治療直腸癌的新藥Avastin ：：

Avastin獲準(zhǔn)作為晚期結(jié)腸癌二線治療藥 (2006-6-22) 生物制藥公司Genentech在6月20日稱，F(xiàn)DA已批準(zhǔn)Avastin的擴(kuò)大適應(yīng)癥，即作為晚期結(jié)腸癌的二線治療藥物。 此前，Avastin+化療聯(lián)用已獲準(zhǔn)作為晚期結(jié)腸癌的一線治療藥。

人類基因知識突飛猛進(jìn)，令開發(fā)癌癥藥物的研究有大突破。三種由生物技術(shù)發(fā)展出來的抗癌新藥，專門對付體內(nèi)某種助長癌瘤生長擴(kuò)散的物質(zhì)，它們在消滅癌細(xì)胞的同時(shí)，并不損害健康細(xì)胞，因此比普通的化療高出一籌。其中最矚目的是治療直腸癌的新藥Avastin ，它能阻止癌瘤自制血管，使其無法吸收養(yǎng)分「餓死」。臨床測試證明，它將可用來治療晚期病人，令其生存率大增50 ％，平均壽命延長5 個(gè)月。研究結(jié)果本月初在美國臨床腫瘤學(xué)會(huì)年會(huì)上公布時(shí)，與會(huì)者都振奮地交頭接耳，因?yàn)樗麄冎肋@些研究成果的劃時(shí)*意義。 明報(bào)報(bào)道，在1970 年*，哈佛大學(xué)研究員福爾曼首次指出，癌癥腫瘤似乎能夠在人體內(nèi)自制新血管，供其吸取氧氣和養(yǎng)分之用，毒瘤藉此不斷擴(kuò)散，由一個(gè)器官擴(kuò)散至另一個(gè)器官，最終奪命。他因此推斷，廢去腫瘤制造血管的能力，使其「餓死」，便能減慢甚或停止腫瘤擴(kuò)散。 平均延長壽命5 個(gè)月 一直以來，科學(xué)家的研究皆不甚成功，直至最近，科學(xué)家終於以其理論制成新藥Avastin ，并首次以大規(guī)模臨床測試證實(shí)福爾曼的假設(shè)。Avastin 是一種蛋白質(zhì)，也是一種人造抗體，專門對付被某些癌瘤用來誘使血管形成的物質(zhì)。 令化療效果更快更持久 Avastin 的臨? 測試有800 人參與，在標(biāo)準(zhǔn)化療之外再服用Avastin 的結(jié)腸直腸癌（Colorectal cancer ）病人，證實(shí)比那些只接受化療的病人，在研究期間的生存機(jī)會(huì)高出一半。 要指出某療法是否有效的指標(biāo)繁多而復(fù)雜，不過一項(xiàng)令人易於理解的計(jì)算方法是有否令病人壽命延長，而Avastin 被發(fā)現(xiàn)令平均壽命由15.6 個(gè)月延長到20.3 個(gè)月?！都~約時(shí)報(bào)》說，若一種新抗癌藥能延長病人壽命兩三個(gè)月便等於成功，Avastin 延命5 個(gè)月，已超出期望。 參與臨床試驗(yàn)的加州大學(xué)三藩市分校胃腸腫瘤專家韋洛克說：你看到的是病人彷佛馬上受惠，在感覺上以及腫瘤負(fù)荷上都減輕了。我想它真的使化療效果加快，而且可能令效果更持久。 研究人員說，副作用基本上可以控制，只是會(huì)令許多病人血壓上升，這可用普通方法治療。Avastin 已顯示對乳癌效果不佳，但該公司正研究它對胰臟癌、前列腺癌、*巢癌和腎癌的效用。 可望明年推出市場 目前，多家生物技術(shù)公司共同研發(fā)出近10 種類似藥理的藥物，Avastin 被視為樣板，備受業(yè)界關(guān)注。由於臨? 測試結(jié)果理據(jù)充足，研發(fā)出Avastin 的美國著名基因工程公司Genentech 可能會(huì)在明年內(nèi)向美國食品及藥物管理局申請推出市場，而不像慣例那樣再作第二次大型研究。 另外兩種藥物，包括紐約生物科技制藥公司ImClone 研發(fā)的治療結(jié)腸直腸癌藥Erbitux ，以及AstraZeneca 公司的肺癌藥Iressa ，都是用以阻擋一種體內(nèi)分子，使其無法協(xié)助癌腫瘤發(fā)展起對化療的抵抗能力。臨? 實(shí)驗(yàn)都證實(shí)，它們能令瀕死病人的癌瘤縮小，只是尚未能如Avastin 那樣延長病人壽命。 癌癥醫(yī)生絕少說「治愈」，因?yàn)榘┌Y隨時(shí)都會(huì)復(fù)發(fā)，但現(xiàn)在很多醫(yī)生都希望，若把這兩三種目前世界上最先進(jìn)的抗癌藥物結(jié)合現(xiàn)有的化療方法，或能長久抑制腫瘤。因此醫(yī)學(xué)界都?xì)g呼，他們即將踏入治癌新紀(jì)元。專家相信，以深厚基因知識為基礎(chǔ)的療法，已開始有效對付各大癌癥殺手，例如肺癌、乳癌、直腸癌和前列腺癌等。 醫(yī)學(xué)界：標(biāo)志治癌新紀(jì)元 對癌病的臨床研究已有15 年的加州大學(xué)腫瘤專家韋洛克說：我向來對所謂研究進(jìn)展有保留，但也不得不說這是劃時(shí)*的。它令研究者、病人和生物醫(yī)藥公司而言都是一大鼓舞，真是令人興奮得不得了。

AVASTIN(Bevacizumab)英文說明書

U.S. BLA Amendment: Bevacizumab—Genentech, Inc.1 of 27: GNE_clean_PI_Feb_131.14.1.3 Labeling Text 1AVASTIN? 2(Bevacizumab) 3For Intravenous Use 4WARNINGS 5Gastrointestinal Perforations/Wound Healing Complications 6AVASTIN administration can result in the development of gastrointestinal 7perforation and wound dehiscence, in some instances resulting in fatality. 8Gastrointestinal perforation, sometimes associated with intra-abdominal 9abscess, occurred throughout treatment with AVASTIN (i.e., was not 10correlated to duration of exposure). The incidence of gastrointestinal 11perforation in patients receiving bolus-IFL with AVASTIN was 2%. The 12typical presentation was reported as abdominal pain associated with 13symptoms such as constipation and vomiting. Gastrointestinal perforation 14should be included in the differential diagnosis of patients presenting with 15abdominal pain on AVASTIN. AVASTIN therapy should be permanently 16discontinued in patients with gastrointestinal perforation or wound 17dehiscence requiring medical intervention. The appropriate interval 18between termination of AVASTIN and subsequent elective surgery 19required to avoid the risks of impaired wound healing/wound dehiscence 20has not been determined. (See WARNINGS: Gastrointestinal 21Perforations/Wound Healing Complications and DOSAGE AND 22ADMINISTRATION: Dose Modifications.) 23Hemorrhage 24Serious, and in some cases fatal, hemoptysis has occurred in patients with 25non–small cell lung cancer treated with chemotherapy and AVASTIN. In 26a small study, the incidence of serious or fatal hemoptysis was 31% in 27patients with squamous histology and 4% in patients with adenocarcinoma 28receiving AVASTIN as compared to no cases in patients treated with 29chemotherapy alone. Patients with recent hemoptysis should not receive 30AVASTIN. (See WARNINGS: Hemorrhage and DOSAGE AND 31ADMINISTRATION: Dose Modifications .) 32U.S. BLA Amendment: Bevacizumab—Genentech, Inc.2 of 27: GNE_clean_PI_Feb_13DESCRIPTION 33AVASTIN? (Bevacizumab) is a recombinant humanized monoclonal 34IgG1 antibody that binds to and inhibits the biologic activity of human 35vascular endothelial growth factor (VEGF) in in vitro and in vivo assay 36systems. Bevacizumab contains human framework regions and the 37complementarity-determining regions of a murine antibody that binds to 38VEGF (1). Bevacizumab is produced in a Chinese Hamster Ovary 39mammalian cell expression system in a nutrient medium containing the 40antibiotic gentamicin and has a molecular weight of approximately 41149 kilodaltons. AVASTIN is a clear to slightly opalescent, colorless to 42pale brown, sterile, pH 6.2 solution for intravenous (IV) infusion. 43AVASTIN is supplied in 100 mg and 400 mg preservative- free, single- use 44vials to deliver 4 mL or 16 mL of AVASTIN (25 mg/mL). The 100 mg 45product is formulated in 240 mg a,a-trehalose dihydrate, 23.2 mg sodium 46phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, 47anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 48400 mg product is formulated in 960 mg a,a-trehalose dihydrate, 92.8 mg 49sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate 50(dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, 51USP. 52CLINICAL PHARMACOLOGY 53Mechanism of Action 54Bevacizumab binds VEGF and prevents the interaction of VEGF to its 55receptors (Flt-1 and KDR) on the surface of endothelial cells. The 56interaction of VEGF with its receptors leads to endothelial cell 57proliferation and new blood vessel formation in in vitro models of 58angiogenesis. Administration of Bevacizumab to xenotransplant models 59of colon cancer in nude (athymic) mice caused reduction of microvascular 60growth and inhibition of metastatic disease progression. 