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) injection, for intravenous use
`Initial U.S. Approval: 2004
`-------------------------RECENT MAJOR CHANGES----------------------------­
`Indications and Usage, Hepatocellular Carcinoma (1.7)
`5/2020
`
`Dosage and Administration (2.1)
`12/2020
`
`Dosage and Administration (2.9)
`10/2020
`
`Dosage and Administration (2.8)
`5/2020
`
`Warnings and Precautions (5 2)
`10/2020
`
`Warnings and Precautions (5 3, 5.9)
`5/2020
`
`---------------------------INDICATIONS AND USAGE----------------------------
`Avastin is a vascular endothelial growth factor inhibitor indicated for the
`treatment of:
`• Metastatic colorectal cancer, in combination with intravenous fluorouracil­
`based chemotherapy for first- or second-line treatment. (1.1)
`• Metastatic colorectal cancer, in combination with fluoropyrimidine­
`irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy for
`second-line treatment in patients who have progressed on a first-line
`Avastin-containing regimen. (1.1)
`
`Limitations of Use: Avastin is not indicated for adjuvant treatment of colon
`cancer. (1.1)
`• Unresectable, locally advanced, recurrent or metastatic non-squamous
`non-small cell lung cancer, in combination with carboplatin and paclitaxel
`for first-line treatment. (1.2)
`• Recurrent glioblastoma in adults. (1.3)
`• Metastatic renal cell carcinoma in combination with interferon alfa. (1.4)
`• Persistent, recurrent, or metastatic cervical cancer, in combination with
`paclitaxel and cisplatin, or paclitaxel and topotecan. (1.5)
`• Epithelial ovarian, fallopian tube, or primary peritoneal cancer:
`o in combination with carboplatin and paclitaxel, followed by Avastin
`as a single agent, for stage III or IV disease following initial surgical
`resection (1.6)
`o in combination with paclitaxel, pegylated liposomal doxorubicin, or
`topotecan for platinum-resistant recurrent disease who received no
`more than 2 prior chemotherapy regimens (1.6)
`o in combination with carboplatin and paclitaxel or carboplatin and
`gemcitabine, followed by Avastin as a single agent, for platinum-
`sensitive recurrent disease (1.6)
`• Hepatocellular Carcinoma (HCC)
`o in combination with atezolizumab for the treatment of patients with
`unresectable or metastatic HCC who have not received prior systemic
`therapy (1.7)
`------------------------DOSAGE AND ADMINISTRATION--------------------­
`Withhold for at least 28 days prior to elective surgery. Do not administer
`
`Avastin for 28 days following major surgery and until adequate wound
`
`healing. (2.1)
`
`Metastatic colorectal cancer (2 2)
`
`• 5 mg/kg every 2 weeks with bolus-IFL
`• 10 mg/kg every 2 weeks with FOLFOX4
`• 5 mg/ kg every 2 weeks or 7.5 mg/kg every 3 weeks with
`fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based
`chemotherapy after progression on a first-line Avastin containing regimen
`First-line non−squamous non−small cell lung cancer (2.3)
`• 15 mg/kg every 3 weeks with carboplatin and paclitaxel
`Recurrent glioblastoma (2.4)
`• 10 mg/kg every 2 weeks
`Metastatic renal cell carcinoma (2.5)
`• 10 mg/kg every 2 weeks with interferon alfa
`Persistent, recurrent, or metastatic cervical cancer (2.6)
`• 15 mg/kg every 3 weeks with paclitaxel and cisplatin, or paclitaxel and
`topotecan
`Stage III or IV epithelial ovarian, fallopian tube or primary peritoneal cancer
`following initial surgical resection (2.7)
`• 15 mg/kg every 3 weeks with carboplatin and paclitaxel for up to 6 cycles,
`followed by 15 mg/kg every 3 weeks as a single agent, for a total of up to
`22 cycles
`
`Platinum-resistant recurrent epithelial ovarian, fallopian tube or primary
`peritoneal cancer (2.7)
`• 10 mg/kg every 2 weeks with paclitaxel, pegylated liposomal doxorubicin,
`or topotecan given every week
`• 15 mg/kg every 3 weeks with topotecan given every 3 weeks
`Platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary
`peritoneal cancer (2.7)
`• 15 mg/kg every 3 weeks with carboplatin and paclitaxel for 6-8 cycles,
`followed by 15 mg/kg every 3 weeks as a single agent
`• 15 mg/kg every 3 weeks with carboplatin and gemcitabine for 6-10 cycles,
