`
`
`
`
`
`
`
`
`
`
` 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
`
`
` 12/2020
`
`
` Dosage and Administration (2.1)
`
` 10/2020
`
`
` Dosage and Administration (2.9)
`
`
` Dosage and Administration (2.8)
` 5/2020
`
` 10/2020
`
`
`
` Warnings and Precautions (5.2)
`
`
`
` 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
`
`Regeneron Exhibit 1186.001
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`
` 1.1 Metastatic Colorectal Cancer
`
` First-Line Non-Squamous Non−Small Cell Lung Cancer
`
` 1.2
`
`
` 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
`
`
`Important Administration Information
`2.1
`
`
`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
`
`Regeneron Exhibit 1186.002
`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
`
`Regeneron Exhibit 1186.003
`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
`
`Regeneron Exhibit 1186.004
`Regeneron v. Novartis
`IPR2021-00816
`
`
`
`
`
` 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
` Dosage Modification
`
`
` Severity
` Discontinue Avastin
`
` • Gastrointestinal perforation, any grade
`
` • Tracheoesophageal fistula, any grade
`
`
`
` • Fistula, Grade 4
`
`
` • Fistula formation involving any internal
`
`
` organ
`
` • Any
`
`
`
`
`
`
`
`2.9 Dosage Modifications for Adverse Reactions
`
`
`
`
`Table 1 describes dosage modifications for specific adverse reactions. No dose reductions for Avastin are
`
`recommended.
`
`
` 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)].
`
`
`
`
`
` • Necrotizing fasciitis
`
`
`
`
` • Grade 3 or 4
`
`
` • Recent history of hemoptysis of 1/2
`
`
` teaspoon (2.5 mL) or more
` • Arterial thromboembolism, severe
`
`
` • Venous thromboembolism, Grade 4
`
`
`
`
`
`
`
` • 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
`
`
`
`
` Congestive Heart Failure [see
`
`
` Warnings and Precautions
`
` (5.12)].
`
` • Mild, clinically insignificant
`
`
` Any
`
`
`
`
`
`
`
`Reference ID: 4714390
`
`
`
` Withhold AVASTIN until
`
`
` adequate wound healing.The
`
` safety of resumption of
`
` AVASTIN after resolution of
`
` wound healing complications
`
`has not been established.
`
` Discontinue Avastin
`
`
`
` Discontinue Avastin
`
` Withhold Avastin
`
`
` Discontinue Avastin
`
` Discontinue Avastin
`
`
`
` 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
`
`
` Decrease infusion rate
`
` Discontinue Avastin
`
`
`
`Regeneron Exhibit 1186.005
`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
`
`Regeneron Exhibit 1186.006
`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
`
`Regeneron Exhibit 1186.007
`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
`
`Regeneron Exhibit 1186.008
`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)].
`
`
`
` 5.9
` Infusion-Related Reactions
`
`
`
`
` 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.
`
`
`
`
`