ERBITUX 5mg / ml solution for infusion medication leaflet

Erbitux 5 mg/mL solution for infusion

Each mL of solution for infusion contains 5 mg cetuximab.

Each vial of 20 mL contains 100 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) byrecombinant DNA technology.

For the 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, RAS 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 whoare 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.

Erbitux must be administered under the supervision of a physician experienced in the use ofantineoplastic medicinal products. Close monitoring is required during the infusion and for at least1 hour after the end of the infusion. Availability of resuscitation equipment must be ensured.

Prior to the first infusion, patients must receive premedication with an antihistamine and acorticosteroid at least 1 hour prior to administration of cetuximab. This premedication is recommendedprior to all subsequent infusions.

In patients with metastatic colorectal cancer, cetuximab is used in combination with chemotherapy oras a single agent (see section 5.1). Evidence of wild-type RAS (KRAS and NRAS) status is requiredbefore initiating treatment with Erbitux. Mutational status should be determined by an experiencedlaboratory using validated test methods for detection of KRAS and NRAS (exons 2, 3, and 4)mutations (see section 4.4 and 5.1).

Erbitux may be administered in a weekly or every other week dose regimen.

Weekly dose regimen

Erbitux is administered once a week. The initial dose is 400 mg cetuximab per m2 body surface area(BSA). All subsequent weekly doses are 250 mg/m2 each.

Biweekly dose regimen

Erbitux is administered once every other week. Each dose is 500 mg cetuximab per m2 body surfacearea.

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 earlierthan 1 hour after the end of the cetuximab infusion.

It is recommended that cetuximab treatment be continued until progression of the underlying disease.

In combination with radiation therapy

In patients with locally advanced squamous cell cancer of the head and neck, cetuximab is usedconcomitantly with radiation therapy. It is recommended to start cetuximab therapy one week beforeradiation therapy and to continue cetuximab therapy until the end of the radiation therapy period.

Erbitux is administered once a week. The initial dose is 400 mg cetuximab per m2 body surface area(BSA). All subsequent weekly doses are 250 mg/m2 each.

In combination with platinum-based chemotherapy

In patients with recurrent and/or metastatic squamous cell cancer of the head and neck, cetuximab isused in combination with platinum-based chemotherapy followed by cetuximab as maintenancetherapy until disease progression (see section 5.1). Chemotherapy must not be administered earlierthan 1 hour after the end of the cetuximab infusion.

Erbitux may be administered in a weekly or every other week dose regimen.

Weekly dose regimen

Erbitux is administered once a week. The initial dose is 400 mg cetuximab per m2 body surface area(BSA). All subsequent weekly doses are 250 mg/m2 each.

Biweekly dose regimen

Erbitux is administered once every other week. Each dose is 500 mg cetuximab per m2 body surfacearea.

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 (seesection 4.4).

No dose adjustment is required in older people, but the experience is limited in patients 75 years ofage and above.

There is no relevant use of cetuximab in the paediatric population for the granted indications.

Erbitux 5 mg/mL is administered intravenously with an infusion pump, gravity drip or a syringe pump(for handling instructions, see section 6.6).

The initial dose should be given slowly to minimize risk of infusion related reactions (see section 4.4).

The recommended infusion period is 120 minutes. For subsequent cetuximab administration theinfusion rate must not exceed 10 mg/min. If initial infusion is well tolerated the recommended infusionperiod for weekly dose regimen of 250 mg/m2 is 60 minutes and recommended infusion period forbiweekly dose regimen of 500 mg/m2 is 120 minutes.

Erbitux is contraindicated in patients with known severe (grade 3 or 4) hypersensitivity reactions tocetuximab.

The combination of Erbitux with oxaliplatin-containing chemotherapy is contraindicated for patientswith mutant RAS metastatic colorectal cancer (mCRC) or for whom RAS mCRC status is unknown(see also section 4.4).

Before initiation of combination treatment, contraindications for concomitantly used chemotherapeuticagents or radiation therapy must be considered.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Severe infusion-related reactions, including anaphylactic reactions, may commonly occur, in somecases with fatal outcome. Occurrence of a severe infusion-related reaction requires immediate andpermanent discontinuation of cetuximab therapy and may necessitate emergency treatment. Some ofthese reactions may be anaphylactic or anaphylactoid in nature or represent a cytokine releasesyndrome (CRS). Symptoms may occur during the first infusion and for up to several hours afterwardsor with subsequent infusions. It is recommended to warn patients of the possibility of such a late onsetand instruct them to contact their physician if symptoms or signs of an infusion-related reaction occur.

