Avastin—是一種抑制腫瘤血管生成的藥物,在乳腺癌和結(jié)腸癌治療中取得滿意的效果(2004年2月26日美國(guó)上市)

來(lái)源：新特藥房藥訊作者：百濟(jì) 瀏覽：發(fā)布時(shí)間：2004/5/1

治療直腸癌的新藥Avastin




2003-12-23
人類(lèi)基因知識(shí)突飛猛進(jìn)，令開(kāi)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(lái)的抗癌新藥，專(zhuān)門(mén)對(duì)付體內(nèi)某種助長(zhǎng)癌瘤生長(zhǎng)擴(kuò)散的物質(zhì)，它們?cè)谙麥绨┘?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(wú)法吸收養(yǎng)分「餓死」。臨床測(cè)試證明，它將可用來(lái)治療晚期病人，令其生存率大增50 ％，平均壽命延長(zhǎng)5 個(gè)月。研究結(jié)果本月初在美國(guó)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)代意義。　　明報(bào)報(bào)道，在1970 年代，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(zhǎng)壽命5 個(gè)月　　一直以來(lái)，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(cè)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(zhuān)門(mén)對(duì)付被某些癌瘤用來(lái)誘使血管形成的物質(zhì)。　　令化療效果更快更持久　　Avastin 的臨? 測(cè)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(guò)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(zhǎng)，而Avastin 被發(fā)現(xiàn)令平均壽命由15.6 個(gè)月延長(zhǎng)到20.3 個(gè)月。《紐約時(shí)報(bào)》說(shuō)，若一種新抗癌藥能延長(zhǎng)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(zhuān)家韋洛克說(shuō)：你看到的是病人彷佛馬上受惠，在感覺(jué)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(shuō)，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(duì)乳癌效果不佳，但該公司正研究它對(duì)胰臟癌、前列腺癌、卵巢癌和腎癌的效用。可望明年推出市場(chǎng) 　　目前，多家生物技術(shù)公司共同研發(fā)出近10 種類(lèi)似藥理的藥物，Avastin 被視為樣板，備受業(yè)界關(guān)注。由於臨? 測(cè)試結(jié)果理?yè)?jù)充足，研發(fā)出Avastin 的美國(guó)著名基因工程公司Genentech 可能會(huì)在明年內(nèi)向美國(guó)食品及藥物管理局申請(qǐng)推出市場(chǎng)，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(wú)法協(xié)助癌腫瘤發(fā)展起對(duì)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(zhǎng)病人壽命。癌癥醫(yī)生絕少說(shuō)「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(zhǎng)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(zhuān)家相信，以深厚基因知識(shí)為基礎(chǔ)的療法，已開(kāi)始有效對(duì)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(duì)癌病的臨床研究已有15 年的加州大學(xué)腫瘤專(zhuān)家韋洛克說(shuō)：我向來(lái)對(duì)所謂研究進(jìn)展有保留，但也不得不說(shuō)這是劃時(shí)代的。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(shuō)明書(shū) U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 1 of 27: GNE_clean_PI_Feb_13 1.14.1.3 Labeling Text 1 AVASTIN™ 2 (Bevacizumab) 3 For Intravenous Use 4 WARNINGS 5 Gastrointestinal Perforations/Wound Healing Complications 6 AVASTIN administration can result in the development of gastrointestinal 7 perforation and wound dehiscence, in some instances resulting in fatality. 8 Gastrointestinal perforation, sometimes associated with intra-abdominal 9 abscess, occurred throughout treatment with AVASTIN (i.e., was not 10 correlated to duration of exposure). The incidence of gastrointestinal 11 perforation in patients receiving bolus-IFL with AVASTIN was 2%. The 12 typical presentation was reported as abdominal pain associated with 13 symptoms such as constipation and vomiting. Gastrointestinal perforation 14 should be included in the differential diagnosis of patients presenting with 15 abdominal pain on AVASTIN. AVASTIN therapy should be permanently 16 discontinued in patients with gastrointestinal perforation or wound 17 dehiscence requiring medical intervention. The appropriate interval 18 between termination of AVASTIN and subsequent elective surgery 19 required to avoid the risks of impaired wound healing/wound dehiscence 20 has not been determined. (See WARNINGS: Gastrointestinal 21 Perforations/Wound Healing Complications and DOSAGE AND 22 ADMINISTRATION: Dose Modifications.) 23 Hemorrhage 24 Serious, and in some cases fatal, hemoptysis has occurred in patients with 25 non–small cell lung cancer treated with chemotherapy and AVASTIN. In 26 a small study, the incidence of serious or fatal hemoptysis was 31% in 27 patients with squamous histology and 4% in patients with adenocarcinoma 28 receiving AVASTIN as compared to no cases in patients treated with 29 chemotherapy alone. Patients with recent hemoptysis should not receive 30 AVASTIN. (See WARNINGS: Hemorrhage and DOSAGE AND 31 ADMINISTRATION: Dose Modifications .) 32 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 2 of 27: GNE_clean_PI_Feb_13 DESCRIPTION 33 AVASTINä (Bevacizumab) is a recombinant humanized monoclonal 34 IgG1 antibody that binds to and inhibits the biologic activity of human 35 vascular endothelial growth factor (VEGF) in in vitro and in vivo assay 36 systems. Bevacizumab contains human framework regions and the 37 complementarity-determining regions of a murine antibody that binds to 38 VEGF (1). Bevacizumab is produced in a Chinese Hamster Ovary 39 mammalian cell expression system in a nutrient medium containing the 40 antibiotic gentamicin and has a molecular weight of approximately 41 149 kilodaltons. AVASTIN is a clear to slightly opalescent, colorless to 42 pale brown, sterile, pH 6.2 solution for intravenous (IV) infusion. 43 AVASTIN is supplied in 100 mg and 400 mg preservative- free, single- use 44 vials to deliver 4 mL or 16 mL of AVASTIN (25 mg/mL). The 100 mg 45 product is formulated in 240 mg a,a-trehalose dihydrate, 23.2 mg sodium 46 phosphate (monobasic, monohydrate), 4.8 mg sodium phosphate (dibasic, 47 anhydrous), 1.6 mg polysorbate 20, and Water for Injection, USP. The 48 400 mg product is formulated in 960 mg a,a-trehalose dihydrate, 92.8 mg 49 sodium phosphate (monobasic, monohydrate), 19.2 mg sodium phosphate 50 (dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, 51 USP. 52 CLINICAL PHARMACOLOGY 53 Mechanism of Action 54 Bevacizumab binds VEGF and prevents the interaction of VEGF to its 55 receptors (Flt-1 and KDR) on the surface of endothelial cells. The 56 interaction of VEGF with its receptors leads to endothelial cell 57 proliferation and new blood vessel formation in in vitro models of 58 angiogenesis. Administration of Bevacizumab to xenotransplant models 59 of colon cancer in nude (athymic) mice caused reduction of microvascular 60 growth and inhibition of metastatic disease progression. 