ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
Erbitux 2 mg/ml solution for infusion
Each ml of solution for infusion contains 2 mg cetuximab.
Each vial of 50 ml contains 100 mg cetuximab.
Cetuximab is a chimeric monoclonal IgG
1
antibody produced in a mammalian cell line (Sp2/0) by
recombinant DNA technology.
For a full list of excipients, see section 6.1.
Solution for infusion.
Colourless solution that may contain product-related whitish and amorphous visible particles.
Erbitux is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-
expressing, KRAS wild-type metastatic colorectal cancer
• in combination with chemotherapy,
• as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who
are intolerant to irinotecan.
Erbitux is indicated for the treatment of patients with squamous cell cancer of the head and neck
• in combination with radiation therapy for locally advanced disease,
• in combination with platinum-based chemotherapy for recurrent and/or metastatic disease.
Erbitux must be administered under the supervision of a physician experienced in the use of
antineoplastic medicinal products. Close monitoring is required during the infusion and for at least
1 hour after the end of the infusion. Availability of resuscitation equipment must be ensured.
Posology
Prior to the first infusion, patients must receive premedication with an antihistamine and a
corticosteroid. This premedication is recommended prior to all subsequent infusions.
In all indications, Erbitux is administered once a week. The initial dose is 400 mg cetuximab per m²
body surface area. All subsequent weekly doses are 250 mg cetuximab per m² each.
2
Colorectal cancer
In patients with metastatic colorectal cancer, cetuximab is used in combination with chemotherapy
or as a single agent (see section 5.1). Detection of KRAS mutational status must be performed prior
to the first cetuximab infusion. It is important that a validated test method is used by an experienced
laboratory (see section 4.4 and 5.1).
For the dosage or recommended dose modifications of concomitantly used chemotherapeutic agents,
refer to the product information for these medicinal products. They must not be administered earlier
than 1 hour after the end of the cetuximab infusion.
It is recommended that cetuximab treatment be continued until progression of the underlying disease.
Squamous cell cancer of the head and neck
In patients with locally advanced squamous cell cancer of the head and neck, cetuximab is used
concomitantly with radiation therapy. It is recommended to start cetuximab therapy one week before
radiation therapy and to continue cetuximab therapy until the end of the radiation therapy period.
In patients with recurrent and/or metastatic squamous cell cancer of the head and neck, cetuximab
is used in combination with platinum-based chemotherapy followed by cetuximab as maintenance
therapy until disease progression (see section 5.1). Chemotherapy must not be administered earlier
than 1 hour after the end of the cetuximab infusion.
Method of administration
Erbitux 2 mg/ml is administered intravenously via in-line filtration with an infusion pump, gravity drip
or a syringe pump (for handling instructions, see section 6.6).
For the initial dose, the recommended infusion period is 120 minutes. For the subsequent weekly
doses, the recommended infusion period is 60 minutes. The maximum infusion rate must not exceed
10 mg/min, equivalent to 5 ml/min of Erbitux 2 mg/ml.
Special populations
Only patients with adequate renal and hepatic function have been investigated to date (see section 4.4).
Cetuximab has not been studied in patients with pre-existing haematological disorders (see
section 4.4).
No dose adjustment is required in the elderly, but the experience is limited in patients 75 years of age
and above.
Paediatric population
There is no experience in children (see section 4.4).
Erbitux is contraindicated in patients with known severe (grade 3 or 4) hypersensitivity reactions to
cetuximab.
Before initiation of combination treatment, contraindications for concomitantly used chemotherapeutic
agents or radiation therapy must be considered.
3
Infusion-related reactions
If the patient experiences a mild or moderate infusion-related reaction, the infusion rate may be
decreased. It is recommended to maintain this lower infusion rate in all subsequent infusions.
Severe infusion-related reactions have been reported in patients treated with cetuximab (see
section 4.8). Symptoms usually occurred during the first infusion and up to 1 hour after the end of
infusion, but may occur after several hours or with subsequent infusions. It is recommended to warn
patients of the possibility of such a late onset and instruct them to contact their physician if symptoms
of an infusion-related reaction occur. Occurrence of a severe infusion-related reaction requires
immediate and permanent discontinuation of cetuximab therapy and may necessitate emergency
treatment.
Special attention is recommended for patients with reduced performance status and pre-existing
cardio-pulmonary disease.
Respiratory disorders
Individual cases of interstitial lung disorders of unknown causal relationship to cetuximab have been
reported. If interstitial lung disease is diagnosed, cetuximab must be discontinued and the patient be
treated appropriately.
Skin reactions
If a patient experiences a severe skin reaction (≥ grade 3; US National Cancer Institute - Common
Terminology Criteria for Adverse Events, CTCAE), cetuximab therapy must be interrupted. Treatment
may only be resumed if the reaction has resolved to grade 2.
If the severe skin reaction occurred for the first time, treatment may be resumed without any change in
dose level.
With the second and third occurrences of severe skin reactions, cetuximab therapy must again be
interrupted. Treatment may only be resumed at a lower dose level (200 mg/m² after the second
occurrence and 150 mg/m² after the third occurrence), if the reaction has resolved to grade 2.
If severe skin reactions occur a fourth time or do not resolve to grade 2 during interruption of
treatment, permanent discontinuation of cetuximab treatment is required.
Electrolyte disturbances
Progressively decreasing serum magnesium levels occur frequently and may lead to severe
hypomagnesaemia. Hypomagnesaemia is reversible following discontinuation of cetuximab. In
addition, hypokalaemia may develop as a consequence of diarrhoea. Hypocalcaemia may also
occur; in particular in combination with platinum-based chemotherapy the frequency of severe
hypocalcaemia may be increased.
Determination of serum electrolyte levels is recommended prior to and periodically during cetuximab
treatment. Electrolyte repletion is recommended, as appropriate.
4
Neutropenia and related infectious complications
Patients who receive cetuximab in combination with platinum-based chemotherapy are at an increased
risk for the occurrence of severe neutropenia, which may lead to subsequent infectious complications
such as febrile neutropenia, pneumonia or sepsis. Careful monitoring is recommended in such patients,
in particular in those who experience skin lesions, mucositis or diarrhoea that may facilitate the
occurrence of infections (see section 4.8).
Cardiovascular disorders
An increased frequency of severe and sometimes fatal cardiovascular events and treatment emergent
deaths has been observed in the treatment of non-small cell lung cancer, squamous cell carcinoma of
the head and neck and colorectal carcinoma. In some studies (non-small cell lung cancer) association
with age ≥ 65 years has been observed. When prescribing cetuximab, the cardiovascular status of the
patients and concomitant administration of cardiotoxic compounds such as fluoropyrimidines should
be taken into account.
Colorectal cancer patients with KRAS mutated tumours
Cetuximab should not be used in the treatment of colorectal cancer patients whose tumours have
KRAS mutations or for whom KRAS tumour status is unknown. Results from clinical studies show a
negative benefit-risk balance in tumours with KRAS mutations.
Special populations
Only patients with adequate renal and hepatic function have been investigated to date (serum
creatinine ≤ 1.5fold, transaminases ≤ 5fold and bilirubin ≤ 1.5fold the upper limit of normal).
Cetuximab has not been studied in patients presenting with one or more of the following laboratory
parameters:
• haemoglobin < 9 g/dl
• leukocyte count < 3000/mm³
• absolute neutrophil count < 1500/mm³
• platelet count < 100000/mm³
There is limited experience in the use of cetuximab in combination with radiation therapy in colorectal
cancer.
Paediatric population
The safety and effectiveness of cetuximab in paediatric patients below the age of 18 years have not
been established.
In combination with platinum-based chemotherapy, the frequency of severe leukopenia or severe
neutropenia may be increased, and thus may lead to a higher rate of infectious complications such
as febrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (see
section 4.4).
In combination with fluoropyrimidines, the frequency of cardiac ischaemia including myocardial
infarction and congestive heart failure as well as the frequency of hand-foot syndrome (palmar-plantar
erythrodysaesthesia) were increased compared to that with fluoropyrimidines.
5
A formal interaction study showed that the pharmacokinetic characteristics of cetuximab remain
unaltered after co-administration of a single dose of irinotecan (350 mg/m² body surface area).
Similarly, the pharmacokinetics of irinotecan were unchanged when cetuximab was co-administered.
No other formal interaction studies with cetuximab have been performed in humans.
EGFR is involved in foetal development. Limited observations in animals are indicative of a placental
transfer of cetuximab, and other IgG
1
antibodies have been found to cross the placental barrier. Animal
data revealed no evidence of teratogenicity. However, dependent on the dose, an increased incidence
of abortion was observed (see section 5.3). Sufficient data from pregnant or lactating women are not
available.
It is strongly recommended that Erbitux be given during pregnancy or to any woman not employing
adequate contraception only if the potential benefit for the mother justifies a potential risk to the
foetus.
It is recommended that women do not breast-feed during treatment with Erbitux and for 2 months after
the last dose, because it is not known whether cetuximab is excreted in breast milk.
No studies on the effects on the ability to drive and use machines have been performed. If patients
experience treatment-related symptoms affecting their ability to concentrate and react, it is
recommended that they do not drive or use machines until the effect subsides.
The main undesirable effects of cetuximab are skin reactions, which occur in more than 80% of
patients, hypomagnesaemia which occurs in more than 10% of patients and infusion-related reactions,
which occur with mild to moderate symptoms in more than 10% of patients and with severe symptoms
in more than 1% of patients.
The following definitions apply to the frequency terminology used hereafter:
Very common (≥ 1/10)
Common (≥ 1/100 to < 1/10)
Uncommon (≥ 1/1,000 to < 1/100)
Rare (≥ 1/10,000 to < 1/1,000)
Very rare (< 1/10,000)
Frequency not known (cannot be estimated from the available data)
An asterisk (*) indicates that additional information on the respective undesirable effect is provided
below the table.
Metabolism and nutrition disorders
Dehydration, in particular secondary to diarrhoea or mucositis; hypocalcaemia
(see section 4.4); anorexia which may lead to weight decrease.
6
Very common: Hypomagnesaemia (see section 4.4).
Common:
Nervous system disorders
Common: Headache.
Frequency not known:Aseptic meningitis.
Eye disorders
Common: Conjunctivitis.
Uncommon: Blepharitis, keratitis.
Vascular disorders
Uncommon: Deep vein thrombosis.
Respiratory, thoracic and mediastinal disorders
Uncommon: Pulmonary embolism.
Gastrointestinal disorders
Common:
Diarrhoea, nausea, vomiting.
Hepatobiliary disorders
Very common: Increase in liver enzyme levels (ASAT, ALAT, AP).
Skin and subcutaneous tissue disorders
Very common: Skin reactions*.
Frequency not known:Superinfection of skin lesions*.
General disorders and administration site conditions
Very common: Mild or moderate infusion-related reactions*; mild to moderate mucositis which
may lead to epistaxis.
Common:
Severe infusion-related reactions*, fatigue.
Additional information
Overall, no clinically relevant difference between genders was observed.
Infusion-related reactions
Mild or moderate infusion-related reactions are very common comprising symptoms such as fever,
chills, dizziness, or dyspnoea that occur in a close temporal relationship mainly to the first cetuximab
infusion.
Severe infusion-related reactions may commonly occur, in rare cases with fatal outcome. They usually
develop during or within 1 hour of the initial cetuximab infusion, but may occur after several hours
or with subsequent infusions. Although the underlying mechanism has not been identified, some
of these reactions may be anaphylactoid/anaphylactic in nature and may include symptoms such as
bronchospasm, urticaria, increase or decrease in blood pressure, loss of consciousness or shock. In rare
cases, angina pectoris, myocardial infarction or cardiac arrest have been observed.
For clinical management of infusion-related reactions, see section 4.4.
7
Skin reactions
Skin reactions may develop in more than 80% of patients and mainly present as acne-like rash and/or,
less frequently, as pruritus, dry skin, desquamation, hypertrichosis, or nail disorders (e.g. paronychia).
Approximately 15% of the skin reactions are severe, including single cases of skin necrosis. The
majority of skin reactions develop within the first three weeks of therapy. They generally resolve,
without sequelae, over time following cessation of treatment if the recommended adjustments in dose
regimen are followed (see section 4.4).