Symptoms may include bronchospasm, urticaria, increase or decrease in blood pressure, loss ofconsciousness or shock. In rare cases, angina pectoris, myocardial infarction or cardiac arrest havebeen observed.

Anaphylactic reactions may occur as early as within a few minutes of the first infusion e.g. due topreformed IgE antibodies cross-reacting with cetuximab. These reactions are commonly associatedwith bronchospasm and urticaria. They can occur despite the use of premedication.

The risk for anaphylactic reactions is much increased in patients with a history of allergy to red meator tick bites or positive results of tests for IgE antibodies against cetuximab (α-1-3-galactose). In thesepatients cetuximab should be administered only after a careful assessment of benefit/risk, includingalternative treatments, and only under close supervision of well trained personnel with resuscitationequipment ready.

The first dose should be administered slowly whilst all vital signs are closely monitored for at leasttwo hours. If during the first infusion, an infusion-related reaction occurs within the first 15 minutes,the infusion should be stopped. A careful benefit/risk assessment should be undertaken includingconsideration whether the patient may have preformed IgE antibodies before a subsequent infusion isgiven.

If an infusion-related reaction develops later during the infusion or at a subsequent infusion furthermanagement will depend on its severity:

a) Grade 1: continue slow infusion under close supervisionb) Grade 2: continue slow infusion and immediately administer treatment for symptomsc) Grade 3 and 4: stop infusion immediately, treat symptoms vigorously and contraindicate furtheruse of cetuximab

A cytokine release syndrome (CRS) typically occurs within one hour after infusion and is lesscommonly associated with bronchospasm and urticaria. CRS is normally most severe in relation to thefirst infusion.

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 cetuximabinfusion. If the patient experiences a mild or moderate infusion-related reaction, the infusion rate maybe decreased. It is recommended to maintain this lower infusion rate in all subsequent infusions.

A close monitoring of patients, particularly during the first administration, is required. Specialattention is recommended for patients with reduced performance status and pre-existing cardio-pulmonary disease.

Cases of interstitial lung disease (ILD), including fatal cases, have been reported, with the majority ofpatients from the Japanese population.

Confounding or contributing factors, such as concomitant chemotherapy known to be associated with

ILD, and pre-existing pulmonary diseases were frequent in fatal cases. Such patients should be closelymonitored. In the event of symptoms (such as dyspnoea, cough, fever) or radiographic findingssuggestive of ILD, prompt diagnostic investigation should occur.

If interstitial lung disease is diagnosed, cetuximab must be discontinued and the patient be treatedappropriately.

Main adverse reactions of cetuximab are skin reactions which may become severe, especially incombination with chemotherapy. The risk for secondary infections (mainly bacterial) is increased andcases of staphylococcal scalded skin syndrome, necrotising fasciitis and sepsis, in some cases withfatal outcome, have been reported (see section 4.8).

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) andtopical application of 1% hydrocortisone cream with moisturiser should be considered. Medium tohigh-potency topical corticosteroids or oral tetracyclines have been used for the treatment of skinreactions.

If a patient experiences an intolerable or severe skin reaction ( grade 3; Common Terminology

Criteria for Adverse Events, CTCAE), cetuximab therapy must be interrupted. Treatment may only beresumed 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 indose level.

With the second and third occurrences of severe skin reactions, cetuximab therapy must again beinterrupted.

If the reaction has resolved to grade 2 treatment may only be resumed with a dose reduction of 20%(200 mg/m² BSA in the weekly dosing regimen, 400 mg/m² BSA in the biweekly dosing regimen)after the second occurrence and with a dose reduction of 40% (150 mg/m² BSA in the weekly dosingregimen, 300 mg/m² BSA in the biweekly dosing regimen) after the third occurrence.

If severe skin reactions occur a fourth time or do not resolve to grade 2 during interruption oftreatment, permanent discontinuation of cetuximab treatment is required.

Progressively decreasing serum magnesium levels occur frequently and may lead to severehypomagnesaemia. Hypomagnesaemia is reversible following discontinuation of cetuximab. Inaddition, hypokalaemia may develop as a consequence of diarrhoea. Hypocalcaemia may also occur;in particular in combination with platinum-based chemotherapy the frequency of severehypocalcaemia may be increased.

