德国默克制药公司１日宣布，该公司研发的肠癌治疗药物“Ｅｒｂｉｔｕｘ”已在瑞士获得许可，将进入临床使用。

　　据德新社报道，这种新药的有效成分是一种名为“Ｃｅｔｕｘｉｍａｂ”的抗体，它可以有的放矢地抑制肿瘤增殖。默克公司称，他们此前在３００多名肠癌患者中进行的试验显示，当这种新药与其他一些药物结合使用时，约有一半病人病情出现好转，其中约１／３病人的肿瘤细胞停止增殖。

　　据悉，这是该药物在全球范围内首次获得临床使用许可。据默克公司董事会主席朔伊布勒透露，这一药物将于明年获得欧洲地区临床使用许可。他同时表示，公司正考虑在这一新药基础上研发一些针对其他种类癌症的新药。

ERBITUX(C225、Cetuximab)英文说明书 

Page 1 of 18
ERBITUXTM Rx only
1
(Cetuximab) 2
For intravenous use only. 3
WARNING 4
Infusion Reactions: Severe infusion reactions occurred with the administration of 5
ERBITUX in approximately 3% of patients, rarely with fatal outcome (<1 in 1000). 6
Approximately 90% of severe infusion reactions were associated with the first infusion of 7
ERBITUX. Severe infusion reactions are characterized by rapid onset of airway 8
obstruction (bronchospasm, stridor, hoarseness), urticaria, and hypotension (see 9
WARNINGS and ADVERSE REACTIONS). Severe infusion reactions require 10
immediate interruption of the ERBITUX infusion and permanent discontinuation from 11
further treatment. (See WARNINGS: Infusion Reactions and DOSAGE AND 12
ADMINISTRATION: Dose Modifications.) 13
DESCRIPTION 14
ERBITUXTM (Cetuximab) is a recombinant, human/mouse chimeric monoclonal 15
antibody that binds specifically to the extracellular domain of the human epidermal 16
growth factor receptor (EGFR). ERBITUX is composed of the Fv regions of a murine 17
anti-EGFR antibody with human IgG1 heavy and kappa light chain constant regions and 18
has an approximate molecular weight of 152 kDa. ERBITUX is produced in mammalian 19
(murine myeloma) cell culture. 20
ERBITUX is a sterile, clear, colorless liquid of pH 7.0 to 7.4, which may contain a small 21
amount of easily visible, white, amorphous, Cetuximab particulates. Each single-use, 22
50-mL vial contains 100 mg of Cetuximab at a concentration of 2 mg/mL and is 23
formulated in a preservative-free solution containing 8.48 mg/mL sodium chloride, 24
1.88 mg/mL sodium phosphate dibasic heptahydrate, 0.42 mg/mL sodium phosphate 25
monobasic monohydrate, and Water for Injection, USP. 26
Page 2 of 18
CLINICAL PHARMACOLOGY 27
General 28
ERBITUX binds specifically to the epidermal growth factor receptor (EGFR, HER1, 29
c-ErbB-1) on both normal and tumor cells, and competitively inhibits the binding of 30
epidermal growth factor (EGF) and other ligands, such as transforming growth factor– 31
alpha. Binding of ERBITUX to the EGFR blocks phosphorylation and activation of 32
receptor-associated kinases, resulting in inhibition of cell growth, induction of apoptosis, 33
and decreased matrix metalloproteinase and vascular endothelial growth factor 34
production. The EGFR is a transmembrane glycoprotein that is a member of a subfamily 35
of type I receptor tyrosine kinases including EGFR (HER1), HER2, HER3, and HER4. 36
The EGFR is constitutively expressed in many normal epithelial tissues, including the 37
skin and hair follicle. Over-expression of EGFR is also detected in many human cancers 38
including those of the colon and rectum. 39
In vitro assays and in vivo animal studies have shown that ERBITUX inhibits the growth 40
and survival of tumor cells that over-express the EGFR. No anti-tumor effects of 41
ERBITUX were observed in human tumor xenografts lacking EGFR expression. The 42
addition of ERBITUX to irinotecan or irinotecan plus 5-fluorouracil in animal studies 43
resulted in an increase in anti-tumor effects compared to chemotherapy alone. 44
Human Pharmacokinetics 45
ERBITUX administered as monotherapy or in combination with concomitant 46
chemotherapy or radiotherapy exhibits nonlinear pharmacokinetics. The area under the 47
concentration time curve (AUC) increased in a greater than dose proportional manner as 48
the dose increased from 20 to 400 mg/m2. ERBITUX clearance (CL) decreased from 0.08 49
to 0.02 L/h/m2 as the dose increased from 20 to 200 mg/m2, and at doses >200 mg/m2, it 50
appeared to plateau. The volume of the distribution (Vd) for ERBITUX appeared to be 51
independent of dose and approximated the vascular space of 2-3 L/m2. 52
Following a 2-hour infusion of 400 mg/m2 of ERBITUX, the maximum mean serum 53
concentration (Cmax) was 184 ?g/mL (range: 92-327 ?g/mL) and the mean elimination 54
half-life was 97 hours (range 41-213 hours). A 1-hour infusion of 250 mg/m2 produced a 55
mean Cmax of 140 ? g/mL (range 120-170 ? g/mL). Following the recommended dose 56
regimen (400 mg/m2 initial dose/250 mg/m2 weekly dose), ERBITUX concentrations 57
