Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 1 of 85 PageID
`#: 37662
`
`DOCKET # 280
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 2 of 85 PageID
`#: 37663
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`
`
`
`
`
`C.A. No. 18-924-CFC
`
`CONFIDENTIAL –
`FILED UNDER SEAL
`
`
`
`
`Plaintiffs,
`
`Defendant.
`
`
`GENENTECH, INC. and CITY OF HOPE,
`
`
`
`v.
`
`AMGEN, INC.,
`
`
`
`
`
`
`
`
`
`
`
`
`
`EXHIBITS 49-114 TO THE DECLARATION OF NORA Q.E. PASSAMANECK
`
`VOLUME 2 OF 3
`
`
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 3 of 85 PageID
`#: 37664
`
`
`
`
`
`MCCARTER & ENGLISH LLP
`
`
`/s/ Michael P. Kelly
`Michael P. Kelly (#2295)
`Daniel M. Silver (#4758)
`Alexandra M. Joyce (#6423)
`Renaissance Centre
`405 N. King Street, 8th Floor
`Wilmington, Delaware 19801
`Tel.: (302) 984-6300
`Fax: (302) 984-6399
`mkelly@mccarter.com
`dsilver@mccarter.com
`ajoyce@mccarter.com
`
`Attorneys for Plaintiffs Genentech,
`Inc. and City of Hope
`
`Date: July 10, 2019
`
`Of Counsel:
`
`William F. Lee
`Lisa J. Pirozzolo
`Emily R. Whelan
`Kevin Prussia
`Andrew J. Danford
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`60 State Street
`Boston, MA 02109
`(627) 526-6000
`william.lee@wilmerhale.com
`lisa.pirozzolo@wilmerhale.com
`emily.whelan@wilmerhale.com
`kevin.prussia@wilmerhale.com
`andrew.danford@wilmerhale.com
`
`Robert J. Gunther Jr.
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`7 World Trade Center
`250 Greenwich Street
`New York, NY 10007
`(212) 230-8800
`robert.gunther@wilmerhale.com
`
`Daralyn J. Durie
`Adam R. Brausa
`DURIE TANGRI LLP
`217 Leidesdorff St.
`San Francisco, CA 94111
`(415) 362-6666
`ddurie@durietangri.com
`abrausa@durietangri.com
`
`
`2
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 4 of 85 PageID
`#: 37665
`
`EXHIBIT 49
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 5 of 85 PageID
`#: 37666
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`AVASTIN safely and effectively. See full presclibing information for
`AVASTIN.
`
`AVASTIN (bevacizumab) injection, for intravenous use
`Initial U.S. Approval: 2004
`
`WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY
`AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE
`See full prescribing information for complete boxed warning.
`• Gastrointestinal Perforations: Discontinue for gastrointestinal
`perforation. (5.1)
`• Surgery and Wound Healing Complications: Discontinue in
`patients who develop wound healing complications that require
`medical intervention. Withhold for at least 28 days prior to
`elective surgery. Do not administer Avastin for at least 28 days
`after surgery and until the wound is fully healed. (5.2)
`• Hemorrhage: Severe or fatal hemorrhages have occurred. Do not
`administer for recent hemoptysis. Discontinue for Grade 3-4
`hemorrhage (5.3)
`
`RECENT MAJOR CHANGES
`
`Indications and Usage, Recurrent Glioblastoma (1.3)
`Indications and Usage, Epithelial Ovarian, Fallopian Tube,
`or Primary Peritoneal Cancer (1.6)
`Dosage and Administration, Recurrent Glioblastoma (2.4)
`Dosage and Administration, Epithelial Ovarian, Fallopian
`Tube, or Primary Peritoneal Cancer (2.7)
`Warnings and Precautions, Congestive Heart Failure (5.12)
`
`12/2017
`06/2018
`
`12/2017
`06/2018
`
`12/2017
`
`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 cancer (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
`Administer as an intravenous infusion. (2.9)
`
`DOSAGE FORMS AND STRENGTHS
`
`Injection: 100 mg/4 mL (25mg/mL) or 400 mg/16 mL (25mg/mL) in a single
`dose vial (3)
`
`CONTRAINDICATIONS
`
`None (4)
`
`INDICATIONS AND USAGE
`
`WARNINGS AND PRECAUTIONS
`
`Avastin is a vascular endothelial growth factor directed antibody indicated for
`the treatment of:
`• Metastatic colorectal cancer, in combination with intravenous
`5-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 wIlo have progressed on a first-line
`Avastin-containing regimen. (1.1)
`
`Limitation 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 doxonthicin, 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)
`
`DOSAGE AND ADMINISTRATION
`
`Do not administer Avastin for 28 days following major surgery and until
`surgical wound is fully healed. (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
`
`• Perforation or Fistula: Discontinue for h-acheoesophageal fistula, grade 4
`fistula, or necrotizing fasciitis. (5.1)
`• 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 Reactions: Decrease rate for infusion reactions. Discontinue for
`severe infusion reactions and administer medical therapy. (5.9)
`• Embryo-fetal Toxicity: 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°/0) 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
`
`• Lactation: Advise not to breast feed. (8.2)
`See 17 for PATIENT COUNSELING INFORMATION.