`followed by 15 mg/kg every 3 weeks as a single agent
`Hepatocellular Carcinoma (2.8)
`• 15 mg/kg after administration of 1,200 mg of atezolizumab every 3 weeks
`Administer as an intravenous infusion. (2 10)
`-----------------------DOSAGE FORMS AND STRENGTHS-------------------­
`Injection: 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) in a
`single-dose vial (3)
`---------------------------CONTRAINDICATIONS--------------------------------­
`None (4)
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`• Gastrointestinal Perforations and Fistula: Discontinue for
`gastrointestinal perforations, tracheoesophageal fistula, grade 4 fistula,
`or fistula formation involving any organ (5.1)
`• Surgery and Wound Healing Complications: In patients who experience
`wound healing complications during Avastin treatment, withhold
`Avastin until adequate wound healing. Withhold for at least 28 days
`prior to elective surgery. Do not administer Avastin for at least 28 days
`following a major surgery, and until adequate wound healing. The
`safety of resumption of AVASTIN after resolution of wound healing
`complication has not been established. Discontinue for wound healing
`complication of necrotizing fasciitis. (5.2)
`• Hemorrhage: Severe or fatal hemorrhages have occurred. Do not
`administer for recent hemoptysis. Discontinue for Grade 3-4
`hemorrhage (5.3)
`• Arterial Thromboembolic Events (ATE): Discontinue for severe ATE.
`(5.4)
`• Venous Thromboembolic Events (VTE): Discontinue for Grade 4 VTE.
`(5.5)
`• Hypertension: Monitor blood pressure and treat hypertension. Withhold if
`not medically controlled; resume once controlled. Discontinue for
`hypertensive crisis or hypertensive encephalopathy. (5.6)
`• Posterior Reversible Encephalopathy Syndrome (PRES): Discontinue.
`(5.7)
`• Renal Injury and Proteinuria: Monitor urine protein. Discontinue for
`nephrotic syndrome. Withhold until less than 2 grams of protein in urine.
`(5.8)
`Infusion-Related Reactions: Decrease rate for infusion-related reactions.
`Discontinue for severe infusion-related reactions and administer medical
`therapy. (5.9)
`• Embryo-Fetal Toxicity: May cause fetal harm. Advise females of potential
`risk to fetus and need for use of effective contraception. (5.10, 8.1, 8.3)
`• Ovarian Failure: Advise females of the potential risk. (5.11, 8.3)
`• Congestive Heart Failure (CHF): Discontinue Avastin in patients who
`develop CHF. (5.12)
`------------------------------ADVERSE REACTIONS-----------------------------­
`Most common adverse reactions incidence (incidence > 10%) are epistaxis,
`headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin,
`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-----------------­
`Lactation: Advise not to breastfeed. (8.2)
`
`•
`
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 12/2020
`
`Reference ID: 4714390
`
`Novartis Exhibit 2285.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Metastatic Colorectal Cancer
`1.2
`First-Line Non-Squamous Non−Small Cell Lung Cancer
`1.3 Recurrent Glioblastoma
`1.4 Metastatic Renal Cell Carcinoma
`1.5
`Persistent, Recurrent, or Metastatic Cervical Cancer
`1.6
`Epithelial Ovarian, Fallopian Tube, or Primary
`Peritoneal Cancer
`1.7 Hepatocellular Carcinoma
`2 DOSAGE AND ADMINISTRATION
`2.1
`Important Administration Information
`2.2 Metastatic Colorectal Cancer
`2.3
`First-Line Non-Squamous Non-Small Cell Lung Cancer
`2.4 Recurrent Glioblastoma
`2.5 Metastatic Renal Cell Carcinoma
`2.6
`Persistent, Recurrent, or Metastatic Cervical Cancer
`2.7
`Epithelial Ovarian, Fallopian Tube or Primary Peritoneal
`Cancer
`2.8 Hepatocellular Carcinoma
`2.9 Dosage Modifications for Adverse Reactions
`2.10 Preparation and Administration
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Gastrointestinal Perforations and Fistulae
`5.2
`Surgery and Wound Healing Complications
`5.3 Hemorrhage
`5.4 Arterial Thromboembolic Events
`5.5 Venous Thromboembolic Events
`5.6 Hypertension
`5.7
`Posterior Reversible Encephalopathy Syndrome (PRES)
`5.8 Renal Injury and Proteinuria
`5.9