reached steady-state levels by the third weekly infusion with mean peak and trough 58
Page 3 of 18
concentrations across studies ranging from 168 to 235 and 41 to 85 ? g/mL, respectively. 59
The mean half-life was 114 hours (range 75-188 hours). 60
Special Populations 61
A population pharmacokinetic analysis was performed to explore the potential effects of 62
selected covariates including race, gender, age, and hepatic and renal function on 63
ERBITUX pharmacokinetics. 64
Female patients had a 25% lower intrinsic ERBITUX clearance than male patients. 65
Similar efficacy and safety were observed for female and male patients in the clinical 66
trials; therefore, dose modification based on gender is not necessary. None of the other 67
covariates explored appeared to have an impact on ERBITUX pharmacokinetics. 68
ERBITUX has not been studied in pediatric populations. 69
CLINICAL STUDIES 70
The efficacy and safety of ERBITUX alone or in combination with irinotecan were 71
studied in a randomized, controlled trial (329 patients) and in combination with 72
irinotecan in an open-label, single-arm trial (138 patients). ERBITUX was further 73
evaluated as a single agent in a third clinical trial (57 patients). Safety data from 111 74
patients treated with single agent ERBITUX was also evaluated. All trials studied 75
patients with EGFR-expressing metastatic colorectal cancer, whose disease had 76
progressed after receiving an irinotecan-containing regimen. 77
Randomized, Controlled Trial 78
A multicenter, randomized, controlled clinical trial was conducted in 329 patients 79
randomized to receive either ERBITUX plus irinotecan (218 patients) or ERBITUX 80
monotherapy (111 patients). In both arms of the study, ERBITUX was administered as a 81
400 mg/m2 initial dose, followed by 250 mg/m2 weekly until disease progression or 82
unacceptable toxicity. All patients received a 20-mg test dose on Day 1. In the 83
ERBITUX plus irinotecan arm, irinotecan was added to ERBITUX using the same dose 84
and schedule for irinotecan as the patient had previously failed. Acceptable irinotecan 85
schedules were 350 mg/m2 every 3 weeks, 180 mg/m2 every 2 weeks, or 125 mg/m2 86
weekly times four doses every 6 weeks. An Independent Radiographic Review 87
Committee (IRC), blinded to the treatment arms, assessed both the progression on prior 88
irinotecan and the response to protocol treatment for all patients. 89
Page 4 of 18
Of the 329 randomized patients, 206 (63%) were male. The median age was 59 years 90
(range 26-84), and the majority was Caucasian (323, 98%). Eighty-eight percent of 91
patients had baseline Karnofsky Performance Status ?80. Fifty-eight percent of patients 92
had colon cancer and 40% rectal cancer. Approximately two-thirds (63%) of patients had 93
previously failed oxaliplatin treatment. 94
The efficacy of ERBITUX plus irinotecan or ERBITUX monotherapy was evaluated in 95
all randomized patients. 96
Analyses were also conducted in two pre-specified subpopulations: irinotecan refractory 97
and irinotecan and oxaliplatin failures. The irinotecan refractory population was defined 98
as randomized patients who had received at least two cycles of irinotecan-based 99
chemotherapy prior to treatment with ERBITUX, and had independent confirmation of 100
disease progression within 30 days of completion of the last cycle of irinotecan-based 101
chemotherapy. 102
The irinotecan and oxaliplatin failure population was defined as irinotecan refractory 103
patients who had previously been treated with and failed an oxaliplatin-containing 104
regimen. 105
The objective response rates (ORR) in these populations are presented in Table 1. 106
Table 1: Objective Response Rates per Independent Review
Populations ERBITUX + Irinotecan ERBITUX
Monotherapy
Difference
(95% CIa)
n ORR (%) n ORR (%) % p-value
CMHb
All Patients 218 22.9 111 10.8 12.1
(4.1 - 20.2) 0.007
? Irinotecan-
Oxaliplatin
Failure
80 23.8 44 11.4 12.4
(-0.8, 25.6) 0.09
? Irinotecan
Refractory
132 25.8 69 14.5 11.3
(0.1 - 22.4)
0.07
a95% confidence interval for the difference in objective response rates. 107
bCochran-Mantel-Haenszel test. 108
109
The median duration of response in the overall population was 5.7 months in the 110
combination arm and 4.2 months in the monotherapy arm. Compared with patients 111
randomized to ERBITUX alone, patients randomized to ERBITUX and irinotecan 112
experienced a significantly longer median time to disease progression (see Table 2). 113