`
`Revised: 02/2019
`
`CONFIDENTIAL
`
`GNE-HER 002979333
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 6 of 85 PageID
`#: 37667
`
`FULL PRESCRIBING INFORMATION: CONTENTS"
`
`1.3
`1.4
`1.5
`1.6
`
`WARNING: GASTROINTESTINAL PERFORATIONS,
`SURGERY AND WOUND HEALING COMPLICATIONS, and
`HEMORRHAGE
`1 INDICATIONS AND USAGE
`1.1
`Metastatic Colorectal Cancer (mCRC)
`1.2
`First-line Non-Squamous Non-Small Cell Lung Cancer
`(NSCLC)
`Recurrent Glioblastoma (GBM)
`Metastatic Renal Cell Carcinoma (mRCC)
`Persistent, Recurrent, or Metastatic Cervical Cancer
`Epithelial Ovarian, Fallopian Tube, or Primary
`Peritoneal Cancer
`2 DOSAGE AND ADMINISTRATION
`2.1
`Important Administration Information
`2.2
`Metastatic Colorectal Cancer (mCRC)
`2.3
`First-Line Non-Squamous Non-Small Cell Lung Cancer
`(NSCLC)
`Recurrent Glioblastoma (GBM)
`Metastatic Renal Cell Carcinoma (mRCC)
`Persistent, Recurrent, or Metastatic Cervical Cancer
`Epithelial Ovarian, Fallopian Tube or Primary Peritoneal
`Cancer
`Dose Modifications for Adverse Reactions
`2.8
`Preparation and Administration
`2.9
`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 Tlu-omboembolic Events
`5.6
`Hypertension
`5.7
`Posterior Reversible Encephalopathy Syndrome (PRES)
`5.8
`Renal Injury and Proteinuria
`5.9
`Infusion Reactions
`5.10 Embryo-Fetal Toxicity
`5.11 Ovarian Failure
`
`2.4
`2.5
`2.6
`2.7
`
`5.12 Congestive Heart Failure
`6 ADVERSE REACTIONS
`6.1
`Clinical Trial 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
`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
`14 CLINICAL STUDIES
`14.1 Metastatic Colorectal Cancer (mCRC)
`14.2 Lack of Efficacy in Adjuvant Treatment of Colon Cancer
`14.3 First-Line Non-Squamous Non-Small Cell Lung Cancer
`(NSCLC)
`14.4 Recurrent Glioblastoma (GBM)
`14.5 Metastatic Renal Cell Carcinoma (mRCC)
`14.6 Persistent, Recurrent, or Metastatic Cervical Cancer
`14.7 Platinum-Resistant Recurrent Epithelial Ovarian,
`Fallopian Tube, or Primary Peritoneal Cancer
`14.8 Platinum-Sensitive Recurrent Epithelial Ovarian,
`Fallopian Tube, or Primary Peritoneal Cancer
`14.9 Stage III or IV Epithelial Ovarian, Fallopian Tube, or
`Primary Peritoneal Cancer Following Initial Surgical
`Resection
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`* Sections or subsections omitted from the Full Prescribing Information are
`not listed.
`
`CONFIDENTIAL
`
`GNE-HER 002979334
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 7 of 85 PageID
`#: 37668
`
`FULL PRESCRIBING INFORMATION
`
`WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND
`HEALING COMPLICATIONS, and HEMORRHAGE
`
`Gastrointestinal Perforations: The incidence of gastrointestinal perforation, some fatal, in
`patients receiving Avastin ranges from 0.3% to 3%. Discontinue Avastin in patients who
`develop gastrointestinal perforation [see 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 patients receiving
`Avastin. Discontinue Avastin in patients who develop wound healing complications that
`require medical intervention. Withhold Avastin at least 28 days prior to elective surgery. Do
`not administer Avastin for at least 28 days after surgery, and until the wound is fully healed
`[see Warnings and Precautions (5.2)].