Skin lesions induced by cetuximab may predispose patients to superinfections (e.g. with
S. aureus
),
which may lead to subsequent complications, e.g. cellulitis, erysipelas, or, potentially with fatal
outcome, staphylococcal scalded skin syndrome or sepsis.
Combination treatment
When cetuximab is used in combination with chemotherapeutic agents, also refer to their respective
product information.
In combination with platinum-based chemotherapy, the frequency of severe leukopenia or severe
neutropenia may be increased, and thus may lead to a higher rate of infectious complications such
as febrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (see
section 4.4).
In combination with fluoropyrimidines, the frequency of cardiac ischaemia including myocardial
infarction and congestive heart failure as well as the frequency of hand-foot syndrome (palmar-plantar
erythrodysaesthesia) were increased compared to that with fluoropyrimidines.
In combination with local radiation therapy of the head and neck area, additional undesirable
effects were those typical of radiation therapy (such as mucositis, radiation dermatitis, dysphagia
or leukopenia, mainly presenting as lymphocytopenia). In a randomised controlled clinical study
with 424 patients, reporting rates of severe acute radiation dermatitis and mucositis as well as of
late radiation-therapy-related events were slightly higher in patients receiving radiation therapy in
combination with cetuximab than in those receiving radiation therapy alone.
There is limited experience with single doses higher than 400 mg/m² body surface area to date or
weekly administrations of doses higher than 250 mg/m² body surface area. In clinical studies with
doses up to 700 mg/m² given every 2 weeks the safety profile was consistent with that described in
section 4.8.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC06
Mechanism of action
Cetuximab is a chimeric monoclonal IgG
1
antibody that is specifically directed against the epidermal
growth factor receptor (EGFR).
8
EGFR signalling pathways are involved in the control of cell survival, cell cycle progression,
angiogenesis, cell migration and cellular invasion/metastasis.
Cetuximab binds to the EGFR with an affinity that is approximately 5- to 10-fold higher than that of
endogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands resulting in inhibition
of the function of the receptor. It further induces the internalisation of EGFR, which can lead to
down-regulation of EGFR. Cetuximab also targets cytotoxic immune effector cells towards EGFR-
expressing tumour cells (antibody dependent cell-mediated cytotoxicity, ADCC).
Cetuximab does not bind to other receptors belonging to the HER family.
The protein product of the proto-oncogene KRAS (Kirsten rat sarcoma 2 viral oncogene homologue)
is a central down-stream signal-transducer of EGFR. In tumours, activation of KRAS by EGFR
contributes to EGFR-mediated increased proliferation, survival and the production of pro-angiogenic
factors.
KRAS is one of the most frequently activated oncogenes in human cancers. Mutations of the KRAS
gene at certain hot-spots (mainly codons 12 and 13) result in constitutive activation of the KRAS
protein independently of EGFR signalling.
Pharmacodynamic effects
In both
in vitro
and
in vivo
assays, cetuximab inhibits the proliferation and induces apoptosis of human
tumour cells that express EGFR.
In vitro
cetuximab inhibits the production of angiogenic factors by
tumour cells and blocks endothelial cell migration.
In vivo
cetuximab inhibits expression of angiogenic
factors by tumour cells and causes a reduction in tumour neo-vascularisation and metastasis.
Immunogenicity
The development of human anti-chimeric antibodies (HACA) is a class effect of monoclonal chimeric
antibodies. Current data on the development of HACAs is limited. Overall, measurable HACA titres
were noted in 3.4% of the patients studied, with incidences ranging from 0% to 9.6% in the target
indication studies. No conclusive data on the neutralising effect of HACAs on cetuximab is available
to date. The appearance of HACA did not correlate with the occurrence of hypersensitivity reactions or
any other undesirable effect to cetuximab.
Colorectal cancer
A diagnostic assay (EGFR pharmDx) was used for immunohistochemical detection of EGFR
expression in tumour material. A tumour was considered to be EGFR-expressing, if one stained cell
could be identified. Approximately 75% of the patients with metastatic colorectal cancer screened for
clinical studies had an EGFR-expressing tumour and were therefore considered eligible for cetuximab
treatment. The efficacy and safety of cetuximab have not been documented in patients with tumours
where EGFR was not detected.
In metastatic colorectal cancer, the incidence of KRAS mutations is in the range of 30 - 50%.
Recent data demonstrate that patients with KRAS wild-type metastatic colorectal cancer have a
significantly higher chance to benefit from treatment with cetuximab or a combination of cetuximab
and chemotherapy.
Cetuximab as a single agent or in combination with chemotherapy was investigated in 5 randomised
controlled clinical studies and several supportive studies. The 5 randomised studies investigated a total
of 3734 patients with metastatic colorectal cancer, in whom EGFR expression was detectable and who
had an ECOG performance status of ≤ 2. The majority of patients included had an ECOG performance
status of ≤ 1. In all studies, cetuximab was administered as described in section 4.2.
9
The KRAS status was recognised as predictive factor for the treatment with cetuximab in 4 of the
randomised controlled studies. KRAS mutational status was available for 2072 patients. Only in study
EMR 62 202-007, an analysis was not possible.
Cetuximab in combination with chemotherapy
• EMR 62 202-013: This randomised study in patients with metastatic colorectal cancer who had
not received prior treatment for metastatic disease compared the combination of cetuximab
and irinotecan plus infusional 5-fluorouracil/folinic acid (5-FU/FA) (599 patients) to the same
chemotherapy alone (599 patients). The proportion of patients with KRAS wild-type tumours
from the patient population evaluable for KRAS status comprised 63%.
The efficacy data generated in this study are summarised in the table below:
KRAS wild-type population
KRAS mutant population
Variable/ statistic
Cetuximab
plus FOLFIRI
FOLFIRI
Cetuximab
plus FOLFIRI
FOLFIRI
(N=316)
(N=350)
(N=214)
(N=183)
OS
months, median
23.5
20.0
16.2
16.7
(95% CI)
(21.2, 26.3) (17.4, 21.7) (14.9, 17.9) (14.9, 19.4)
Hazard Ratio (95% CI)
0.796 (0.670, 0.946)
1.035 (0.834, 1.284)
p-value
0.0093
0.7549
PFS
months, median
9.9
8.4
7.4
7.7
(95% CI)
(9.0, 11.3)
(7.4, 9.2)
(6.1, 8.0)
(7.3, 9.2)
Hazard Ratio (95% CI)
0.696 (0.558, 0.867)
1.171 (0.887, 1.544)
p-value
0.0012
0.2648
ORR
% 57.3 39.7 31.3 36.1
(95% CI) (51.6, 62.8) (34.6, 45.1) (25.2, 38.0) (29.1, 43.5)
Odds Ratio (95% CI) 2.069 (1.515, 2.826) 0.822 (0.544, 1.242)
p-value <0.0001 0.3475
CI = confidence interval, FOLFIRI = irinotecan plus infusional 5-FU/FA, ORR = objective response rate
(patients with complete response or partial response), OS = overall survival time, PFS = progression-free
survival time
• EMR 62 202-047: This randomised study in patients with metastatic colorectal cancer who had
not received prior treatment for metastatic disease compared the combination of cetuximab
and oxaliplatin plus infusional 5-fluorouracil/folinic acid (5-FU/FA) (169 patients) to the same
chemotherapy alone (168 patients). The proportion of patients with KRAS wild-type tumours
from the patient population evaluable for KRAS status comprised 57%.
10
The efficacy data generated in this study are summarised in the table below:
KRAS wild-type population
KRAS mutant population
Variable/ statistic
Cetuximab
plus FOLFOX
FOLFOX
Cetuximab
plus FOLFOX
FOLFOX
(N=82)
(N=97)
(N=77)
(N=59)
OS
months, median
22.8
18.5
13.4
17.5
(95% CI)
(19.3, 25.9) (16.4, 22.6) (10.5, 17.7) (14.7, 24.8)
Hazard Ratio (95% CI)
0.855 (0.599, 1.219)
1.290 (0.873, 1.906)
p-value
0.3854
0.2004
PFS
months, median
8.3
7.2
5.5
8.6
(95% CI)
(7.2, 12.0)
(5.6, 7.4)
(4.0, 7.3)
(6.5, 9.4)
Hazard Ratio (95% CI)
0.567 (0.375, 0.856)
1.720 (1.104, 2.679)
p-value
0.0064
0.0153
ORR
% 57.3 34.0 33.8 52.5
(95% CI) (45.9, 68.2) (24.7, 44.3) (23.4, 45.5) (39.1, 65.7)
Odds Ratio (95% CI) 2.551 (1.380, 4.717) 0.459 (0.228, 0.924)
p-value 0.0027 0.0290
CI = confidence interval, FOLFOX = oxaliplatin plus infusional 5-FU/FA, ORR = objective response rate
(patients with complete response or partial response), OS = overall survival time, PFS = progression-free
survival time
• CA225006: This randomised study in patients with metastatic colorectal cancer who had
received initial combination treatment with oxaliplatin plus fluoropyrimidine for metastatic
disease compared the combination of cetuximab and irinotecan (648 patients) with irinotecan
alone (650 patients). The proportion of patients with KRAS wild-type tumours from the patient
population evaluable for KRAS status comprised 64%.
A significant difference in overall survival time could not be shown in this study.
Following disease progression, treatment with EGFR-targeting agents was initiated in
50% of patients in the irinotecan-alone arm, which most likely impacted survival results.
Objective response rate and progression free survival time were significantly improved
with cetuximab. However, as no independent review of imaging data was conducted,
these results have to be interpreted with caution.
• EMR 62 202-007: This randomised study in patients with metastatic colorectal cancer after
failure of irinotecan-based treatment for metastatic disease as the last treatment before study
entry compared the combination of cetuximab and irinotecan (218 patients) with cetuximab
monotherapy (111 patients).
The combination of cetuximab with irinotecan compared to cetuximab alone reduced the
overall risk of disease progression by 46% and significantly increased objective response
rate. In the randomised trial, the improvement in overall survival time did not reach
statistical significance; however, in the follow-up treatment, nearly 50% of the patients
of the cetuximab alone arm received a combination of cetuximab and irinotecan after
progression of disease, which may have influenced overall survival time.
11
Cetuximab as a single agent
• CA225025: This randomised study in patients with metastatic colorectal cancer who had
received prior oxaliplatin-, irinotecan- and fluoropyrimidine-based treatment for metastatic
disease compared the addition of cetuximab as a single agent to best supportive care (BSC)
(287 patients) with best supportive care (285 patients). The proportion of patients with KRAS
wild-type tumours from the patient population evaluable for KRAS status comprised 58%.
The efficacy data generated in this study are summarised in the table below:
KRAS wild-type population
KRAS mutant population
Variable/ statistic
Cetuximab
plus BSC
BSC
Cetuximab
plus BSC
BSC
(N=117)
(N=113)
(N=81)
(N=83)
OS
months, median
9.5
4.8
4.5
4.6
(95% CI)
(7.7, 10.3)
(4.2, 5.5)
(3.8, 5.6)
(3.6, 5.5)
Hazard Ratio (95% CI)
0.552 (0.408, 0.748)
0.990 (0.705, 1.389)
p-value
<0.0001
0.9522
PFS
months, median
3.7
1.9
1.8
1.8
(95% CI)
(3.1, 5.1)
(1.8, 2.0)
(1.7, 1.8)
(1.7, 1.8)
Hazard Ratio (95% CI)
0.401 (0.299, 0.536)
1.002 (0.732, 1.371)
p-value
<0.0001
0.9895
ORR
%
12.8
0
1.2
0
(95% CI)
(7.4, 20.3)
(-)
(0.0, 6.7)
(-)
p-value <0.001 0.314
BSC = best supportive care, CI = confidence interval, ORR = objective response rate (patients with complete
response or partial response), OS = overall survival time, PFS = progression-free survival time
Squamous cell cancer of the head and neck
Immunohistochemical detection of EGFR expression was not performed since more than 90% of
patients with squamous cell cancer of the head and neck have tumours that express EGFR.