61 Pharmacokinetics 62 The pharmacokinetic profile of Bevacizumab was assessed using an assay 63 that measures total serum Bevacizumab concentrations (i.e., the assay did 64 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 3 of 27: GNE_clean_PI_Feb_13 not distinguish between free Bevacizumab and Bevacizumab bound to 65 VEGF ligand). Based on a population pharmacokinetic analysis of 66 491 patients who received 1 to 20 mg/kg of AVASTIN weekly, every 67 2 weeks, or every 3 weeks, the estimated half-life of Bevacizumab was 68 approximately 20 days (range 11-50 days). The predicted time to reach 69 steady state was 100 days. The accumulation ratio following a dose of 70 10 mg/kg of Bevacizumab every 2 weeks was 2.8. 71 The clearance of Bevacizumab varied by body weight, by gender, and by 72 tumor burden. After correcting for body weight, males had a higher 73 Bevacizumab 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 75 above median value of tumor surface area) had a higher Bevacizumab 76 clearance (0.249 L/day vs. 0.199 L/day) than patients with tumor burdens 77 below the median. In a randomized study of 813 patients (Study 1), there 78 was no evidence of lesser efficacy (hazard ratio for overall survival) in 79 males or patients with higher tumor burden treated with AVASTIN as 80 compared to females and patients with low tumor burden. The 81 relationship between Bevacizumab exposure and clinical outcomes has not 82 been explored. 83 Special Populations 84 Analyses of demographic data suggest that no dose adjustments are 85 necessary for age or sex. 86 Patients with renal impairment. No studies have been conducted to 87 examine the pharmacokinetics of Bevacizumab in patients with renal 88 impairment. 89 Patients with hepatic dysfunction. No studies have been conducted to 90 examine the pharmacokinetics of Bevacizumab in patients with hepatic 91 impairment. 92 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 4 of 27: GNE_clean_PI_Feb_13 CLINICAL STUDIES 93 The safety and efficacy of AVASTIN in the initial treatment of patients 94 with metastatic carcinoma of the colon and rectum were studied in two 95 randomized, controlled clinical trials in combination with intravenous 96 5-fluorouracil–based chemotherapy. 97 AVASTIN in Combination with Bolus-IFL 98 Study 1 was a randomized, double-blind, active-controlled clinical trial 99 evaluating AVASTIN as first- line treatment of metastatic carcinoma of the 100 colon or rectum. Patients were randomized to bolus-IFL (irinotecan 101 125 mg/m2 IV, 5-fluorouracil 500 mg/m2 IV, and leucovorin 20 mg/m2 IV 102 given once weekly for 4 weeks every 6 weeks) plus placebo (Arm 1), 103 bolus-IFL plus AVASTIN (5 mg/kg every 2 weeks) (Arm 2), or 5-FU/LV 104 plus AVASTIN (5 mg/kg every 2 weeks) (Arm 3). Enrollment in Arm 3 105 was discontinued, as pre-specified, when the toxicity of AVASTIN in 106 combination with the bolus-IFL regimen was deemed acceptable. 107 Of the 813 patients randomized to Arms 1 and 2, the median age was 60, 108 40% were female, and 79% were Caucasian. Fifty-seven percent had an 109 ECOG performance status of 0. Twenty-one percent had a rectal primary 110 and 28% received prior adjuvant chemotherapy. In the majority of 111 patients, 56%, the dominant site of disease was extra-abdominal, while the 112 liver was the dominant site in 38% of patients. The patient characteristics 113 were similar across the study arms. The primary endpoint of this trial was 114 overall survival. Results are presented in Table 1 and Figure 1. 115 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 5 of 27: GNE_clean_PI_Feb_13 Table 1 Study 1 Efficacy Results IFL + Placebo IFL + AVASTIN 5 mg/kg q 2 wks Number of Patients 411 402 Overall Survivala Median (months) 15.6 20.3 Hazard ratio 0.66 Progression-Free Survivala Median (months) 6.4 10.6 Hazard ratio 0.54 Overall Response Rateb Rate (percent) 35% 45% Duration of Response Median (months) 7.1 10.4 a p < 0.001 by stratified logrank test. b p < 0.01 by c2 test. 116 Figure 1 117 Duration of Survival in Study 1 118 119 Error bars represent 95% confidence intervals. 120 The clinical benefit of AVASTIN, as measured by survival in the two 121 principal arms, was seen in all subgroups tested. The subgroups examined 122 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 6 of 27: GNE_clean_PI_Feb_13 were based on age, sex, race, ECOG performance status, location of 123 primary tumor, prior adjuvant therapy, number of metastatic sites, and 124 tumor burden. 125 Among the 110 patients enrolled in Arm 3, median overall survival was 126 18.3 months, median progression- free survival was 8.8 months, overall 127 response rate was 39%, and median duration of response was 8.5 months. 128 AVASTIN in Combination with 5-FU/LV Chemotherapy 129 Study 2 was a randomized, active-controlled clinical trial testing 130 AVASTIN in combination with 5-FU/LV as first- line treatment of 131 metastatic colorectal cancer. Patients were randomized to receive 132 5-FU/LV (5- fluorouracil 500 mg/m2, leucovorin 500 mg/m2 weekly for 133 6 weeks every 8 weeks) or 5-FU/LV plus AVASTIN (5 mg/kg every 134 2 weeks) or 5-FU/LV plus AVASTIN (10 mg/kg every 2 weeks). Patients 135 were treated until disease progression. The primary endpoints of the trial 136 were objective response rate and progression-free survival. Results are 137 presented in Table 2. 