
`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
`
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`139
`
`
`140
`
`
`

`
`
`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, renal 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
`
`
`and Administration (2.4).]
`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 2.4% compared to
`0.7% 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.
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`Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within
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`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
`and Administration (2.4).]
`
`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 with a 24-hour urine collection.
`Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when
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`proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from
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`a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine
`Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [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.
`
`[See Dosage and Administration (2.4).]
`
`
`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).]
`
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`• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions
`
`(5.3).]
`
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`• Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and
`Precautions (5.4).]
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`• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and
`Precautions (5.5).]
`
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`• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]
`
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`• 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).]
`
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`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, back pain and exfoliative dermatitis.
`Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse
`reactions.
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`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 2661 patients with mCRC, non-squamous NSCLC,
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`243
`244 MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm
`(Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of
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` 246 Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0%
`247 male and 84.1% 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
`248
`249 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, 163 glioblastoma patients who received a median
`250
`of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.
`Surgery and Wound Healing Complications
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`
`
`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.
`254
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` 255 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
`256
`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).]
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`261
`262 Hemorrhage
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`The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus-IFL
`
`263
`plus Avastin compared with patients receiving bolus-IFL plus placebo. All but one of these events
`264
`265 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
`266
`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
`
`
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`272 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
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`274 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
`275
`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).
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`Neutropenia and Infection
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`
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`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
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`290 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.
`291
`1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus
`292
`293 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
`294
`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
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`300 Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.
`Proteinuria
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`301
`Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of
`
`proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%.
`303
`304 Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin.
`305 Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not
`resolve in 40% of patients aft