`Infusion-Related Reactions
`5.10 Embryo-Fetal Toxicity
`5.11 Ovarian Failure
`5.12 Congestive Heart Failure
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2
`Immunogenicity
`6.3
`Postmarketing Experience
`7 DRUG INTERACTIONS
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.3
`Females and Males of Reproductive Potential
`8.4
`Pediatric Use
`8.5 Geriatric Use
`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
`14 CLINICAL STUDIES
`14.1 Metastatic Colorectal Cancer
`14.2 Lack of Efficacy in Adjuvant Treatment of Colon Cancer
`14.3 First-Line Non-Squamous Non-Small Cell Lung Cancer
`14.4 Recurrent Glioblastoma
`14.5 Metastatic Renal Cell Carcinoma
`14.6 Persistent, Recurrent, or Metastatic Cervical Cancer
`14.7 Stage III or IV Epithelial Ovarian, Fallopian Tube, or
`Primary Peritoneal Cancer Following Initial Surgical
`Resection
`14.8 Platinum-Resistant Recurrent Epithelial Ovarian,
`Fallopian Tube, or Primary Peritoneal Cancer
`14.9 Platinum-Sensitive Recurrent Epithelial Ovarian,
`Fallopian Tube, or Primary Peritoneal Cancer
`14.10 Hepatocellular Carcinoma
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the Full Prescribing Information are
`not listed.
`
`Reference ID: 4714390
`
`Novartis Exhibit 2285.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`1.1 Metastatic Colorectal Cancer
`Avastin, in combination with intravenous fluorouracil-based chemotherapy, is indicated for the first-or
`second-line treatment of patients with metastatic colorectal cancer (mCRC).
`
`Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy,
`is indicated for the second-line treatment of patients with mCRC who have progressed on a first-line Avastin­
`containing regimen.
`
`Limitations of Use: Avastin is not indicated for adjuvant treatment of colon cancer [see Clinical Studies (14.2)].
`
`1.2 First-Line Non-Squamous Non–Small Cell Lung Cancer
`Avastin, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of patients with
`unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer (NSCLC).
`
`1.3 Recurrent Glioblastoma
`Avastin is indicated for the treatment of recurrent glioblastoma (GBM) in adults.
`
`1.4 Metastatic Renal Cell Carcinoma
`Avastin, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell carcinoma
`(mRCC).
`
`1.5 Persistent, Recurrent, or Metastatic Cervical Cancer
`Avastin, in combination with paclitaxel and cisplatin or paclitaxel and topotecan, is indicated for the treatment
`of patients with persistent, recurrent, or metastatic cervical cancer.
`
`1.6 Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
`Avastin, in combination with carboplatin and paclitaxel, followed by Avastin as a single agent, is indicated for
`the treatment of patients with stage III or IV epithelial ovarian, fallopian tube, or primary peritoneal cancer
`following initial surgical resection.
`
`Avastin, in combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan, is indicated for the
`treatment of patients with platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal
`cancer who received no more than 2 prior chemotherapy regimens.
`
`Avastin, in combination with carboplatin and paclitaxel, or with carboplatin and gemcitabine, followed by
`Avastin as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial
`ovarian, fallopian tube, or primary peritoneal cancer.
`
`1.7 Hepatocellular Carcinoma
`Avastin, in combination with atezolizumab, is indicated for the treatment of patients with unresectable or
`metastatic hepatocellular carcinoma (HCC) who have not received prior systemic therapy.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Important Administration Information
`Withhold for at least 28 days prior to elective surgery. Do not administer Avastin until at least 28 days
`following major surgery and until adequate wound healing.
`
`Reference ID: 4714390
`
`Novartis Exhibit 2285.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`2.2 Metastatic Colorectal Cancer
`The recommended dosage when Avastin is administered in combination with intravenous fluorouracil-based
`chemotherapy is:
`5 mg/kg intravenously every 2 weeks in combination with bolus-IFL.