61Pharmacokinetics 62The pharmacokinetic profile of Bevacizumab was assessed using an assay 63that measures total serum Bevacizumab concentrations (i.e., the assay did 64U.S. BLA Amendment: Bevacizumab—Genentech, Inc.3 of 27: GNE_clean_PI_Feb_13not distinguish between free Bevacizumab and Bevacizumab bound to 65VEGF ligand). Based on a population pharmacokinetic analysis of 66491 patients who received 1 to 20 mg/kg of AVASTIN weekly, every 672 weeks, or every 3 weeks, the estimated half-life of Bevacizumab was 68approximately 20 days (range 11-50 days). The predicted time to reach 69steady state was 100 days. The accumulation ratio following a dose of 7010 mg/kg of Bevacizumab every 2 weeks was 2.8. 71The clearance of Bevacizumab varied by body weight, by gender, and by 72tumor burden. After correcting for body weight, males had a higher 73Bevacizumab clearance (0.262 L/day vs. 0.207 L/day) and a larger Vc 74(3.25 L vs. 2.66 L) than females. Patients with higher tumor burden (at or 75above median value of tumor surface area) had a higher Bevacizumab 76clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens 77below the median. In a randomized study of 813 patients (Study 1), there 78was no evidence of lesser efficacy (hazard ratio for overall survival) in 79males or patients with higher tumor burden treated with AVASTIN as 80compared to females and patients with low tumor burden. The 81relationship between Bevacizumab exposure and clinical outcomes has not 82been explored. 83Special Populations 84Analyses of demographic data suggest that no dose adjustments are 85necessary for age or sex. 86Patients with renal impairment. No studies have been conducted to 87examine the pharmacokinetics of Bevacizumab in patients with renal 88impairment. 89Patients with hepatic dysfunction. No studies have been conducted to 90examine the pharmacokinetics of Bevacizumab in patients with hepatic 91impairment. 92U.S. BLA Amendment: Bevacizumab—Genentech, Inc.4 of 27: GNE_clean_PI_Feb_13CLINICAL STUDIES 93The safety and efficacy of AVASTIN in the initial treatment of patients 94with metastatic carcinoma of the colon and rectum were studied in two 95randomized, controlled clinical trials in combination with intravenous 965-fluorouracil–based chemotherapy. 97AVASTIN in Combination with Bolus-IFL 98Study 1 was a randomized, double-blind, active-controlled clinical trial 99evaluating AVASTIN as first- line treatment of metastatic carcinoma of the 100colon or rectum. Patients were randomized to bolus-IFL (irinotecan 101125 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV 102given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), 103bolus-IFL plus AVASTIN (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV 104plus AVASTIN (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 105was discontinued, as pre-specified, when the toxicity of AVASTIN in 106combination with the bolus-IFL regimen was deemed acceptable. 107Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 10840% were female, and 79% were Caucasian. Fifty-seven percent had an 109ECOG performance status of 0. Twenty-one percent had a rectal primary 110and 28% received prior adjuvant chemotherapy. In the majority of 111patients, 56%, the dominant site of disease was extra-abdominal, while the 112liver was the dominant site in 38% of patients. The patient characteristics 113were similar across the study arms. The primary endpoint of this trial was 114overall survival. Results are presented in Table 1 and Figure 1. 115U.S. BLA Amendment: Bevacizumab—Genentech, Inc.5 of 27: GNE_clean_PI_Feb_13Table 1Study 1 Efficacy ResultsIFL + PlaceboIFL + AVASTIN5 mg/kg q 2 wksNumber of Patients 411 402Overall SurvivalaMedian (months) 15.6 20.3Hazard ratio 0.66Progression-Free SurvivalaMedian (months) 6.4 10.6Hazard ratio 0.54Overall Response RatebRate (percent) 35% 45%Duration of ResponseMedian (months) 7.1 10.4a p < 0.001 by stratified logrank test.b p < 0.01 by c2 test.116Figure 1 117Duration of Survival in Study 1 118119Error bars represent 95% confidence intervals. 120The clinical benefit of AVASTIN, as measured by survival in the two 121principal arms, was seen in all subgroups tested. The subgroups examined 122U.S. BLA Amendment: Bevacizumab—Genentech, Inc.6 of 27: GNE_clean_PI_Feb_13were based on age, sex, race, ECOG performance status, location of 123primary tumor, prior adjuvant therapy, number of metastatic sites, and 124tumor burden. 125Among the 110 patients enrolled in Arm 3, median overall survival was 12618.3 months, median progression- free survival was 8.8 months, overall 127response rate was 39%, and median duration of response was 8.5 months. 128AVASTIN in Combination with 5-FU/LV Chemotherapy 129Study 2 was a randomized, active-controlled clinical trial testing 130AVASTIN in combination with 5-FU/LV as first- line treatment of 131metastatic colorectal cancer. Patients were randomized to receive 1325-FU/LV (5- fluorouracil 500 mg/m2, leucovorin 500 mg/m2 weekly for 1336 weeks every 8 weeks) or 5-FU/LV plus AVASTIN (5 mg/kg every 1342 weeks) or 5-FU/LV plus AVASTIN (10 mg/kg every 2 weeks). Patients 135were treated until disease progression. The primary endpoints of the trial 136were objective response rate and progression-free survival. Results are 137presented in Table 2. 