Cetuximab in combination with radiation therapy for locally advanced disease
• EMR 62 202-006: This randomised study compared the combination of cetuximab and
radiation therapy (211 patients) with radiation therapy alone (213 patients) in patients with
locally advanced squamous cell cancer of the head and neck. Cetuximab was started one week
before radiation therapy and administered at the doses described in section 4.2 until the end of
the radiation therapy period.
12
The efficacy data generated in this study are summarised in the table below:
Variable/ statistic
Radiation therapy + cetuximab
Radiation therapy alone
(N=211)
(N=213)
Locoregional control
months, median (95% CI) 24.4
(15.7, 45.1)
14.9
(11.8, 19.9)
Hazard Ratio (95% CI)
0.68 (0.52, 0.89)
p-value
0.005
OS
months, median (95% CI) 49.0
(32.8, 62.6+)
29.3
(20.6, 42.8)
Hazard Ratio (95% CI) 0.74 (0.56, 0.97)
p-value 0.032
CI = confidence interval, OS = overall survival time, a '+' denotes that the upper bound limit had not been
reached at cut-off
Patients with a good prognosis as indicated by tumour stage, Karnofsky performance
status (KPS) and age had a more pronounced benefit, when cetuximab was added to
radiation therapy. No clinical benefit could be demonstrated in patients with KPS ≤ 80
who were 65 years of age or older.
The use of cetuximab in combination with chemo-radiotherapy has so far not been adequately
investigated. Thus, a benefit-risk ratio for this combination has not yet been established.
Cetuximab in combination with platinum-based chemotherapy in recurrent and/or metastatic disease
• EMR 62 202-002: This randomised study in patients with recurrent and/or metastatic squamous
cell cancer of the head and neck who had not received prior chemotherapy for this disease
compared the combination of cetuximab and cisplatin or carboplatin plus infusional 5-
fluorouracil (222 patients) to the same chemotherapy alone (220 patients). Treatment in the
cetuximab arm consisted of up to 6 cycles of platinum-based chemotherapy in combination
with cetuximab followed by cetuximab as maintenance therapy until disease progression.
The efficacy data generated in this study are summarised in the table below:
Variable/ statistic
Cetuximab + CTX
CTX
(N=222)
(N=220)
OS
months, median (95% CI)
10.1 (8.6, 11.2)
7.4 (6.4, 8.3)
Hazard Ratio (95% CI)
0.797 (0.644, 0.986)
p-value
0.0362
PFS
months, median (95% CI)
5.6 (5.0, 6.0)
3.3 (2.9, 4.3)
Hazard Ratio (95% CI)
0.538 (0.431, 0.672)
p-value
<0.0001
ORR
% (95% CI)
35.6 (29.3, 42.3)
19.5 (14.5, 25.4)
p-value 0.0001
CI = confidence interval, CTX = platinum-based chemotherapy, ORR = objective response rate,
OS = overall survival time, PFS = progression-free survival time
Patients with a good prognosis as indicated by tumour stage, Karnofsky performance
status (KPS) and age had a more pronounced benefit, when cetuximab was added to
platinum-based chemotherapy. In contrast to progression free survival time, no benefit
in overall survival time could be demonstrated in patients with KPS ≤ 80 who were
65 years of age or older.
13
5.2 Pharmacokinetic properties
Cetuximab pharmacokinetics were studied when cetuximab was administered as monotherapy or
in combination with concomitant chemotherapy or radiation therapy in clinical studies. Intravenous
infusions of cetuximab exhibited dose-dependent pharmacokinetics at weekly doses ranging from 5 to
500 mg/m² body surface area.
When cetuximab was administered at an initial dose of 400 mg/m² body surface area, the mean volume
of distribution was approximately equivalent to the vascular space (2.9 l/m² with a range of 1.5 to
6.2 l/m²). The mean C
max
(± standard deviation) was 185±55 microgram per ml. The mean clearance
was 0.022 l/h per m² body surface area. Cetuximab has a long elimination half-life with values ranging
from 70 to 100 hours at the target dose.
Cetuximab serum concentrations reached stable levels after three weeks of cetuximab monotherapy.
Mean peak cetuximab concentrations were 155.8 microgram per ml in week 3 and 151.6 microgram
per ml in week 8, whereas the corresponding mean trough concentrations were 41.3 and
55.4 microgram per ml, respectively. In a study of cetuximab administered in combination
with irinotecan, the mean cetuximab trough levels were 50.0 microgram per ml in week 12 and
49.4 microgram per ml in week 36.
Several pathways have been described that may contribute to the metabolism of antibodies. All of
these pathways involve the biodegradation of the antibody to smaller molecules, i.e. small peptides or
amino acids.
Pharmacokinetics in special populations
An integrated analysis across all clinical studies showed that the pharmacokinetic characteristics of
cetuximab are not influenced by race, age, gender, renal or hepatic status.
Only patients with adequate renal and hepatic function have been investigated to date (serum
creatinine ≤ 1.5fold, transaminases ≤ 5fold and bilirubin ≤ 1.5fold the upper limit of normal).
5.3 Preclinical safety data
Dose-dependent skin alterations, starting at dose levels equivalent to those used in humans, were the
major findings observed in toxicity studies with Cynomolgus monkeys (a chronic repeat-dose toxicity
study and an embryo-foetal development study).
An embryo-foetal toxicity study in Cynomolgus monkeys revealed no signs of teratogenicity.
However, dependent on the dose, an increased incidence of abortion was observed.
Non-clinical data on genotoxicity and local tolerance including accidental administration by routes
other than the intended infusion revealed no special hazard for humans.
No formal animal studies have been performed to establish the carcinogenic potential of cetuximab or
to determine its effects on male and female fertility.
Toxicity studies with co-administration of cetuximab and chemotherapeutic agents have not been
performed.
No non-clinical data on the effect of cetuximab on wound healing are available to date. However, in
preclinical wound healing models EGFR selective tyrosine kinase inhibitors were shown to retard
wound healing.
14
6.1 List of excipients
Sodium dihydrogen phosphate
Disodium phosphate
Sodium chloride
Water for injections
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal
products.
6.3 Shelf life
2 years.
Chemical and physical in-use stability of Erbitux 2 mg/ml has been demonstrated for 20 hours at 25ºC.
Erbitux does not contain any antimicrobial preservative or bacteriostatic agent. From a microbiological
point of view, the product shall be used immediately after opening. If not used immediately, in-use
storage times and conditions prior to use are the responsibility of the user and would normally not be
longer than 24 hours at 2 to 8ºC, unless opening has taken place in controlled and validated aseptic
conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C). Do not freeze.
For storage conditions after opening, see section 6.3.
6.5 Nature and contents of container
50 ml of solution in a vial (Type I glass) with a stopper (teflon-coated bromobutyl rubber) and a seal
(aluminium).
Pack size of 1 vial.
6.6 Special precautions for disposal and other handling
Erbitux may be administered via a gravity drip, an infusion pump or a syringe pump. A separate
infusion line must be used for the infusion, and the line must be flushed with sterile sodium chloride
9 mg/ml (0.9%) solution for injection at the end of infusion.
Erbitux 2 mg/ml is a colourless solution that may contain product-related whitish and amorphous
visible particles. These particles do not affect the quality of the product. Nevertheless, the solution
must be filtered with an in-line filter of 0.2 micrometer or 0.22 micrometer nominal pore size during
administration.
Erbitux 2 mg/ml is compatible
• with polyethylene, ethyl vinyl acetate or polyvinyl chloride bags,
• with polyethylene, ethyl vinyl acetate, polyvinyl chloride, polybutadiene or polyurethane
infusion sets,
• with polyethersulfone, polyamide or polysulfone in-line filters.
15
Care must be taken to ensure aseptic handling when preparing the infusion.
Erbitux 2 mg/ml must be prepared as follows:
•
In-line filtration with an infusion pump or gravity drip:
Take an appropriate sterile syringe
(minimum 50 ml) and attach a suitable needle. Draw up the required volume of Erbitux from a
vial. Transfer the Erbitux into a sterile evacuated container or bag. Repeat this procedure until
the calculated volume has been reached. Insert a suitable in-line filter into the infusion line and
prime it with Erbitux or sterile sodium chloride 9 mg/ml (0.9%) solution before starting the
infusion. Use a gravity drip or an infusion pump for administration. Set and control the rate as
explained in section 4.2.
•
In-line filtration with a syringe pump:
Take an appropriate sterile syringe (minimum 50 ml)
and attach a suitable needle. Draw up the required volume of Erbitux from a vial. Remove the
needle and put the syringe into the syringe pump. Take a suitable in-line filter and connect
it to the application set. Connect the infusion line to the syringe, set and control the rate as
explained in section 4.2 and start the infusion after priming the line with Erbitux or sterile
sodium chloride 9 mg/ml (0.9%) solution. Repeat this procedure until the calculated volume
has been infused.
Filters may occasionally clog up during the infusion. If there is evidence of filter clogging, the filter
must be replaced.
Merck KGaA
64271 Darmstadt
Germany
8. MARKETING AUTHORISATION NUMBER
EU/1/04/281/001
Date of first authorisation: 29/06/2004
Date of renewal: 29/06/2009
MM/YYYY
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
16
Erbitux 5 mg/ml solution for infusion
Each ml of solution for infusion contains 5 mg cetuximab.
Each vial of 10 ml contains 50 mg cetuximab.
Each vial of 20 ml contains 100 mg cetuximab.
Each vial of 50 ml contains 250 mg cetuximab.
Each vial of 100 ml contains 500 mg cetuximab.
Cetuximab is a chimeric monoclonal IgG
1
antibody produced in a mammalian cell line (Sp2/0) by
recombinant DNA technology.
For a full list of excipients, see section 6.1.
Solution for infusion.
Colourless solution.
Erbitux is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-
expressing, KRAS wild-type metastatic colorectal cancer
• in combination with chemotherapy,
• as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who
are intolerant to irinotecan.
Erbitux is indicated for the treatment of patients with squamous cell cancer of the head and neck
• in combination with radiation therapy for locally advanced disease,
• in combination with platinum-based chemotherapy for recurrent and/or metastatic disease.
Erbitux must be administered under the supervision of a physician experienced in the use of
antineoplastic medicinal products. Close monitoring is required during the infusion and for at least
1 hour after the end of the infusion. Availability of resuscitation equipment must be ensured.
Posology
Prior to the first infusion, patients must receive premedication with an antihistamine and a
corticosteroid. This premedication is recommended prior to all subsequent infusions.
In all indications, Erbitux is administered once a week. The initial dose is 400 mg cetuximab per m²
body surface area. All subsequent weekly doses are 250 mg cetuximab per m² each.
17
Colorectal cancer
In patients with metastatic colorectal cancer, cetuximab is used in combination with chemotherapy
or as a single agent (see section 5.1). Detection of KRAS mutational status must be performed prior
to the first cetuximab infusion. It is important that a validated test method is used by an experienced
laboratory (see section 4.4 and 5.1).
For the dosage or recommended dose modifications of concomitantly used chemotherapeutic agents,
refer to the product information for these medicinal products. They must not be administered earlier
than 1 hour after the end of the cetuximab infusion.
It is recommended that cetuximab treatment be continued until progression of the underlying disease.
Squamous cell cancer of the head and neck
In patients with locally advanced squamous cell cancer of the head and neck, cetuximab is used
concomitantly with radiation therapy. It is recommended to start cetuximab therapy one week before
radiation therapy and to continue cetuximab therapy until the end of the radiation therapy period.
In patients with recurrent and/or metastatic squamous cell cancer of the head and neck, cetuximab
is used in combination with platinum-based chemotherapy followed by cetuximab as maintenance
therapy until disease progression (see section 5.1). Chemotherapy must not be administered earlier
than 1 hour after the end of the cetuximab infusion.
Method of administration
Erbitux 5 mg/ml is administered intravenously with an infusion pump, gravity drip or a syringe pump
(for handling instructions, see section 6.6).
For the initial dose, the recommended infusion period is 120 minutes. For the subsequent weekly
doses, the recommended infusion period is 60 minutes. The maximum infusion rate must not exceed
10 mg/min.
Special populations
Only patients with adequate renal and hepatic function have been investigated to date (see section 4.4).
