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`1.14.1.3
`
`Labeling Text
`
`AVASTIN™
`(Bevacizumab)
`
`For Intravenous Use
`
`
`WARNINGS
`Gastrointestinal Perforations/Wound Healing Complications
`AVASTIN administration can result in the development of gastrointestinal
`perforation and wound dehiscence, in some instances resulting in fatality.
`Gastrointestinal perforation, sometimes associated with intra-abdominal
`abscess, occurred throughout treatment with AVASTIN (i.e., was not
`correlated to duration of exposure). The incidence of gastrointestinal
`perforation in patients receiving bolus-IFL with AVASTIN was 2%. The
`typical presentation was reported as abdominal pain associated with
`symptoms such as constipation and vomiting. Gastrointestinal perforation
`should be included in the differential diagnosis of patients presenting with
`abdominal pain on AVASTIN. AVASTIN therapy should be permanently
`discontinued in patients with gastrointestinal perforation or wound
`dehiscence requiring medical intervention. The appropriate interval
`between termination of AVASTIN and subsequent elective surgery
`required to avoid the risks of impaired wound healing/wound dehiscence
`has not been determined. (See WARNINGS: Gastrointestinal
`Perforations/Wound Healing Complications and DOSAGE AND
`ADMINISTRATION: Dose Modifications .)
`
`Hemorrhage
`Serious, and in some cases fatal, hemoptysis has occurred in patients with
`non–small cell lung cancer treated with chemotherapy and AVASTIN. In
`a small study, the incidence of serious or fatal hemoptysis was 31% in
`patients with squamous histology and 4% in patients with adenocarcinoma
`receiving AVASTIN as compared to no cases in patients treated with
`chemotherapy alone. Patients with recent hemoptysis should not receive
`AVASTIN. (See WARNINGS: Hemorrhage and DOSAGE AND
`ADMINISTRATION: Dose Modifications.)
`
`U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
`1 of 27: GNE_clean_PI_Feb_13
`
`Samsung et al. v. Regeneron IPR2023-00884
`Regeneron Pharmaceuticals, Inc. Exhibit 2107 Page 1
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`DESCRIPTION
`AVASTIN(cid:228)
` (Bevacizumab) is a recombinant humanized monoclonal
`IgG1 antibody that binds to and inhibits the biologic activity of human
`vascular endothelial growth factor (VEGF) in in vitro and in vivo assay
`systems. Bevacizumab contains human framework regions and the
`complementarity-determining regions of a murine antibody that binds to
`VEGF (1). Bevacizumab is produced in a Chinese Hamster Ovary
`mammalian cell expression system in a nutrient medium containing the
`antibiotic gentamicin and has a molecular weight of approximately
`149 kilodaltons. AVASTIN is a clear to slightly opalescent, colorless to
`pale brown, sterile, pH 6.2 solution for intravenous (IV) infusion.
`AVASTIN is supplied in 100 mg and 400 mg preservative-free, single-use
`vials to deliver 4 mL or 16 mL of AVASTIN (25 mg/mL). The 100 mg
`product is formulated in 240 mg a
`,a-
`trehalose dihydrate, 23.2 mg sodium
`phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic,
`anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The
`400 mg product is formulated in 960 mg a
`,a
`-trehalose dihydrate, 92.8 mg
`sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate
`(dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection,
`USP.
`
`CLINICAL PHARMACOLOGY
`Mechanism of Action
`Bevacizumab binds VEGF and prevents the interaction of VEGF to its
`receptors (Flt-1 and KDR) on the surface of endothelial cells. The
`interaction of VEGF with its receptors leads to endothelial cell
`proliferation and new blood vessel formation in in vitro models of
`angiogenesis. Administration of Bevacizumab to xenotransplant models
`of colon cancer in nude (athymic) mice caused reduction of microvascular
`growth and inhibition of metastatic disease progression.