138Table 2Study 2 Efficacy Results5-FU/LV5-FU/LV +AVASTIN5 mg/kg5-FU/LV +AVASTIN10 mg/kgNumber of Patients 36 35 33Overall SurvivalMedian (months) 13.6 17.7 15.2Progression-Free SurvivalMedian (months) 5.2 9.0 7.2Overall Response RateRate (percent) 17 40 24139Progression-free survival was significantly better in patients receiving 1405-FU/LV plus AVASTIN at 5 mg/kg when compared to those not 141receiving AVASTIN. However, overall survival and overall response rate 142U.S. BLA Amendment: Bevacizumab—Genentech, Inc.7 of 27: GNE_clean_PI_Feb_13were not significantly different. Outcomes for patients receiving 5-FU/LV 143plus AVASTIN at 10 mg/kg were not significantly different than for 144patients who did not receive AVASTIN. 145AVASTIN as a Single Agent 146The efficacy of AVASTIN as a single agent in colorectal cancer has not 147been established. However, in an ongoing, randomized study of patients 148with metastatic colorectal cancer that had progressed following a 1495-fluorouracil and irinotecan-based regimen, the arm in which patients 150were treated with single-agent AVASTIN was closed early due to 151evidence of an inferior survival in that arm as compared with patients 152treated with the FOLFOX regimen of 5-fluorouracil, leucovorin, and 153oxaliplatin. 154INDICATIONS AND USAGE 155AVASTIN, used in combination with intravenous 5- fluorouracil–based 156chemotherapy, is indicated for first- line treatment of patients with 157metastatic carcinoma of the colon or rectum. 158CONTRAINDICATIONS 159There are no known contraindications to the use of AVASTIN. 160WARNINGS 161Gastrointestinal Perforations/Wound Healing Complications 162(See DOSAGE AND ADMINISTRATION: Dose Modifications) 163Gastrointestinal perforation and wound dehiscence, complicated by 164intra-abdominal abscesses, occurred at an increased incidence in patients 165receiving AVASTIN as compared to controls. AVASTIN has also been 166shown to impair wound healing in pre-clinical animal models. 167In Study 1, one of 396 (0.3%) patients receiving bolus-IFL plus placebo, 168six of 392 (2%) patients receiving bolus-IFL plus AVASTlN, and four of 169109 (4%) patients receiving 5-FU/LV plus AVASTIN developed 170gastrointestinal perforation, in some instances with fatal outcome. These 171episodes occurred with or without intra-abdominal abscesses and at 172U.S. BLA Amendment: Bevacizumab—Genentech, Inc.8 of 27: GNE_clean_PI_Feb_13various time points during treatment. The typical presentation was 173reported as abdominal pain associated with symptoms such as constipation 174and vomiting. 175In addition, two of 396 (0.5%) patients receiving bolus-IFL plus placebo, 176four of 392 (1%) patients receiving bolus-IFL plus AVASTIN, and one of 177109 (1%) patients receiving 5-FU/LV plus AVASTIN developed a wound 178dehiscence during study treatment. 179The appropriate interval between surgery and subsequent initiation of 180AVASTIN required to avoid the risks of impaired wound healing has not 181been determined. In Study 1, the clinical protocol did not permit initiation 182of AVASTIN for at least 28 days following surgery. There was one 183patient (among 501 patients receiving AVASTIN on Study 1) in whom an 184anastomotic dehiscence occurred when AVASTIN was initiated per 185protocol. In this patient, the interval between surgery and initiation of 186AVASTIN was greater than 2 months. 187Similarly, the appropriate interval between termination of AVASTIN and 188subsequent elective surgery required to avoid the risks of impaired wound 189healing has not been determined. In Study 1, 39 patients who were 190receiving bolus-IFL plus AVASTIN underwent surgery following 191AVASTIN therapy and, of these patients, six (15%) had wound 192healing/bleeding complications. In the same study, 25 patients in the 193bolus-IFL arm underwent surgery and, of these patients, one of 25 (4%) 194had wound healing/bleeding complications. The longest interval between 195last dose of study drug and dehiscence was 56 days; this occurred in a 196patient on the bolus-IFL plus AVASTIN arm. The interval between 197termination of AVASTIN and subsequent elective surgery should take into 198consideration the calculated half-life of AVASTIN (approximately 19920 days). 200AVASTIN therapy should be discontinued in patients with gastrointestinal 201perforation or wound dehiscence requiring medical intervention. 202U.S. BLA Amendment: Bevacizumab—Genentech, Inc.9 of 27: GNE_clean_PI_Feb_13Hemorrhage (See DOSAGE AND ADMINISTRATION: Dose 203Modifications) 204Two distinct patterns of bleeding have occurred in patients receiving 205AVASTIN. The first is minor hemorrhage, most commonly Grade 1 206epistaxis. The second is serious, and in some cases fatal, hemorrhagic 207events. Serious hemorrhagic events occurred primarily in patients with 208non–small cell lung cancer, an indication for which AVASTIN is not 209approved. In a randomized study in patients with non-small cell lung 210cancer receiving chemotherapy with or without AVASTIN, four of 13 211(31%) AVASTIN-treated patients with squamous cell histology and two 212of 53 (4%) AVASTIN-treated patients with non-squamous histology 213experienced life-threatening or fatal pulmonary hemorrhage as compared 214to none of the 32 (0%) patients receiving chemotherapy alone. Of the 215patients experiencing events of life-threatening pulmonary hemorrhage, 216many had cavitation and/or necrosis of the tumor, either pre-existing or 217developing during AVASTIN therapy. These serious hemorrhagic events 218occurred suddenly and presented as major or massive hemoptysis. 219The risk of central nervous system (CNS) bleeding in patients with CNS 220metastases receiving AVASTIN has not been evaluated because these 221patients were excluded from Genentech-sponsored studies following 222development of CNS hemorrhage in a patient with a CNS metastasis in 223Phase 1 studies. 