Cetuximab has not been studied in patients with pre-existing haematological disorders (see
section 4.4).
No dose adjustment is required in the elderly, but the experience is limited in patients 75 years of age
and above.
Paediatric population
There is no experience in children (see section 4.4).
Erbitux is contraindicated in patients with known severe (grade 3 or 4) hypersensitivity reactions to
cetuximab.
Before initiation of combination treatment, contraindications for concomitantly used chemotherapeutic
agents or radiation therapy must be considered.
18
Infusion-related reactions
If the patient experiences a mild or moderate infusion-related reaction, the infusion rate may be
decreased. It is recommended to maintain this lower infusion rate in all subsequent infusions.
Severe infusion-related reactions have been reported in patients treated with cetuximab (see
section 4.8). Symptoms usually occurred during the first infusion and up to 1 hour after the end of
infusion, but may occur after several hours or with subsequent infusions. It is recommended to warn
patients of the possibility of such a late onset and instruct them to contact their physician if symptoms
of an infusion-related reaction occur. Occurrence of a severe infusion-related reaction requires
immediate and permanent discontinuation of cetuximab therapy and may necessitate emergency
treatment.
Special attention is recommended for patients with reduced performance status and pre-existing
cardio-pulmonary disease.
Respiratory disorders
Individual cases of interstitial lung disorders of unknown causal relationship to cetuximab have been
reported. If interstitial lung disease is diagnosed, cetuximab must be discontinued and the patient be
treated appropriately.
Skin reactions
If a patient experiences a severe skin reaction (≥ grade 3; US National Cancer Institute - Common
Terminology Criteria for Adverse Events, CTCAE), cetuximab therapy must be interrupted. Treatment
may only be resumed if the reaction has resolved to grade 2.
If the severe skin reaction occurred for the first time, treatment may be resumed without any change in
dose level.
With the second and third occurrences of severe skin reactions, cetuximab therapy must again be
interrupted. Treatment may only be resumed at a lower dose level (200 mg/m² after the second
occurrence and 150 mg/m² after the third occurrence), if the reaction has resolved to grade 2.
If severe skin reactions occur a fourth time or do not resolve to grade 2 during interruption of
treatment, permanent discontinuation of cetuximab treatment is required.
Electrolyte disturbances
Progressively decreasing serum magnesium levels occur frequently and may lead to severe
hypomagnesaemia. Hypomagnesaemia is reversible following discontinuation of cetuximab. In
addition, hypokalaemia may develop as a consequence of diarrhoea. Hypocalcaemia may also
occur; in particular in combination with platinum-based chemotherapy the frequency of severe
hypocalcaemia may be increased.
Determination of serum electrolyte levels is recommended prior to and periodically during cetuximab
treatment. Electrolyte repletion is recommended, as appropriate.
19
Neutropenia and related infectious complications
Patients who receive cetuximab in combination with platinum-based chemotherapy are at an increased
risk for the occurrence of severe neutropenia, which may lead to subsequent infectious complications
such as febrile neutropenia, pneumonia or sepsis. Careful monitoring is recommended in such patients,
in particular in those who experience skin lesions, mucositis or diarrhoea that may facilitate the
occurrence of infections (see section 4.8).
Cardiovascular disorders
An increased frequency of severe and sometimes fatal cardiovascular events and treatment emergent
deaths has been observed in the treatment of non-small cell lung cancer, squamous cell carcinoma of
the head and neck and colorectal carcinoma. In some studies (non-small cell lung cancer) association
with age ≥ 65 years has been observed. When prescribing cetuximab, the cardiovascular status of the
patients and concomitant administration of cardiotoxic compounds such as fluoropyrimidines should
be taken into account.
Colorectal cancer patients with KRAS mutated tumours
Cetuximab should not be used in the treatment of colorectal cancer patients whose tumours have
KRAS mutations or for whom KRAS tumour status is unknown. Results from clinical studies show a
negative benefit-risk balance in tumours with KRAS mutations.
Special populations
Only patients with adequate renal and hepatic function have been investigated to date (serum
creatinine ≤ 1.5fold, transaminases ≤ 5fold and bilirubin ≤ 1.5fold the upper limit of normal).
Cetuximab has not been studied in patients presenting with one or more of the following laboratory
parameters:
• haemoglobin < 9 g/dl
• leukocyte count < 3000/mm³
• absolute neutrophil count < 1500/mm³
• platelet count < 100000/mm³
There is limited experience in the use of cetuximab in combination with radiation therapy in colorectal
cancer.
Paediatric population
The safety and effectiveness of cetuximab in paediatric patients below the age of 18 years have not
been established.
In combination with platinum-based chemotherapy, the frequency of severe leukopenia or severe
neutropenia may be increased, and thus may lead to a higher rate of infectious complications such
as febrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (see
section 4.4).
In combination with fluoropyrimidines, the frequency of cardiac ischaemia including myocardial
infarction and congestive heart failure as well as the frequency of hand-foot syndrome (palmar-plantar
erythrodysaesthesia) were increased compared to that with fluoropyrimidines.
20
A formal interaction study showed that the pharmacokinetic characteristics of cetuximab remain
unaltered after co-administration of a single dose of irinotecan (350 mg/m² body surface area).
Similarly, the pharmacokinetics of irinotecan were unchanged when cetuximab was co-administered.
No other formal interaction studies with cetuximab have been performed in humans.
EGFR is involved in foetal development. Limited observations in animals are indicative of a placental
transfer of cetuximab, and other IgG
1
antibodies have been found to cross the placental barrier. Animal
data revealed no evidence of teratogenicity. However, dependent on the dose, an increased incidence
of abortion was observed (see section 5.3). Sufficient data from pregnant or lactating women are not
available.
It is strongly recommended that Erbitux be given during pregnancy or to any woman not employing
adequate contraception only if the potential benefit for the mother justifies a potential risk to the
foetus.
It is recommended that women do not breast-feed during treatment with Erbitux and for 2 months after
the last dose, because it is not known whether cetuximab is excreted in breast milk.
No studies on the effects on the ability to drive and use machines have been performed. If patients
experience treatment-related symptoms affecting their ability to concentrate and react, it is
recommended that they do not drive or use machines until the effect subsides.
The main undesirable effects of cetuximab are skin reactions, which occur in more than 80% of
patients, hypomagnesaemia which occurs in more than 10% of patients and infusion-related reactions,
which occur with mild to moderate symptoms in more than 10% of patients and with severe symptoms
in more than 1% of patients.
The following definitions apply to the frequency terminology used hereafter:
Very common (≥ 1/10)
Common (≥ 1/100 to < 1/10)
Uncommon (≥ 1/1,000 to < 1/100)
Rare (≥ 1/10,000 to < 1/1,000)
Very rare (< 1/10,000)
Frequency not known (cannot be estimated from the available data)
An asterisk (*) indicates that additional information on the respective undesirable effect is provided
below the table.
Metabolism and nutrition disorders
Dehydration, in particular secondary to diarrhoea or mucositis; hypocalcaemia
(see section 4.4); anorexia which may lead to weight decrease.
21
Very common: Hypomagnesaemia (see section 4.4).
Common:
Nervous system disorders
Common: Headache.
Frequency not known:Aseptic meningitis.
Eye disorders
Common: Conjunctivitis.
Uncommon: Blepharitis, keratitis.
Vascular disorders
Uncommon: Deep vein thrombosis.
Respiratory, thoracic and mediastinal disorders
Uncommon: Pulmonary embolism.
Gastrointestinal disorders
Common:
Diarrhoea, nausea, vomiting.
Hepatobiliary disorders
Very common: Increase in liver enzyme levels (ASAT, ALAT, AP).
Skin and subcutaneous tissue disorders
Very common: Skin reactions*.
Frequency not known:Superinfection of skin lesions*.
General disorders and administration site conditions
Very common: Mild or moderate infusion-related reactions*; mild to moderate mucositis which
may lead to epistaxis.
Common:
Severe infusion-related reactions*, fatigue.
Additional information
Overall, no clinically relevant difference between genders was observed.
Infusion-related reactions
Mild or moderate infusion-related reactions are very common comprising symptoms such as fever,
chills, dizziness, or dyspnoea that occur in a close temporal relationship mainly to the first cetuximab
infusion.
Severe infusion-related reactions may commonly occur, in rare cases with fatal outcome. They usually
develop during or within 1 hour of the initial cetuximab infusion, but may occur after several hours
or with subsequent infusions. Although the underlying mechanism has not been identified, some
of these reactions may be anaphylactoid/anaphylactic in nature and may include symptoms such as
bronchospasm, urticaria, increase or decrease in blood pressure, loss of consciousness or shock. In rare
cases, angina pectoris, myocardial infarction or cardiac arrest have been observed.
For clinical management of infusion-related reactions, see section 4.4.
22
Skin reactions
Skin reactions may develop in more than 80% of patients and mainly present as acne-like rash and/or,
less frequently, as pruritus, dry skin, desquamation, hypertrichosis, or nail disorders (e.g. paronychia).
Approximately 15% of the skin reactions are severe, including single cases of skin necrosis. The
majority of skin reactions develop within the first three weeks of therapy. They generally resolve,
without sequelae, over time following cessation of treatment if the recommended adjustments in dose
regimen are followed (see section 4.4).
Skin lesions induced by cetuximab may predispose patients to superinfections (e.g. with
S. aureus
),
which may lead to subsequent complications, e.g. cellulitis, erysipelas, or, potentially with fatal
outcome, staphylococcal scalded skin syndrome or sepsis.
Combination treatment
When cetuximab is used in combination with chemotherapeutic agents, also refer to their respective
product information.
In combination with platinum-based chemotherapy, the frequency of severe leukopenia or severe
neutropenia may be increased, and thus may lead to a higher rate of infectious complications such
as febrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (see
section 4.4).
In combination with fluoropyrimidines, the frequency of cardiac ischaemia including myocardial
infarction and congestive heart failure as well as the frequency of hand-foot syndrome (palmar-plantar
erythrodysaesthesia) were increased compared to that with fluoropyrimidines.
In combination with local radiation therapy of the head and neck area, additional undesirable
effects were those typical of radiation therapy (such as mucositis, radiation dermatitis, dysphagia
or leukopenia, mainly presenting as lymphocytopenia). In a randomised controlled clinical study
with 424 patients, reporting rates of severe acute radiation dermatitis and mucositis as well as of
late radiation-therapy-related events were slightly higher in patients receiving radiation therapy in
combination with cetuximab than in those receiving radiation therapy alone.
There is limited experience with single doses higher than 400 mg/m² body surface area to date or
weekly administrations of doses higher than 250 mg/m² body surface area. In clinical studies with
doses up to 700 mg/m² given every 2 weeks the safety profile was consistent with that described in
section 4.8.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC06
Mechanism of action
Cetuximab is a chimeric monoclonal IgG
1
antibody that is specifically directed against the epidermal
growth factor receptor (EGFR).
23
EGFR signalling pathways are involved in the control of cell survival, cell cycle progression,
angiogenesis, cell migration and cellular invasion/metastasis.
Cetuximab binds to the EGFR with an affinity that is approximately 5- to 10-fold higher than that of
endogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands resulting in inhibition
of the function of the receptor. It further induces the internalisation of EGFR, which can lead to
down-regulation of EGFR. Cetuximab also targets cytotoxic immune effector cells towards EGFR-
expressing tumour cells (antibody dependent cell-mediated cytotoxicity, ADCC).
Cetuximab does not bind to other receptors belonging to the HER family.
The protein product of the proto-oncogene KRAS (Kirsten rat sarcoma 2 viral oncogene homologue)
is a central down-stream signal-transducer of EGFR. In tumours, activation of KRAS by EGFR
contributes to EGFR-mediated increased proliferation, survival and the production of pro-angiogenic
factors.
KRAS is one of the most frequently activated oncogenes in human cancers. Mutations of the KRAS
gene at certain hot-spots (mainly codons 12 and 13) result in constitutive activation of the KRAS
protein independently of EGFR signalling.
Pharmacodynamic effects
In both
in vitro
and
in vivo
assays, cetuximab inhibits the proliferation and induces apoptosis of human
tumour cells that express EGFR.