`
`Pharmacokinetics
`The pharmacokinetic profile of Bevacizumab was assessed using an assay
`that measures total serum Bevacizumab concentrations (i.e., the assay did
`
`U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
`2 of 27: GNE_clean_PI_Feb_13
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`not distinguish between free Bevacizumab and Bevacizumab bound to
`VEGF ligand). Based on a population pharmacokinetic analysis of
`491 patients who received 1 to 20 mg/kg of AVASTIN weekly, every
`2 weeks, or every 3 weeks, the estimated half-life of Bevacizumab was
`approximately 20 days (range 11-50 days). The predicted time to reach
`steady state was 100 days. The accumulation ratio following a dose of
`10 mg/kg of Bevacizumab every 2 weeks was 2.8.
`
`The clearance of Bevacizumab varied by body weight, by gender, and by
`tumor burden. After correcting for body weight, males had a higher
`Bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a larger Vc
`(3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or
`above median value of tumor surface area) had a higher Bevacizumab
`clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens
`below the median. In a randomized study of 813 patients (Study 1), there
`was no evidence of lesser efficacy (hazard ratio for overall survival) in
`males or patients with higher tumor burden treated with AVASTIN as
`compared to females and patients with low tumor burden. The
`relationship between Bevacizumab exposure and clinical outcomes has not
`been explored.
`
`Special Populations
`Analyses of demographic data suggest that no dose adjustments are
`necessary for age or sex.
`
`Patients with renal impairment. No studies have been conducted to
`examine the pharmacokinetics of Bevacizumab in patients with renal
`impairment.
`
`Patients with hepatic dysfunction. No studies have been conducted to
`examine the pharmacokinetics of Bevacizumab in patients with hepatic
`impairment.
`
`U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
`3 of 27: GNE_clean_PI_Feb_13
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`CLINICAL STUDIES
`The safety and efficacy of AVASTIN in the initial treatment of patients
`with metastatic carcinoma of the colon and rectum were studied in two
`randomized, controlled clinical trials in combination with intravenous
`5-fluorouracil–based chemotherapy.
`
`AVASTIN in Combination with Bolus-IFL
`Study 1 was a randomized, double-blind, active-controlled clinical trial
`evaluating AVASTIN as first-line treatment of metastatic carcinoma of the
`colon or rectum. Patients were randomized to bolus-IFL (irinotecan
`125 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV
`given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1),
`bolus-IFL plus AVASTIN (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV
`plus AVASTIN (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3
`was discontinued, as pre-specified, when the toxicity of AVASTIN in
`combination with the bolus-IFL regimen was deemed acceptable.
`
`Of the 813 patients randomized to Arms 1 and 2, the median age was 60,
`40% were female, and 79% were Caucasian. Fifty-seven percent had an
`ECOG performance status of 0. Twenty-one percent had a rectal primary
`and 28% received prior adjuvant chemotherapy. In the majority of
`patients, 56%, the dominant site of disease was extra-abdominal, while the
`liver was the dominant site in 38% of patients. The patient characteristics
`were similar across the study arms. The primary endpoint of this trial was
`overall survival. Results are presented in Table 1 and Figure 1.
`
`U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
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`

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`Table 1
`Study 1 Efficacy Results
`
`
`
`IFL + Placebo
`
`IFL + AVASTIN
`5 mg/kg q 2 wks
`
`Number of Patients
`
`Overall Survivala
`Median (months)
`Hazard ratio
`
`Progression-Free Survivala
`Median (months)
`Hazard ratio
`
`Overall Response Rateb
`Rate (percent)
`
`411
`
`
`15.6
`
`
`
`6.4
`
`
`
`35%
`
`
`Duration of Response
`7.1
`Median (months)
` a p < 0.001 by stratified logrank test.
` b p < 0.01 by c 2 test.
`
`402
`
`
`20.3
`0.66
`
`
`10.6
`0.54
`
`
`45%
`
`
`10.4
`
`Figure 1
`Duration of Survival in Study 1
`
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`Error bars represent 95% confidence intervals.
`
`The clinical benefit of AVASTIN, as measured by survival in the two
`principal arms, was seen in all subgroups tested. The subgroups examined
`
`
`
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`were based on age, sex, race, ECOG performance status, location of
`primary tumor, prior adjuvant therapy, number of metastatic sites, and
`tumor burden.
