Avastin

导读：疗直肠癌的新药Avastin

治疗直肠癌的新药Avastin 2003-12-23 　　人类基因知识突飞猛进，令开发癌症药物的研究有大突破。三种由生物技术发展出来的抗癌新药，专门对付体内某种助长癌瘤生长扩散的物质，它们在消灭癌细胞的同时，并不损害健康细胞，因此比普通的化疗高出一筹。其中最瞩目的是治疗直肠癌的新药Avastin ，它能阻止癌瘤自制血管，使其无法吸收养分「饿死」。临床测试证明，它将可用来治疗晚期病人，令其生存率大增50 ％，平均寿命延长5 个月。研究结果本月初在美国临床肿瘤学会年会上公布时，与会者都振奋地交头接耳，因为他们知道这些研究成果的划时代意义。

　　明报报道，在1970 年代，哈佛大学研究员福尔曼首次指出，癌症肿瘤似乎能够在人体内自制新血管，供其吸取氧气和养分之用，毒瘤藉此不断扩散，由一个器官扩散至另一个器官，最终夺命。他因此推断，废去肿瘤制造血管的能力，使其「饿死」，便能减慢甚或停止肿瘤扩散。

　　平均延长寿命5 个月
　　一直以来，科学家的研究皆不甚成功，直至最近，科学家终於以其理论制成新药Avastin ，并首次以大规模临床测试证实福尔曼的假设。Avastin 是一种蛋白质，也是一种人造抗体，专门对付被某些癌瘤用来诱使血管形成的物质。

　　令化疗效果更快更持久
　　Avastin 的临? 测试有800 人参与，在标准化疗之外再服用Avastin 的结肠直肠癌（Colorectal cancer ）病人，证实比那些只接受化疗的病人，在研究期间的生存机会高出一半。

要指出某疗法是否有效的指标繁多而复杂，不过一项令人易於理解的计算方法是有否令病人寿命延长，而Avastin 被发现令平均寿命由15.6 个月延长到20.3 个月。《纽约时报》说，若一种新抗癌药能延长病人寿命两三个月便等於成功，Avastin 延命5 个月，已超出期望。

　　参与临床试验的加州大学三藩市分校胃肠肿瘤专家韦洛克说：你看到的是病人彷佛马上受惠，在感觉上以及肿瘤负荷上都减轻了。我想它真的使化疗效果加快，而且可能令效果更持久。

　　研究人员说，副作用基本上可以控制，只是会令许多病人血压上升，这可用普通方法治疗。Avastin 已显示对乳癌效果不佳，但该公司正研究它对胰脏癌、前列腺癌、卵巢癌和肾癌的效用。 可望明年推出市场
　　目前，多家生物技术公司共同研发出近10 种类似药理的药物，Avastin 被视为样板，备受业界关注。由於临? 测试结果理据充足，研发出Avastin 的美国著名基因工程公司Genentech 可能会在明年内向美国食品及药物管理局申请推出市场，而不像惯例那样再作第二次大型研究。

　　另外两种药物，包括纽约生物科技制药公司ImClone 研发的治疗结肠直肠癌药Erbitux ，以及AstraZeneca 公司的肺癌药Irea ，都是用以阻挡一种体内分子，使其无法协助癌肿瘤发展起对化疗的抵抗能力。临? 实验都证实，它们能令濒死病人的癌瘤缩小，只是尚未能如Avastin 那样延长病人寿命。

癌症医生绝少说「治愈」，因为癌症随时都会复发，但现在很多医生都希望，若把这两三种目前世界上最先进的抗癌药物结合现有的化疗方法，或能长久抑制肿瘤。因此医学界都欢呼，他们即将踏入治癌新纪元。专家相信，以深厚基因知识为基础的疗法，已开始有效对付各大癌症杀手，例如肺癌、乳癌、直肠癌和前列腺癌等。

　　医学界：标志治癌新纪元
　　对癌病的临床研究已有15 年的加州大学肿瘤专家韦洛克说：我向来对所谓研究进展有保留，但也不得不说这是划时代的。它令研究者、病人和生物医药公司而言都是一大鼓舞，真是令人兴奋得不得了。