Determination of serum electrolyte levels is recommended prior to and periodically during cetuximabtreatment. Electrolyte repletion is recommended, as appropriate.

Patients who receive cetuximab in combination with platinum-based chemotherapy are at an increasedrisk for the occurrence of severe neutropenia, which may lead to subsequent infectious complicationssuch 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 theoccurrence of infections (see section 4.8).

An increased frequency of severe and sometimes fatal cardiovascular events and treatment emergentdeaths has been observed in the treatment of non-small cell lung cancer, squamous cell carcinoma ofthe head and neck and colorectal carcinoma. In some studies association with age ≥ 65 years orperformance status has been observed. When prescribing cetuximab, the cardiovascular andperformance status of the patients and concomitant administration of cardiotoxic compounds such asfluoropyrimidines should be taken into account.

Patients presenting with signs and symptoms suggestive of keratitis such as acute or worsening: eyeinflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be referredpromptly to an ophthalmology specialist.

If a diagnosis of ulcerative keratitis is confirmed, treatment with cetuximab should be interrupted ordiscontinued. If keratitis is diagnosed, the benefits and risks of continuing treatment should becarefully considered.

Cetuximab should be used with caution in patients with a history of keratitis, ulcerative keratitis orsevere dry eye. Contact lens use is also a risk factor for keratitis and ulceration.

Cetuximab should not be used in the treatment of colorectal cancer patients whose tumours have RASmutations or for whom RAS tumour status is unknown. Results from clinical studies show a negativebenefit-risk balance in tumours with RAS mutations. In particular, in these patients negative effects onprogression-free survival (PFS) and overall survival (OS) were seen as add-on to FOLFOX4 (seesection 5.1).

Similar findings were also reported when cetuximab was given as add-on to XELOX in combinationwith bevacizumab (CAIRO2). However, in this study no positive effects on PFS or OS weredemonstrated in patients with KRAS wild-type tumours, either.

Only patients with adequate renal and hepatic function have been investigated to date (serumcreatinine  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 laboratoryparameters:

* haemoglobin < 9 g/dL

* leukocyte count < 3 000/mm³

* absolute neutrophil count < 1 500/mm³

* platelet count < 100 000/mm³

There is limited experience in the use of cetuximab in combination with radiation therapy in colorectalcancer.

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.

In combination with platinum-based chemotherapy, the frequency of severe leukopenia or severeneutropenia may be increased, and thus may lead to a higher rate of infectious complications such asfebrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (seesection 4.4).

In combination with fluoropyrimidines, the frequency of cardiac ischaemia including myocardialinfarction and congestive heart failure as well as the frequency of hand-foot syndrome (palmar-plantarerythrodysaesthesia) were increased compared to that with fluoropyrimidines.

In combination with capecitabine and oxaliplatin (XELOX) the frequency of severe diarrhoea may beincreased.

A formal interaction study showed that the pharmacokinetic characteristics of cetuximab remainunaltered 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 placentaltransfer of cetuximab, and other IgG1 antibodies have been found to cross the placental barrier. Animaldata revealed no evidence of teratogenicity. However, dependent on the dose, an increased incidenceof abortion was observed (see section 5.3). Sufficient data from pregnant or lactating women are notavailable.

It is strongly recommended that Erbitux be given during pregnancy or to any woman not employingadequate contraception only if the potential benefit for the mother justifies a potential risk to thefoetus.

It is recommended that women do not breast-feed during treatment with Erbitux and for 2 months afterthe last dose, because it is not known whether cetuximab is excreted in breast milk.

There are no data on the effect of cetuximab on human fertility. Effects on male and female fertilityhave not been evaluated within formal animal studies (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. If patientsexperience treatment-related symptoms affecting their ability to concentrate and react, it isrecommended 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% ofpatients, 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 symptomsin 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 providedbelow the table.

Very common: Hypomagnesaemia (see section 4.4).

Common: Dehydration, in particular secondary to diarrhoea or mucositis; hypocalcaemia(see section 4.4); anorexia which may lead to weight decrease.

Common: Headache.

Frequency not known: Aseptic meningitis.

Common: Conjunctivitis.

Uncommon: Blepharitis; keratitis.

Uncommon: Deep vein thrombosis.

Uncommon: Pulmonary embolism; interstitial lung disease, which may be fatal (seesection 4.4).

Common: Diarrhoea; nausea; vomiting.

Very common: Increase in liver enzyme levels (ASAT, ALAT, AP).