Page 5 of 18
Table 2: Time to Progression per Independent Review
Populations ERBITUX +
Irinotecan
(median)
ERBITUX
Monotherapy
(median)
Hazard Ratio
(95% CIa)
Log-rank
p-value
All Patients 4.1 mo 1.5 mo 0.54 (0.42 – 0.71) <0.001
? Irinotecan-
Oxaliplatin
Failure
2.9 mo 1.5 mo 0.48 (0.31 - 0.72) <0.001
? Irinotecan
Refractory
4.0 mo 1.5 mo 0.52 (0.37 - 0.73) <0.001
aHazard ratio of ERBITUX + irinotecan: ERBITUX monotherapy with 95% confidence interval. 114
. 115
Single-Arm Trials 116
ERBITUX, in combination with irinotecan, was studied in a single-arm, multicenter, 117
open-label clinical trial in 138 patients with EGFR-expressing metastatic colorectal 118
cancer who had progressed following an irinotecan containing regimen. Patients received 119
a 20-mg test dose of ERBITUX on day 1, followed by a 400-mg/m2 initial dose, and 120
250 mg/m2 weekly until disease progression or unacceptable toxicity. Patients received 121
the same dose and schedule for irinotecan as the patient had previously failed. Acceptable 122
irinotecan schedules were 350 mg/m2 every 3 weeks or 125 mg/m2 weekly times four 123
doses every 6 weeks. Of 138 patients enrolled, 74 patients had documented progression 124
to irinotecan as determined by an IRC. The overall response rate was 15% for the overall 125
population and 12% for the irinotecan failure population. The median durations of 126
response were 6.5 and 6.7 months, respectively. 127
ERBITUX was studied as a single agent in a multicenter, open-label, single-arm clinical 128
trial in patients with EGFR-expressing metastatic colorectal cancer who progressed 129
following an irinotecan-containing regimen. Of 57 patients enrolled, 28 patients had 130
documented progression to irinotecan. The overall response rate was 9% for the all 131
treated group and 14% for the irinotecan failure group. The median times to progression 132
were 1.4 and 1.3 months, respectively. The median duration of response was 4.2 months 133
for both groups. 134
EGFR Expression and Response 135
Patients enrolled in the clinical studies were required to have immunohistochemical 136
evidence of positive EGFR expression. Primary tumor or tumor from a metastatic site 137
was tested with the DakoCytomation EGFR pharmDxTM test kit. Specimens were scored 138
Page 6 of 18
based on the percentage of cells expressing EGFR and intensity (barely/faint, weak to 139
moderate, and strong). Response rate did not correlate with either the percentage of 140
positive cells or the intensity of EGFR expression. 141
INDICATIONS AND USAGE 142
ERBITUX, used in combination with irinotecan, is indicated for the treatment of EGFR- 143
expressing, metastatic colorectal carcinoma in patients who are refractory to irinotecan- 144
based chemotherapy. 145
ERBITUX administered as a single agent is indicated for the treatment of EGFR- 146
expressing, metastatic colorectal carcinoma in patients who are intolerant to irinotecan- 147
based chemotherapy. 148
The effectiveness of ERBITUX is based on objective response rates (see CLINICAL 149
STUDIES). Currently, no data are available that demonstrate an improvement in disease- 150
related symptoms or increased survival with ERBITUX. 151
CONTRAINDICATIONS 152
None. 153
WARNINGS 154
Infusion Reactions (See BOXED WARNINGS: Infusion 155
Reactions, ADVERSE REACTIONS: Infusion Reactions, and 156
DOSAGE AND ADMINISTRATION: Dose Modifications) 157
Severe infusion reactions occurred with the administration of ERBITUX in 158
approximately 3% (17/633) of patients, rarely with fatal outcome (<1 in 1000). 159
Approximately 90% of severe infusion reactions were associated with the first infusion of 160
ERBITUX despite the use of prophylactic antihistamines. These reactions were 161
characterized by the rapid onset of airway obstruction (bronchospasm, stridor, 162
hoarseness), urticaria, and/or hypotension. Caution must be exercised with every 163
ERBITUX infusion, as there were patients who experienced their first severe infusion 164
reaction during later infusions. 165
Severe infusion reactions require the immediate interruption of ERBITUX therapy and 166
permanent discontinuation from further treatment. Appropriate medical therapy 167
Page 7 of 18
including epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and 168
oxygen should be available for use in the treatment of such reactions. Patients should be 169
carefully observed until the complete resolution of all signs and symptoms. 170