138 Table 2 Study 2 Efficacy Results 5-FU/LV 5-FU/LV + AVASTIN 5 mg/kg 5-FU/LV + AVASTIN 10 mg/kg Number of Patients 36 35 33 Overall Survival Median (months) 13.6 17.7 15.2 Progression-Free Survival Median (months) 5.2 9.0 7.2 Overall Response Rate Rate (percent) 17 40 24 139 Progression-free survival was significantly better in patients receiving 140 5-FU/LV plus AVASTIN at 5 mg/kg when compared to those not 141 receiving AVASTIN. However, overall survival and overall response rate 142 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 7 of 27: GNE_clean_PI_Feb_13 were not significantly different. Outcomes for patients receiving 5-FU/LV 143 plus AVASTIN at 10 mg/kg were not significantly different than for 144 patients who did not receive AVASTIN. 145 AVASTIN as a Single Agent 146 The efficacy of AVASTIN as a single agent in colorectal cancer has not 147 been established. However, in an ongoing, randomized study of patients 148 with metastatic colorectal cancer that had progressed following a 149 5-fluorouracil and irinotecan-based regimen, the arm in which patients 150 were treated with single-agent AVASTIN was closed early due to 151 evidence of an inferior survival in that arm as compared with patients 152 treated with the FOLFOX regimen of 5-fluorouracil, leucovorin, and 153 oxaliplatin. 154 INDICATIONS AND USAGE 155 AVASTIN, used in combination with intravenous 5- fluorouracil–based 156 chemotherapy, is indicated for first- line treatment of patients with 157 metastatic carcinoma of the colon or rectum. 158 CONTRAINDICATIONS 159 There are no known contraindications to the use of AVASTIN. 160 WARNINGS 161 Gastrointestinal Perforations/Wound Healing Complications 162 (See DOSAGE AND ADMINISTRATION: Dose Modifications) 163 Gastrointestinal perforation and wound dehiscence, complicated by 164 intra-abdominal abscesses, occurred at an increased incidence in patients 165 receiving AVASTIN as compared to controls. AVASTIN has also been 166 shown to impair wound healing in pre-clinical animal models. 167 In Study 1, one of 396 (0.3%) patients receiving bolus-IFL plus placebo, 168 six of 392 (2%) patients receiving bolus-IFL plus AVASTlN, and four of 169 109 (4%) patients receiving 5-FU/LV plus AVASTIN developed 170 gastrointestinal perforation, in some instances with fatal outcome. These 171 episodes occurred with or without intra-abdominal abscesses and at 172 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 8 of 27: GNE_clean_PI_Feb_13 various time points during treatment. The typical presentation was 173 reported as abdominal pain associated with symptoms such as constipation 174 and vomiting. 175 In addition, two of 396 (0.5%) patients receiving bolus-IFL plus placebo, 176 four of 392 (1%) patients receiving bolus-IFL plus AVASTIN, and one of 177 109 (1%) patients receiving 5-FU/LV plus AVASTIN developed a wound 178 dehiscence during study treatment. 179 The appropriate interval between surgery and subsequent initiation of 180 AVASTIN required to avoid the risks of impaired wound healing has not 181 been determined. In Study 1, the clinical protocol did not permit initiation 182 of AVASTIN for at least 28 days following surgery. There was one 183 patient (among 501 patients receiving AVASTIN on Study 1) in whom an 184 anastomotic dehiscence occurred when AVASTIN was initiated per 185 protocol. In this patient, the interval between surgery and initiation of 186 AVASTIN was greater than 2 months. 187 Similarly, the appropriate interval between termination of AVASTIN and 188 subsequent elective surgery required to avoid the risks of impaired wound 189 healing has not been determined. In Study 1, 39 patients who were 190 receiving bolus-IFL plus AVASTIN underwent surgery following 191 AVASTIN therapy and, of these patients, six (15%) had wound 192 healing/bleeding complications. In the same study, 25 patients in the 193 bolus-IFL arm underwent surgery and, of these patients, one of 25 (4%) 194 had wound healing/bleeding complications. The longest interval between 195 last dose of study drug and dehiscence was 56 days; this occurred in a 196 patient on the bolus-IFL plus AVASTIN arm. The interval between 197 termination of AVASTIN and subsequent elective surgery should take into 198 consideration the calculated half-life of AVASTIN (approximately 199 20 days). 200 AVASTIN therapy should be discontinued in patients with gastrointestinal 201 perforation or wound dehiscence requiring medical intervention. 202 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 9 of 27: GNE_clean_PI_Feb_13 Hemorrhage (See DOSAGE AND ADMINISTRATION: Dose 203 Modifications) 204 Two distinct patterns of bleeding have occurred in patients receiving 205 AVASTIN. The first is minor hemorrhage, most commonly Grade 1 206 epistaxis. The second is serious, and in some cases fatal, hemorrhagic 207 events. Serious hemorrhagic events occurred primarily in patients with 208 non–small cell lung cancer, an indication for which AVASTIN is not 209 approved. In a randomized study in patients with non-small cell lung 210 cancer receiving chemotherapy with or without AVASTIN, four of 13 211 (31%) AVASTIN-treated patients with squamous cell histology and two 212 of 53 (4%) AVASTIN-treated patients with non-squamous histology 213 experienced life-threatening or fatal pulmonary hemorrhage as compared 214 to none of the 32 (0%) patients receiving chemotherapy alone. Of the 215 patients experiencing events of life-threatening pulmonary hemorrhage, 216 many had cavitation and/or necrosis of the tumor, either pre-existing or 217 developing during AVASTIN therapy. These serious hemorrhagic events 218 occurred suddenly and presented as major or massive hemoptysis. 