Very common: Skin reactions*.

Very rare: Stevens-Johnson syndrome/toxic epidermal necrolysis.

Frequency not known: Superinfection of skin lesions*.

Very common: Mild or moderate infusion-related reactions (see section 4.4); mucositis, insome cases severe. Mucositis may lead to epistaxis.

Common: Severe infusion-related reactions, in some cases with fatal outcome(see section 4.4); fatigue.

Overall, no clinically relevant difference between genders was observed.

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. Themajority 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 doseregimen 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 fataloutcome, staphylococcal scalded skin syndrome, necrotising fasciitis or sepsis.

When cetuximab is used in combination with chemotherapeutic agents, also refer to their respectiveproduct information.

In combination with platinum-based chemotherapy, the frequency of severe leukopenia or severeneutropenia may be increased, and thus may lead to a higher rate of infectious complications such asfebrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (seesection 4.4).

In combination with fluoropyrimidines, the frequency of cardiac ischaemia including myocardialinfarction and congestive heart failure as well as the frequency of hand-foot syndrome (palmar-plantarerythrodysaesthesia) were increased compared to that with fluoropyrimidines.

In combination with local radiation therapy of the head and neck area, additional undesirable effectswere those typical of radiation therapy (such as mucositis, radiation dermatitis, dysphagia orleukopenia, mainly presenting as lymphocytopenia). In a randomised controlled clinical study with424 patients, reporting rates of severe acute radiation dermatitis and mucositis as well as of lateradiation-therapy-related events were slightly higher in patients receiving radiation therapy incombination with cetuximab than in those receiving radiation therapy alone.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is limited experience with weekly administrations of doses higher than 250 mg/m² body surfacearea or biweekly administrations of doses higher than 500 mg/m² body surface area. In clinical studieswith doses up to 700 mg/m2 given every 2 weeks the safety profile was consistent with that describedin section 4.8.

Pharmacotherapeutic group: Antineoplastic agents, monoclonal antibodies, ATC code: L01FE01

Cetuximab is a chimeric monoclonal IgG1 antibody that is specifically directed against the epidermalgrowth 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 ofendogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands resulting in inhibition ofthe 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 RAS (rat sarcoma) is a central down-stream signal-transducer of EGFR. In tumours, activation of RAS by EGFR contributes to EGFR-mediatedincreased proliferation, survival and the production of pro-angiogenic factors.

RAS is one of the most frequently activated family of oncogenes in human cancers. Mutations of RASgenes at certain hot-spots on exons 2, 3 and 4 result in constitutive activation of RAS proteinsindependently of EGFR signalling.

In both in vitro and in vivo assays, cetuximab inhibits the proliferation and induces apoptosis of humantumour cells that express EGFR. In vitro cetuximab inhibits the production of angiogenic factors bytumour cells and blocks endothelial cell migration. In vivo cetuximab inhibits expression of angiogenicfactors by tumour cells and causes a reduction in tumour neo-vascularisation and metastasis.

The development of human anti-chimeric antibodies (HACA) is a class effect of monoclonal chimericantibodies. Current data on the development of HACAs is limited. Overall, measurable HACA titreswere noted in 3.4% of the patients studied, with incidences ranging from 0% to 9.6% in the targetindication studies. No conclusive data on the neutralising effect of HACAs on cetuximab is availableto date. The appearance of HACA did not correlate with the occurrence of hypersensitivity reactionsor any other undesirable effect to cetuximab.

A diagnostic assay (EGFR pharmDx) was used for immunohistochemical detection of EGFRexpression in tumour material. A tumour was considered to be EGFR-expressing, if one stained cellcould be identified. Approximately 75% of the patients with metastatic colorectal cancer screened forclinical studies had an EGFR-expressing tumour and were therefore considered eligible for cetuximabtreatment. The efficacy and safety of cetuximab have not been documented in patients with tumourswhere EGFR was not detected.

Study data demonstrate that patients with metastatic colorectal cancer and activating RAS mutationsare highly unlikely to benefit from treatment with cetuximab or a combination of cetuximab andchemotherapy and as add-on to FOLFOX4 a significant negative effect on progression-free survivaltime (PFS) was shown.

Cetuximab as a single agent or in combination with chemotherapy was investigated in 5 randomisedcontrolled clinical studies and several supportive studies. The 5 randomised studies investigated a totalof 3734 patients with metastatic colorectal cancer, in whom EGFR expression was detectable and whohad an ECOG performance status of ≤ 2. The majority of patients included had an ECOG performancestatus of ≤ 1. In all studies, cetuximab was administered as described in section 4.2.