In clinical trials, mild to moderate infusion reactions were managed by slowing the 171
infusion rate of ERBITUX and by continued use of antihistamine medications (eg, 172
diphenhydramine) in subsequent doses (see DOSAGE AND ADMINSTRATION: 173
Dose Modifications). 174
Pulmonary Toxicity 175
Interstitial lung disease (ILD) was reported in 3 of 633 (<0.5%) patients with advanced 176
colorectal cancer receiving ERBITUX. Interstitial pneumonitis with non-cardiogenic 177
pulmonary edema resulting in death was reported in one case. Two patients had pre- 178
existing fibrotic lung disease and experienced an acute exacerbation of their disease while 179
receiving ERBITUX in combination with irinotecan. In the clinical investigational 180
program, an additional case of interstitial pneumonitis was reported in a patient with head 181
and neck cancer treated with ERBITUX and cisplatin. The onset of symptoms occurred 182
between the fourth and eleventh doses of treatment in all reported cases. 183
In the event of acute onset or worsening pulmonary symptoms, ERBITUX therapy should 184
be interrupted and a prompt investigation of these symptoms should occur. If ILD is 185
confirmed, ERBITUX should be discontinued and the patient should be treated 186
appropriately. 187
Dermatologic Toxicity (See ADVERSE REACTIONS: 188
Dermatologic Toxicity and DOSAGE AND ADMINISTRATION: 189
Dose Modifications) 190
In cynomolgus monkeys, ERBITUX, when administered at doses of approximately 0.4 to 191
4 times the weekly human exposure (based on total body surface area), resulted in 192
dermatologic findings, including inflammation at the injection site and desquamation of 193
the external integument. At the highest dose level, the epithelial mucosa of the nasal 194
passage, esophagus, and tongue were similarly affected, and degenerative changes in the 195
renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of 196
the animals at the highest dose level beginning after approximately 13 weeks of 197
treatment. 198
Page 8 of 18
In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin 199
drying and fissuring, and inflammatory and infectious sequelae (eg, blepharitis, cheilitis, 200
cellulitis, cyst) were reported. In patients with advanced colorectal cancer, acneform rash 201
was reported in 88% (560/633) of all treated patients, and was severe (Grade 3 or 4) in 202
12% (79/633) of these patients. Subsequent to the development of severe dermatologic 203
toxicities, complications including S. aureus sepsis and abscesses requiring incision and 204
drainage were reported. 205
Patients developing dermatologic toxicities while receiving ERBITUX should be 206
monitored for the development of inflammatory or infectious sequelae, and appropriate 207
treatment of these symptoms initiated. Dose modifications of any future ERBITUX 208
infusions should be instituted in case of severe acneform rash (see DOSAGE AND 209
ADMINISTRATION, Table 4). Treatment with topical and/or oral antibiotics should be 210
considered; topical corticosteroids are not recommended. 211
PRECAUTIONS 212
General 213
ERBITUX therapy should be used with caution in patients with known hypersensitivity 214
to Cetuximab, murine proteins, or any component of this product. 215
It is recommended that patients wear sunscreen and hats and limit sun exposure while 216
receiving ERBITUX as sunlight can exacerbate any skin reactions that may occur. 217
EGF Receptor Testing 218
Patients enrolled in the clinical studies were required to have immunohistochemical 219
evidence of positive EGFr expression using the DakoCytomation EGFr pharmDx™ test 220
kit. Assessment for EGFR expression should be performed by laboratories with 221
demonstrated proficiency in the specific technology being utilized. Improper assay 222
performance, including use of suboptimally fixed tissue, failure to utilize specified 223
reagents, deviation from specific assay instructions, and failure to include appropriate 224
controls for assay validation, can lead to unreliable results. Refer to the DakoCytomation 225
test kit package insert for full instructions on assay performance. (See CLINICAL 226
STUDIES: EGFR Expression and Response.) 227
Page 9 of 18
Drug Interactions 228
A drug interaction study was performed in which ERBITUX was administered in 229
combination with irinotecan. There was no evidence of any pharmacokinetic interactions 230
between ERBITUX and irinotecan. 231
Immunogenicity 232
