1. Name Of The Medicinal Product
Erbitux 5 mg/ml solution for infusion
2. Qualitative And Quantitative Composition
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 IgG1 antibody produced in a mammalian cell line (Sp2/0) by recombinant DNA technology.
For the full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for infusion.
Colourless solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Erbitux is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer
• in combination with irinotecan-based chemotherapy,
• in first-line in combination with FOLFOX,
• as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.
For details, see section 5.1.
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.
4.2 Posology And Method Of Administration
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.
Colorectal cancer
In patients with metastatic colorectal cancer, cetuximab is used in combination with chemotherapy or as a single agent (see section 5.1). Wild-type KRAS tumour status must be verified 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.
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
The efficacy of cetuximab in paediatric patients below the age of 18 years has not been established. No new safety signals were identified in paediatric patients as reported from a phase-I study.
There is no relevant use of cetuximab in the paediatric population in the granted indications.
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.
4.3 Contraindications
Erbitux is contraindicated in patients with known severe (grade 3 or 4) hypersensitivity reactions to cetuximab.
The combination of Erbitux with oxaliplatin-containing chemotherapy is contraindicated for patients with mutant KRAS metastatic colorectal cancer (mCRC) or for whom KRAS mCRC status is unknown (see also section 4.4).
Before initiation of combination treatment, contraindications for concomitantly used chemotherapeutic agents or radiation therapy must be considered.
4.4 Special Warnings And Precautions For Use
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
Cases of interstitial lung disease have been reported, with the majority of patients from the Japanese population. If interstitial lung disease is diagnosed, cetuximab must be discontinued and the patient be treated appropriately.
Skin reactions
Skin reactions are very common and treatment interruption or discontinuation may be required. According to clinical practice guidelines prophylactic use of oral tetracyclines (6 - 8 weeks) and topical application of 1% hydrocortisone cream with moisturiser should be considered. Medium to high-potency topical corticosteroids or oral tetracyclines have been used for the treatment of skin reactions.
If a patient experiences a severe skin reaction (
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.
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 association with age
Eye disorders
Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referred promptly to an ophthalmology specialist.
If a diagnosis of ulcerative keratitis is confirmed, treatment with cetuximab should be interrupted or discontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should be carefully considered.
Cetuximab should be used with caution in patients with a history of keratitis, ulcerative keratitis or severe dry eye. Contact lens use is also a risk factor for keratitis and ulceration.
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. In particular, in these patients negative effects on progression-free survival (PFS) and overall survival (OS) were seen as add-on to FOLFOX4 (see section 5.1).
Similar findings were also reported when cetuximab was given as add-on to XELOX in combination with bevacizumab (CAIRO2). However, in this study no positive effects on PFS or OS were demonstrated in patients with KRAS wild-type tumours, either.
Special populations
Only patients with adequate renal and hepatic function have been investigated to date (serum creatinine
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 efficacy of cetuximab in paediatric patients below the age of 18 years has not been established. No new safety signals were identified in paediatric patients as reported from a phase-I study.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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 capecitabine and oxaliplatin (XELOX) the frequency of severe diarrhoea may be increased.
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.
4.6 Pregnancy And Lactation
Pregnancy
EGFR is involved in foetal development. Limited observations in animals are indicative of a placental transfer of cetuximab, and other IgG1 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.
Breast-feeding
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.
Fertility
There are no data on the effect of cetuximab on human fertility. Effects on male and female fertility have not been evaluated within formal animal studies (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
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.
4.8 Undesirable Effects
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 (
Common (
Uncommon (
Rare (
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.
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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.
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.
4.9 Overdose
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. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01XC06
Mechanism of action
Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the epidermal growth factor receptor (EGFR).
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%. Study data demonstrate that patients with metastatic colorectal cancer and activating KRAS mutations are highly unlikely to benefit from treatment with cetuximab or a combination of cetuximab and chemotherapy and as add-on to FOLFOX4 a significant negative effect on progression-free survival time (PFS) was shown.
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
The KRAS status was recognised as predictive factor for the treatment with cetuximab in 4 of the randomised controlled studies (EMR 62 202-013, EMR 62 202-047, CA225006, and CA225025). KRAS mutational status was available for 2072 patients. Only in study EMR 62 202-007, an analysis was not possible.
In addition, cetuximab was investigated in combination with chemotherapy in an investigator-initiated randomised controlled phase-III study (COIN, COntinuous chemotherapy plus cetuximab or INtermittent chemotherapy). In this study EGFR expression was not an inclusion criterion. Tumour samples from approximately 81% of patients were analysed retrospectively for KRAS expression.
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 (FOLFIRI) (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:
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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 continuous infusional 5-fluorouracil/folinic acid (FOLFOX4) (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%.
The efficacy data generated in this study are summarised in the table below:
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CI = confidence interval, FOLFOX4 = oxaliplatin plus continuous infusional 5-FU/FA, ORR = objective response rate (patients with complete response or partial response), OS = overall survival time, PFS = progression-free survival time
In particular a negative effect of cetuximab add-on in the KRAS mutant population was observed.
• COIN: This was an open-label, 3-arm, randomised study in 2445 patients with inoperable metastatic or locoregional colorectal cancer who had not received prior treatment for metastatic disease and compared oxaliplatin plus fluoropyrimidines (infusional 5-fluorouracil/folinic acid [OxMdG] or capecitabine [XELOX]) in combination with cetuximab to the same chemotherapy regimen alone. The third experimental arm used an intermittent OxMdG or XELOX regimen without cetuximab. Data for the XELOX regimen and the third experimental arm are not presented.
Tumour samples from approximately 81% of patients were analysed retrospectively for KRAS expression, of which 55% were KRAS wild-type. Of these, 362 patients received cetuximab and oxaliplatin plus fluoropyrimidines (117 patients OxMdG and 245 patients XELOX) and 367 patients received oxaliplatin plus fluoropyrimidines alone (127 patients OxMdG and 240 patients XELOX). Of the KRAS mutant population, 297 patients received cetuximab and oxaliplatin plus fluoropyrimidines (101 patients OxMdG and 196 patients XELOX) and 268 patients received oxaliplatin plus fluoropyrimidines alone (78 patients OxMdG and 190 patients XELOX).
The efficacy data on the OxMdG regimen generated in this study are summarised in the table below:
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