224Other serious bleeding events reported in patients receiving AVASTIN 225were uncommon and included gastrointestinal hemorrhage, subarachnoid 226hemorrhage, and hemorrhagic stroke. 227Patients with serious hemorrhage i.e., requiring medical intervention, 228should have AVASTIN treatment discontinued and receive aggressive 229medical management. Patients with recent hemoptysis should not receive 230AVASTIN. 231U.S. BLA Amendment: Bevacizumab—Genentech, Inc.10 of 27: GNE_clean_PI_Feb_13Hypertension (See DOSAGE AND ADMINISTRATION: Dose 232Modifications) 233The incidence of hypertension and severe hypertension was increased in 234patients receiving AVASTIN in Study 1 (see Table 3). 235Table 3Incidence of Hypertension and Severe Hypertension in Study 1Arm 1IFL + Placebo(n = 394)Arm 2IFL + AVASTIN(n = 392)Arm 35-FU/LV + AVASTIN(n = 109)Hypertensiona( > 150/100 mmHg)43% 60% 67%Severe Hypertensiona( > 200/110 mmHg)2% 7% 10%a This includes patients with either a systolic or diastolic reading greater than thecutoff value on one or more occasions.236Among patients with severe hypertension in the AVASTIN arms, slightly 237over half the patients (51%) had a diastolic reading greater than 110 238associated with a systolic reading less than 200. 239Medication classes used for management of patients with Grade 3 240hypertension receiving AVASTIN included angiotensin-converting 241enzyme inhibitors, beta blockers, diuretics, and calcium channel blockers. 242Four months after discontinuation of therapy, persistent hypertension was 243present in 18 of 26 patients that received bolus-IFL plus AVASTIN and 2448 of 10 patients that received bolus-IFL plus placebo. 245Across all clinical studies (n = 1032), development or worsening of 246hypertension resulted in hospitalization or discontinuation of AVASTIN in 24717 patients. Four of these 17 patients developed hypertensive 248encephalopathy. Severe hypertension was complicated by subarachnoid 249hemorrhage in one patient. 250U.S. BLA Amendment: Bevacizumab—Genentech, Inc.11 of 27: GNE_clean_PI_Feb_13AVASTIN should be permanently discontinued in patients with 251hypertensive crisis. Temporary suspension is recommended in patients 252with severe hypertension that is not controlled with medical management. 253Proteinuria (See DOSAGE AND ADMINISTRATION: Dose 254Modifications) 255In Study 1, both the incidence and severity of proteinuria (defined as a 256urine dipstick reading of 1+ or greater) was increased in patients receiving 257AVASTIN as compared to those receiving bolus-IFL plus placebo. 258Urinary dipstick readings of 2+ or greater occurred in 14% of patients 259receiving bolus-IFL plus placebo, 17% receiving bolus-IFL plus 260AVASTIN, and in 28% of patients receiving 5-FU/LV plus AVASTIN. 261Twenty- four–hour urine collections were obtained in patients with new 262onset or worsening proteinuria. None of the 118 patients receiving 263bolus-IFL plus placebo, three of 158 patients (2%) receiving 264bolus-IFL plus AVASTIN, and two of 50 (4%) patients receiving 2655-FU/LV plus AVASTIN who had a 24- hour collection experienced 266NCI-CTC Grade 3 proteinuria ( > 3.5 gm protein/24 hours). 267In a dose-ranging, placebo-controlled, randomized study of AVASTIN in 268patients with metastatic renal cell carcinoma, an indication for which 269AVASTIN is not approved, 24-hour urine collections were obtained in 270approximately half the patients enrolled. Among patients in whom 27124-hour urine collections were obtained, four of 19 (21%) patients 272receiving AVASTIN at 10 mg/kg every two weeks, two of 14 (14%) 273receiving AVASTIN at 3 mg/kg every two weeks, and none of the 27415 placebo patients experienced NCI-CTC Grade 3 proteinuria ( > 3.5 gm 275protein/24 hours). 276Nephrotic syndrome occurred in five of 1032 (0.5%) patients receiving 277AVASTIN in Genentech-sponsored studies. One patient died and one 278required dialysis. In three patients, proteinuria decreased in severity 279several months after discontinuation of AVASTIN. No patient had 280U.S. BLA Amendment: Bevacizumab—Genentech, Inc.12 of 27: GNE_clean_PI_Feb_13normalization of urinary protein levels (by 24-hour urine) following 281discontinuation of AVASTIN. 282AVASTIN should be discontinued in patients with nephrotic syndrome. 283The safety of continued AVASTIN treatment in patients with moderate to 284severe proteinuria has not been evaluated. In most clinical studies, 285AVASTIN was interrupted for 3 2 grams of proteinuria/24 hours and 286resumed when proteinuria was < 2 gm/24 hours. Patients with moderate 287to severe proteinuria based on 24-hour collections should be monitored 288regularly until improvement and/or resolution is observed. 289Congestive Heart Failure 290Congestive heart failure (CHF), defined as NCI-CTC Grade 2-4 left 291ventricular dysfunction, was reported in 22 of 1032 (2%) patients 292receiving AVASTIN in Genentech-sponsored studies. Congestive heart 293failure occurred in six of 44 (14%) patients receiving AVASTIN and 294concurrent anthracyclines. Congestive heart failure occurred in 13 of 299 295(4%) patients who received prior anthracyclines and/or left chest wall 296irradiation. In a controlled study, the incidence was higher in patients 297receiving AVASTIN plus chemotherapy as compared to patients receiving 298chemotherapy alone. The safety of continuation or resumption of 299AVASTIN in patients with cardiac dysfunction has not been studied. 300PRECAUTIONS 301General 302AVASTIN should be used with caution in patients with known 303hypersensitivity to AVASTIN or any component of this drug product. 