`
`Among the 110 patients enrolled in Arm 3, median overall survival was
`18.3 months, median progression-free survival was 8.8 months, overall
`response rate was 39%, and median duration of response was 8.5 months.
`
`AVASTIN in Combination with 5-FU/LV Chemotherapy
`Study 2 was a randomized, active-controlled clinical trial testing
`AVASTIN in combination with 5-FU/LV as first-line treatment of
`metastatic colorectal cancer. Patients were randomized to receive
`5-FU/LV (5-fluorouracil 500 mg/m2, leucovorin 500 mg/m2 weekly for
`6 weeks every 8 weeks) or 5-FU/LV plus AVASTIN (5 mg/kg every
`2 weeks) or 5-FU/LV plus AVASTIN (10 mg/kg every 2 weeks). Patients
`were treated until disease progression. The primary endpoints of the trial
`were objective response rate and progression-free survival. Results are
`presented in Table 2.
`
`Table 2
`Study 2 Efficacy Results
`
`
`Number of Patients
`
`Overall Survival
`Median (months)
`
`Progression-Free Survival
`Median (months)
`
`Overall Response Rate
`Rate (percent)
`
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`AVASTIN
`5 mg/kg
`
`5-FU/LV +
`AVASTIN
`10 mg/kg
`
`5-FU/LV
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`13.6
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`5.2
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`17
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`35
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`17.7
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`9.0
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`33
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`15.2
`
`
`7.2
`
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`24
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`Progression-free survival was significantly better in patients receiving
`5-FU/LV plus AVASTIN at 5 mg/kg when compared to those not
`receiving AVASTIN. However, overall survival and overall response rate
`
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`were not significantly different. Outcomes for patients receiving 5-FU/LV
`plus AVASTIN at 10 mg/kg were not significantly different than for
`patients who did not receive AVASTIN.
`
`AVASTIN as a Single Agent
`The efficacy of AVASTIN as a single agent in colorectal cancer has not
`been established. However, in an ongoing, randomized study of patients
`with metastatic colorectal cancer that had progressed following a
`5-fluorouracil and irinotecan-based regimen, the arm in which patients
`were treated with single-agent AVASTIN was closed early due to
`evidence of an inferior survival in that arm as compared with patients
`treated with the FOLFOX regimen of 5-fluorouracil, leucovorin, and
`oxaliplatin.
`
`INDICATIONS AND USAGE
`AVASTIN, used in combination with intravenous 5-fluorouracil–based
`chemotherapy, is indicated for first-line treatment of patients with
`metastatic carcinoma of the colon or rectum.
`
`CONTRAINDICATIONS
`There are no known contraindications to the use of AVASTIN.
`
`WARNINGS
`Gastrointestinal Perforations/Wound Healing Complications
`(See DOSAGE AND ADMINISTRATION: Dose Modifications)
`Gastrointestinal perforation and wound dehiscence, complicated by
`intra-abdominal abscesses, occurred at an increased incidence in patients
`receiving AVASTIN as compared to controls. AVASTIN has also been
`shown to impair wound healing in pre-clinical animal models.
`
`In Study 1, one of 396 (0.3%) patients receiving bolus-IFL plus placebo,
`six of 392 (2%) patients receiving bolus-IFL plus AVASTlN, and four of
`109 (4%) patients receiving 5-FU/LV plus AVASTIN developed
`gastrointestinal perforation, in some instances with fatal outcome. These
`episodes occurred with or without intra-abdominal abscesses and at
`
`U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
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`various time points during treatment. The typical presentation was
`reported as abdominal pain associated with symptoms such as constipation
`and vomiting.
`
`In addition, two of 396 (0.5%) patients receiving bolus-IFL plus placebo,
`four of 392 (1%) patients receiving bolus-IFL plus AVASTIN, and one of
`109 (1%) patients receiving 5-FU/LV plus AVASTIN developed a wound
`dehiscence during study treatment.