219 The risk of central nervous system (CNS) bleeding in patients with CNS 220 metastases receiving AVASTIN has not been evaluated because these 221 patients were excluded from Genentech-sponsored studies following 222 development of CNS hemorrhage in a patient with a CNS metastasis in 223 Phase 1 studies. 224 Other serious bleeding events reported in patients receiving AVASTIN 225 were uncommon and included gastrointestinal hemorrhage, subarachnoid 226 hemorrhage, and hemorrhagic stroke. 227 Patients with serious hemorrhage i.e., requiring medical intervention, 228 should have AVASTIN treatment discontinued and receive aggressive 229 medical management. Patients with recent hemoptysis should not receive 230 AVASTIN. 231 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 10 of 27: GNE_clean_PI_Feb_13 Hypertension (See DOSAGE AND ADMINISTRATION: Dose 232 Modifications) 233 The incidence of hypertension and severe hypertension was increased in 234 patients receiving AVASTIN in Study 1 (see Table 3). 235 Table 3 Incidence of Hypertension and Severe Hypertension in Study 1 Arm 1 IFL + Placebo (n = 394) Arm 2 IFL + AVASTIN (n = 392) Arm 3 5-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 the cutoff value on one or more occasions. 236 Among patients with severe hypertension in the AVASTIN arms, slightly 237 over half the patients (51%) had a diastolic reading greater than 110 238 associated with a systolic reading less than 200. 239 Medication classes used for management of patients with Grade 3 240 hypertension receiving AVASTIN included angiotensin-converting 241 enzyme inhibitors, beta blockers, diuretics, and calcium channel blockers. 242 Four months after discontinuation of therapy, persistent hypertension was 243 present in 18 of 26 patients that received bolus-IFL plus AVASTIN and 244 8 of 10 patients that received bolus-IFL plus placebo. 245 Across all clinical studies (n = 1032), development or worsening of 246 hypertension resulted in hospitalization or discontinuation of AVASTIN in 247 17 patients. Four of these 17 patients developed hypertensive 248 encephalopathy. Severe hypertension was complicated by subarachnoid 249 hemorrhage in one patient. 250 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 11 of 27: GNE_clean_PI_Feb_13 AVASTIN should be permanently discontinued in patients with 251 hypertensive crisis. Temporary suspension is recommended in patients 252 with severe hypertension that is not controlled with medical management. 253 Proteinuria (See DOSAGE AND ADMINISTRATION: Dose 254 Modifications) 255 In Study 1, both the incidence and severity of proteinuria (defined as a 256 urine dipstick reading of 1+ or greater) was increased in patients receiving 257 AVASTIN as compared to those receiving bolus-IFL plus placebo. 258 Urinary dipstick readings of 2+ or greater occurred in 14% of patients 259 receiving bolus-IFL plus placebo, 17% receiving bolus-IFL plus 260 AVASTIN, and in 28% of patients receiving 5-FU/LV plus AVASTIN. 261 Twenty- four–hour urine collections were obtained in patients with new 262 onset or worsening proteinuria. None of the 118 patients receiving 263 bolus-IFL plus placebo, three of 158 patients (2%) receiving 264 bolus-IFL plus AVASTIN, and two of 50 (4%) patients receiving 265 5-FU/LV plus AVASTIN who had a 24- hour collection experienced 266 NCI-CTC Grade 3 proteinuria ( > 3.5 gm protein/24 hours). 267 In a dose-ranging, placebo-controlled, randomized study of AVASTIN in 268 patients with metastatic renal cell carcinoma, an indication for which 269 AVASTIN is not approved, 24-hour urine collections were obtained in 270 approximately half the patients enrolled. Among patients in whom 271 24-hour urine collections were obtained, four of 19 (21%) patients 272 receiving AVASTIN at 10 mg/kg every two weeks, two of 14 (14%) 273 receiving AVASTIN at 3 mg/kg every two weeks, and none of the 274 15 placebo patients experienced NCI-CTC Grade 3 proteinuria ( > 3.5 gm 275 protein/24 hours). 276 Nephrotic syndrome occurred in five of 1032 (0.5%) patients receiving 277 AVASTIN in Genentech-sponsored studies. One patient died and one 278 required dialysis. In three patients, proteinuria decreased in severity 279 several months after discontinuation of AVASTIN. No patient had 280 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 12 of 27: GNE_clean_PI_Feb_13 normalization of urinary protein levels (by 24-hour urine) following 281 discontinuation of AVASTIN. 282 AVASTIN should be discontinued in patients with nephrotic syndrome. 283 The safety of continued AVASTIN treatment in patients with moderate to 284 severe proteinuria has not been evaluated. In most clinical studies, 285 AVASTIN was interrupted for ³ 2 grams of proteinuria/24 hours and 286 resumed when proteinuria was < 2 gm/24 hours. Patients with moderate 287 to severe proteinuria based on 24-hour collections should be monitored 288 regularly until improvement and/or resolution is observed. 289 Congestive Heart Failure 290 Congestive heart failure (CHF), defined as NCI-CTC Grade 2-4 left 291 ventricular dysfunction, was reported in 22 of 1032 (2%) patients 292 receiving AVASTIN in Genentech-sponsored studies. Congestive heart 293 failure occurred in six of 44 (14%) patients receiving AVASTIN and 294 concurrent anthracyclines. Congestive heart failure occurred in 13 of 299 295 (4%) patients who received prior anthracyclines and/or left chest wall 296 irradiation. In a controlled study, the incidence was higher in patients 297 receiving AVASTIN plus chemotherapy as compared to patients receiving 298 chemotherapy alone. The safety of continuation or resumption of 299 AVASTIN in patients with cardiac dysfunction has not been studied. 