`
`Hemorrhages: Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding,
`hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occur up to 5-fold more
`frequently in patients receiving Avastin. Do not administer Avastin to patients with a recent
`history of hemoptysis. Discontinue in patients who develop Grade 3-4 hemorrhage [see
`Warnings and Precautions (5.3)1
`
`1 INDICATIONS AND USAGE
`1.1 Metastatic Colorectal Cancer (mCRC)
`Avastin, in combination with intravenous 5-fluorouracil-based chemotherapy, is indicated for the
`first- or second-line treatment of patients with metastatic colorectal cancer.
`
`Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based
`chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer
`who have progressed on a first-line Avastin-containing regimen.
`
`Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer [see Clinical
`Studies (14.2)].
`
`1.2 First-Line Non-Squamous Non—Small Cell Lung Cancer (NSCLC)
`Avastin, in combination with carboplatin and paclitaxel, is indicated for the first-line treatment of
`patients with unresectable, locally advanced, recurrent or metastatic non—squamous non—small cell
`lung cancer.
`
`1 1.3 Recurrent Glioblastoma (GBM)
`I Avastin is indicated for the treatment of recurrent glioblastoma in adults.
`
`1.4 Metastatic Renal Cell Carcinoma (mRCC)
`Avastin, in combination with interferon alfa, is indicated for the treatment of metastatic renal cell
`carcinoma.
`
`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.
`
`CONFIDENTIAL
`
`GNE-HER 002979335
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 8 of 85 PageID
`#: 37669
`
`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.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Important Administration Information
`Do not administer Avastin until at least 28 days following surgery and the wound is fully healed.
`
`2.2 Metastatic Colorectal Cancer (mCRC)
`The recommended dose when Avastin is administered in combination with intravenous
`5-fluorouracil-based chemotherapy is:
`5 mg/kg every 2 weeks intravenously in combination with bolus-1FL.
`10 mg/kg every 2 weeks intravenously 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 (NSCLC)
`The recommended dose is 15 mg/kg intravenously every 3 weeks in combination with carboplatin
`and paclitaxel.
`
`2.4 Recurrent Glioblastoma (GBM)
`The recommended dose is 10 mg/kg intravenously every 2 weeks.
`
`2.5 Metastatic Renal Cell Carcinoma (mRCC)
`The recommended dose is 10 mg/kg intravenously every 2 weeks in combination with interferon
`alfa.
`
`2.6 Persistent, Recurrent, or Metastatic Cervical Cancer
`The recommended dose of Avastin 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
`Treatment of Stage III or IV Disease Following Initial Surgical Resection:
`
`The recommended dose 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.
`
`CONFIDENTIAL
`
`GNE-HER 002979336
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 9 of 85 PageID
`#: 37670
`
`Treatment of Recurrent Disease:
`
`Platinum Resistant
`The recommended dose is 10 mg/kg intravenously every 2 weeks in combination with paclitaxel,
`pegylated liposomal doxorubicin, or topotecan (every week).
`
`The recommended dose is 15 mg/kg intravenously every 3 weeks in combination with topotecan
`(every 3 weeks).
`
`Platinum Sensitive
`The recommended dose 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 dose 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 Dose Modifications for Adverse Reactions
`Table 1 describes dose modifications for specific adverse reactions [see Warnings and Precautions
`(5)]. No dose reductions for Avastin are recommended.
`
`Table 1: Dose Modifications for Adverse Reactions
`
`Adverse Reaction
`Gastrointestinal Perforation
`and fistulae [see Warnings
`and Precautions (5.1)].
`
`Wound Healing
`Complications [see
`Warnings and Precautions
`(5.2)].
`Hemorrhage [see Warnings
`and Precautions (5.3)].
`
`Thromboembolic Events [see
`Warnings and Precautions
`(5.4, 5.5)].
`
`Hypertension [see Warnings
`and Precautions (5.6)].
`
`Severity
`• Gastrointestinal perforation, any grade
`• Tracheoesophageal fistula, any grade
`• Fistula, Grade 4
`• Fistula formation involving any internal
`organ
`
`• Wound healing complications requiring
`medical intervention
`• Necrotizing fasciitis
`
`Dose Modification
`Discontinue Avastin
`
`Discontinue Avastin
`
`• 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
`
`Discontinue Avastin
`
`Withhold Avastin if not
`controlled with medical
`management; resume once
`controlled
`
`CONFIDENTIAL
`
`GNE-HER 002979337
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 10 of 85 PageID
`#: 37671
`
`Adverse Reaction
`Posterior Reversible
`Encephalopathy Syndrome
`(PRES) [see Warnings and
`Precautions (5.7)].