`•
`10 mg/kg intravenously every 2 weeks in combination with FOLFOX4.
`•
`5 mg/kg intravenously every 2 weeks or 7.5 mg/kg intravenously every 3 weeks in combination with
`•
`fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based chemotherapy in patients who have
`progressed on a first-line Avastin-containing regimen.
`
`2.3 First-Line Non-Squamous Non-Small Cell Lung Cancer
`The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and
`paclitaxel.
`
`2.4 Recurrent Glioblastoma
`The recommended dosage is 10 mg/kg intravenously every 2 weeks.
`
`2.5 Metastatic Renal Cell Carcinoma
`The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with interferon alfa.
`
`2.6 Persistent, Recurrent, or Metastatic Cervical Cancer
`The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with paclitaxel and cisplatin
`or in combination with paclitaxel and topotecan.
`
`2.7 Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
`Stage III or IV Disease Following Initial Surgical Resection
`The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with carboplatin and
`paclitaxel for up to 6 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent for a total of up to
`22 cycles or until disease progression, whichever occurs earlier.
`
`Recurrent Disease
`Platinum Resistant
`The recommended dosage is 10 mg/kg intravenously every 2 weeks in combination with paclitaxel, pegylated
`liposomal doxorubicin, or topotecan (every week).
`
`The recommended dosage is 15 mg/kg intravenously every 3 weeks in combination with topotecan (every 3
`weeks).
`
`Platinum Sensitive
`The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and
`paclitaxel for 6 to 8 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent until disease
`progression.
`
`The recommended dosage is 15 mg/kg intravenously every 3 weeks, in combination with carboplatin and
`gemcitabine for 6 to 10 cycles, followed by Avastin 15 mg/kg every 3 weeks as a single agent until disease
`progression.
`
`2.8 Hepatocellular Carcinoma
`The recommended dosage is 15 mg/kg intravenously after administration of 1,200 mg of atezolizumab
`intravenously on the same day, every 3 weeks until disease progression or unacceptable toxicity.
`Refer to the Prescribing Information for atezolizumab prior to initiation for recommended dosage information.
`
`Reference ID: 4714390
`
`Novartis Exhibit 2285.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`2.9 Dosage Modifications for Adverse Reactions
`Table 1 describes dosage modifications for specific adverse reactions. No dose reductions for Avastin are
`recommended.
`
`Adverse Reaction
`Gastrointestinal Perforations
`and Fistulae [see Warnings
`and Precautions (5.1)].
`
`Wound Healing
`Complications [see Warnings
`and Precautions (5.2)].
`
`Table 1: Dosage Modifications for Adverse Reactions
`Severity
`Dosage Modification
`Discontinue Avastin
`• Gastrointestinal perforation, any grade
`• Tracheoesophageal fistula, any grade
`• Fistula, Grade 4
`• Fistula formation involving any internal
`organ
`• Any
`
`Withhold AVASTIN until
`adequate wound healing.The
`safety of resumption of
`AVASTIN after resolution of
`wound healing complications
`has not been established.
`Discontinue Avastin
`
`• Necrotizing fasciitis
`
`Hemorrhage [see Warnings
`and Precautions (5.3)].
`
`Thromboembolic Events [see
`Warnings and Precautions
`(5.4, 5.5)].
`
`Hypertension [see Warnings
`and Precautions (5.6)].
`
`Posterior Reversible
`Encephalopathy Syndrome
`(PRES) [see Warnings and
`Precautions (5.7)].
`Renal Injury and Proteinuria
`[see Warnings and
`Precautions (5.8)].
`
`Infusion-Related Reactions
`[see Warnings and
`Precautions (5.9)].
`
`Congestive Heart Failure [see
`Warnings and Precautions
`(5.12)].