AVASTIN(Bevacizumab)英文说明书

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1.14.1.3 Labeling Text 1
AVASTI#8482; 2
(Bevacizumab) 3
For Intravenous Use 4
WARNINGS 5
Gastrointestinal Perforatio/Wound Healing Complicatio 6
AVASTIN administration can result in the development of gastrointestinal 7
perforation and wound dehiscence, in some itances resulting in fatality. 8
Gastrointestinal perforation, sometimes aociated with intra-abdominal 9
ace, 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 aociated with 13
symptoms such as cotipation 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 aropriate interval 18
between termination of AVASTIN and suequent elective surgery 19
required to avoid the risks of impaired wound healing/wound dehiscence 20
has not been determined. (See WARNINGS: Gastrointestinal 21
Perforatio/Wound Healing Complicatio and DOSAGE AND 22
ADMINISTRATION: Dose Modificatio.) 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 Modificatio .) 32
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DESCRIPTION 33
AVASTIauml; (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 aay 36
systems. Bevacizumab contai human framework regio and the 37
complementarity-determining regio of a murine antibody that binds to 38
VEGF (1). Bevacizumab is produced in a Chinese Hamster Ovary 39
mammalian cell expreion system in a nutrient medium containing the 40
antibiotic gentamicin and has a molecular weight of aroximately 41
149 kilodalto. AVASTIN is a clear to slightly opalescent, colorle to 42
pale brown, sterile, pH 6.2 solution for intravenous (IV) infusion. 43
AVASTIN is sulied 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
phohate (monobasic, monohydrate), 4.8 mg sodium phohate (dibasic, 47
anhydrous), 1.6 mg polysorbate 20, and Water for Injection, U. The 48
400 mg product is formulated in 960 mg a,a-trehalose dihydrate, 92.8 mg 49
sodium phohate (monobasic, monohydrate), 19.2 mg sodium phohate 50
(dibasic, anhydrous), 6.4 mg polysorbate 20, and Water for Injection, 51
U. 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 veel formation in in vitro models of 58
angiogenesis. Administration of Bevacizumab to xenotralant models 59
of colon cancer in nude (athymic) mice caused reduction of microvascular 60
growth and inhibition of metastatic disease progreion. 61
Pharmacokinetics 62
The pharmacokinetic profile of Bevacizumab was aeed using an aay 63
that measures total serum Bevacizumab concentratio (i.e., the aay did 64
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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
aroximately 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 burde 77
below the median. In a randomized study of 813 patients (Study 1), there 78
was no evidence of leer 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
relatiohip between Bevacizumab exposure and clinical outcomes has not 82
been explored. 83
ecial Populatio 84
Analyses of demographic data suggest that no dose adjustments are 85
neceary 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
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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-ecified, 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 acro the study arms. The primary endpoint of this trial was 114
overall survival. Results are presented in Table 1 and Figure 1. 115
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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
Progreion-Free Survivala
Median (months) 6.4 10.6
Hazard ratio 0.54
Overall Reoe Rateb
Rate (percent) 35% 45%
Duration of Reoe
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 subgrou tested. The subgrou examined 122
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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 progreion- free survival was 8.8 months, overall 127
reoe rate was 39%, and median duration of reoe 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 progreion. The primary endpoints of the trial 136
were objective reoe rate and progreion-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
Progreion-Free Survival
Median (months) 5.2 9.0 7.2
Overall Reoe Rate
Rate (percent) 17 40 24
139
Progreion-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 reoe rate 142
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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 progreed 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
INDICATIO 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
CONTRAINDICATIO 159
There are no known contraindicatio to the use of AVASTIN. 160
WARNINGS 161
Gastrointestinal Perforatio/Wound Healing Complicatio 162
(See DOSAGE AND ADMINISTRATION: Dose Modificatio) 163
Gastrointestinal perforation and wound dehiscence, complicated by 164
intra-abdominal acees, 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 itances with fatal outcome. These 171
episodes occurred with or without intra-abdominal acees and at 172
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various time points during treatment. The typical presentation was 173
reported as abdominal pain aociated with symptoms such as cotipation 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 aropriate interval between surgery and suequent 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 aropriate interval between termination of AVASTIN and 188
suequent 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 complicatio. 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 complicatio. The longest interval between 195
last dose of study drug and dehiscence was 56 day this occurred in a 196