300 PRECAUTIONS 301 General 302 AVASTIN should be used with caution in patients with known 303 hypersensitivity to AVASTIN or any component of this drug product. 304 Infusion Reactions 305 Infusion reactions with the first dose of AVASTIN were uncommon 306 (< 3%). Severe reactions during the infusion of AVASTIN occurred in 307 two patients. One patient developed stridor and wheezing during their 308 first dose. A second patient, receiving paclitaxel followed by AVASTIN, 309 developed a Grade 3 hypersensitivity reaction requiring hospitalization 310 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 13 of 27: GNE_clean_PI_Feb_13 during their third infusion of AVASTIN. Both patients responded to 311 medical management. Information on rechallenge is not available. 312 AVASTIN infusion should be interrupted in all patients with severe 313 infusion reactions and appropriate medical therapy administered. 314 There are no data regarding the most appropriate method of identification 315 of patients who may safely be retreated with AVASTIN after experiencing 316 a severe infusion reaction. 317 Surgery 318 AVASTIN therapy should not be initiated for at least 28 days following 319 major surgery. The surgical incision should be fully healed prior to 320 initiation of AVASTIN. Because of the potential for impaired wound 321 healing, AVASTIN should be suspended prior to elective surgery. The 322 appropriate interval between the last dose of AVASTIN and elective 323 surgery is unknown; however, the half- life of AVASTIN is estimated to be 324 20 days (see CLINICAL PHARMACOLOGY: Pharmacokinetics) and 325 the interval chosen should take into consideration the half- life of the drug. 326 (See WARNINGS: Gastrointestinal Perforations/Wound Healing 327 Complications.) 328 Cardiovascular Disease 329 Patients were excluded from participation in AVASTIN clinical trials if, in 330 the previous year, they had experienced clinically significant 331 cardiovascular disease. Thus, the safety of AVASTIN in patients with 332 clinically significant cardiovascular disease has not been adequately 333 evaluated. 334 Immunogenicity 335 As with all therapeutic proteins, there is a potential for immunogenicity. 336 The incidence of antibody development in patients receiving AVASTIN 337 has not been adequately determined because the assay sensitivity was 338 inadequate to reliably detect lower titers. Enzyme-linked immunosorbant 339 assays (ELISAs) were performed on sera from approximately 500 patients 340 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 14 of 27: GNE_clean_PI_Feb_13 treated with AVASTIN, primarily in combination with chemotherapy. 341 High titer human anti-AVASTIN antibodies were not detected. 342 Immunogenicity data are highly dependent on the sensitivity and 343 specificity of the assay. Additionally, the observed incidence of antibody 344 positivity in an assay may be influenced by several factors, including 345 sample handling, timing of sample collection, concomitant medications, 346 and underlying disease. For these reasons, comparison of the incidence of 347 antibodies to AVASTIN with the incidence of antibodies to other products 348 may be misleading. 349 Laboratory Tests 350 Blood pressure monitoring should be conducted every two to three weeks 351 during treatment with AVASTIN. Patients who develop hypertension on 352 AVASTIN may require blood pressure monitoring at more frequent 353 intervals. Patients with AVASTIN-induced or -exacerbated hypertension 354 who discontinue AVASTIN should continue to have their blood pressure 355 monitored at regular intervals. 356 Patients receiving AVASTIN should be monitored for the development or 357 worsening of proteinuria with serial urinalyses. Patients with a 2+ or 358 greater urine dipstick reading should undergo further assessment, e.g., a 359 24-hour urine collection. (See WARNINGS: Proteinuria and DOSAGE 360 AND ADMINISTRATION: Dose Modifications.) 361 Drug Interactions 362 No formal drug interaction studies with anti-neoplastic agents have been 363 conducted. In Study 1, patients with colorectal cancer were given 364 irinotecan/5-FU/leucovorin (bolus-IFL) with or without AVASTIN. 365 Irinotecan concentrations were similar in patients receiving bolus-IFL 366 alone and in combination with AVAS TIN. The concentrations of SN38, 367 the active metabolite of irinotecan, were on average 33% higher in patients 368 receiving bolus-IFL in combination with AVASTIN when compared with 369 bolus-IFL alone. In Study 1, patients receiving bolus-IFL plus AVASTIN 370 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 15 of 27: GNE_clean_PI_Feb_13 had a higher incidence of Grade 3-4 diarrhea and neutropenia. Due to 371 high inter-patient variability and limited sampling, the extent of the 372 increase in SN38 levels in patients receiving concurrent irinotecan and 373 AVASTIN is uncertain. 374 Carcinogenesis, Mutagenesis, Impairment of Fertility 375 No carcinogenicity data are available for AVASTIN in animals or 376 humans. 377 AVASTIN may impair fertility. Dose-related decreases in ovarian and 378 uterine weights, endometrial proliferation, number of menstrual cycles, and 379 arrested follicular development or absent corpora lutea were observed in 380 female cynomolgus monkeys treated with 10 or 50 mg/kg of AVASTIN for 381 13 or 26 weeks. Following a 4- or 12-week recovery period, which 382 examined only the high–dose group, trends suggestive of reversibility were 383 noted in the two females for each regimen that were assigned to recover. 