`
`• Grade 3 or 4
`• Recent history of hemoptysis of 1/2
`teaspoon (2.5 mL) or more
`• Arterial thromboembolism, severe
`• Venous thromboembolism, Grade 4
`
`Discontinue Avastin
`Withhold Avastin
`
`Discontinue Avastin
`Discontinue Avastin
`
`• Hypertensive crisis
`• Hypertensive encephalopathy
`• Hypertension, severe
`
`• Any
`
`• Nephrotic syndrome
`• Proteinuria greater than or equal to
`2 grams per 24 hours in absence of
`nephrotic syndrome
`• Severe
`• Clinically significant
`
`Discontinue Avastin
`
`Withhold Avastin if not
`controlled with medical
`management; resume once
`controlled
`Discontinue Avastin
`
`Discontinue Avastin
`Withhold Avastin until
`proteinuria less than 2 grams
`per 24 hours
`Discontinue Avastin
`Interrupt infusion; resume at a
`decreased rate of infusion after
`symptoms resolve
`
`• Mild, clinically insignificant
`Any
`
`Decrease infusion rate
`Discontinue Avastin
`
`Reference ID: 4714390
`
`Novartis Exhibit 2285.005
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`2.10 Preparation and Administration
`Preparation
`• Use appropriate aseptic technique.
`• Visually inspect vial for particulate matter and discoloration prior to preparation for administration. Discard
`vial if solution is cloudy, discolored or contains particulate matter.
`• Withdraw necessary amount of Avastin and dilute in a total volume of 100 mL of 0.9% Sodium Chloride
`Injection, USP. DO NOT ADMINISTER OR MIX WITH DEXTROSE SOLUTION.
`• Discard any unused portion left in a vial, as the product contains no preservatives.
`• Store diluted Avastin solution at 2°C to 8°C (36°F to 46°F) for up to 8 hours.
`• No incompatibilities between Avastin and polyvinylchloride or polyolefin bags have been observed.
`
`Administration
`• Administer as an intravenous infusion.
`• 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 second infusion over 60 minutes is tolerated.
`
`3 DOSAGE FORMS AND STRENGTHS
`Injection: 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) clear to slightly opalescent, colorless to pale
`brown solution in a single-dose vial.
`
`4 CONTRAINDICATIONS
`None.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Gastrointestinal Perforations and Fistulae
`Serious, and sometimes fatal, gastrointestinal perforation occurred at a higher incidence in patients receiving
`Avastin compared to patients receiving chemotherapy. The incidence ranged from 0.3% to 3% across clinical
`studies, with the highest incidence in patients with a history of prior pelvic radiation. Perforation can be
`complicated by intra-abdominal abscess, fistula formation, and the need for diverting ostomies. The majority of
`perforations occurred within 50 days of the first dose [see Adverse Reactions (6.1)].
`
`Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder sites)
`occurred at a higher incidence in patients receiving Avastin compared to patients receiving chemotherapy. The
`incidence ranged from < 1% to 1.8% across clinical studies, with the highest incidence in patients with cervical
`cancer. The majority of fistulae occurred within 6 months of the first dose. Patients who develop a
`gastrointestinal vaginal fistula may also have a bowel obstruction and require surgical intervention, as well as a
`diverting ostomy.
`
`Avoid Avastin in patients with ovarian cancer who have evidence of recto-sigmoid involvement by pelvic
`examination or bowel involvement on CT scan or clinical symptoms of bowel obstruction. Discontinue in
`patients who develop gastrointestinal perforation, tracheoesophageal fistula or any Grade 4 fistula. Discontinue
`in patients with fistula formation involving any internal organ.
`
`Reference ID: 4714390
`
`Novartis Exhibit 2285.006
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`5.2 Surgery and Wound Healing Complications
`In a controlled clinical study in which Avastin was not administered within 28 days of major surgical
`procedures, the incidence of wound healing complications, including serious and fatal complications, was 15%
`in patients with mCRC who underwent surgery while receiving Avastin and 4% in patients who did not receive
`Avastin. In a controlled clinical study in patients with relapsed or recurrent GBM, the incidence of wound
`healing events was 5% in patients who received Avastin and 0.7% in patients who did not receive Avastin [see
`Adverse Reactions (6.1)].
`
`In patients who experience wound healing complications during Avastin treatment, withhold Avastin until
`adequate wound healing. Withhold for at least 28 days prior to elective surgery. Do not administer for at least
`28 days following major surgery and until adequate wound healing. The safety of resumption of AVASTIN
`after resolution of wound healing complications has not been established [see Dosage and Administration
`(2.9)].
`
`Necrotizing fasciitis including fatal cases, has been reported in patients receiving Avastin, usually secondary to
`wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin in patients
`who develop necrotizing fasciitis.