In vitro
cetuximab inhibits the production of angiogenic factors by
tumour cells and blocks endothelial cell migration.
In vivo
cetuximab inhibits expression of angiogenic
factors by tumour cells and causes a reduction in tumour neo-vascularisation and metastasis.
Immunogenicity
The development of human anti-chimeric antibodies (HACA) is a class effect of monoclonal chimeric
antibodies. Current data on the development of HACAs is limited. Overall, measurable HACA titres
were noted in 3.4% of the patients studied, with incidences ranging from 0% to 9.6% in the target
indication studies. No conclusive data on the neutralising effect of HACAs on cetuximab is available
to date. The appearance of HACA did not correlate with the occurrence of hypersensitivity reactions or
any other undesirable effect to cetuximab.
Colorectal cancer
A diagnostic assay (EGFR pharmDx) was used for immunohistochemical detection of EGFR
expression in tumour material. A tumour was considered to be EGFR-expressing, if one stained cell
could be identified. Approximately 75% of the patients with metastatic colorectal cancer screened for
clinical studies had an EGFR-expressing tumour and were therefore considered eligible for cetuximab
treatment. The efficacy and safety of cetuximab have not been documented in patients with tumours
where EGFR was not detected.
In metastatic colorectal cancer, the incidence of KRAS mutations is in the range of 30 - 50%.
Recent data demonstrate that patients with KRAS wild-type metastatic colorectal cancer have a
significantly higher chance to benefit from treatment with cetuximab or a combination of cetuximab
and chemotherapy.
Cetuximab as a single agent or in combination with chemotherapy was investigated in 5 randomised
controlled clinical studies and several supportive studies. The 5 randomised studies investigated a total
of 3734 patients with metastatic colorectal cancer, in whom EGFR expression was detectable and who
had an ECOG performance status of ≤ 2. The majority of patients included had an ECOG performance
status of ≤ 1. In all studies, cetuximab was administered as described in section 4.2.
24
The KRAS status was recognised as predictive factor for the treatment with cetuximab in 4 of the
randomised controlled studies. KRAS mutational status was available for 2072 patients. Only in study
EMR 62 202-007, an analysis was not possible.
Cetuximab in combination with chemotherapy
• EMR 62 202-013: This randomised study in patients with metastatic colorectal cancer who had
not received prior treatment for metastatic disease compared the combination of cetuximab
and irinotecan plus infusional 5-fluorouracil/folinic acid (5-FU/FA) (599 patients) to the same
chemotherapy alone (599 patients). The proportion of patients with KRAS wild-type tumours
from the patient population evaluable for KRAS status comprised 63%.
The efficacy data generated in this study are summarised in the table below:
KRAS wild-type population
KRAS mutant population
Variable/ statistic
Cetuximab
plus FOLFIRI
FOLFIRI
Cetuximab
plus FOLFIRI
FOLFIRI
(N=316)
(N=350)
(N=214)
(N=183)
OS
months, median
23.5
20.0
16.2
16.7
(95% CI)
(21.2, 26.3) (17.4, 21.7) (14.9, 17.9) (14.9, 19.4)
Hazard Ratio (95% CI)
0.796 (0.670, 0.946)
1.035 (0.834, 1.284)
p-value
0.0093
0.7549
PFS
months, median
9.9
8.4
7.4
7.7
(95% CI)
(9.0, 11.3)
(7.4, 9.2)
(6.1, 8.0)
(7.3, 9.2)
Hazard Ratio (95% CI)
0.696 (0.558, 0.867)
1.171 (0.887, 1.544)
p-value
0.0012
0.2648
ORR
% 57.3 39.7 31.3 36.1
(95% CI) (51.6, 62.8) (34.6, 45.1) (25.2, 38.0) (29.1, 43.5)
Odds Ratio (95% CI) 2.069 (1.515, 2.826) 0.822 (0.544, 1.242)
p-value <0.0001 0.3475
CI = confidence interval, FOLFIRI = irinotecan plus infusional 5-FU/FA, ORR = objective response rate
(patients with complete response or partial response), OS = overall survival time, PFS = progression-free
survival time
• EMR 62 202-047: This randomised study in patients with metastatic colorectal cancer who had
not received prior treatment for metastatic disease compared the combination of cetuximab
and oxaliplatin plus infusional 5-fluorouracil/folinic acid (5-FU/FA) (169 patients) to the same
chemotherapy alone (168 patients). The proportion of patients with KRAS wild-type tumours
from the patient population evaluable for KRAS status comprised 57%.
25
The efficacy data generated in this study are summarised in the table below:
KRAS wild-type population
KRAS mutant population
Variable/ statistic
Cetuximab
plus FOLFOX
FOLFOX
Cetuximab
plus FOLFOX
FOLFOX
(N=82)
(N=97)
(N=77)
(N=59)
OS
months, median
22.8
18.5
13.4
17.5
(95% CI)
(19.3, 25.9) (16.4, 22.6) (10.5, 17.7) (14.7, 24.8)
Hazard Ratio (95% CI)
0.855 (0.599, 1.219)
1.290 (0.873, 1.906)
p-value
0.3854
0.2004
PFS
months, median
8.3
7.2
5.5
8.6
(95% CI)
(7.2, 12.0)
(5.6, 7.4)
(4.0, 7.3)
(6.5, 9.4)
Hazard Ratio (95% CI)
0.567 (0.375, 0.856)
1.720 (1.104, 2.679)
p-value
0.0064
0.0153
ORR
% 57.3 34.0 33.8 52.5
(95% CI) (45.9, 68.2) (24.7, 44.3) (23.4, 45.5) (39.1, 65.7)
Odds Ratio (95% CI) 2.551 (1.380, 4.717) 0.459 (0.228, 0.924)
p-value 0.0027 0.0290
CI = confidence interval, FOLFOX = oxaliplatin plus infusional 5-FU/FA, ORR = objective response rate
(patients with complete response or partial response), OS = overall survival time, PFS = progression-free
survival time
• CA225006: This randomised study in patients with metastatic colorectal cancer who had
received initial combination treatment with oxaliplatin plus fluoropyrimidine for metastatic
disease compared the combination of cetuximab and irinotecan (648 patients) with irinotecan
alone (650 patients). The proportion of patients with KRAS wild-type tumours from the patient
population evaluable for KRAS status comprised 64%.
A significant difference in overall survival time could not be shown in this study.
Following disease progression, treatment with EGFR-targeting agents was initiated in
50% of patients in the irinotecan-alone arm, which most likely impacted survival results.
Objective response rate and progression free survival time were significantly improved
with cetuximab. However, as no independent review of imaging data was conducted,
these results have to be interpreted with caution.
• EMR 62 202-007: This randomised study in patients with metastatic colorectal cancer after
failure of irinotecan-based treatment for metastatic disease as the last treatment before study
entry compared the combination of cetuximab and irinotecan (218 patients) with cetuximab
monotherapy (111 patients).
The combination of cetuximab with irinotecan compared to cetuximab alone reduced the
overall risk of disease progression by 46% and significantly increased objective response
rate. In the randomised trial, the improvement in overall survival time did not reach
statistical significance; however, in the follow-up treatment, nearly 50% of the patients
of the cetuximab alone arm received a combination of cetuximab and irinotecan after
progression of disease, which may have influenced overall survival time.
26
Cetuximab as a single agent
• CA225025: This randomised study in patients with metastatic colorectal cancer who had
received prior oxaliplatin-, irinotecan- and fluoropyrimidine-based treatment for metastatic
disease compared the addition of cetuximab as a single agent to best supportive care (BSC)
(287 patients) with best supportive care (285 patients). The proportion of patients with KRAS
wild-type tumours from the patient population evaluable for KRAS status comprised 58%.
The efficacy data generated in this study are summarised in the table below:
KRAS wild-type population
KRAS mutant population
Variable/ statistic
Cetuximab
plus BSC
BSC
Cetuximab
plus BSC
BSC
(N=117)
(N=113)
(N=81)
(N=83)
OS
months, median
9.5
4.8
4.5
4.6
(95% CI)
(7.7, 10.3)
(4.2, 5.5)
(3.8, 5.6)
(3.6, 5.5)
Hazard Ratio (95% CI)
0.552 (0.408, 0.748)
0.990 (0.705, 1.389)
p-value
<0.0001
0.9522
PFS
months, median
3.7
1.9
1.8
1.8
(95% CI)
(3.1, 5.1)
(1.8, 2.0)
(1.7, 1.8)
(1.7, 1.8)
Hazard Ratio (95% CI)
0.401 (0.299, 0.536)
1.002 (0.732, 1.371)
p-value
<0.0001
0.9895
ORR
%
12.8
0
1.2
0
(95% CI)
(7.4, 20.3)
(-)
(0.0, 6.7)
(-)
p-value <0.001 0.314
BSC = best supportive care, CI = confidence interval, ORR = objective response rate (patients with complete
response or partial response), OS = overall survival time, PFS = progression-free survival time
Squamous cell cancer of the head and neck
Immunohistochemical detection of EGFR expression was not performed since more than 90% of
patients with squamous cell cancer of the head and neck have tumours that express EGFR.
Cetuximab in combination with radiation therapy for locally advanced disease
• EMR 62 202-006: This randomised study compared the combination of cetuximab and
radiation therapy (211 patients) with radiation therapy alone (213 patients) in patients with
locally advanced squamous cell cancer of the head and neck. Cetuximab was started one week
before radiation therapy and administered at the doses described in section 4.2 until the end of
the radiation therapy period.
27
The efficacy data generated in this study are summarised in the table below:
Variable/ statistic
Radiation therapy + cetuximab
Radiation therapy alone
(N=211)
(N=213)
Locoregional control
months, median (95% CI) 24.4
(15.7, 45.1)
14.9
(11.8, 19.9)
Hazard Ratio (95% CI)
0.68 (0.52, 0.89)
p-value
0.005
OS
months, median (95% CI) 49.0
(32.8, 62.6+)
29.3
(20.6, 42.8)
Hazard Ratio (95% CI) 0.74 (0.56, 0.97)
p-value 0.032
CI = confidence interval, OS = overall survival time, a '+' denotes that the upper bound limit had not been
reached at cut-off
Patients with a good prognosis as indicated by tumour stage, Karnofsky performance
status (KPS) and age had a more pronounced benefit, when cetuximab was added to
radiation therapy. No clinical benefit could be demonstrated in patients with KPS ≤ 80
who were 65 years of age or older.
The use of cetuximab in combination with chemo-radiotherapy has so far not been adequately
investigated. Thus, a benefit-risk ratio for this combination has not yet been established.
Cetuximab in combination with platinum-based chemotherapy in recurrent and/or metastatic disease
• EMR 62 202-002: This randomised study in patients with recurrent and/or metastatic squamous
cell cancer of the head and neck who had not received prior chemotherapy for this disease
compared the combination of cetuximab and cisplatin or carboplatin plus infusional 5-
fluorouracil (222 patients) to the same chemotherapy alone (220 patients). Treatment in the
cetuximab arm consisted of up to 6 cycles of platinum-based chemotherapy in combination
with cetuximab followed by cetuximab as maintenance therapy until disease progression.
The efficacy data generated in this study are summarised in the table below:
Variable/ statistic
Cetuximab + CTX
CTX
(N=222)
(N=220)
OS
months, median (95% CI)
10.1 (8.6, 11.2)
7.4 (6.4, 8.3)
Hazard Ratio (95% CI)
0.797 (0.644, 0.986)
p-value
0.0362
PFS
months, median (95% CI)
5.6 (5.0, 6.0)
3.3 (2.9, 4.3)
Hazard Ratio (95% CI)
0.538 (0.431, 0.672)
p-value
<0.0001
ORR
% (95% CI)
35.6 (29.3, 42.3)
19.5 (14.5, 25.4)
p-value 0.0001
CI = confidence interval, CTX = platinum-based chemotherapy, ORR = objective response rate,
OS = overall survival time, PFS = progression-free survival time
Patients with a good prognosis as indicated by tumour stage, Karnofsky performance
status (KPS) and age had a more pronounced benefit, when cetuximab was added to
platinum-based chemotherapy. In contrast to progression free survival time, no benefit
in overall survival time could be demonstrated in patients with KPS ≤ 80 who were
65 years of age or older.