`
`The appropriate interval between surgery and subsequent initiation of
`AVASTIN required to avoid the risks of impaired wound healing has not
`been determined. In Study 1, the clinical protocol did not permit initiation
`of AVASTIN for at least 28 days following surgery. There was one
`patient (among 501 patients receiving AVASTIN on Study 1) in whom an
`anastomotic dehiscence occurred when AVASTIN was initiated per
`protocol. In this patient, the interval between surgery and initiation of
`AVASTIN was greater than 2 months.
`
`Similarly, the appropriate interval between termination of AVASTIN and
`subsequent elective surgery required to avoid the risks of impaired wound
`healing has not been determined. In Study 1, 39 patients who were
`receiving bolus-IFL plus AVASTIN underwent surgery following
`AVASTIN therapy and, of these patients, six (15%) had wound
`healing/bleeding complications. In the same study, 25 patients in the
`bolus-IFL arm underwent surgery and, of these patients, one of 25 (4%)
`had wound healing/bleeding complications. The longest interval between
`last dose of study drug and dehiscence was 56 days; this occurred in a
`patient on the bolus-IFL plus AVASTIN arm. The interval between
`termination of AVASTIN and subsequent elective surgery should take into
`consideration the calculated half-life of AVASTIN (approximately
`20 days).
`
`AVASTIN therapy should be discontinued in patients with gastrointestinal
`perforation or wound dehiscence requiring medical intervention.
`
`U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
`8 of 27: GNE_clean_PI_Feb_13
`
`Samsung et al. v. Regeneron IPR2023-00884
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`

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`Hemorrhage (See DOSAGE AND ADMINISTRATION: Dose
`Modifications)
`Two distinct patterns of bleeding have occurred in patients receiving
`AVASTIN. The first is minor hemorrhage, most commonly Grade 1
`epistaxis. The second is serious, and in some cases fatal, hemorrhagic
`events. Serious hemorrhagic events occurred primarily in patients with
`non–small cell lung cancer, an indication for which AVASTIN is not
`approved. In a randomized study in patients with non-small cell lung
`cancer receiving chemotherapy with or without AVASTIN, four of 13
`(31%) AVASTIN-treated patients with squamous cell histology and two
`of 53 (4%) AVASTIN-treated patients with non-squamous histology
`experienced life-threatening or fatal pulmonary hemorrhage as compared
`to none of the 32 (0%) patients receiving chemotherapy alone. Of the
`patients experiencing events of life-threatening pulmonary hemorrhage,
`many had cavitation and/or necrosis of the tumor, either pre-existing or
`developing during AVASTIN therapy. These serious hemorrhagic events
`occurred suddenly and presented as major or massive hemoptysis.
`
`The risk of central nervous system (CNS) bleeding in patients with CNS
`metastases receiving AVASTIN has not been evaluated because these
`patients were excluded from Genentech-sponsored studies following
`development of CNS hemorrhage in a patient with a CNS metastasis in
`Phase 1 studies.
`
`Other serious bleeding events reported in patients receiving AVASTIN
`were uncommon and included gastrointestinal hemorrhage, subarachnoid
`hemorrhage, and hemorrhagic stroke.
`
`Patients with serious hemorrhage i.e., requiring medical intervention,
`should have AVASTIN treatment discontinued and receive aggressive
`medical management. Patients with recent hemoptysis should not receive
`AVASTIN.
`
`U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
`9 of 27: GNE_clean_PI_Feb_13
`
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`Hypertension (See DOSAGE AND ADMINISTRATION: Dose
`Modifications)
`The incidence of hypertension and severe hypertension was increased in
`patients receiving AVASTIN in Study 1 (see Table 3).
`
`Table 3
`Incidence of Hypertension and Severe Hypertension in Study 1
`
`Arm 1
`IFL + Placebo
`(n = 394)
`43%
`
`Arm 2
`IFL + AVASTIN
`(n = 392)
`60%
`
`Arm 3
`5-FU/LV + AVASTIN
`(n = 109)
`67%
`
`
`Hypertensiona
` ( > 150/100 mmHg)
`
`Severe Hypertensiona
` ( > 200/110 mmHg)
` a This includes patients with either a systolic or diastolic reading greater than the
`cutoff value on one or more occasions.