`Renal Toxicity and
`Proteinuria [see Warnings
`and Precautions (5.8)].
`
`Infusion Reaction [see
`Warnings and Precautions
`(5.10)].
`
`Congestive Heart Failure [see
`Warnings and Precautions
`(5.12)].
`
`Severity
`• Any
`
`Dose Modification
`Discontinue Avastin
`
`• Nephrotic syndrome
`• Proteinuria greater than or equal to
`2 grams per 24 hours in absence of
`nephrotic syndrome
`• Severe infusion reaction
`• Clinically significant
`
`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
`
`2.9 Preparation and Administration
`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.
`
`Preparation
`• Use appropriate aseptic technique.
`• Parenteral drug products should be inspected visually for particulate matter and discoloration
`prior to administration.
`• 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 2-8°C (36-46°F) for up to 8 hours.
`• No incompatibilities between Avastin and polyvinylchloride or polyolefin bags have been
`observed.
`
`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 single-dose vial
`
`4 CONTRAINDICATIONS
`None.
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Gastrointestinal Perforations and Fistulae
`Serious and sometimes fatal gastrointestinal perforation occur 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
`
`CONFIDENTIAL
`
`GNE-HER 002979338
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 11 of 85 PageID
`#: 37672
`
`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.
`
`Serious fistulae (including, tracheoesophageal, bronchopleural, biliary, vaginal, renal and bladder
`sites) occur 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 [see
`Adverse Reactions (6.1)].
`
`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)].
`
`Discontinue Avastin in patients with wound healing complications requiring medical intervention.
`Withhold for at least 28 days prior to elective surgery. Do not administer for at least 28 days
`following surgery and until the wound is fully healed.
`
`Necrotizing fasciitis including fatal cases, has been reported in patients receiving Avastin, usually
`secondary to wound healing complications, gastrointestinal perforation or fistula formation.
`Discontinue in patients who develop necrotizing fasciitis [see Adverse Reactions (6.3)].
`
`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, hemorrhage. 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.
`
`Do not administer Avastin to patients with recent history of hemoptysis of1/2 teaspoon or more of
`red blood. Discontinue in patients who develop a Grade 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
`
`CONFIDENTIAL
`
`GNE-HER 002979339
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 12 of 85 PageID
`#: 37673
`
`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 greater than 65 years old [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.
`
`5.5 Venous Thromboembolic Events
`An increased risk of venous thromboembolic events (VTE) was observed across clinical studies. In
`Study GOG-0240, Grade 3-4 VTE was reported in 11% of patients receiving Avastin with
`chemotherapy compared with 5% of patients receiving chemotherapy alone. In EORTC 26101, the
`incidence of Grade 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 [see Adverse
`Reactions (6.1)].
`
`5.6 Hypertension
`The incidence of severe hypertension is increased in patients receiving Avastin as compared to
`patients receiving chemotherapy alone. Across clinical studies, the incidence of Grade 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 (PRES)
`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 is 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 B017705, 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
`
`CONFIDENTIAL
`
`GNE-HER 002979340
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 13 of 85 PageID
`#: 37674
`
`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.
`
`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 Grade 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 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)].
`
`5.9 Infusion Reactions
`Infusion reactions reported across clinical studies 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 occurred in <3% of patients and severe reactions
`occurred in 0.2% of patients.
`
`Decrease the rate of infusion for mild, clinically insignificant infusion reactions. Interrupt the
`infusion in patients with clinically significant infusion reactions and consider resuming at a slower
`rate following resolution. Discontinue in patients who develop a severe infusion reaction and
`administer appropriate medical therapy (e.g., epinephrine, corticosteroids, intravenous
`antihistamines, bronchodilators and/or oxygen).
`
`5.10 Embryo-Fetal Toxicity
`Avastin may cause fetal harm based on its mechanism of action and findings from animal studies.
`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 VEGFR 2 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 and for 6 months after the last dose of Avastin [see Use in Specific Populations (8.1, 8.3),
`Clinical Pharmacology (12.1)1
`
`CONFIDENTIAL
`
`GNE-HER 002979341
`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 563-8 Filed 11/09/20 Page 14 of 85 PageID
`#: 37675
`
`5.11 Ovarian Failure
`The incidence of ovarian failure was 34% vs. 2% in premenopausal women receiving Avastin with
`chemotherapy as compared