As with all therapeutic proteins, there is potential for immunogenicity. Potential 233
immunogenic responses to ERBITUX were assessed using either a double antigen 234
radiometric assay or an enzyme-linked immunosorbant assay. Due to limitations in assay 235
performance and sample timing, the incidence of antibody development in patients 236
receiving ERBITUX has not been adequately determined. The incidence of antibodies to 237
ERBITUX was measured by collecting and analyzing serum pre-study, prior to selected 238
infusions and during treatment follow-up. Patients were considered evaluable if they had 239
a negative pre-treatment sample and a post-treatment sample. Non-neutralizing anti- 240
ERBITUX antibodies were detected in 5% (28 of 530) of evaluable patients. In patients 241
positive for anti-ERBITUX antibody, the median time to onset was 44 days (range 8-281 242
days). Although the number of sero-positive patients is limited, there does not appear to 243
be any relationship between the appearance of antibodies to ERBITUX and the safety or 244
antitumor activity of the molecule. 245
The observed incidence of anti-ERBITUX antibody responses may be influenced by the 246
low sensitivity of available assays, inadequate to reliably detect lower antibody titers. 247
Other factors which might influence the incidence of anti-ERBITUX antibody response 248
include sample handling, timing of sample collection, concomitant medications, and 249
underlying disease. For these reasons, comparison of the incidence of antibodies to 250
ERBITUX with the incidence of antibodies to other products may be misleading. 251
Carcinogenesis, Mutagenesis, Impairment of Fertility 252
Long-term animal studies have not been performed to test ERBITUX for carcinogenic 253
potential. No mutagenic or clastogenic potential of ERBITUX was observed in the 254
Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. A 39- 255
week toxicity study in cynomolgus monkeys receiving 0.4 to 4 times the human dose of 256
ERBITUX (based on total body surface area) revealed a tendency for impairment of 257
menstrual cycling in treated female monkeys, including increased incidences of 258
irregularity or absence of cycles, when compared to control animals, and beginning from 259
Page 10 of 18
week 25 of treatment and continuing through the 6 week recovery period. Serum 260
testosterone levels and analysis of sperm counts, viability, and motility were not 261
remarkably different between ERBITUX-treated and control male monkeys. It is not 262
known if ERBITUX can impair fertility in humans. 263
Pregnancy Category C 264
Animal reproduction studies have not been conducted with ERBITUX. However, the 265
EGFR has been implicated in the control of prenatal development and may be essential 266
for normal organogenesis, proliferation, and differentiation in the developing embryo. In 267
addition, human IgG1 is known to cross the placental barrier; therefore ERBITUX has 268
the potential to be transmitted from the mother to the developing fetus. It is not known 269
whether ERBITUX can cause fetal harm when administered to a pregnant woman or 270
whether ERBITUX can affect reproductive capacity. There are no adequate and well- 271
controlled studies of ERBITUX in pregnant women. ERBITUX should only be given to 272
a pregnant woman, or any woman not employing adequate contraception if the potential 273
benefit justifies the potential risk to the fetus. All patients should be counseled regarding 274
the potential risk of ERBITUX treatment to the developing fetus prior to initiation of 275
therapy. If the patient becomes pregnant while receiving this drug, she should be 276
apprised of the potential hazard to the fetus and/or the potential risk for loss of the 277
pregnancy. 278
Nursing Mothers 279
It is not known whether ERBITUX is secreted in human milk. Since human IgG1 is 280
secreted in human milk, the potential for absorption and harm to the infant after ingestion 281
is unknown. Based on the mean half-life of ERBITUX after multiple dosing of 114 hours 282
 (see CLINICAL PHARMACOLOGY: Human 283
Pharmacokinetics), women should be advised to discontinue nursing during treatment 284
with ERBITUX and for 60 days following the last dose of ERBITUX. 285
Pediatric Use 286
The safety and effectiveness of ERBITUX in pediatric patients has not been established. 287
Geriatric Use 288
Of the 633 patients who received ERBITUX with irinotecan or ERBITUX monotherapy 289