304Infusion Reactions 305Infusion reactions with the first dose of AVASTIN were uncommon 306(< 3%). Severe reactions during the infusion of AVASTIN occurred in 307two patients. One patient developed stridor and wheezing during their 308first dose. A second patient, receiving paclitaxel followed by AVASTIN, 309developed a Grade 3 hypersensitivity reaction requiring hospitalization 310U.S. BLA Amendment: Bevacizumab—Genentech, Inc.13 of 27: GNE_clean_PI_Feb_13during their third infusion of AVASTIN. Both patients responded to 311medical management. Information on rechallenge is not available. 312AVASTIN infusion should be interrupted in all patients with severe 313infusion reactions and appropriate medical therapy administered. 314There are no data regarding the most appropriate method of identification 315of patients who may safely be retreated with AVASTIN after experiencing 316a severe infusion reaction. 317Surgery 318AVASTIN therapy should not be initiated for at least 28 days following 319major surgery. The surgical incision should be fully healed prior to 320initiation of AVASTIN. Because of the potential for impaired wound 321healing, AVASTIN should be suspended prior to elective surgery. The 322appropriate interval between the last dose of AVASTIN and elective 323surgery is unknown; however, the half- life of AVASTIN is estimated to be 32420 days (see CLINICAL PHARMACOLOGY: Pharmacokinetics) and 325the interval chosen should take into consideration the half- life of the drug. 326(See WARNINGS: Gastrointestinal Perforations/Wound Healing 327Complications.) 328Cardiovascular Disease 329Patients were excluded from participation in AVASTIN clinical trials if, in 330the previous year, they had experienced clinically significant 331cardiovascular disease. Thus, the safety of AVASTIN in patients with 332clinically significant cardiovascular disease has not been adequately 333evaluated. 334Immunogenicity 335As with all therapeutic proteins, there is a potential for immunogenicity. 336The incidence of antibody development in patients receiving AVASTIN 337has not been adequately determined because the assay sensitivity was 338inadequate to reliably detect lower titers. Enzyme-linked immunosorbant 339assays (ELISAs) were performed on sera from approximately 500 patients 340U.S. BLA Amendment: Bevacizumab—Genentech, Inc.14 of 27: GNE_clean_PI_Feb_13treated with AVASTIN, primarily in combination with chemotherapy. 341High titer human anti-AVASTIN antibodies were not detected. 342Immunogenicity data are highly dependent on the sensitivity and 343specificity of the assay. Additionally, the observed incidence of antibody 344positivity in an assay may be influenced by several factors, including 345sample handling, timing of sample collection, concomitant medications, 346and underlying disease. For these reasons, comparison of the incidence of 347antibodies to AVASTIN with the incidence of antibodies to other products 348may be misleading. 349Laboratory Tests 350Blood pressure monitoring should be conducted every two to three weeks 351during treatment with AVASTIN. Patients who develop hypertension on 352AVASTIN may require blood pressure monitoring at more frequent 353intervals. Patients with AVASTIN-induced or -exacerbated hypertension 354who discontinue AVASTIN should continue to have their blood pressure 355monitored at regular intervals. 356Patients receiving AVASTIN should be monitored for the development or 357worsening of proteinuria with serial urinalyses. Patients with a 2+ or 358greater urine dipstick reading should undergo further assessment, e.g., a 35924-hour urine collection. (See WARNINGS: Proteinuria and DOSAGE 360AND ADMINISTRATION: Dose Modifications.) 361Drug Interactions 362No formal drug interaction studies with anti-neoplastic agents have been 363conducted. In Study 1, patients with colorectal cancer were given 364irinotecan/5-FU/leucovorin (bolus-IFL) with or without AVASTIN. 365Irinotecan concentrations were similar in patients receiving bolus-IFL 366alone and in combination with AVAS TIN. The concentrations of SN38, 367the active metabolite of irinotecan, were on average 33% higher in patients 368receiving bolus-IFL in combination with AVASTIN when compared with 369bolus-IFL alone. In Study 1, patients receiving bolus-IFL plus AVASTIN 370U.S. BLA Amendment: Bevacizumab—Genentech, Inc.15 of 27: GNE_clean_PI_Feb_13had a higher incidence of Grade 3-4 diarrhea and neutropenia. Due to 371high inter-patient variability and limited sampling, the extent of the 372increase in SN38 levels in patients receiving concurrent irinotecan and 373AVASTIN is uncertain. 374Carcinogenesis, Mutagenesis, Impairment of Fertility 375No carcinogenicity data are available for AVASTIN in animals or 376humans. 377AVASTIN may impair fertility. Dose-related decreases in ovarian and 378uterine weights, endometrial proliferation, number of menstrual cycles, and 379arrested follicular development or absent corpora lutea were observed in 380female cynomolgus monkeys treated with 10 or 50 mg/kg of AVASTIN for 38113 or 26 weeks. Following a 4- or 12-week recovery period, which 382examined only the high–dose group, trends suggestive of reversibility were 383noted in the two females for each regimen that were assigned to recover. 384After the 12-week recovery period, follicular maturation arrest was no 385longer observed, but ovarian weights were still moderately decreased. 386Reduced endometrial proliferation was no longer observed at the 12-week 387recovery time point, but uterine weight decreases were still notable, 388corpora lutea were absent in 1 out of 2 animals, and the number of 389menstrual cycles remained reduced (67%). 