384 After the 12-week recovery period, follicular maturation arrest was no 385 longer observed, but ovarian weights were still moderately decreased. 386 Reduced endometrial proliferation was no longer observed at the 12-week 387 recovery time point, but uterine weight decreases were still notable, 388 corpora lutea were absent in 1 out of 2 animals, and the number of 389 menstrual cycles remained reduced (67%). 390 Pregnancy Category C 391 AVASTIN has been shown to be teratogenic in rabbits when administered 392 in doses that are two-fold greater than the recommended human dose on a 393 mg/kg basis. Observed effects included decreases in maternal and fetal 394 body weights, an increased number of fetal resorptions, and an increased 395 incidence of specific gross and skeletal fetal alterations. Adverse fetal 396 outcomes were observed at all doses tested. 397 Angiogenesis is critical to fetal development and the inhibition of 398 angiogenesis following administration of AVASTIN is likely to result in 399 adverse effects on pregnancy. There are no adequate and well-controlled 400 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 16 of 27: GNE_clean_PI_Feb_13 studies in pregnant women. AVASTIN should be used during pregnancy 401 or in any woman not employing adequate contraception only if the 402 potential benefit jus tifies the potential risk to the fetus. All patients should 403 be counseled regarding the potential risk of AVASTIN to the developing 404 fetus prior to initiation of therapy. If the patient becomes pregnant while 405 receiving AVASTIN, she should be apprised of the potential hazard to the 406 fetus and/or the potential risk of loss of pregnancy. Patients who 407 discontinue AVASTIN should also be counseled concerning the prolonged 408 exposure following discontinuation of therapy (half- life of approximately 409 20 days) and the possible effects of AVASTIN on fetal development. 410 Nursing Mothers 411 It is not known whether AVASTIN is secreted in human milk. Because 412 human IgG1 is secreted into human milk, the potential for absorption and 413 harm to the infant after ingestion is unknown. Women should be advised 414 to discontinue nursing during treatment with AVASTIN and for a 415 prolonged period following the use of AVASTIN, taking into account the 416 half- life of the product, approximately 20 days . (See 417 CLINICAL PHARMACOLOGY: Pharmacokinetics.) 418 Pediatric Use 419 The safety and effectiveness of AVASTIN in pediatric patients has not 420 been studied. However, physeal dysplasia was observed in juvenile 421 cynomolgus monkeys with open growth plates treated for four weeks with 422 doses that were less than the recommended human dose based on mg/kg 423 and exposure. The incidence and severity of physeal dysplasia were 424 dose-related and were at least partially reversible upon cessation of 425 treatment. 426 Geriatric Use 427 In Study 1, NCI-CTC Grade 3-4 adverse eve nts were collected in all 428 patients receiving study drug (396 bolus-IFL plus placebo; 392 bolus-IFL 429 plus AVASTIN; 109 5-FU/LV plus AVASTIN), while NCI-CTC Grade 1 430 and 2 adverse events were collected in a subset of 309 patients. There 431 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 17 of 27: GNE_clean_PI_Feb_13 were insufficient numb ers of patients 65 years and older in the subset in 432 which Grade 1-4 adverse events were collected to determine whether the 433 overall adverse event profile was different in the elderly as compared to 434 younger patients. Among the 392 patients receiving bolus-IFL plus 435 AVASTIN, 126 were at least 65 years of age. Severe adverse events that 436 occurred at a higher incidence ( ³ 2%) in the elderly when compared to 437 those less than 65 years were asthenia, sepsis, deep thrombophlebitis, 438 hypertension, hypotension, myocardial infarction, congestive heart failure, 439 diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, 440 hypokalemia, and hyponatremia. The effect of AVASTIN on overall 441 survival was similar in elderly patients as compared to younger patients. 442 Of the 742 patients enrolled in Genentech-sponsored clinical studies in 443 which all adverse events were captured, 212 (29%) were age 65 or older 444 and 43 (6%) were age 75 or older. Adverse events of any severity that 445 occurred at a higher incidence in the elderly as compared to younger 446 patients, in addition to those described above, were dyspepsia, 447 gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice 448 alteration. 449 ADVERSE EVENTS 450 The most serious adverse events associated with AVASTIN were: 451 · Gastrointestinal Perforations/Wound Healing Complications (see 452 WARNINGS) 453 · Hemorrhage (see WARNINGS) 454 · Hypertensive Crises (see WARNINGS) 455 · Nephrotic Syndrome (see WARNINGS) 456 · Congestive Heart Failure (see WARNINGS) 457 The most common severe (NCI-CTC Grade 3-4) adverse events among 458 1032 patients receiving AVASTIN in Genentech-sponsored studies were 459 asthenia, pain, hypertension, diarrhea, and leukopenia. 460 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 18 of 27: GNE_clean_PI_Feb_13 The most common adverse events of any severity among the 742 patients 461 receiving AVASTIN in Genentech-sponsored studies were asthenia, pain, 462 abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, 463 anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, 464 dyspnea, exfoliative dermatitis, and proteinuria. 