The KRAS exon 2 status was recognised as predictive factor for the treatment with cetuximab in 4 ofthe randomised controlled studies (EMR 62 202-013, EMR 62 202-047, CA225006, and CA225025).

KRAS mutational status was available for 2072 patients. Further post-hoc analyses were performed forstudies EMR 62 202-013 and EMR 62 202-047, where also mutations on RAS genes (NRAS and

KRAS) other than KRAS exon 2 have been determined. Only in study EMR 62 202-007, a post-hocanalysis was not possible.

In addition, cetuximab was investigated in combination with chemotherapy in an investigator-initiatedrandomised controlled phase-III study (COIN, COntinuous chemotherapy plus cetuximab or

INtermittent chemotherapy). In this study EGFR expression was not an inclusion criterion. Tumoursamples from approximately 81% of patients were analysed retrospectively for KRAS expression.

FIRE-3, an investigator-sponsored clinical phase-III study, compared the treatment of FOLFIRI incombination with either cetuximab or bevacizumab in the first-line treatment of patients with KRASexon 2 wild-type mCRC. Further post-hoc analyses on mutations on RAS genes other than KRASexon 2 have been evaluated.

* EMR 62 202-013: This randomised study in patients with metastatic colorectal cancer who hadnot received prior treatment for metastatic disease compared the combination of cetuximab andirinotecan plus infusional 5-fluorouracil/folinic acid (FOLFIRI) (599 patients) to the samechemotherapy alone (599 patients). The proportion of patients with KRAS wild-type tumoursfrom the patient population evaluable for KRAS status comprised 63%. For the assessment ofthe RAS status, mutations other than those on exon 2 of the KRAS gene were determined fromall evaluable tumour samples within the KRAS exon 2 wild-type population (65%). The RASmutant population consists of patients with known KRAS exon 2 mutations as well asadditionally identified RAS mutations.

The efficacy data generated in this study are summarised in the table below:

RAS wild-type population RAS mutant population

Variable/ statistic Cetuximab FOLFIRI Cetuximab FOLFIRIplus FOLFIRI plus FOLFIRI(N=178) (N=189) (N=246) (N=214)

OSmonths, median 28.4 20.2 16.4 17.7(95% CI) (24.7, 31.6) (17.0, 24.5) (14.9, 18.4) (15.4, 19.6)

Hazard Ratio (95% CI) 0.69 (0.54, 0.88) 1.05 (0.86, 1.28)p-value 0.0024 0.6355

PFSmonths, median 11.4 8.4 7.4 7.5(95% CI) (10.0, 14.6) (7.4, 9.4) (6.4, 8.0) (7.2, 8.5)

Hazard Ratio (95% CI) 0.56 (0.41, 0.76) 1.10 (0.85, 1.42)p-value 0.0002 0.4696

ORR% 66.3 38.6 31.7 36.0(95% CI) (58.8, 73.2) (31.7, 46.0) (25.9, 37.9) (29.6, 42.8)

Odds Ratio (95% CI) 3.1145 (2.0279, 4.7835) 0.8478 (0.5767, 1.2462)p-value <0.0001 0.3970

CI = confidence interval, FOLFIRI = irinotecan plus infusional 5-FU/FA, ORR = objective response rate (patientswith 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 hadnot received prior treatment for metastatic disease compared the combination of cetuximab andoxaliplatin plus continuous infusional 5-fluorouracil/folinic acid (FOLFOX4) (169 patients) tothe same chemotherapy alone (168 patients). The proportion of patients with KRAS wild-typetumours from the patient population evaluable for KRAS status comprised 57%. For theassessment of the RAS status, mutations other than those on exon 2 of the KRAS gene weredetermined from all evaluable tumour samples within the KRAS exon 2 wild-type population.

The RAS mutant population consists of patients with known KRAS exon 2 mutations as well asadditionally identified RAS mutations.