patient on the bolus-IFL plus AVASTIN arm. The interval between 197
termination of AVASTIN and suequent elective surgery should take into 198
coideration the calculated half-life of AVASTIN (aroximately 199
20 days). 200
AVASTIN therapy should be discontinued in patients with gastrointestinal 201
perforation or wound dehiscence requiring medical intervention. 202
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Hemorrhage (See DOSAGE AND ADMINISTRATION: Dose 203
Modificatio) 204
Two distinct patter 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
aroved. 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 maive hemoptysis. 219
The risk of central nervous system (C) bleeding in patients with C 220
metastases receiving AVASTIN has not been evaluated because these 221
patients were excluded from Genentech-oored studies following 222
development of C hemorrhage in a patient with a C 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 aggreive 229
medical management. Patients with recent hemoptysis should not receive 230
AVASTIN. 231
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Hyperteion (See DOSAGE AND ADMINISTRATION: Dose 232
Modificatio) 233
The incidence of hyperteion and severe hyperteion was increased in 234
patients receiving AVASTIN in Study 1 (see Table 3). 235
Table 3
Incidence of Hyperteion and Severe Hyperteion in Study 1
Arm 1
IFL + Placebo
(n = 394)
Arm 2
IFL + AVASTIN
(n = 392)
Arm 3
5-FU/LV + AVASTIN
(n = 109)
Hyperteiona
( > 150/100 mmHg)
43% 60% 67%
Severe Hyperteiona
( > 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 occasio.
236
Among patients with severe hyperteion in the AVASTIN arms, slightly 237
over half the patients (51%) had a diastolic reading greater than 110 238
aociated with a systolic reading le than 200. 239
Medication claes used for management of patients with Grade 3 240
hyperteion receiving AVASTIN included angiotein-converting 241
enzyme inhibitors, beta blockers, diuretics, and calcium chael blockers. 242
Four months after discontinuation of therapy, persistent hyperteion 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
Acro all clinical studies (n = 1032), development or worsening of 246
hyperteion resulted in hoitalization or discontinuation of AVASTIN in 247
17 patients. Four of these 17 patients developed hyperteive 248
encephalopathy. Severe hyperteion was complicated by subarachnoid 249
hemorrhage in one patient. 250
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AVASTIN should be permanently discontinued in patients with 251
hyperteive crisis. Temporary sueion is recommended in patients 252
with severe hyperteion that is not controlled with medical management. 253
Proteinuria (See DOSAGE AND ADMINISTRATION: Dose 254
Modificatio) 255
In Study 1, both the incidence and severity of proteinuria (defined as a 256
urine ditick reading of 1+ or greater) was increased in patients receiving 257
AVASTIN as compared to those receiving bolus-IFL plus placebo. 258
Urinary ditick 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 collectio were obtained in patients with new 262
oet 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 aroved, 24-hour urine collectio were obtained in 270
aroximately half the patients enrolled. Among patients in whom 271
24-hour urine collectio 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-oored 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
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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 up3; 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 collectio should be monitored 288
regularly until improvement and/or resolution is oerved. 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-oored 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
PRECAUTIO 301
General 302
AVASTIN should be used with caution in patients with known 303
hyperseitivity to AVASTIN or any component of this drug product. 304
Infusion Reactio 305
Infusion reactio with the first dose of AVASTIN were uncommon 306
(< 3%). Severe reactio 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 hyperseitivity reaction requiring hoitalization 310
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during their third infusion of AVASTIN. Both patients reonded to 311
medical management. Information on rechallenge is not available. 312
AVASTIN infusion should be interrupted in all patients with severe 313
infusion reactio and aropriate medical therapy administered. 314
There are no data regarding the most aropriate 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 suended prior to elective surgery. The 322
aropriate interval between the last dose of AVASTIN and elective 323
surgery is unknow 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 coideration the half- life of the drug. 326
(See WARNINGS: Gastrointestinal Perforatio/Wound Healing 327
Complicatio.) 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 protei, there is a potential for immunogenicity. 336
The incidence of antibody development in patients receiving AVASTIN 337
has not been adequately determined because the aay seitivity was 338
inadequate to reliably detect lower titers. Enzyme-linked immunosorbant 339
aays (ELISAs) were performed on sera from aroximately 500 patients 340
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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 seitivity and 343
ecificity of the aay. Additionally, the oerved incidence of antibody 344
positivity in an aay may be influenced by several factors, including 345
sample handling, timing of sample collection, concomitant medicatio, 346