28
5.2 Pharmacokinetic properties
Cetuximab pharmacokinetics were studied when cetuximab was administered as monotherapy or
in combination with concomitant chemotherapy or radiation therapy in clinical studies. Intravenous
infusions of cetuximab exhibited dose-dependent pharmacokinetics at weekly doses ranging from 5 to
500 mg/m² body surface area.
When cetuximab was administered at an initial dose of 400 mg/m² body surface area, the mean volume
of distribution was approximately equivalent to the vascular space (2.9 l/m² with a range of 1.5 to
6.2 l/m²). The mean C
max
(± standard deviation) was 185±55 microgram per ml. The mean clearance
was 0.022 l/h per m² body surface area. Cetuximab has a long elimination half-life with values ranging
from 70 to 100 hours at the target dose.
Cetuximab serum concentrations reached stable levels after three weeks of cetuximab monotherapy.
Mean peak cetuximab concentrations were 155.8 microgram per ml in week 3 and 151.6 microgram
per ml in week 8, whereas the corresponding mean trough concentrations were 41.3 and
55.4 microgram per ml, respectively. In a study of cetuximab administered in combination
with irinotecan, the mean cetuximab trough levels were 50.0 microgram per ml in week 12 and
49.4 microgram per ml in week 36.
Several pathways have been described that may contribute to the metabolism of antibodies. All of
these pathways involve the biodegradation of the antibody to smaller molecules, i.e. small peptides or
amino acids.
Pharmacokinetics in special populations
An integrated analysis across all clinical studies showed that the pharmacokinetic characteristics of
cetuximab are not influenced by race, age, gender, renal or hepatic status.
Only patients with adequate renal and hepatic function have been investigated to date (serum
creatinine ≤ 1.5fold, transaminases ≤ 5fold and bilirubin ≤ 1.5fold the upper limit of normal).
5.3 Preclinical safety data
Dose-dependent skin alterations, starting at dose levels equivalent to those used in humans, were the
major findings observed in toxicity studies with Cynomolgus monkeys (a chronic repeat-dose toxicity
study and an embryo-foetal development study).
An embryo-foetal toxicity study in Cynomolgus monkeys revealed no signs of teratogenicity.
However, dependent on the dose, an increased incidence of abortion was observed.
Non-clinical data on genotoxicity and local tolerance including accidental administration by routes
other than the intended infusion revealed no special hazard for humans.
No formal animal studies have been performed to establish the carcinogenic potential of cetuximab or
to determine its effects on male and female fertility.
Toxicity studies with co-administration of cetuximab and chemotherapeutic agents have not been
performed.
No non-clinical data on the effect of cetuximab on wound healing are available to date. However, in
preclinical wound healing models EGFR selective tyrosine kinase inhibitors were shown to retard
wound healing.
29
6.1 List of excipients
Sodium chloride
Glycine
Polysorbate 80
Citric acid monohydrate
Sodium hydroxide
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
3 years.
Chemical and physical in-use stability of Erbitux 5 mg/ml has been demonstrated for 48 hours at 25ºC,
if the solution is prepared as described in section 6.6.
Erbitux does not contain any antimicrobial preservative or bacteriostatic agent. From a microbiological
point of view, the product shall be used immediately after opening. If not used immediately, in-use
storage times and conditions prior to use are the responsibility of the user and would normally not be
longer than 24 hours at 2 to 8ºC, unless opening has taken place in controlled and validated aseptic
conditions.
6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).
For storage conditions after opening, see section 6.3.
6.5 Nature and contents of container
10 ml, 20 ml, 50 ml or 100 ml of solution in a vial (Type I glass) with a stopper (flurotec-coated
bromobutyl rubber) and a seal (aluminium/polypropylen).
Pack size of 1 vial.
Not all vial sizes may be marketed.
6.6 Special precautions for disposal and other handling
Erbitux may be administered via a gravity drip, an infusion pump or a syringe pump. A separate
infusion line must be used for the infusion, and the line must be flushed with sterile sodium chloride
9 mg/ml (0.9%) solution for injection at the end of infusion.
Erbitux 5 mg/ml is compatible
• with polyethylene (PE), ethyl vinyl acetate (EVA) or polyvinyl chloride (PVC) bags,
• with polyethylene (PE), polyurethane (PUR), ethyl vinyl acetate (EVA), polyolefine
thermoplastic (TP) or polyvinyl chloride (PVC) infusion sets,
• with polypropylene (PP) syringes for syringe pump.
30
Care must be taken to ensure aseptic handling when preparing the infusion.
Erbitux 5 mg/ml must be prepared as follows:
•
For administration with infusion pump or gravity drip (diluted with sterile sodium chloride
9 mg/ml (0.9%) solution):
Take an infusion bag of adequate size of sterile sodium chloride
9 mg/ml (0.9%) solution. Calculate the required volume of Erbitux. Remove an adequate
volume of the sodium chloride solution from the infusion bag, using an appropriate sterile
syringe with a suitable needle. Take an appropriate sterile syringe and attach a suitable needle.
Draw up the required volume of Erbitux from a vial. Transfer the Erbitux into the prepared
infusion bag. Repeat this procedure until the calculated volume has been reached. Connect the
infusion line and prime it with the diluted Erbitux before starting the infusion. Use a gravity
drip or an infusion pump for administration. Set and control the rate as explained in section 4.2.
•
For administration with infusion pump or gravity drip (undiluted):
Calculate the required
volume of Erbitux. Take an appropriate sterile syringe (minimum 50 ml) and attach a suitable
needle. Draw up the required volume of Erbitux from a vial. Transfer the Erbitux into a sterile
evacuated container or bag. Repeat this procedure until the calculated volume has been reached.
Connect the infusion line and prime it with Erbitux before starting the infusion. Set and control
the rate as explained in section 4.2.
•
For administration with a syringe pump:
Calculate the required volume of Erbitux. Take an
appropriate sterile syringe and attach a suitable needle. Draw up the required volume of Erbitux
from a vial. Remove the needle and put the syringe into the syringe pump. Connect the infusion
line to the syringe, set and control the rate as explained in section 4.2 and start the infusion after
priming the line with Erbitux or sterile sodium chloride 9 mg/ml (0.9%) solution. If necessary,
repeat this procedure until the calculated volume has been infused.
Merck KGaA
64271 Darmstadt
Germany
8. MARKETING AUTHORISATION NUMBERS
EU/1/04/281/002
EU/1/04/281/003
EU/1/04/281/004
EU/1/04/281/005
Date of first authorisation: 29/06/2004
Date of renewal: 29/06/2009
MM/YYYY
31
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
32
ANNEX II
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
33
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers of the biological active substance
Merck KGaA
Frankfurter Straße 250
64293 Darmstadt
Germany
Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Str. 65
88397 Biberach
Germany
Name and address of the manufacturer responsible for batch release
Merck KGaA
Frankfurter Straße 250
64293 Darmstadt
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 9.0 presented
in Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 12.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use,
the updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
34
In addition, an updated RMP should be submitted
• When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
• Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
• At the request of the EMEA
35
ANNEX III
LABELLING AND PACKAGE LEAFLET
36
A. LABELLING
37
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
Erbitux 2 mg/ml solution for infusion
Cetuximab
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial of 50 ml contains 100 mg cetuximab (2 mg/ml).
3. LIST OF EXCIPIENTS
Sodium dihydrogen phosphate, disodium phosphate, sodium chloride, water for injections
Solution for infusion
1 vial of 100 mg/50 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Administer via in-line filtration.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
38
9. SPECIAL STORAGE CONDITIONS
Store in a refrigerator. Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck KGaA
64271 Darmstadt
Germany
12. MARKETING AUTHORISATION NUMBER
EU/1/04/281/001
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
39
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
Erbitux 2 mg/ml solution for infusion
Cetuximab
Intravenous use.
2. METHOD OF ADMINISTRATION
Administer via in-line filtration.
Read the package leaflet before use.
3. EXPIRY DATE
EXP
4. BATCH NUMBER
BN
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
100 mg/50 ml
6. OTHER
Store in a refrigerator. Do not freeze.
Merck KGaA
64271 Darmstadt
Germany
40
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
Erbitux 5 mg/ml solution for infusion
Cetuximab
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial of 10 ml contains 50 mg cetuximab (5 mg/ml).
3. LIST OF EXCIPIENTS
Sodium chloride, glycine, polysorbate 80, citric acid monohydrate, sodium hydroxide, water for
injections
Solution for infusion
1 vial of 50 mg/10 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
41
9. SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck KGaA
64271 Darmstadt
Germany
12. MARKETING AUTHORISATION NUMBER
EU/1/04/281/002
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
42
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
Erbitux 5 mg/ml solution for infusion
Cetuximab
Intravenous use.
2. METHOD OF ADMINISTRATION
Read the package leaflet before use.
3. EXPIRY DATE
EXP
4. BATCH NUMBER
BN
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
50 mg/10 ml
6. OTHER
Store in a refrigerator.
Merck KGaA
64271 Darmstadt
Germany
43
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
Erbitux 5 mg/ml solution for infusion
Cetuximab
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial of 20 ml contains 100 mg cetuximab (5 mg/ml).
3. LIST OF EXCIPIENTS
Sodium chloride, glycine, polysorbate 80, citric acid monohydrate, sodium hydroxide, water for
injections
Solution for infusion
1 vial of 100 mg/20 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
44
9. SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck KGaA
64271 Darmstadt
Germany
12. MARKETING AUTHORISATION NUMBER
EU/1/04/281/003
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
45
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
Erbitux 5 mg/ml solution for infusion
Cetuximab
Intravenous use.
2. METHOD OF ADMINISTRATION
Read the package leaflet before use.
3. EXPIRY DATE
EXP
4. BATCH NUMBER
BN
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
100 mg/20 ml
6. OTHER
Store in a refrigerator.
Merck KGaA
64271 Darmstadt
Germany
46
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
Erbitux 5 mg/ml solution for infusion
Cetuximab
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial of 50 ml contains 250 mg cetuximab (5 mg/ml).
3. LIST OF EXCIPIENTS
Sodium chloride, glycine, polysorbate 80, citric acid monohydrate, sodium hydroxide, water for
injections
Solution for infusion
1 vial of 250 mg/50 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
47
9. SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck KGaA
64271 Darmstadt
Germany
12. MARKETING AUTHORISATION NUMBER
EU/1/04/281/004
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
48
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
Erbitux 5 mg/ml solution for infusion
Cetuximab
Intravenous use.
2. METHOD OF ADMINISTRATION
Read the package leaflet before use.
3. EXPIRY DATE
EXP
4. BATCH NUMBER
BN
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
250 mg/50 ml
6. OTHER
Store in a refrigerator.
Merck KGaA
64271 Darmstadt
Germany
49
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
Erbitux 5 mg/ml solution for infusion
Cetuximab
2. STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial of 100 ml contains 500 mg cetuximab (5 mg/ml).
3. LIST OF EXCIPIENTS
Sodium chloride, glycine, polysorbate 80, citric acid monohydrate, sodium hydroxide, water for
injections
Solution for infusion
1 vial of 500 mg/100 ml
5. METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use.
Read the package leaflet before use.
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7. OTHER SPECIAL WARNING(S), IF NECESSARY
8. EXPIRY DATE
EXP
50
9. SPECIAL STORAGE CONDITIONS
Store in a refrigerator.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Merck KGaA
64271 Darmstadt
Germany
12. MARKETING AUTHORISATION NUMBER
EU/1/04/281/005
13. BATCH NUMBER
BN
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
51
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
Erbitux 5 mg/ml solution for infusion
Cetuximab
Intravenous use.
2. METHOD OF ADMINISTRATION
Read the package leaflet before use.
3. EXPIRY DATE
EXP
4. BATCH NUMBER
BN
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
500 mg/100 ml
6. OTHER
Store in a refrigerator.