The efficacy data generated in this study are summarised in the table below:

RAS wild-type population RAS mutant population

Variable/ statistic Cetuximab FOLFOX4 Cetuximab FOLFOX4plus FOLFOX4 plus FOLFOX4(N=38) (N=49) (N=92) (N=75)

OSmonths, median 19.8 17.8 13.5 17.8(95% CI) (16.6, 25.4) (13.8, 23.9) (12.1, 17.7) (15.9, 23.6)

Hazard Ratio (95% CI) 0.94 (0.56, 1.56) 1.29 (0.91, 1.84)p-value 0.8002 0.1573

PFSmonths, median 12.0 5.8 5.6 7.8(95% CI) (5.8, NE) (4.7, 7.9) (4.4, 7.5) (6.7, 9.3)

Hazard Ratio (95% CI) 0.53 (0.27, 1.04) 1.54 (1.04, 2.29)p-value 0.0615 0.0309

ORR% 57.9 28.6 37.0 50.7(95% CI) (40.8, 73.7) (16.6, 43.3) (27.1, 47.7) (38.9, 62.4)

Odds Ratio (95% CI) 3.3302 (1.375, 8.172) 0.580 (0.311, 1.080)p-value 0.0084 0.0865

CI = confidence interval, FOLFOX4 = oxaliplatin plus continuous infusional 5-FU/FA, ORR = objective responserate (patients with complete response or partial response), OS = overall survival time, PFS = progression-free survivaltime, NE = not estimable

In particular a negative effect of cetuximab add-on in the RAS mutant population was observed.

* COIN: This was an open-label, 3-arm, randomised study in 2445 patients with inoperablemetastatic or locoregional colorectal cancer who had not received prior treatment for metastaticdisease and compared oxaliplatin plus fluoropyrimidines (infusional 5-fluorouracil/folinic acid[OxMdG] or capecitabine [XELOX]) in combination with cetuximab to the same chemotherapyregimen alone. The third experimental arm used an intermittent OxMdG or XELOX regimenwithout cetuximab. Data for the XELOX regimen and the third experimental arm are notpresented.

Tumour samples from approximately 81% of patients were analysed retrospectively for KRASexpression, of which 55% were KRAS wild-type. Of these, 362 patients received cetuximaband oxaliplatin plus fluoropyrimidines (117 patients OxMdG and 245 patients XELOX) and367 patients received oxaliplatin plus fluoropyrimidines alone (127 patients OxMdG and240 patients XELOX). Of the KRAS mutant population, 297 patients received cetuximab andoxaliplatin plus fluoropyrimidines (101 patients OxMdG and 196 patients XELOX) and268 patients received oxaliplatin plus fluoropyrimidines alone (78 patients OxMdG and190 patients XELOX).

The efficacy data on the OxMdG regimen generated in this study are summarised in the tablebelow:

KRAS wild-type population KRAS mutant population

Variable/ statistic Cetuximab OxMdG Cetuximab OxMdGplus OxMdG plus OxMdG(N=117) (N=127) (N=101) (N=78)

OSmonths, median 16.3 18.2 13.1 14.6(95% CI) (10.3, 32.2) (9.8, 27.5) (8.0, 23.9) (9.5, 22.0)

Hazard Ratio (95% CI) 0.93 (0.72, 1.19) 0.99 (0.75, 1.30)p-value 0.617 0.931

PFSmonths, median 9.0 9.2 6.8 8.5(95% CI) (5.8, 15.5) (5.8, 12.7) (5.0, 10.7) (3.4, 10.8)

Hazard Ratio (95% CI) 0.77 (0.59, 1.01) 1.05 (0.77, 1.41)p-value 0.056 0.78

Best overall responserate% 68 59 47 51(95% CI) (58, 76) (50, 68) (37, 57) (40, 63)

Odds Ratio (95% CI) 1.44 (0.85, 2.43) 0.83 (0.46, 1.49)p-value 0.171 0.529

CI = confidence interval, OxMdG = oxaliplatin plus infusional 5-FU/FA, OS = overall survival time,

PFS = progression-free survival time

In time related endpoints no trends indicating clinical benefit could be shown for patients whoreceived cetuximab in combination with the XELOX regimen.

There were significant dose reductions and delays of capecitabine or oxaliplatin administrationmainly due to higher frequency of diarrhoea in the cetuximab containing arm. In addition,significantly fewer patients treated with cetuximab received second-line therapy.