and underlying disease. For these reaso, 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 preure monitoring should be conducted every two to three weeks 351
during treatment with AVASTIN. Patients who develop hyperteion on 352
AVASTIN may require blood preure monitoring at more frequent 353
intervals. Patients with AVASTIN-induced or -exacerbated hyperteion 354
who discontinue AVASTIN should continue to have their blood preure 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 ditick reading should undergo further aement, e.g., a 359
24-hour urine collection. (See WARNINGS: Proteinuria and DOSAGE 360
AND ADMINISTRATION: Dose Modificatio.) 361
Drug Interactio 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 concentratio were similar in patients receiving bolus-IFL 366
alone and in combination with AVAS TIN. The concentratio of 38, 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
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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 38 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
huma. 377
AVASTIN may impair fertility. Dose-related decreases in ovarian and 378
uterine weights, endometrial proliferation, number of metrual cycles, and 379
arrested follicular development or aent corpora lutea were oerved 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 aigned to recover. 384
After the 12-week recovery period, follicular maturation arrest was no 385
longer oerved, but ovarian weights were still moderately decreased. 386
Reduced endometrial proliferation was no longer oerved at the 12-week 387
recovery time point, but uterine weight decreases were still notable, 388
corpora lutea were aent in 1 out of 2 animals, and the number of 389
metrual cycles remained reduced (67%). 390
Pregnancy Category C 391
AVASTIN has been shown to be teratogenic in raits when administered 392
in doses that are two-fold greater than the recommended human dose on a 393
mg/kg basis. Oerved effects included decreases in maternal and fetal 394
body weights, an increased number of fetal resorptio, and an increased 395
incidence of ecific gro and skeletal fetal alteratio. Adverse fetal 396
outcomes were oerved 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
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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 coueled 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 arised of the potential hazard to the 406
fetus and/or the potential risk of lo of pregnancy. Patients who 407
discontinue AVASTIN should also be coueled concerning the prolonged 408
exposure following discontinuation of therapy (half- life of aroximately 409
20 days) and the poible 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 aorption 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, aroximately 20 days . (See 417
CLINICAL PHARMACOLOGY: Pharmacokinetics.) 418
Pediatric Use 419
The safety and effectivene of AVASTIN in pediatric patients has not 420
been studied. However, physeal dylasia was oerved in juvenile 421
cynomolgus monkeys with open growth plates treated for four weeks with 422
doses that were le than the recommended human dose based on mg/kg 423
and exposure. The incidence and severity of physeal dylasia were 424
dose-related and were at least partially reversible upon ceation 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 AVASTI 109 5-FU/LV plus AVASTIN), while NCI-CTC Grade 1 430
and 2 adverse events were collected in a suet of 309 patients. There 431
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were iufficient numb ers of patients 65 years and older in the suet 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 ( up3; 2%) in the elderly when compared to 437
those le than 65 years were asthenia, seis, deep thrombophlebitis, 438
hyperteion, hypoteion, myocardial infarction, congestive heart failure, 439
diarrhea, cotipation, 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-oored 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 dyeia, 447
gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice 448
alteration. 449
ADVERSE EVENTS 450
The most serious adverse events aociated with AVASTIN were: 451
· Gastrointestinal Perforatio/Wound Healing Complicatio (see 452
WARNINGS) 453
· Hemorrhage (see WARNINGS) 454
· Hyperteive 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-oored studies were 459
asthenia, pain, hyperteion, diarrhea, and leukopenia. 460
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The most common adverse events of any severity among the 742 patients 461
receiving AVASTIN in Genentech-oored studies were asthenia, pain, 462
abdominal pain, headache, hyperteion, diarrhea, nausea, vomiting, 463
anorexia, stomatitis, cotipation, uer reiratory infection, epistaxis, 464
dyea, exfoliative dermatitis, and proteinuria. 465
Because clinical trials are conducted under widely varying conditio, 466
adverse reaction rates oerved in the clinical trials of a drug caot be 467
directly compared to rates in the clinical trials of another drug and may not 468
reflect the rates oerved in practice. The adverse reaction information 469
from clinical trials does, however, provide a basis for identifying the 470
adverse events that aear to be related to drug use and for aroximating 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-oored clinical trials. All adverse events were collected in 476
742 of the 1032 patient for the remaining 290, all NCI-CTC Grade 3 477
and 4 adverse events and only selected Grade 1 and 2 adverse events 478
(hyperteion, proteinuria, thromboembolic events) were collected. 479