390Pregnancy Category C 391AVASTIN has been shown to be teratogenic in rabbits when administered 392in doses that are two-fold greater than the recommended human dose on a 393mg/kg basis. Observed effects included decreases in maternal and fetal 394body weights, an increased number of fetal resorptions, and an increased 395incidence of specific gross and skeletal fetal alterations. Adverse fetal 396outcomes were observed at all doses tested. 397Angiogenesis is critical to fetal development and the inhibition of 398angiogenesis following administration of AVASTIN is likely to result in 399adverse effects on pregnancy. There are no adequate and well-controlled 400U.S. BLA Amendment: Bevacizumab—Genentech, Inc.16 of 27: GNE_clean_PI_Feb_13studies in pregnant women. AVASTIN should be used during pregnancy 401or in any woman not employing adequate contraception only if the 402potential benefit jus tifies the potential risk to the fetus. All patients should 403be counseled regarding the potential risk of AVASTIN to the developing 404fetus prior to initiation of therapy. If the patient becomes pregnant while 405receiving AVASTIN, she should be apprised of the potential hazard to the 406fetus and/or the potential risk of loss of pregnancy. Patients who 407discontinue AVASTIN should also be counseled concerning the prolonged 408exposure following discontinuation of therapy (half- life of approximately 40920 days) and the possible effects of AVASTIN on fetal development. 410Nursing Mothers 411It is not known whether AVASTIN is secreted in human milk. Because 412human IgG1 is secreted into human milk, the potential for absorption and 413harm to the infant after ingestion is unknown. Women should be advised 414to discontinue nursing during treatment with AVASTIN and for a 415prolonged period following the use of AVASTIN, taking into account the 416half- life of the product, approximately 20 days . (See 417CLINICAL PHARMACOLOGY: Pharmacokinetics.) 418Pediatric Use 419The safety and effectiveness of AVASTIN in pediatric patients has not 420been studied. However, physeal dysplasia was observed in juvenile 421cynomolgus monkeys with open growth plates treated for four weeks with 422doses that were less than the recommended human dose based on mg/kg 423and exposure. The incidence and severity of physeal dysplasia were 424dose-related and were at least partially reversible upon cessation of 425treatment. 426Geriatric Use 427In Study 1, NCI-CTC Grade 3-4 adverse eve nts were collected in all 428patients receiving study drug (396 bolus-IFL plus placebo; 392 bolus-IFL 429plus AVASTIN; 109 5-FU/LV plus AVASTIN), while NCI-CTC Grade 1 430and 2 adverse events were collected in a subset of 309 patients. There 431U.S. BLA Amendment: Bevacizumab—Genentech, Inc.17 of 27: GNE_clean_PI_Feb_13were insufficient numb ers of patients 65 years and older in the subset in 432which Grade 1-4 adverse events were collected to determine whether the 433overall adverse event profile was different in the elderly as compared to 434younger patients. Among the 392 patients receiving bolus-IFL plus 435AVASTIN, 126 were at least 65 years of age. Severe adverse events that 436occurred at a higher incidence ( 3 2%) in the elderly when compared to 437those less than 65 years were asthenia, sepsis, deep thrombophlebitis, 438hypertension, hypotension, myocardial infarction, congestive heart failure, 439diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, 440hypokalemia, and hyponatremia. The effect of AVASTIN on overall 441survival was similar in elderly patients as compared to younger patients. 442Of the 742 patients enrolled in Genentech-sponsored clinical studies in 443which all adverse events were captured, 212 (29%) were age 65 or older 444and 43 (6%) were age 75 or older. Adverse events of any severity that 445occurred at a higher incidence in the elderly as compared to younger 446patients, in addition to those described above, were dyspepsia, 447gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice 448alteration. 449ADVERSE EVENTS 450The most serious adverse events associated with AVASTIN were: 451· Gastrointestinal Perforations/Wound Healing Complications (see 452WARNINGS) 453· Hemorrhage (see WARNINGS) 454· Hypertensive Crises (see WARNINGS) 455· Nephrotic Syndrome (see WARNINGS) 456· Congestive Heart Failure (see WARNINGS) 457The most common severe (NCI-CTC Grade 3-4) adverse events among 4581032 patients receiving AVASTIN in Genentech-sponsored studies were 459asthenia, pain, hypertension, diarrhea, and leukopenia. 460U.S. BLA Amendment: Bevacizumab—Genentech, Inc.18 of 27: GNE_clean_PI_Feb_13The most common adverse events of any severity among the 742 patients 461receiving AVASTIN in Genentech-sponsored studies were asthenia, pain, 462abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, 463anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, 464dyspnea, exfoliative dermatitis, and proteinuria. 465Because clinical trials are conducted under widely varying conditions, 466adverse reaction rates observed in the clinical trials of a drug cannot be 467directly compared to rates in the clinical trials of another drug and may not 468reflect the rates observed in practice. The adverse reaction information 469from clinical trials does, however, provide a basis for identifying the 470adverse events that appear to be related to drug use and for approximating 471rates. 472A total of 1032 patients with metastatic colorectal cancer (n = 568) and 473with other cancers (n = 464) received AVASTIN either as a single agent 474(n = 157) or in combination with chemotherapy (n = 875) in 475Genentech-sponsored clinical trials. All adverse events were collected in 476742 of the 1032 patients; for the remaining 290, all NCI-CTC Grade 3 477and 4 adverse events and only selected Grade 1 and 2 adverse events 478(hypertension, proteinuria, thromboembolic events) were collected. 