465 Because clinical trials are conducted under widely varying conditions, 466 adverse reaction rates observed in the clinical trials of a drug cannot be 467 directly compared to rates in the clinical trials of another drug and may not 468 reflect the rates observed in practice. The adverse reaction information 469 from clinical trials does, however, provide a basis for identifying the 470 adverse events that appear to be related to drug use and for approximating 471 rates. 472 A total of 1032 patients with metastatic colorectal cancer (n = 568) and 473 with other cancers (n = 464) received AVASTIN either as a single agent 474 (n = 157) or in combination with chemotherapy (n = 875) in 475 Genentech-sponsored clinical trials. All adverse events were collected in 476 742 of the 1032 patients; for the remaining 290, all NCI-CTC Grade 3 477 and 4 adverse events and only selected Grade 1 and 2 adverse events 478 (hypertension, proteinuria, thromboembolic events) were collected. 479 Adverse events across all Genentech-sponsored studies were used to 480 further characterize specific adverse events. (See WARNINGS: 481 Hemorrhage, Hypertension, Proteinuria, Congestive Heart Failure 482 and PRECAUTIONS: Geriatric Use.) 483 Comparative data on adverse experiences, except where indicated, are 484 limited to Study 1, a randomized, active-controlled study in 897 patients 485 receiving initial treatment for metastatic colorectal cancer. All NCI-CTC 486 Grade 3 and 4 adverse events and selected Grade 1 and 2 adverse events 487 (hypertension, proteinuria, thromboembolic events) were reported for the 488 overall study population. In Study 1, the median age was 60, 60% were 489 male, 78% had colon primary lesion, and 29% had prior adjuvant or 490 neoadjuvant chemotherapy. The median duration of exposure to 491 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 19 of 27: GNE_clean_PI_Feb_13 AVASTIN in Study 1 was 8 months in Arm 2 and 7 months in Arm 3. All 492 adverse events, including all NCI-CTC Grade 1 and 2 events, were 493 reported in a subset of 309 patients. The baseline entry characteristics in 494 the 309 patient safety subset were similar to the overall study population 495 and well-balanced across the three study arms. 496 Severe and life-threatening (NCI-CTC Grade 3 and 4) adverse events, 497 which occurred at a higher incidence ( ³ 2%) in patients receiving 498 bolus-IFL plus AVASTIN as compared to bolus-IFL plus placebo, are 499 presented in Table 4. 500 Table 4 NCI-CTC Grade 3 and 4 Adverse Events in Study 1 (Occurring at Higher Incidence (³ 2%) in AVASTIN vs. Control) Arm 1 IFL + Placebo (n = 396) Arm 2 IFL + AVASTIN (n = 392) Grade 3-4 Events 295 (74%) 340 (87%) Body as a Whole Asthenia 28 (7%) 38 (10%) Abdominal Pain 20 (5%) 32 (8%) Pain 21 (5%) 30 (8%) Cardiovascular Deep Vein Thrombosis 19 (5%) 34 (9%) Hypertension 10 (2%) 46 (12%) Intra-Abdominal Thrombosis 5 (1%) 13 (3%) Syncope 4 (1%) 11 (3%) Digestive Diarrhea 99 (25%) 133 (34%) Constipation 9 (2%) 14 (4%) Hemic/Lymphatic Leukopenia 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. 501 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 20 of 27: GNE_clean_PI_Feb_13 Adverse 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 504 the bolus-IFL plus placebo arm, are presented in Table 5. 505 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 21 of 27: GNE_clean_PI_Feb_13 Table 5 NCI-CTC Grade 1-4 Adverse Events in Study 1 Subset (Occurring at Higher Incidence (³ 5%) in AVASTIN vs. Control) Arm 1 IFL + Placebo (n = 98) Arm 2 IFL + AVASTIN (n = 102) Arm 3 5-FU/LV + AVASTIN (n = 109) Body as a Whole Asthenia 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%) Cardiovascular Hypertension 14 (14%) 23 (23%) 37 (34%) Hypotension 7 (7%) 15 (15%) 8 (7%) Deep Vein Thrombosis 3 (3%) 9 (9%) 6 (6%) Digestive Vomiting 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/Lymphatic Thrombocytopenia 0 5 (5%) 5 (5%) Metabolic/Nutrition Hypokalemia 11 (11%) 12 (12%) 18 (16%) Bilirubinemia 0 1 (1%) 7 (6%) Musculoskeletal Myalgia 7 (7%) 8 (8%) 16 (15%) Nervous Dizziness 20 (20%) 27 (26%) 21 (19%) Confusion 1 (1%) 1 (1%) 6 (6%) Abnormal Gait 0 1 (1%) 5 (5%) 506 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 22 of 27: GNE_clean_PI_Feb_13 Table 5 (cont’d) NCI-CTC Grade 1-4 Adverse Events in Study 1 Subset Arm 1 IFL + Placebo (n = 98) Arm 2 IFL + AVASTIN (n = 102) Arm 3 5-FU/LV + AVASTIN (n = 109) Respiratory Upper 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/Appendages Alopecia 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 Senses Taste Disorder 9 (9%) 14 (14%) 23 (21%) Excess Lacrimation 2 (2%) 6 (6%) 20 (18%) Urogenital Proteinuria 24 (24%) 37 (36%) 39 (36%) Urinary Frequency/Urgency 1 (1%) 3 (3%) 6 (6%) 507 Mucocutaneous Hemorrhage 508 In Study 1, both serious and non-serious hemorrhagic events occurred at a 509 higher incidence in patients receiving AVASTIN. (See WARNINGS: 510 Hemorrhage.) In the 309 patients in which Grade 1-4 events were 511 collected, epistaxis was common and reported in 35% of patients receiving 512 bolus-IFL plus AVASTIN compared with 10% of patients receiving 513 bolus-IFL plus placebo. These events were generally mild in severity 514 (NCI-CTC Grade 1) and resolved without medical intervention. Other 515 mild to moderate hemorrhagic events reported more frequently in patients 516 receiving bolus-IFL plus AVASTIN when compared to those receiving 517 bolus-IFL plus placebo included gastrointestinal hemorrhage (24% vs. 518 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 23 of 27: GNE_clean_PI_Feb_13 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 519 2%). 