Adverse events acro all Genentech-oored studies were used to 480
further characterize ecific adverse events. (See WARNINGS: 481
Hemorrhage, Hyperteion, Proteinuria, Congestive Heart Failure 482
and PRECAUTIO: 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
(hyperteion, 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
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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 suet of 309 patients. The baseline entry characteristics in 494
the 309 patient safety suet were similar to the overall study population 495
and well-balanced acro the three study arms. 496
Severe and life-threatening (NCI-CTC Grade 3 and 4) adverse events, 497
which occurred at a higher incidence ( up3; 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 (up3; 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%)
Hyperteion 10 (2%) 46 (12%)
Intra-Abdominal Thrombosis 5 (1%) 13 (3%)
Syncope 4 (1%) 11 (3%)
Digestive
Diarrhea 99 (25%) 133 (34%)
Cotipation 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
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Adverse events of any severity, which occurred at a higher incidence 502
( up3; 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
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Table 5
NCI-CTC Grade 1-4 Adverse Events in Study 1 Suet
(Occurring at Higher Incidence (up3; 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
Hyperteion 14 (14%) 23 (23%) 37 (34%)
Hypoteion 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%)
Cotipation 28 (29%) 41 (40%) 32 (29%)
Stomatitis 18 (18%) 33 (32%) 33 (30%)
Dyeia 15 (15%) 25 (24%) 19 (17%)
Weight Lo 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
Dizzine 20 (20%) 27 (26%) 21 (19%)
Confusion 1 (1%) 1 (1%) 6 (6%)
Aormal Gait 0 1 (1%) 5 (5%)
506
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Table 5 (cont’d)
NCI-CTC Grade 1-4 Adverse Events in Study 1 Suet
Arm 1
IFL + Placebo
(n = 98)
Arm 2
IFL + AVASTIN
(n = 102)
Arm 3
5-FU/LV + AVASTIN
(n = 109)
Reiratory
Uer Reiratory Infection 38 (39%) 48 (47%) 44 (40%)
Dyea 15 (15%) 26 (26%) 27 (25%)
Epistaxis 10 (10%) 36 (35%) 35 (32%)
Voice Alteration 2 (2%) 9 (9%) 6 (6%)
Skin/Aendages
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%)
ecial Sees
Taste Disorder 9 (9%) 14 (14%) 23 (21%)
Exce 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
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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
complicatio. In the two patients treated with full-dose warfarin and 535
AVASTIN, these events were aociated with marked elevatio 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 coidered 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 otruction, intestinal necrosis, mesenteric venous 545
occlusion, anastomotic ulceration 546
Hemic and lymphatic: pancytopenia 547
Metabolic and nutritional disorders: hyponatremia. 548
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Urogenital: ureteral stricture 549
OVERDOSAGE 550
The maximum tolerated dose of AVASTIN has not been determined. The 551
highest dose tested in huma (20 mg/kg IV) was aociated 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 progreion 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 Modificatio 561
There are no recommended dose reductio for the use of AVASTIN. If 562
needed, AVASTIN should be either discontinued or temporarily 563
suended 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 hyperteive crisis. 567
Temporary sueion of AVASTIN is recommended in patients with 568
evidence of moderate to severe proteinuria pending further evaluation and 569
in patients with severe hyperteion that is not controlled with medical 570
management. The risk of continuation or temporary sueion of 571
AVASTIN in patients with moderate to severe proteinuria is unknown. 572
AVASTIN should be suended at least several weeks prior to elective 573
surgery. (See WARNINGS: Gastrointestinal Perforation/Wound 574
Healing Complicatio and PRECAUTIO: Surgery.) AVASTIN 575
should not be resumed until the surgical incision is fully healed. 576
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Preparation for Administration 577
AVASTIN should be diluted for infusion by a healthcare profeional 578
using aseptic technique. Withdraw the neceary 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, U. Discard any unused portion left in a 581
vial, as the product contai no preservatives. Parenteral drug products 582
should be iected visually for particulate matter and discoloration prior 583
to administration. 584
Diluted AVASTIN solutio 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 oerved. 587
AVASTIN infusio should not be administered or mixed with 588
dextrose solutio. 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 suequent infusio 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 SULIED 601
AVASTIN is sulied as 4 mL and 16 mL of a sterile solution in single? 602
use gla vials to deliver 100 and 400 mg of Bevacizumab per vial, 603
reectively. 604
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Single unit 100 mg carton: Contai one 4 mL vial of AVASTIN 605
(25 mg/mL). NDC 50242-060-01 606
Single unit 400 mg carton: Contai one 16 mL vial of AVASTIN 607
(25 mg/mL). NDC 50242-060-02 608
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REFERENCES 609
1. Presta LG, Chen H, O’Coor 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
AVASTI#8482;
(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

Avastin获准作为晚期结肠癌二线治疗药(2006-6-22)

生物制药公司Genentech在6月20日称，FDA已批准Avastin的扩大适应症，即作为晚期结肠癌的二线治疗药物。

此前，Avastin+化疗联用已获准作为晚期结肠癌的一线治疗药。