in four advanced colorectal cancer studies, 206 patients (33%) were 65 years of age or 290
Page 11 of 18
older. No overall differences in safety or efficacy were observed between these patients 291
and younger patients. 292
ADVERSE REACTIONS 293
Except where indicated, the data described below reflect exposure to ERBITUX in 633 294
patients with advanced metastatic colorectal cancer. ERBITUX was studied in 295
combination with irinotecan (n=354) or as monotherapy (n=279). Patients receiving 296
ERBITUX plus irinotecan received a median of 12 doses (with 88/354 <25%> treated for 297
over 6 months), and patients receiving ERBITUX monotherapy received a median of 7 298
doses (with 26/279 <9%> treated for over 6 months). The population had a median age of 299
59 and was 60% male and 91% Caucasian. The range of dosing for patients receiving 300
ERBITUX plus irinotecan was 1-84 infusions, and the range of dosing for patients 301
receiving ERBITUX monotherapy was 1-63 infusions. 302
The most serious adverse reactions associated with ERBITUX were: 303
? Infusion reaction (3%) (See BOXED WARNINGS, WARNINGS, and 304
DOSAGE AND ADMINISTRATION: Dose Modifications); 305
? Dermatologic toxicity (1%) (See WARNINGS and DOSAGE AND 306
ADMINISTRATION: Dose Modifications); 307
? Interstitial lung disease (0.5%) (See WARNINGS); 308
? Fever (5%); 309
? Sepsis (3%); 310
? Kidney failure (2%); 311
? Pulmonary embolus (1%); 312
? Dehydration (5%) in patients receiving ERBITUX plus irinotecan, 2% in patients 313
receiving ERBITUX monotherapy; 314
? Diarrhea (6%) in patients receiving ERBITUX plus irinotecan, 0% in patients 315
receiving ERBITUX monotherapy. 316
Thirty-seven (10%) patients receiving ERBITUX plus irinotecan and 14 (5%) patients 317
receiving ERBITUX monotherapy discontinued treatment primarily because of adverse 318
events. 319
Page 12 of 18
The most common adverse events seen in 354 patients receiving ERBITUX plus 320
irinotecan were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), nausea 321
(55%), abdominal pain (45%), and vomiting (41%). 322
The most common adverse events seen in 279 patients receiving ERBITUX monotherapy 323
were acneform rash (90%), asthenia/malaise (49%), fever (33%), nausea (29%), 324
constipation (28%), and diarrhea (28%). 325
Because clinical trials are conducted under widely varying conditions, adverse reaction 326
rates observed in the clinical trials of a drug cannot be directly compared to rates in the 327
clinical trials of another drug and may not reflect the rates observed in practice. The 328
adverse reaction information from clinical trials does, however, provide a basis for 329
identifying the adverse events that appear to be related to drug use and for approximating 330
rates. 331
Data in patients with advanced colorectal carcinoma in Table 3 are based on the 332
experience of 354 patients treated with ERBITUX plus irinotecan and 279 patients 333
treated with ERBITUX monotherapy. 334
Table 3: Incidence of Adverse Events (? 10%) in Patients with Advanced
Colorectal Carcinoma
ERBITUX plus Irinotecan
(n=354)
ERBITUX Monotherapy
(n=279)
Grades
1 - 4
Grades
3 and 4
Grades
1 - 4
Grades
3 and 4 Body System
Preferred Term1 % of Patients
Body as a Whole
Asthenia/Malaise2 73 16 49 10
Abdominal Pain 45 8 25 7
Fever3 34 4 33 0
Pain 23 6 19 5
Infusion Reaction4 19 3 25 2
Infection 16 1 11 1
Back Pain 16 3 11 3
Headache 14 2 25 3
Digestive
Diarrhea 72 22 28 2
Nausea 55 6 29 2
Vomiting 41 7 25 3
Anorexia 36 4 25 3
Constipation 30 2 28 1
Page 13 of 18
Table 3: Incidence of Adverse Events (? 10%) in Patients with Advanced
Colorectal Carcinoma
ERBITUX plus Irinotecan
(n=354)
ERBITUX Monotherapy
(n=279)
Grades
1 - 4
Grades
3 and 4
Grades
1 - 4
Grades
3 and 4 Body System
Preferred Term1 % of Patients
Stomatitis 26 2 11 <1
Dyspepsia 14 0 7 0
Hematic/Lymphatic
Leukopenia 25 17 1 0
Anemia 16 5 10 4
Metabolic/Nutritional
Weight Loss 21 0 9 1
Peripheral Edema 16 1 10 <1
Dehydration 15 6 9 2
Nervous
Insomnia 12 0 10 <1
Depression 10 0 9 0
Respiratory
Dyspnea3 23 2 20 7
Cough Increased 20 0 10 1
Skin/Appendages
Acneform Rash5 88 14 90 10
Alopecia 21 0 5 0
Skin Disorder 15 1 5 0
Nail Disorder 12 <1 16 <1
Pruritus 10 1 10 <1
Conjunctivitis 14 1 7 <1
1 Adverse events that occurred (toxicity Grades 1 through 4) in ?10% of patients with refractory colorectal
carcinoma treated with ERBITUX plus irinotecan or in ?10% of patients with refractory colorectal
carcinoma treated with ERBITUX monotherapy.