`
`2%
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`7%
`
`10%
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`Among patients with severe hypertension in the AVASTIN arms, slightly
`over half the patients (51%) had a diastolic reading greater than 110
`associated with a systolic reading less than 200.
`
`Medication classes used for management of patients with Grade 3
`hypertension receiving AVASTIN included angiotensin-converting
`enzyme inhibitors, beta blockers, diuretics, and calcium channel blockers.
`Four months after discontinuation of therapy, persistent hypertension was
`present in 18 of 26 patients that received bolus-IFL plus AVASTIN and
`8 of 10 patients that received bolus-IFL plus placebo.
`
`Across all clinical studies (n = 1032), development or worsening of
`hypertension resulted in hospitalization or discontinuation of AVASTIN in
`17 patients. Four of these 17 patients developed hypertensive
`encephalopathy. Severe hypertension was complicated by subarachnoid
`hemorrhage in one patient.
`
`U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
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`
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`AVASTIN should be permanently discontinued in patients with
`hypertensive crisis. Temporary suspension is recommended in patients
`with severe hypertension that is not controlled with medical management.
`
`Proteinuria (See DOSAGE AND ADMINISTRATION: Dose
`Modifications)
`In Study 1, both the incidence and severity of proteinuria (defined as a
`urine dipstick reading of 1+ or greater) was increased in patients receiving
`AVASTIN as compared to those receiving bolus-IFL plus placebo.
`Urinary dipstick readings of 2+ or greater occurred in 14% of patients
`receiving bolus-IFL plus placebo, 17% receiving bolus-IFL plus
`AVASTIN, and in 28% of patients receiving 5-FU/LV plus AVASTIN.
`Twenty-four–hour urine collections were obtained in patients with new
`onset or worsening proteinuria. None of the 118 patients receiving
`bolus-IFL plus placebo, three of 158 patients (2%) receiving
`bolus-IFL plus AVASTIN, and two of 50 (4%) patients receiving
`5-FU/LV plus AVASTIN who had a 24-hour collection experienced
`NCI-CTC Grade 3 proteinuria ( > 3.5 gm protein/24 hours).
`
`In a dose-ranging, placebo-controlled, randomized study of AVASTIN in
`patients with metastatic renal cell carcinoma, an indication for which
`AVASTIN is not approved, 24-hour urine collections were obtained in
`approximately half the patients enrolled. Among patients in whom
`24-hour urine collections were obtained, four of 19 (21%) patients
`receiving AVASTIN at 10 mg/kg every two weeks, two of 14 (14%)
`receiving AVASTIN at 3 mg/kg every two weeks, and none of the
`15 placebo patients experienced NCI-CTC Grade 3 proteinuria ( > 3.5 gm
`protein/24 hours).
`
`Nephrotic syndrome occurred in five of 1032 (0.5%) patients receiving
`AVASTIN in Genentech-sponsored studies. One patient died and one
`required dialysis. In three patients, proteinuria decreased in severity
`several months after discontinuation of AVASTIN. No patient had
`
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`normalization of urinary protein levels (by 24-hour urine) following
`discontinuation of AVASTIN.
`
`AVASTIN should be discontinued in patients with nephrotic syndrome.
`The safety of continued AVASTIN treatment in patients with moderate to
`severe proteinuria has not been evaluated. In most clinical studies,
`AVASTIN was interrupted for ‡ 2 grams of proteinuria/24 hours and
`resumed when proteinuria was < 2 gm/24 hours. Patients with moderate
`to severe proteinuria based on 24-hour collections should be monitored
`regularly until improvement and/or resolution is observed.