`
`5.3 Hemorrhage
`Avastin can result in two distinct patterns of bleeding: minor hemorrhage, which is most commonly Grade 1
`epistaxis, and serious hemorrhage, which in some cases has been fatal. Severe or fatal hemorrhage, including
`hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding, occurred
`up to 5-fold more frequently in patients receiving Avastin compared to patients receiving chemotherapy alone.
`Across clinical studies, the incidence of Grades 3-5 hemorrhagic events ranged from 0.4% to 7% in patients
`receiving Avastin [see Adverse Reactions (6.1)].
`
`Serious or fatal pulmonary hemorrhage occurred in 31% of patients with squamous NSCLC and 4% of patients
`with non-squamous NSCLC receiving Avastin with chemotherapy compared to none of the patients receiving
`chemotherapy alone.
`
`An evaluation for the presence of varices is recommended within 6 months of initiation of Avastin in patients
`with HCC. There is lack of clinical data to support the safety of Avastin in patients with variceal bleeding
`within 6 months prior to treatment, untreated or incompletely treated varices with bleeding, or high risk of
`bleeding because these patients were excluded from clinical trials of Avastin in HCC [see Clinical Studies
`(14.10)].
`
`Do not administer Avastin to patients with recent history of hemoptysis of 1/2 teaspoon or more of red blood.
`Discontinue in patients who develop a Grades 3-4 hemorrhage.
`
`5.4 Arterial Thromboembolic Events
`Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient
`ischemic attacks, myocardial infarction, and angina, occurred at a higher incidence in patients receiving Avastin
`compared to patients receiving chemotherapy. Across clinical studies, the incidence of Grades 3-5 ATE was 5%
`in patients receiving Avastin with chemotherapy compared to ≤2% in patients receiving chemotherapy alone;
`the highest incidence occurred in patients with GBM. The risk of developing ATE was increased in patients
`with a history of arterial thromboembolism, diabetes, or >65 years [see Use in Specific Populations (8.5)].
`
`Discontinue in patients who develop a severe ATE. The safety of reinitiating Avastin after an ATE is resolved
`is not known.
`
`Reference ID: 4714390
`
`Novartis Exhibit 2285.007
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`5.5 Venous Thromboembolic Events
`An increased risk of venous thromboembolic events (VTE) was observed across clinical studies [see Adverse
`Reactions (6.1)]. In Study GOG-0240, Grades 3-4 VTE occurred in 11% of patients receiving Avastin with
`chemotherapy compared with 5% of patients receiving chemotherapy alone. In EORTC 26101, the incidence of
`Grades 3-4 VTE was 5% in patients receiving Avastin with chemotherapy compared to 2% in patients receiving
`chemotherapy alone.
`
`Discontinue Avastin in patients with a Grade 4 VTE, including pulmonary embolism.
`
`5.6 Hypertension
`Severe hypertension occurred at a higher incidence in patients receiving Avastin as compared to patients
`receiving chemotherapy alone. Across clinical studies, the incidence of Grades 3-4 hypertension ranged from
`5% to 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 discontinuing Avastin. Withhold
`Avastin in patients with severe hypertension that is not controlled with medical management; resume once
`controlled with medical management. Discontinue in patients who develop hypertensive crisis or hypertensive
`encephalopathy.
`
`5.7 Posterior Reversible Encephalopathy Syndrome
`Posterior reversible encephalopathy syndrome (PRES) was reported in < 0.5% of patients across clinical studies.
`The onset of symptoms occurred from 16 hours to 1 year after the first dose. PRES 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 is necessary to confirm
`the diagnosis of PRES.
`
`Discontinue Avastin in patients who develop PRES. Symptoms usually resolve or improve within days after
`discontinuing Avastin, although some patients have experienced ongoing neurologic sequelae. The safety of
`reinitiating Avastin in patients who developed PRES is not known.
`
`5.8 Renal Injury and Proteinuria
`The incidence and severity of proteinuria was higher in patients receiving Avastin as compared to patients
`receiving chemotherapy. Grade 3 (defined as urine dipstick 4+ or > 3.5 grams of protein per 24 hours) to Grade
`4 (defined as nephrotic syndrome) ranged from 0.7% to 7% in clinical studies. The overall incidence of
`proteinuria (all grades) was only adequately assessed in Study BO17705, in which the incidence was 20%.