Merck KGaA
64271 Darmstadt
Germany
52
B. PACKAGE LEAFLET
53
PACKAGE LEAFLET: INFORMATION FOR THE USER
Erbitux 2 mg/ml solution for infusion
Cetuximab
Read all of this leaflet carefully before you start using this medicine.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor.
• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet:
1. What Erbitux is and what it is used for
2. Before you use Erbitux
3. How to use Erbitux
4. Possible side effects
5. How to store Erbitux
6. Further information
1. WHAT ERBITUX IS AND WHAT IT IS USED FOR
What Erbitux is
Erbitux contains cetuximab, a monoclonal antibody. Monoclonal antibodies are proteins that
specifically recognise and bind to other unique proteins called antigens. Cetuximab binds to the
epidermal growth factor receptor (EGFR), an antigen on the surface of certain cancer cells. As a result
of this binding, the cancer cell can no longer receive the messages it needs for growth, progression and
metastasis.
What Erbitux is used for
Erbitux is used to treat two different types of cancer:
• metastatic cancer of the large intestine. In these patients, Erbitux is used alone or in
combination with other anticancer medicines.
• a certain type of cancer of the head and neck (squamous cell cancer). In these patients, Erbitux
is used in combination with radiation therapy or with other anticancer medicines.
2. BEFORE YOU USE ERBITUX
Do not use Erbitux
Do not use Erbitux if you have ever had a severe hypersensitivity (allergic) reaction to cetuximab.
Take special care with Erbitux
Erbitux may cause infusion-related side effects. Such reactions may be allergic in nature. Please read
'Infusion-related side effects' in section 4 for details, as they may have serious consequences for you,
including life-threatening conditions. These side effects normally occur during the infusion, within
1 hour afterwards, or sometimes also after this period. To recognise early signs of such effects, your
condition will be checked regularly while you receive each infusion of Erbitux and for at least 1 hour
afterwards.
54
If you receive Erbitux in combination with anticancer medicines including platinum, it is more likely
that your white blood cell count may be reduced. Your doctor will therefore monitor your blood and
general condition for signs of infection (see also 'Side effects in combination with other anticancer
treatments' in section 4).
If you receive Erbitux in combination with other anticancer medicines, including fluoropyrimidines,
it may be more likely that you experience heart problems which may be life-threatening. Your doctor
will discuss with you whether you may need any particular supervision (see also 'Side effects in
combination with other anticancer treatments' in section 4).
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
Pregnancy
Tell your doctor if you are pregnant or if you are not using reliable contraception (speak to your doctor
if you are not sure). Your doctor will then discuss with you the risks and benefits of using Erbitux in
these situations.
Breast-feeding
Do not breast-feed your baby during the period over which you are being treated with Erbitux and for
two months after the last dose.
Driving and using machines
Do not drive or use any tools or machines if you experience treatment-related symptoms that affect
your ability to concentrate and react.
3. HOW TO USE ERBITUX
A doctor experienced in the use of anticancer medicines will supervise your Erbitux therapy. During
each infusion and for at least 1 hour afterwards, your condition will be checked regularly for early
signs of a possible infusion-related side effect.
Pre-treatment
Before the first dose, you will receive an antiallergic medicine in order to reduce the risk of an allergic
reaction. Your doctor will decide whether such pre-treatment is necessary for subsequent doses.
Dosage and administration
Erbitux is usually infused into a vein (given as a drip) once a week. Your doctor will calculate the
correct dose of Erbitux for you because it depends on your body surface area. The first dose (400 mg/
m² body surface area) is infused over a period of approximately 2 hours. Each subsequent dose
(250 mg/m²) is infused in approximately 1 hour. Erbitux must not be infused more rapidly than 10 mg/
min.
Detailed instructions for your doctor or your nurse on how to prepare the Erbitux infusion are included
at the end of this package leaflet (see 'Handling instructions').
Duration of treatment
Erbitux is usually infused once a week. The duration of treatment may vary depending on your disease
as well as from person to person and your doctor will therefore discuss with you how long you will
receive Erbitux.
55
Combination with other anticancer treatments
If you receive Erbitux in combination with other anticancer medicines, these medicines must be
administered at least 1 hour after the end of the Erbitux infusion.
If you receive Erbitux in combination with radiation therapy, treatment with Erbitux is usually started
one week before radiation therapy.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Erbitux can cause side effects, although not everybody gets them.
The main side effects of Erbitux are infusion-related side effects and side effects concerning the skin:
Infusion-related side effects
More than 10 out of 100 patients are likely to experience infusion-related side effects; in more than 1
out of 100 patients these side effects are likely to be severe. Such reactions may be allergic in nature.
They normally occur during the infusion, within 1 hour afterwards, or sometimes also after this period.
Mild or moderate infusion-related side effects
include:
• fever
• chills
• dizziness
• breathing difficulties
If such symptoms occur, please inform your doctor as soon as possible.
Your doctor may consider
reducing the infusion rate of Erbitux to manage these symptoms.
Severe infusion-related side effects
include:
• severe breathing difficulties which develop rapidly
• hives
• fainting
• chest pain (a symptom of side effects on your heart)
If such symptoms occur, speak to a doctor immediately.
These side effects may have serious
consequences, in rare cases including life-threatening conditions, and require immediate attention.
Treatment with Erbitux must then be stopped.
Side effects concerning the skin
More than 80 out of 100 patients are likely to experience side effects involving the skin. In about
15 out of 100 patients these skin reactions are likely to be severe. Most of these side effects develop
within the first three weeks of treatment. They usually disappear over time after the end of Erbitux
therapy.
Main side effects concerning the skin include:
• acne-like skin alterations
• itching
• dry skin
• scaling
• excessive growth of hair
• nail disorders, for example inflammation of the nail bed
56
If you notice extensive skin alterations, please inform your doctor as soon as possible
because the
Erbitux dose or the time between infusions may need to be changed. Your doctor will decide whether
treatment has to be stopped if skin reactions reappear after several dose reductions.
If you notice that already affected areas of your skin get worse, speak to a doctor immediately,
especially if you also experience general signs of infection such as fever and tiredness. These signs
may indicate a skin infection, which may have serious consequences including life-threatening
conditions.
Other side effects
Very common side effects
(may affect more than 1 user in 10)
• inflammation of the lining of the intestine, mouth, and nose which may lead to nose bleeding in
some patients
• decrease in blood levels of magnesium
• increase in blood levels of certain liver enzymes
Common side effects
(may affect 1 to 10 users in 100)
• headache
• tiredness
• irritation and redness of the eye
• diarrhoea
• drying out which may be due to diarrhoea or reduced fluid intake
• feeling sick
• vomiting
• loss of appetite, leading to weight decrease
• decrease in blood levels of calcium
Uncommon side effects
(may affect 1 to 10 users in 1,000)
• blood clots in the veins of the legs
• blood clots in the lungs
• inflammation of the eye lid or the front part of the eye
Side effects of which the frequency is not known
• inflammation of the lining of the brain (aseptic meningitis)
Side effects in combination with other anticancer treatments
If you receive Erbitux in combination with other anticancer medicines, some of the side effects you
may experience can also be related to the combination or the other medicines. Therefore, please make
sure that you also read the package leaflet for the other medicines.
If you receive Erbitux in combination with anticancer medicines including platinum, it is more likely
that your white blood cell count may be reduced. This may lead to infectious complications including
life-threatening conditions, especially if you experience skin reactions, inflammation of the lining of
the intestine and mouth or diarrhoea.
Therefore, if you experience general signs of infection such as
fever and tiredness, please speak to a doctor immediately.
If you receive Erbitux in combination with an anticancer medicine containing fluoropyrimidines, it is
more likely that you experience the following side effects of this other medicine:
• chest pain
• heart attack
• heart failure
• redness and swelling of the palms of the hands or the soles of the feet which may cause the skin
to peel (hand-foot syndrome)
57
If you receive Erbitux with radiation therapy, some of the side effects you may experience can also be
related to this combination, such as:
• inflammation of the lining of the intestine and mouth
• skin reactions typical for radiation therapy
• difficulty in swallowing
• reduction in the number of white blood cells
5. HOW TO STORE ERBITUX
Keep out of the reach and sight of children.
Do not use Erbitux after the expiry date which is stated on the label and the carton after EXP. The
expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C). Do not freeze.
Once opened, Erbitux is intended for immediate use.
6. FURTHER INFORMATION
What Erbitux contains
• The active substance is cetuximab.
Each ml of the solution for infusion contains 2 mg cetuximab.
Each vial of 50 ml contains 100 mg cetuximab.
• The other ingredients are sodium dihydrogen phosphate, disodium phosphate, sodium chloride
and water for injections.
What Erbitux looks like and contents of the pack
Erbitux 2 mg/ml solution for infusion is supplied in vials containing 50 ml.
Each pack contains 1 vial.
Marketing Authorisation Holder and Manufacturer
Merck KGaA
64271 Darmstadt
Germany
This leaflet was last approved in MM/YYYY.
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site:
http://www.emea.europa.eu/
.
The following information is intended for medical or healthcare professionals only:
Handling instructions
Erbitux may be administered via a gravity drip, an infusion pump or a syringe pump. It must not be
mixed with other intravenously applied medicinal products. A separate infusion line must be used for
the infusion, and the line must be flushed with sterile sodium chloride 9 mg/ml (0.9%) solution for
injection at the end of infusion.
58
Erbitux 2 mg/ml is a colourless solution that may contain product-related whitish and amorphous
visible particles. These particles do not affect the quality of the product. Nevertheless, the solution
must be filtered with an in-line filter of 0.2 micrometer or 0.22 micrometer nominal pore size during
administration.
Erbitux 2 mg/ml is compatible
• with polyethylene, ethyl vinyl acetate or polyvinyl chloride bags,
• with polyethylene, ethyl vinyl acetate, polyvinyl chloride, polybutadiene or polyurethane
infusion sets,
• with polyethersulfone, polyamide or polysulfone in-line filters.
Erbitux 2 mg/ml is chemically and physically stable for up to 20 hours at 25°C. However, since it does
not contain any antimicrobial preservative or bacteriostatic agent, it is intended for immediate use.
Care must be taken to ensure aseptic handling when preparing the infusion. Erbitux 2 mg/ml must be
prepared as follows:
•
In-line filtration with an infusion pump or gravity drip:
Take an appropriate sterile syringe
(minimum 50 ml) and attach a suitable needle. Draw up the required volume of Erbitux from a
vial. Transfer the Erbitux into a sterile evacuated container or bag. Repeat this procedure until
the calculated volume has been reached. Insert a suitable in-line filter into the infusion line and
prime it with Erbitux or sterile sodium chloride 9 mg/ml (0.9%) solution before starting the
infusion. Use a gravity drip or an infusion pump for administration. The first dose is 400 mg/
m² body surface area infused over a period of approximately 2 hours. Each subsequent dose
is 250 mg/m² infused in approximately 1 hour. Erbitux must not be infused more rapidly than
10 mg/min.
•
In-line filtration with a syringe pump:
Take an appropriate sterile syringe (minimum 50 ml)
and attach a suitable needle. Draw up the required volume of Erbitux from a vial. Remove the
needle and put the syringe into the syringe pump. Take a suitable in-line filter and connect it to
the application set. Connect the infusion line to the syringe and start the infusion after priming
the line with Erbitux or sterile sodium chloride 9 mg/ml (0.9%) solution. Repeat this procedure
until the calculated volume has been infused. The first dose is 400 mg/m² body surface area
infused over a period of approximately 2 hours. Each subsequent dose is 250 mg/m² infused in
approximately 1 hour. Erbitux must not be infused more rapidly than 10 mg/min.
Filters may occasionally clog up during the infusion. If there is evidence of filter clogging, the filter
must be replaced.
59
PACKAGE LEAFLET: INFORMATION FOR THE USER
Erbitux 5 mg/ml solution for infusion
Cetuximab
Read all of this leaflet carefully before you start using this medicine.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor.
• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet:
1. What Erbitux is and what it is used for
2. Before you use Erbitux
3. How to use Erbitux
4. Possible side effects
5. How to store Erbitux
6. Further information
1. WHAT ERBITUX IS AND WHAT IT IS USED FOR
What Erbitux is
Erbitux contains cetuximab, a monoclonal antibody. Monoclonal antibodies are proteins that
specifically recognise and bind to other unique proteins called antigens. Cetuximab binds to the
epidermal growth factor receptor (EGFR), an antigen on the surface of certain cancer cells. As a result
of this binding, the cancer cell can no longer receive the messages it needs for growth, progression and
metastasis.