479Adverse events across all Genentech-sponsored studies were used to 480further characterize specific adverse events. (See WARNINGS: 481Hemorrhage, Hypertension, Proteinuria, Congestive Heart Failure 482and PRECAUTIONS: Geriatric Use.) 483Comparative data on adverse experiences, except where indicated, are 484limited to Study 1, a randomized, active-controlled study in 897 patients 485receiving initial treatment for metastatic colorectal cancer. All NCI-CTC 486Grade 3 and 4 adverse events and selected Grade 1 and 2 adverse events 487(hypertension, proteinuria, thromboembolic events) were reported for the 488overall study population. In Study 1, the median age was 60, 60% were 489male, 78% had colon primary lesion, and 29% had prior adjuvant or 490neoadjuvant chemotherapy. The median duration of exposure to 491U.S. BLA Amendment: Bevacizumab—Genentech, Inc.19 of 27: GNE_clean_PI_Feb_13AVASTIN in Study 1 was 8 months in Arm 2 and 7 months in Arm 3. All 492adverse events, including all NCI-CTC Grade 1 and 2 events, were 493reported in a subset of 309 patients. The baseline entry characteristics in 494the 309 patient safety subset were similar to the overall study population 495and well-balanced across the three study arms. 496Severe and life-threatening (NCI-CTC Grade 3 and 4) adverse events, 497which occurred at a higher incidence ( 3 2%) in patients receiving 498bolus-IFL plus AVASTIN as compared to bolus-IFL plus placebo, are 499presented in Table 4. 500Table 4NCI-CTC Grade 3 and 4 Adverse Events in Study 1(Occurring at Higher Incidence (3 2%) in AVASTIN vs. Control)Arm 1IFL + Placebo(n = 396)Arm 2IFL + AVASTIN(n = 392)Grade 3-4 Events 295 (74%) 340 (87%)Body as a WholeAsthenia 28 (7%) 38 (10%)Abdominal Pain 20 (5%) 32 (8%)Pain 21 (5%) 30 (8%)CardiovascularDeep Vein Thrombosis 19 (5%) 34 (9%)Hypertension 10 (2%) 46 (12%)Intra-Abdominal Thrombosis 5 (1%) 13 (3%)Syncope 4 (1%) 11 (3%)DigestiveDiarrhea 99 (25%) 133 (34%)Constipation 9 (2%) 14 (4%)Hemic/LymphaticLeukopenia 122 (31%) 145 (37%)Neutropeniaa 41 (14%) 58 (21%)a Central laboratories were collected on Days 1 and 21 of each cycle.Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.501U.S. BLA Amendment: Bevacizumab—Genentech, Inc.20 of 27: GNE_clean_PI_Feb_13Adverse events of any severity, which occurred at a higher incidence 502( 3 5%) in the initial phase of the study in patients receiving AVASTIN 503(bolus-IFL plus AVASTIN or 5-FU/LV plus AVASTIN) as compared to 504the bolus-IFL plus placebo arm, are presented in Table 5. 505U.S. BLA Amendment: Bevacizumab—Genentech, Inc.21 of 27: GNE_clean_PI_Feb_13Table 5NCI-CTC Grade 1-4 Adverse Events in Study 1 Subset(Occurring at Higher Incidence (3 5%) in AVASTIN vs. Control)Arm 1IFL + Placebo(n = 98)Arm 2IFL + AVASTIN(n = 102)Arm 35-FU/LV + AVASTIN(n = 109)Body as a WholeAsthenia 68 (70%) 75 (74%) 80 (73%)Pain 54 (55%) 62 (61%) 67 (62%)Abdominal Pain 54 (55%) 62 (61%) 55 (50%)Headache 19 (19%) 27 (26%) 30 (26%)CardiovascularHypertension 14 (14%) 23 (23%) 37 (34%)Hypotension 7 (7%) 15 (15%) 8 (7%)Deep Vein Thrombosis 3 (3%) 9 (9%) 6 (6%)DigestiveVomiting 46 (47%) 53 (52%) 51 (47%)Anorexia 29 (30%) 44 (43%) 38 (35%)Constipation 28 (29%) 41 (40%) 32 (29%)Stomatitis 18 (18%) 33 (32%) 33 (30%)Dyspepsia 15 (15%) 25 (24%) 19 (17%)Weight Loss 10 (10%) 15 (15%) 18 (16%)Flatulence 10 (10%) 11 (11%) 21 (19%)GI Hemorrhage 6 (6%) 25 (24%) 21 (19%)Dry Mouth 2 (2%) 7 (7%) 4 (4%)Colitis 1 (1%) 6 (6%) 1 (1%)Hemic/LymphaticThrombocytopenia 0 5 (5%) 5 (5%)Metabolic/NutritionHypokalemia 11 (11%) 12 (12%) 18 (16%)Bilirubinemia 0 1 (1%) 7 (6%)MusculoskeletalMyalgia 7 (7%) 8 (8%) 16 (15%)NervousDizziness 20 (20%) 27 (26%) 21 (19%)Confusion 1 (1%) 1 (1%) 6 (6%)Abnormal Gait 0 1 (1%) 5 (5%)506U.S. BLA Amendment: Bevacizumab—Genentech, Inc.22 of 27: GNE_clean_PI_Feb_13Table 5 (cont’d)NCI-CTC Grade 1-4 Adverse Events in Study 1 SubsetArm 1IFL + Placebo(n = 98)Arm 2IFL + AVASTIN(n = 102)Arm 35-FU/LV + AVASTIN(n = 109)RespiratoryUpper Respiratory Infection 38 (39%) 48 (47%) 44 (40%)Dyspnea 15 (15%) 26 (26%) 27 (25%)Epistaxis 10 (10%) 36 (35%) 35 (32%)Voice Alteration 2 (2%) 9 (9%) 6 (6%)Skin/AppendagesAlopecia 25 (26%) 33 (32%) 6 (6%)Dry Skin 7 (7%) 7 (7%) 22 (20%)Exfoliative Dermatitis 3 (3%) 3 (3%) 21 (19%)Nail Disorder 3 (3%) 2 (2%) 9 (8%)Skin Discoloration 3 (3%) 2 (2%) 17 (16%)Skin Ulcer 1 (1%) 6 (6%) 7 (6%)Special SensesTaste Disorder 9 (9%) 14 (14%) 23 (21%)Excess Lacrimation 2 (2%) 6 (6%) 20 (18%)UrogenitalProteinuria 24 (24%) 37 (36%) 39 (36%)Urinary Frequency/Urgency 1 (1%) 3 (3%) 6 (6%)507Mucocutaneous Hemorrhage 508In Study 1, both serious and non-serious hemorrhagic events occurred at a 509higher incidence in patients receiving AVASTIN. (See WARNINGS: 510Hemorrhage.) In the 309 patients in which Grade 1-4 events were 511collected, epistaxis was common and reported in 35% of patients receiving 512bolus-IFL plus AVASTIN compared with 10% of patients receiving 513bolus-IFL plus placebo. These events were generally mild in severity 514(NCI-CTC Grade 1) and resolved without medical intervention. Other 515mild to moderate hemorrhagic events reported more frequently in patients 516receiving bolus-IFL plus AVASTIN when compared to those receiving 517bolus-IFL plus placebo included gastrointestinal hemorrhage (24% vs. 518U.S. BLA Amendment: Bevacizumab—Genentech, Inc.23 of 27: GNE_clean_PI_Feb_136%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 5192%). 