AVASTIN(Bevacizumab)英文說明書 
 
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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
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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
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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
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
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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-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
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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
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
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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 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
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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 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
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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
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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
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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
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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
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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 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
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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
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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 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
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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 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
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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 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
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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
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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
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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 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
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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
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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
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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
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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
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
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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 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
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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
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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
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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
  

Avastin獲準作為晚期結腸癌二線治療藥 (2006-6-22)