`
`Congestive Heart Failure
`Congestive heart failure (CHF), defined as NCI-CTC Grade 2-4 left
`ventricular dysfunction, was reported in 22 of 1032 (2%) patients
`receiving AVASTIN in Genentech-sponsored studies. Congestive heart
`failure occurred in six of 44 (14%) patients receiving AVASTIN and
`concurrent anthracyclines. Congestive heart failure occurred in 13 of 299
`(4%) patients who received prior anthracyclines and/or left chest wall
`irradiation. In a controlled study, the incidence was higher in patients
`receiving AVASTIN plus chemotherapy as compared to patients receiving
`chemotherapy alone. The safety of continuation or resumption of
`AVASTIN in patients with cardiac dysfunction has not been studied.
`
`PRECAUTIONS
`General
`AVASTIN should be used with caution in patients with known
`hypersensitivity to AVASTIN or any component of this drug product.
`
`Infusion Reactions
`Infusion reactions with the first dose of AVASTIN were uncommon
`(< 3%). Severe reactions during the infusion of AVASTIN occurred in
`two patients. One patient developed stridor and wheezing during their
`first dose. A second patient, receiving paclitaxel followed by AVASTIN,
`developed a Grade 3 hypersensitivity reaction requiring hospitalization
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`during their third infusion of AVASTIN. Both patients responded to
`medical management. Information on rechallenge is not available.
`
`AVASTIN infusion should be interrupted in all patients with severe
`infusion reactions and appropriate medical therapy administered.
`
`There are no data regarding the most appropriate method of identification
`of patients who may safely be retreated with AVASTIN after experiencing
`a severe infusion reaction.
`
`Surgery
`AVASTIN therapy should not be initiated for at least 28 days following
`major surgery. The surgical incision should be fully healed prior to
`initiation of AVASTIN. Because of the potential for impaired wound
`healing, AVASTIN should be suspended prior to elective surgery. The
`appropriate interval between the last dose of AVASTIN and elective
`surgery is unknown; however, the half-life of AVASTIN is estimated to be
`20 days (see CLINICAL PHARMACOLOGY: Pharmacokinetics) and
`the interval chosen should take into consideration the half-life of the drug.
`(See WARNINGS: Gastrointestinal Perforations/Wound Healing
`Complications.)
`
`Cardiovascular Disease
`Patients were excluded from participation in AVASTIN clinical trials if, in
`the previous year, they had experienced clinically significant
`cardiovascular disease. Thus, the safety of AVASTIN in patients with
`clinically significant cardiovascular disease has not been adequately
`evaluated.
`
`Immunogenicity
`As with all therapeutic proteins, there is a potential for immunogenicity.
`The incidence of antibody development in patients receiving AVASTIN
`has not been adequately determined because the assay sensitivity was
`inadequate to reliably detect lower titers. Enzyme-linked immunosorbant
`assays (ELISAs) were performed on sera from approximately 500 patients
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`treated with AVASTIN, primarily in combination with chemotherapy.
`High titer human anti-AVASTIN antibodies were not detected.
`
`Immunogenicity data are highly dependent on the sensitivity and
`specificity of the assay. Additionally, the observed incidence of antibody
`positivity in an assay may be influenced by several factors, including
`sample handling, timing of sample collection, concomitant medications,
`and underlying disease. For these reasons, comparison of the incidence of
`antibodies to AVASTIN with the incidence of antibodies to other products
`may be misleading.
`
`Laboratory Tests
`Blood pressure monitoring should be conducted every two to three weeks
`during treatment with AVASTIN. Patients who develop hypertension on
`AVASTIN may require blood pressure monitoring at more frequent
`intervals. Patients with AVASTIN-induced or -exacerbated hypertension
`who discontinue AVASTIN should continue to have their blood pressure
`monitored at regular intervals.
`
`Patients receiving AVASTIN should be monitored for the development or
`worsening of proteinuria with serial urinalyses. Patients with a 2+ or
`greater urine dipstick reading should undergo further assessment, e.g., a
`24-hour urine collection. (See WARNINGS: Proteinuria and DOSAGE
`AND ADMINISTRATION: Dose Modifications .)
`
`Drug Interactions
`No formal drug interaction studies with anti-neoplastic agents have been
`conducted. In Study 1, patients with colorectal cancer were given
`irinotecan/5-FU/leucovorin (bolus-IFL) with or without AVASTIN.