2 Asthenia/malaise is defined as any event described as “asthenia”, “malaise”, or “somnolence”.
3 Includes cases reported as infusion reaction.
4 Infusion reaction is defined as any event described at any time during the clinical study as “allergic
reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as
“allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and feve r” or “dyspnea”.
5 Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”,
“dry skin”, or “exfoliative dermatitis”.
335
Page 14 of 18
Infusion Reactions (see BOXED WARNING: Infusion Reactions) 336
In clinical trials, severe, potentially fatal infusion reactions were reported. These events 337
include the rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), 338
urticaria, and/or hypotension. In studies in advanced colorectal cancer, severe infusion 339
reactions were observed in 3% of patients receiving ERBITUX plus irinotecan and 2% of 340
patients receiving ERBITUX monotherapy. Grade 1 and 2 infusion reactions, including 341
chills, fever, and dyspnea usually occurring on the first day of initial dosing, were 342
observed in 16% of patients receiving ERBITUX plus irinotecan and 23% of patients 343
receiving ERBITUX monotherapy. (See WARNINGS: Infusion Reactions and 344
DOSAGE AND ADMINISTRATION: Dose Modifications.) 345
In the clinical studies described above, a 20-mg test dose was administered intravenously 346
over 10 minutes prior to the loading dose to all patients. The test dose did not reliably 347
identify patients at risk for severe allergic reactions. 348
Dermatologic Toxicity and Related Disorders 349
Non-suppurative acneform rash described as “acne”, “rash”, “maculopapular rash”, 350
“pustular rash”, “dry skin”, or “exfoliative dermatitis” was observed in patients receiving 351
ERBITUX plus irinotecan or ERBITUX monotherapy. One or more of the 352
dermatological adverse events were reported in 88% (14% Grade 3) of patients receiving 353
ERBITUX plus irinotecan and in 90% (10% Grade 3) of patients receiving ERBITUX 354
monotherapy. Acneform rash most commonly occurred on the face, upper chest, and 355
back, but could extend to the extremities and was characterized by multiple follicular- or 356
pustular-appearing lesions. Skin drying and fissuring were common in some instances, 357
and were associated with inflammatory and infectious sequelae (eg, blepharitis, cellulitis, 358
cyst). Two cases of S. aureus sepsis were reported. The onset of acneform rash was 359
generally within the first two weeks of therapy. Although in a majority of the patients the 360
event resolved following cessation of treatment, in nearly half of the cases, the event 361
continued beyond 28 days. (See WARNINGS: Dermatologic Toxicity and DOSAGE 362
AND ADMINISTRATION: Dose Modifications.) 363
A related nail disorder, occurring in 14% of patients (0.3% Grade 3), was characterized 364
as a paronychial inflammation with associated swelling of the lateral nail folds of the toes 365
and fingers, with the great toes and thumbs as the most commonly affected digits. 366
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Use with Radiation Therapy 367
In a study of 21 patients with locally advanced squamous cell cancer of the head and 368
neck, patients treated with ERBITUX, cisplatin, and radiation had a 95% incidence of 369
rash (19% Grade 3). The incidence and severity of cutaneous reactions with combined 370
modality therapy appears to be additive, particularly within the radiation port. The 371
addition of radiation to ERBITUX therapy in patients with colorectal cancer should be 372
done with appropriate caution. 373
OVERDOSAGE 374
Single doses of ERBITUX higher than 500 mg/m2 have not been tested. There is no 375
experience with overdosage in human clinical trials. 376
DOSAGE AND ADMINISTRATION 377
The recommended dose of ERBITUX, in combination with irinotecan or as monotherapy, 378
is 400 mg/m2 as an initial loading dose (first infusion) administered as a 120-minute IV 379
infusion (maximum infusion rate 5 mL/min). The recommended weekly maintenance 380
dose (all other infusions) is 250 mg/m2 infused over 60 minutes (maximum infusion rate 381
5 mL/min). Premedication with an H1 antagonist (eg, 50 mg of diphenhydramine IV) is 382
recommended. Appropriate medical resources for the treatment of severe infusion 383
reactions should be available during ERBITUX infusions. (See WARNINGS: Infusion 384
Reactions.) 385
Dose Modifications 386
Infusion Reactions 387
If the patient experiences a mild or moderate (Grade 1 or 2) infusion reaction, the 388
infusion rate should be permanently reduced by 50%. 389
ERBITUX should be immediately and permanently discontinued in patients who 390