`Median onset of proteinuria was 5.6 months (15 days to 37 months) after initiating Avastin. Median time to
`resolution was 6.1 months (95% CI: 2.8, 11.3). Proteinuria did not resolve in 40% of patients after median
`follow-up of 11.2 months and required discontinuation of Avastin in 30% of the patients who developed
`proteinuria [see Adverse Reactions (6.1)].
`
`In an exploratory, pooled analysis of patients from seven randomized clinical studies, 5% of patients receiving
`Avastin with chemotherapy experienced Grades 2-4 (defined as urine dipstick 2+ or greater or > 1 gram of
`protein per 24 hours or nephrotic syndrome) proteinuria. Grades 2-4 proteinuria resolved in 74% of patients.
`Avastin was reinitiated in 42% of patients. Of the 113 patients who reinitiated Avastin, 48% experienced a
`second episode of Grades 2-4 proteinuria.
`
`Nephrotic syndrome occurred in < 1% of patients receiving Avastin across clinical studies, in some instances
`with fatal outcome. In a published case series, kidney biopsy of 6 patients with proteinuria showed findings
`consistent with thrombotic microangiopathy. Results of a retrospective analysis of 5805 patients who received
`
`Reference ID: 4714390
`
`Novartis Exhibit 2285.008
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Avastin with chemotherapy and 3713 patients who received chemotherapy alone, showed higher rates of
`elevated serum creatinine levels (between 1.5 to 1.9 times baseline levels) in patients who received Avastin.
`Serum creatinine levels did not return to baseline in approximately one-third of patients who received Avastin.
`
`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. Withhold for proteinuria greater than or equal to 2 grams per
`24 hours and resume when less than 2 grams per 24 hours. Discontinue in patients who develop nephrotic
`syndrome.
`
`Data from 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)].
`
`Infusion-Related Reactions
`5.9
`Infusion-related reactions reported across clinical studies and postmarketing 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-related reactions
`with the first dose occurred in < 3% of patients and severe reactions occurred in 0.4% of patients.
`
`Decrease the rate of infusion for mild, clinically insignificant infusion-related reactions. Interrupt the infusion in
`patients with clinically significant infusion-related reactions and consider resuming at a slower rate following
`resolution. Discontinue in patients who develop a severe infusion-related reaction and administer appropriate
`medical therapy (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators and/or oxygen).
`
`5.10 Embryo-Fetal Toxicity
`Based on its mechanism of action and findings from animal studies, Avastin may cause fetal harm when
`administered to pregnant women. Congenital malformations were observed with the administration of
`bevacizumab to pregnant rabbits during organogenesis every 3 days at a dose as low as a clinical dose of 10
`mg/kg. Furthermore, animal models link angiogenesis and VEGF and VEGFR2 to critical aspects of female
`reproduction, embryo-fetal development, and postnatal development. Advise pregnant women of the potential
`risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with
`Avastin and for 6 months after the last dose [see Use in Specific Populations (8.1, 8.3)].
`
`5.11 Ovarian Failure
`The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving Avastin with
`chemotherapy as compared to those receiving chemotherapy alone for adjuvant treatment of a solid tumor. After
`discontinuing Avastin, recovery of ovarian function at all time points during the post-treatment period was
`demonstrated in 22% of women receiving Avastin. Recovery of ovarian function is defined as resumption of
`menses, a positive serum β-HCG pregnancy test, or an FSH level < 30 mIU/mL during the post-treatment
`period. Long-term effects of Avastin on fertility are unknown. Inform females of reproductive potential of the
`risk of ovarian failure prior to initiating Avastin [see Adverse Reactions (6.1), Use in Specific Populations
`(8.3)].
`
`5.12 Congestive Heart Failure (CHF)
`Avastin is not indicated for use with anthracycline-based chemotherapy. The incidence of Grade > 3 left
`ventricular dysfunction was 1% in patients receiving Avastin compared to 0.6% of patients receiving
`chemotherapy alone. Among patients who received prior anthracycline treatment, the rate of CHF was 4% for
`patients receiving Avastin with chemotherapy as compared to 0.6% for patients receiving chemotherapy alone.
`
`In previously untreated patients with a hematological malignancy, the incidence of CHF and decline in left
`ventric