520 Thromboembolism 521 In Study 1, 18% of patients receiving bolus-IFL plus AVASTIN and 15% 522 of patients receiving bolus-IFL plus placebo experienced a Grade 3-4 523 thromboembolic event. The incidence of the following Grade 3 and 4 524 thromboembolic events were higher in patients receiving bolus-IFL plus 525 AVASTIN as compared to patients receiving bolus-IFL plus placebo: 526 cerebrovascular events (4 vs. 0 patients), myocardial infarction (6 vs. 3), 527 deep venous thrombosis (34 vs. 19), and intra-abdominal thrombosis (13 528 vs. 5). In contrast, the incidence of pulmonary embolism was higher in 529 patients receiving bolus-IFL plus placebo (16 vs. 20). 530 In Study 1, 53 of 392 (14%) patients who received bolus-IFL plus 531 AVASTIN and 30 of 396 (8%) patients who received bolus-IFL plus 532 placebo had a thromboembolic event and received full-dose warfarin. 533 Two patients in each treatment arm (four total) developed bleeding 534 complications. In the two patients treated with full-dose warfarin and 535 AVASTIN, these events were associated with marked elevations in their 536 INR. Eleven of 53 (21%) patients receiving bolus-IFL plus AVASTIN 537 and one of 30 (3%) patients receiving bolus-IFL developed an additional 538 thromboembolic event. 539 Other Serious Adverse Events 540 The following other serious adverse events are considered unusual in 541 cancer patients receiving cytotoxic chemotherapy and occurred in at least 542 one subject treated with AVASTIN in clinical studies. 543 Body as a Whole: polyserositis 544 Digestive: intestinal obstruction, intestinal necrosis, mesenteric venous 545 occlusion, anastomotic ulceration 546 Hemic and lymphatic: pancytopenia 547 Metabolic and nutritional disorders: hyponatremia. 548 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 24 of 27: GNE_clean_PI_Feb_13 Urogenital: ureteral stricture 549 OVERDOSAGE 550 The maximum tolerated dose of AVASTIN has not been determined. The 551 highest dose tested in humans (20 mg/kg IV) was associated with 552 headache in nine of 16 patients and with severe headache in three of 553 16 patients. 554 DOSAGE AND ADMINISTRATION 555 The recommended dose of AVASTIN is 5 mg/kg given once every 556 14 days as an IV infusion until disease progression is detected. 557 AVASTIN therapy should not be initiated for at least 28 days following 558 major surgery. The surgical incision should be fully healed prior to 559 initiation of AVASTIN. 560 Dose Modifications 561 There are no recommended dose reductions for the use of AVASTIN. If 562 needed, AVASTIN should be either discontinued or temporarily 563 suspended as described below. 564 AVASTIN should be permanently discontinued in patients who develop 565 gastrointestinal perforation, wound dehiscence requiring medical 566 intervention, serious bleeding, nephrotic syndrome, or hypertensive crisis. 567 Temporary suspension of AVASTIN is recommended in patients with 568 evidence of moderate to severe proteinuria pending further evaluation and 569 in patients with severe hypertension that is not controlled with medical 570 management. The risk of continuation or temporary suspension of 571 AVASTIN in patients with moderate to severe proteinuria is unknown. 572 AVASTIN should be suspended at least several weeks prior to elective 573 surgery. (See WARNINGS: Gastrointestinal Perforation/Wound 574 Healing Complications and PRECAUTIONS: Surgery.) AVASTIN 575 should not be resumed until the surgical incision is fully healed. 576 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 25 of 27: GNE_clean_PI_Feb_13 Preparation for Administration 577 AVASTIN should be diluted for infusion by a healthcare professional 578 using aseptic technique. Withdraw the necessary amount of AVASTIN 579 for a dose of 5 mg/kg and dilute in a total volume of 100 mL of 0.9% 580 Sodium Chloride Injection, USP. Discard any unused portion left in a 581 vial, as the product contains no preservatives. Parenteral drug products 582 should be inspected visually for particulate matter and discoloration prior 583 to administration. 584 Diluted 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 586 polyvinylchloride or polyolefin bags have been observed. 587 AVASTIN infusions should not be administered or mixed with 588 dextrose solutions. 589 Administration 590 DO NOT ADMINISTER AS AN IV PUSH OR BOLUS. The initial 591 AVASTIN dose should be delivered over 90 minutes as an IV infusion 592 following chemotherapy. If the first infusion is well tolerated, the second 593 infusion may be administered over 60 minutes. If the 60- minute infusion 594 is well tolerated, all subsequent infusions may be administered over 595 30 minutes. 596 Stability and Storage 597 AVASTIN vials must be refrigerated at 2-8°C (36-46°F). AVASTIN 598 vials should be protected from light. Store in the original carton until time 599 of use. DO NOT FREEZE. DO NOT SHAKE. 600 HOW SUPPLIED 601 AVASTIN is supplied as 4 mL and 16 mL of a sterile solution in single– 602 use glass vials to deliver 100 and 400 mg of Bevacizumab per vial, 603 respectively. 604 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 26 of 27: GNE_clean_PI_Feb_13 Single unit 100 mg carton: Contains one 4 mL vial of AVASTIN 605 (25 mg/mL). NDC 50242-060-01 606 Single unit 400 mg carton: Contains one 16 mL vial of AVASTIN 607 (25 mg/mL). NDC 50242-060-02 608 U.S. BLA Amendment: Bevacizumab—Genentech, Inc. 27 of 27: GNE_clean_PI_Feb_13 REFERENCES 609 1. Presta LG, Chen H, O’Connor SJ, Chisholm V, Meng YG, 610 Krummen L, et al. Humanization of an anti- vascular endothelial 611 growth factor monoclonal antibody for the therapy of solid tumors 612 and other disorders. Cancer Res 1997;57:4593-9. 613 614 AVASTIN™ (Bevacizumab) For Intravenous Use Manufactured by: Genentech, Inc. 1 DNA Way South San Francisco, CA 94080-4990 G#####-R0 February 2004 Ó2004 Genentech, Inc. 615