FIRE-3 (First-line combination of cetuximab with FOLFIRI): The FIRE-3 study was amulticentre randomised phase-III study investigating head-to-head 5-FU, folinic acid andirinotecan (FOLFIRI) combined with either cetuximab or bevacizumab in patients with KRASexon 2 wild-type metastatic colorectal cancer (mCRC). RAS status was evaluable in tumoursamples of 407 KRAS exon 2 wild-type patients reflecting 69% of the overall KRAS exon 2wild-type patient population (592 patients). Of these, 342 patients had RAS wild-type tumourswhile RAS mutations were identified in 65 patients. The RAS mutant population comprisesthese 65 patients together with 113 patients with KRAS exon 2 mutant tumours treated beforestudy enrolment was restricted to patients with KRAS exon 2 wild-type mCRC.

The efficacy data generated in this study are summarised in the table below:

RAS wild-type population RAS mutant population

Variable/ statistic Cetuximab Bevacizumab Cetuximab Bevacizumabplus FOLFIRI plus FOLFIRI plus FOLFIRI plus FOLFIRI(N=171) (N=171) (N=92) (N=86)

OSmonths, median 33.1 25.6 20.3 20.6(95% CI) (24.5, 39.4) (22.7, 28.6) (16.4,23.4) (17.0, 26.7)

Hazard Ratio (95% CI) 0.70 (0.53, 0.92) 1.09 (0.78, 1.52)p-value 0.011 0.60

PFSmonths, median 10.4 10.2 7.5 10.1(95% CI) (9.5, 12.2) (9.3, 11.5) (6.1, 9.0) (8.9, 12.2)

Hazard Ratio (95% CI) 0.93 (0.74, 1.17) 1.31 (0.96, 1.78)p-value 0.54 0.085

ORR% 65.5 59.6 38.0 51.2(95% CI) (57.9, 72.6) (51.9, 67.1) (28.1, 48.8) (40.1, 62.1)

Odds Ratio (95% CI) 1.28 (0.83, 1.99) 0.59 (0.32, 1.06)p-value 0.32 0. 097

CI = confidence interval, FOLFIRI = irinotecan plus infusional 5-FU/FA, ORR = objective response rate (patientswith complete response or partial response), OS = overall survival time, PFS = progression-free survival time

In the KRAS wild-type population of the CALGB/SWOG 80405 study (n=1137), superiority ofcetuximab plus chemotherapy over bevacizumab plus chemotherapy was not shown.

* CA225006: This randomised study in patients with metastatic colorectal cancer who hadreceived initial combination treatment with oxaliplatin plus fluoropyrimidine for metastaticdisease compared the combination of cetuximab and irinotecan (648 patients) with irinotecanalone (650 patients). Following disease progression, treatment with EGFR-targeting agents wasinitiated in 50% of patients in the irinotecan-alone arm.

In the overall population, irrespective of KRAS status, the results reported for cetuximab plusirinotecan (648 patients) vs. irinotecan alone (650 patients) were: median overall survival time(OS) 10.71 vs. 9.99 months (HR 0.98), median progression free survival time (PFS) 4.0 vs.

2.6 months (HR 0.69), and objective response rate (ORR) 16.4% vs. 4.2%.

With respect to the KRAS status, tumour samples were only available from 23% of the patients(300 of 1298). From the KRAS evaluated population 64% of the patients (192) had KRAS wild-type tumours and 108 patients KRAS mutations. On the basis of this data and since noindependent review of imaging data was conducted, results in relation to mutation status areconsidered non-interpretable.

* EMR 62 202-007: This randomised study in patients with metastatic colorectal cancer afterfailure of irinotecan-based treatment for metastatic disease as the last treatment before studyentry compared the combination of cetuximab and irinotecan (218 patients) with cetuximabmonotherapy (111 patients).

The combination of cetuximab with irinotecan compared to cetuximab alone reduced the overallrisk of disease progression by 46% and significantly increased objective response rate. In therandomised 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 armreceived a combination of cetuximab and irinotecan after progression of disease, which mayhave influenced overall survival time.

* CA225025: This randomised study in patients with metastatic colorectal cancer who hadreceived prior oxaliplatin-, irinotecan- and fluoropyrimidine-based treatment for metastaticdisease 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 KRASwild-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 BSC Cetuximab BSCplus BSC plus BSC(N=117) (N=113) (N=81) (N=83)

OSmonths, 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

PFSmonths, 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 completeresponse or partial response), OS = overall survival time, PFS = progression-free survival time

Immunohistochemical detection of EGFR expression was not performed since more than 90% ofpatients with squamous cell cancer of the head and neck have tumours that express EGFR.