What Erbitux is used for
Erbitux is used to treat two different types of cancer:
• metastatic cancer of the large intestine. In these patients, Erbitux is used alone or in
combination with other anticancer medicines.
• a certain type of cancer of the head and neck (squamous cell cancer). In these patients, Erbitux
is used in combination with radiation therapy or with other anticancer medicines.
2. BEFORE YOU USE ERBITUX
Do not use Erbitux
Do not use Erbitux if you have ever had a severe hypersensitivity (allergic) reaction to cetuximab.
Take special care with Erbitux
Erbitux may cause infusion-related side effects. Such reactions may be allergic in nature. Please read
'Infusion-related side effects' in section 4 for details, as they may have serious consequences for you,
including life-threatening conditions. These side effects normally occur during the infusion, within
1 hour afterwards, or sometimes also after this period. To recognise early signs of such effects, your
condition will be checked regularly while you receive each infusion of Erbitux and for at least 1 hour
afterwards.
60
If you receive Erbitux in combination with anticancer medicines including platinum, it is more likely
that your white blood cell count may be reduced. Your doctor will therefore monitor your blood and
general condition for signs of infection (see also 'Side effects in combination with other anticancer
treatments' in section 4).
If you receive Erbitux in combination with other anticancer medicines, including fluoropyrimidines,
it may be more likely that you experience heart problems which may be life-threatening. Your doctor
will discuss with you whether you may need any particular supervision (see also 'Side effects in
combination with other anticancer treatments' in section 4).
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription.
Pregnancy
Tell your doctor if you are pregnant or if you are not using reliable contraception (speak to your doctor
if you are not sure). Your doctor will then discuss with you the risks and benefits of using Erbitux in
these situations.
Breast-feeding
Do not breast-feed your baby during the period over which you are being treated with Erbitux and for
two months after the last dose.
Driving and using machines
Do not drive or use any tools or machines if you experience treatment-related symptoms that affect
your ability to concentrate and react.
3. HOW TO USE ERBITUX
A doctor experienced in the use of anticancer medicines will supervise your Erbitux therapy. During
each infusion and for at least 1 hour afterwards, your condition will be checked regularly for early
signs of a possible infusion-related side effect.
Pre-treatment
Before the first dose, you will receive an antiallergic medicine in order to reduce the risk of an allergic
reaction. Your doctor will decide whether such pre-treatment is necessary for subsequent doses.
Dosage and administration
Erbitux is usually infused into a vein (given as a drip) once a week. Your doctor will calculate the
correct dose of Erbitux for you because it depends on your body surface area. The first dose (400 mg/
m² body surface area) is infused over a period of approximately 2 hours. Each subsequent dose
(250 mg/m²) is infused in approximately 1 hour. Erbitux must not be infused more rapidly than 10 mg/
min.
Detailed instructions for your doctor or your nurse on how to prepare the Erbitux infusion are included
at the end of this package leaflet (see 'Handling instructions').
Duration of treatment
Erbitux is usually infused once a week. The duration of treatment may vary depending on your disease
as well as from person to person and your doctor will therefore discuss with you how long you will
receive Erbitux.
61
Combination with other anticancer treatments
If you receive Erbitux in combination with other anticancer medicines, these medicines must be
administered at least 1 hour after the end of the Erbitux infusion.
If you receive Erbitux in combination with radiation therapy, treatment with Erbitux is usually started
one week before radiation therapy.
4. POSSIBLE SIDE EFFECTS
Like all medicines, Erbitux can cause side effects, although not everybody gets them.
The main side effects of Erbitux are infusion-related side effects and side effects concerning the skin:
Infusion-related side effects
More than 10 out of 100 patients are likely to experience infusion-related side effects; in more than 1
out of 100 patients these side effects are likely to be severe. Such reactions may be allergic in nature.
They normally occur during the infusion, within 1 hour afterwards, or sometimes also after this period.
Mild or moderate infusion-related side effects
include:
• fever
• chills
• dizziness
• breathing difficulties
If such symptoms occur, please inform your doctor as soon as possible.
Your doctor may consider
reducing the infusion rate of Erbitux to manage these symptoms.
Severe infusion-related side effects
include:
• severe breathing difficulties which develop rapidly
• hives
• fainting
• chest pain (a symptom of side effects on your heart)
If such symptoms occur, speak to a doctor immediately.
These side effects may have serious
consequences, in rare cases including life-threatening conditions, and require immediate attention.
Treatment with Erbitux must then be stopped.
Side effects concerning the skin
More than 80 out of 100 patients are likely to experience side effects involving the skin. In about
15 out of 100 patients these skin reactions are likely to be severe. Most of these side effects develop
within the first three weeks of treatment. They usually disappear over time after the end of Erbitux
therapy.
Main side effects concerning the skin include:
• acne-like skin alterations
• itching
• dry skin
• scaling
• excessive growth of hair
• nail disorders, for example inflammation of the nail bed
62
If you notice extensive skin alterations, please inform your doctor as soon as possible
because the
Erbitux dose or the time between infusions may need to be changed. Your doctor will decide whether
treatment has to be stopped if skin reactions reappear after several dose reductions.
If you notice that already affected areas of your skin get worse, speak to a doctor immediately,
especially if you also experience general signs of infection such as fever and tiredness. These signs
may indicate a skin infection, which may have serious consequences including life-threatening
conditions.
Other side effects
Very common side effects
(may affect more than 1 user in 10)
• inflammation of the lining of the intestine, mouth, and nose which may lead to nose bleeding in
some patients
• decrease in blood levels of magnesium
• increase in blood levels of certain liver enzymes
Common side effects
(may affect 1 to 10 users in 100)
• headache
• tiredness
• irritation and redness of the eye
• diarrhoea
• drying out which may be due to diarrhoea or reduced fluid intake
• feeling sick
• vomiting
• loss of appetite, leading to weight decrease
• decrease in blood levels of calcium
Uncommon side effects
(may affect 1 to 10 users in 1,000)
• blood clots in the veins of the legs
• blood clots in the lungs
• inflammation of the eye lid or the front part of the eye
Side effects of which the frequency is not known
• inflammation of the lining of the brain (aseptic meningitis)
Side effects in combination with other anticancer treatments
If you receive Erbitux in combination with other anticancer medicines, some of the side effects you
may experience can also be related to the combination or the other medicines. Therefore, please make
sure that you also read the package leaflet for the other medicines.
If you receive Erbitux in combination with anticancer medicines including platinum, it is more likely
that your white blood cell count may be reduced. This may lead to infectious complications including
life-threatening conditions, especially if you experience skin reactions, inflammation of the lining of
the intestine and mouth or diarrhoea.
Therefore, if you experience general signs of infection such as
fever and tiredness, please speak to a doctor immediately.
If you receive Erbitux in combination with an anticancer medicine containing fluoropyrimidines, it is
more likely that you experience the following side effects of this other medicine:
• chest pain
• heart attack
• heart failure
• redness and swelling of the palms of the hands or the soles of the feet which may cause the skin
to peel (hand-foot syndrome)
63
If you receive Erbitux with radiation therapy, some of the side effects you may experience can also be
related to this combination, such as:
• inflammation of the lining of the intestine and mouth
• skin reactions typical for radiation therapy
• difficulty in swallowing
• reduction in the number of white blood cells
5. HOW TO STORE ERBITUX
Keep out of the reach and sight of children.
Do not use Erbitux after the expiry date which is stated on the label and the carton after EXP. The
expiry date refers to the last day of that month.
Store in a refrigerator (2°C - 8°C).
Once opened, Erbitux is intended for immediate use.
6. FURTHER INFORMATION
What Erbitux contains
• The active substance is cetuximab.
Each ml of the solution for infusion contains 5 mg cetuximab.
Each vial of 10 ml contains 50 mg cetuximab.
Each vial of 20 ml contains 100 mg cetuximab.
Each vial of 50 ml contains 250 mg cetuximab.
Each vial of 100 ml contains 500 mg cetuximab.
• The other ingredients are sodium chloride, glycine, polysorbate 80, citric acid monohydrate,
sodium hydroxide and water for injections.
What Erbitux looks like and contents of the pack
Erbitux 5 mg/ml solution for infusion is supplied in vials containing 10 ml, 20 ml, 50 ml or 100 ml.
Each pack contains 1 vial.
Not all vial sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Merck KGaA
64271 Darmstadt
Germany
This leaflet was last approved in MM/YYYY.
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site:
http://www.emea.europa.eu/
.
64
The following information is intended for medical or healthcare professionals only:
Handling instructions
Erbitux may be administered via a gravity drip, an infusion pump or a syringe pump. Since Erbitux
is only compatible with sterile sodium chloride 9 mg/ml (0.9%) solution for injection, it must not be
mixed with other intravenously applied medicinal products. A separate infusion line must be used for
the infusion, and the line must be flushed with sterile sodium chloride 9 mg/ml (0.9%) solution for
injection at the end of infusion.
Erbitux 5 mg/ml is compatible
• with polyethylene (PE), ethyl vinyl acetate (EVA) or polyvinyl chloride (PVC) bags,
• with polyethylene (PE), polyurethane (PUR), ethyl vinyl acetate (EVA), polyolefine
thermoplastic (TP) or polyvinyl chloride (PVC) infusion sets,
• with polypropylene (PP) syringes for syringe pump.
Erbitux 5 mg/ml is chemically and physically stable for up to 48 hours at 25°C, if the solution is
prepared as described hereafter. However, since it does not contain any antimicrobial preservative or
bacteriostatic agent, it is intended for immediate use. Care must be taken to ensure aseptic handling
when preparing the infusion. Erbitux 5 mg/ml must be prepared as follows:
•
For administration with infusion pump or gravity drip (diluted with sterile sodium chloride
9 mg/ml (0.9%) solution):
Take an infusion bag of adequate size of sterile sodium chloride
9 mg/ml (0.9%) solution. Calculate the required volume of Erbitux. Remove an adequate
volume of the sodium chloride solution from the infusion bag, using an appropriate sterile
syringe with a suitable needle. Take an appropriate sterile syringe and attach a suitable needle.
Draw up the required volume of Erbitux from a vial. Transfer the Erbitux into the prepared
infusion bag. Repeat this procedure until the calculated volume has been reached. Connect the
infusion line and prime it with the diluted Erbitux before starting the infusion. Use a gravity
drip or an infusion pump for administration. The first dose is 400 mg/m² body surface area
infused over a period of approximately 2 hours. Each subsequent dose is 250 mg/m² infused in
approximately 1 hour. Erbitux must not be infused more rapidly than 10 mg/min.
•
For administration with infusion pump or gravity drip (undiluted):
Calculate the required
volume of Erbitux. Take an appropriate sterile syringe (minimum 50 ml) and attach a suitable
needle. Draw up the required volume of Erbitux from a vial. Transfer the Erbitux into a sterile
evacuated container or bag. Repeat this procedure until the calculated volume has been reached.
Connect the infusion line and prime it with Erbitux before starting the infusion. The first dose is
400 mg/m² body surface area infused over a period of approximately 2 hours. Each subsequent
dose is 250 mg/m² infused in approximately 1 hour. Erbitux must not be infused more rapidly
than 10 mg/min.
•
For administration with a syringe pump:
Calculate the required volume of Erbitux. Take an
appropriate sterile syringe and attach a suitable needle. Draw up the required volume of Erbitux
from a vial. Remove the needle and put the syringe into the syringe pump. Connect the infusion
line to the syringe and start the infusion after priming the line with Erbitux or sterile sodium
chloride 9 mg/ml (0.9%) solution. Repeat this procedure until the calculated volume has been
infused. The first dose is 400 mg/m² body surface area infused over a period of approximately
2 hours. Each subsequent dose is 250 mg/m² infused in approximately 1 hour. Erbitux must not
be infused more rapidly than 10 mg/min.
65
Source: European Medicines Agency
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