`Irinotecan concentrations were similar in patients receiving bolus-IFL
`alone and in combination with AVAS TIN. The concentrations of SN38,
`the active metabolite of irinotecan, were on average 33% higher in patients
`receiving bolus-IFL in combination with AVASTIN when compared with
`bolus-IFL alone. In Study 1, patients receiving bolus-IFL plus AVASTIN
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`had a higher incidence of Grade 3-4 diarrhea and neutropenia. Due to
`high inter-patient variability and limited sampling, the extent of the
`increase in SN38 levels in patients receiving concurrent irinotecan and
`AVASTIN is uncertain.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`No carcinogenicity data are available for AVASTIN in animals or
`humans.
`
`AVASTIN may impair fertility. Dose-related decreases in ovarian and
`uterine weights, endometrial proliferation, number of menstrual cycles, and
`arrested follicular development or absent corpora lutea were observed in
`female cynomolgus monkeys treated with 10 or 50 mg/kg of AVASTIN for
`13 or 26 weeks. Following a 4- or 12-week recovery period, which
`examined only the high–dose group, trends suggestive of reversibility were
`noted in the two females for each regimen that were assigned to recover.
`After the 12-week recovery period, follicular maturation arrest was no
`longer observed, but ovarian weights were still moderately decreased.
`Reduced endometrial proliferation was no longer observed at the 12-week
`recovery time point, but uterine weight decreases were still notable,
`corpora lutea were absent in 1 out of 2 animals, and the number of
`menstrual cycles remained reduced (67%).
`
`Pregnancy Category C
`AVASTIN has been shown to be teratogenic in rabbits when administered
`in doses that are two-fold greater than the recommended human dose on a
`mg/kg basis. Observed effects included decreases in maternal and fetal
`body weights, an increased number of fetal resorptions, and an increased
`incidence of specific gross and skeletal fetal alterations. Adverse fetal
`outcomes were observed at all doses tested.
`
`Angiogenesis is critical to fetal development and the inhibition of
`angiogenesis following administration of AVASTIN is likely to result in
`adverse effects on pregnancy. There are no adequate and well-controlled
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`studies in pregnant women. AVASTIN should be used during pregnancy
`or in any woman not employing adequate contraception only if the
`potential benefit justifies the potential risk to the fetus. All patients should
`be counseled regarding the potential risk of AVASTIN to the developing
`fetus prior to initiation of therapy. If the patient becomes pregnant while
`receiving AVASTIN, she should be apprised of the potential hazard to the
`fetus and/or the potential risk of loss of pregnancy. Patients who
`discontinue AVASTIN should also be counseled concerning the prolonged
`exposure following discontinuation of therapy (half-life of approximately
`20 days) and the possible effects of AVASTIN on fetal development.
`
`Nursing Mothers
`It is not known whether AVASTIN is secreted in human milk. Because
`human IgG1 is secreted into human milk, the potential for absorption and
`harm to the infant after ingestion is unknown. Women should be advised
`to discontinue nursing during treatment with AVASTIN and for a
`prolonged period following the use of AVASTIN, taking into account the
`half-life of the product, approximately 20 days [range 11-50 days]. (See
`CLINICAL PHARMACOLOGY: Pharmacokinetics.)
`
`Pediatric Use
`The safety and effectiveness of AVASTIN in pediatric patients has not
`been studied. However, physeal dysplasia was observed in juvenile
`cynomolgus monkeys with open growth plates treated for four weeks with
`doses that were less than the recommended human dose based on mg/kg
`and exposure. The incidence and severity of physeal dysplasia were
`dose-related and were at least partially reversible upon cessation of
`treatment.
`
`Geriatric Use
`In Study 1, NCI-CTC Grade 3-4 adverse eve nts were collected in all
`patients receiving study drug (396 bolus-IFL plus placebo; 392 bolus-IFL
`plus AVASTIN; 109 5-FU/LV plus AVASTIN), while NCI-CTC Grade 1
`and 2 adverse events were collected in a subset of 309 patients. There
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`U.S. BLA Amendment: Bevacizumab—Genentech, Inc.
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