experience severe (Grade 3 or 4) infusion reactions. (See WARNINGS and ADVERSE 391
REACTIONS.) 392
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Dermatologic Toxicity and Related Disorders 393
If a patient experiences severe acneform rash, ERBITUX treatment adjustments should 394
be made according to Table 4. In patients with mild and moderate skin toxicity, treatment 395
should continue without dose modification. (See WARNINGS and ADVERSE 396
REACTIONS.) 397
Table 4: ERBITUX Dose Modification Guidelines
Severe Acneform
Rash
ERBITUX Outcome ERBITUX Dose
Modification
1st occurrence Delay infusion 1 to 2 weeks Improvement Continue at 250 mg/m2
No Improvement Discontinue ERBITUX
2nd occurrence Delay infusion 1 to 2 weeks Improvement Reduce dose to 200 mg/m2
No Improvement Discontinue ERBITUX
3rd occurrence Delay infusion 1 to 2 weeks Improvement Reduce dose to 150 mg/m2
No Improvement Discontinue ERBITUX
4th occurrence Discontinue ERBITUX
398
Preparation for Administration 399
DO NOT ADMINISTER ERBITUX AS AN IV PUSH OR BOLUS. 400
ERBITUX must be administered with the use of a low protein binding 0.22- 401
micrometer in-line filter. 402
ERBITUX is supplied as a 50-mL, single-use vial containing 100 mg of Cetuximab at a 403
concentration of 2 mg/mL in phosphate buffered saline. The solution should be clear and 404
colorless and may contain a small amount of easily visible white amorphous Cetuximab 405
particulates. DO NOT SHAKE OR DILUTE. 406
ERBITUX CAN BE ADMINISTERED VIA INFUSION PUMP OR SYRINGE PUMP. 407
Infusion Pump: 408
? Draw up the volume of a vial using a sterile syringe attached to an appropriate 409
needle (a vented spike or other appropriate transfer device may be used). 410
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? Fill ERBITUX into a sterile evacuated container or bag such as glass containers, 411
polyolefin bags (eg, Baxter Intravia), ethylene vinyl acetate bags (eg, Baxter 412
Clintec), DEHP plasticized PVC bags (eg, Abbott Lifecare), or PVC bags. 413
? Repeat procedure until the calculated volume has been put in to the container. 414
Use a new needle for each vial. 415
? Administer through a low protein binding 0.22-micrometer in-line filter (placed as 416
proximal to the patient as practical). 417
? Affix the infusion line and prime it with ERBITUX before starting the infusion. 418
? Maximum infusion rate should not exceed 5 mL/min. 419
? Use 0.9% saline solution to flush line at the end of infusion. 420
Syringe Pump: 421
? Draw up the volume of a vial using a sterile syringe attached to an appropriate 422
needle (a vented spike may be used). 423
? Place the syringe into the syringe driver of a syringe pump and set the rate. 424
? Administer through a low protein binding 0.22-micrometer in-line filter rated for 425
syringe pump use (placed as proximal to the patient as practical). 426
? Connect up the infusion line and start the infusion after priming the line with 427
ERBITUX. 428
? Repeat procedure until the calculated volume has been infused. 429
? Use a new needle and filter for each vial. 430
? Maximum infusion rate should not exceed 5 mL/min. 431
? Use 0.9% saline solution to flush line at the end of infusion. 432
ERBITUX should be piggybacked to the patient’s infusion line. 433
Following the ERBITUX infusion, a 1-hour observation period is recommended. 434
HOW SUPPLIED 435
ERBITUX? (Cetuximab) is supplied as a single-use, 50-mL vial containing 100 mg of 436
Cetuximab as a sterile, preservative-free, injectable liquid. Each carton contains one 437
ERBITUX vial (NDC 66733-948-23). 438
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Stability and Storage 439
Store vials under refrigeration at 2? C to 8? C (36? F to 46? F). DO NOT FREEZE. 440
Increased particulate formation may occur at temperatures at or below 0?C. This product 441
contains no preservatives. Preparations of ERBITUX in infusion containers are 442
chemically and physically stable for up to 12 hours at 2? C to 8? C (36? F to 46? F) and 443
up to 8 hours at controlled room temperature (20? C to 25? C; 68? F to 77? F). Discard 444
any remaining solution in the infusion container after 8 hours at controlled room 445
temperature or after 12 hours at 2? to 8? C. Discard any unused portion of the vial. 446
447
US Patent No. 6,217,866 448
ERBITUX? is a trademark of ImClone Systems Incorporated. 449
Manufactured by ImClone Systems Incorporated, Branchburg, NJ 08876 450
Distributed and Marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 451
452
453
454
Copyright ? 2004 by ImClone Systems Incorporated and Bristol-Myers Squibb Company. All rights 455
reserved. 456
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xxxxxx Issued _____________ 459