520Thromboembolism 521In Study 1, 18% of patients receiving bolus-IFL plus AVASTIN and 15% 522of patients receiving bolus-IFL plus placebo experienced a Grade 3-4 523thromboembolic event. The incidence of the following Grade 3 and 4 524thromboembolic events were higher in patients receiving bolus-IFL plus 525AVASTIN as compared to patients receiving bolus-IFL plus placebo: 526cerebrovascular events (4 vs. 0 patients), myocardial infarction (6 vs. 3), 527deep venous thrombosis (34 vs. 19), and intra-abdominal thrombosis (13 528vs. 5). In contrast, the incidence of pulmonary embolism was higher in 529patients receiving bolus-IFL plus placebo (16 vs. 20). 530In Study 1, 53 of 392 (14%) patients who received bolus-IFL plus 531AVASTIN and 30 of 396 (8%) patients who received bolus-IFL plus 532placebo had a thromboembolic event and received full-dose warfarin. 533Two patients in each treatment arm (four total) developed bleeding 534complications. In the two patients treated with full-dose warfarin and 535AVASTIN, these events were associated with marked elevations in their 536INR. Eleven of 53 (21%) patients receiving bolus-IFL plus AVASTIN 537and one of 30 (3%) patients receiving bolus-IFL developed an additional 538thromboembolic event. 539Other Serious Adverse Events 540The following other serious adverse events are considered unusual in 541cancer patients receiving cytotoxic chemotherapy and occurred in at least 542one subject treated with AVASTIN in clinical studies. 543Body as a Whole: polyserositis 544Digestive: intestinal obstruction, intestinal necrosis, mesenteric venous 545occlusion, anastomotic ulceration 546Hemic and lymphatic: pancytopenia 547Metabolic and nutritional disorders: hyponatremia. 548U.S. BLA Amendment: Bevacizumab—Genentech, Inc.24 of 27: GNE_clean_PI_Feb_13Urogenital: ureteral stricture 549OVERDOSAGE 550The maximum tolerated dose of AVASTIN has not been determined. The 551highest dose tested in humans (20 mg/kg IV) was associated with 552headache in nine of 16 patients and with severe headache in three of 55316 patients. 554DOSAGE AND ADMINISTRATION 555The recommended dose of AVASTIN is 5 mg/kg given once every 55614 days as an IV infusion until disease progression is detected. 557AVASTIN therapy should not be initiated for at least 28 days following 558major surgery. The surgical incision should be fully healed prior to 559initiation of AVASTIN. 560Dose Modifications 561There are no recommended dose reductions for the use of AVASTIN. If 562needed, AVASTIN should be either discontinued or temporarily 563suspended as described below. 564AVASTIN should be permanently discontinued in patients who develop 565gastrointestinal perforation, wound dehiscence requiring medical 566intervention, serious bleeding, nephrotic syndrome, or hypertensive crisis. 567Temporary suspension of AVASTIN is recommended in patients with 568evidence of moderate to severe proteinuria pending further evaluation and 569in patients with severe hypertension that is not controlled with medical 570management. The risk of continuation or temporary suspension of 571AVASTIN in patients with moderate to severe proteinuria is unknown. 572AVASTIN should be suspended at least several weeks prior to elective 573surgery. (See WARNINGS: Gastrointestinal Perforation/Wound 574Healing Complications and PRECAUTIONS: Surgery.) AVASTIN 575should not be resumed until the surgical incision is fully healed. 576U.S. BLA Amendment: Bevacizumab—Genentech, Inc.25 of 27: GNE_clean_PI_Feb_13Preparation for Administration 577AVASTIN should be diluted for infusion by a healthcare professional 578using aseptic technique. Withdraw the necessary amount of AVASTIN 579for a dose of 5 mg/kg and dilute in a total volume of 100 mL of 0.9% 580Sodium Chloride Injection, USP. Discard any unused portion left in a 581vial, as the product contains no preservatives. Parenteral drug products 582should be inspected visually for particulate matter and discoloration prior 583to administration. 584Diluted AVASTIN solutions for infusion may be stored at 2-8°C 585(36-46°F) for up to 8 hours. No incompatibilities between AVASTIN and 586polyvinylchloride or polyolefin bags have been observed. 587AVASTIN infusions should not be administered or mixed with 588dextrose solutions. 589Administration 590DO NOT ADMINISTER AS AN IV PUSH OR BOLUS. The initial 591AVASTIN dose should be delivered over 90 minutes as an IV infusion 592following chemotherapy. If the first infusion is well tolerated, the second 593infusion may be administered over 60 minutes. If the 60- minute infusion 594is well tolerated, all subsequent infusions may be administered over 59530 minutes. 596Stability and Storage 597AVASTIN vials must be refrigerated at 2-8°C (36-46°F). AVASTIN 598vials should be protected from light. Store in the original carton until time 599of use. DO NOT FREEZE. DO NOT SHAKE. 600HOW SUPPLIED 601AVASTIN is supplied as 4 mL and 16 mL of a sterile solution in single– 602use glass vials to deliver 100 and 400 mg of Bevacizumab per vial, 603respectively. 604U.S. BLA Amendment: Bevacizumab—Genentech, Inc.26 of 27: GNE_clean_PI_Feb_13Single unit 100 mg carton: Contains one 4 mL vial of AVASTIN 605(25 mg/mL). NDC 50242-060-01 606Single unit 400 mg carton: Contains one 16 mL vial of AVASTIN 607(25 mg/mL). NDC 50242-060-02 608U.S. BLA Amendment: Bevacizumab—Genentech, Inc.27 of 27: GNE_clean_PI_Feb_13REFERENCES 6091. Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, 610Krummen L, et al. Humanization of an anti- vascular endothelial 611growth factor monoclonal antibody for the therapy of solid tumors 612and other disorders. Cancer Res 1997;57:4593-9. 613614AVASTIN?(Bevacizumab)For Intravenous UseManufactured by:Genentech, Inc.1 DNA WaySouth San Francisco, CA 94080-4990G#####-R0February 2004ó2004 Genentech, Inc.615