* EMR 62 202-006: This randomised study compared the combination of cetuximab and radiationtherapy (211 patients) with radiation therapy alone (213 patients) in patients with locallyadvanced squamous cell cancer of the head and neck. Cetuximab was started one week beforeradiation therapy and administered at the doses described in section 4.2 until the end of theradiation therapy period.

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 controlmonths, 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

OSmonths, median (95% CI) 49.0 (32.8, 69.5+) 29.3 (20.6, 41.4)

Hazard Ratio (95% CI) 0.73 (0.56, 0.95)p-value 0.018median follow-up, months 60.0 60.11-year OS rate, % (95% CI) 77.6 (71.4, 82.7) 73.8 (67.3, 79.2)2-year OS rate, % (95% CI) 62.2 (55.2, 68.4) 55.2 (48.2, 61.7)3-year OS rate, % (95% CI) 54.7 (47.7, 61.2) 45.2 (38.3, 51.9)5-year OS rate, % (95% CI) 45.6 (38.5, 52.4) 36.4 (29.7, 43.1)

CI = confidence interval, OS = overall survival time, a '+' denotes that the upper bound limit had not been reached atcut-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 ageor older.

The use of cetuximab in combination with chemo-radiotherapy has so far not been adequatelyinvestigated. Thus, a benefit-risk ratio for this combination has not yet been established.

* EMR 62 202-002: This randomised study in patients with recurrent and/or metastatic squamouscell cancer of the head and neck who had not received prior chemotherapy for this diseasecompared the combination of cetuximab and cisplatin or carboplatin plus infusional5-fluorouracil (222 patients) to the same chemotherapy alone (220 patients). Treatment in thecetuximab arm consisted of up to 6 cycles of platinum-based chemotherapy in combination withcetuximab 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)

OSmonths, 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

PFSmonths, median (95% CI) 5.6 (5.0, 6.0) 3.3 (2.9, pct. 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 = overallsurvival 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-basedchemotherapy. In contrast to progression free survival time, no benefit in overall survival timecould be demonstrated in patients with KPS ≤ 80 who were 65 years of age or older.

The European Medicines Agency has waived the obligation to submit the results of studies withcetuximab in all subsets of the paediatric population in the indications adenocarcinoma of the colonand rectum and oropharyngeal, laryngeal or nasal epithelial carcinoma (excluding nasopharyngealcarcinoma or lymphoepithelioma, see section 4.2 for information on paediatric use).

Cetuximab pharmacokinetics were studied when cetuximab was administered as monotherapy or incombination with concomitant chemotherapy or radiation therapy in clinical studies. Intravenousinfusions of cetuximab exhibited dose-dependent pharmacokinetics at weekly doses ranging from 5 to500 mg/m2 body surface area.

When cetuximab was administered at an initial dose of 400 mg/m2 body surface area, the meanvolume of distribution was approximately equivalent to the vascular space (2.9 L/m2 with a range of1.5 to 6.2 L/m2). The mean Cmax ( standard deviation) was 18555 microgram per mL. The meanclearance was 0.022 L/h per m² body surface area. Cetuximab has a long elimination half-life withvalues ranging from 70 to 100 hours.

When cetuximab was administered in a weekly dose regimen (400 mg/m² loading dose followed by250 mg/m² weekly dose), cetuximab serum concentrations reached stable levels after three weeks ofcetuximab monotherapy. Mean peak cetuximab concentrations were 155.8 microgram per mL inweek 3 and 151.6 microgram per mL in week 8, whereas the corresponding mean troughconcentrations were 41.3 and 55.4 microgram per mL, respectively. In a study of cetuximabadministered in combination with irinotecan, the mean cetuximab trough levels were 50.0 microgramper mL in week 12 and 49.4 microgram per mL in week 36.

When cetuximab was administered in a biweekly dose regimen (500 mg/m² every other week), serumconcentrations reached stable levels after five weeks of cetuximab monotherapy. Mean peakcetuximab concentration was 297 microgram per mL in week 5, the corresponding mean troughconcentration was 31.0 microgram per mL.

Several pathways have been described that may contribute to the metabolism of antibodies. All ofthese pathways involve the biodegradation of the antibody to smaller molecules, i.e. small peptides oramino acids.

An integrated analysis across all clinical studies showed that the pharmacokinetic characteristics ofcetuximab are not influenced by race, age, gender, renal or hepatic status.

Only patients with adequate renal and hepatic function have been investigated to date (serumcreatinine  1.5fold, transaminases  5fold and bilirubin  1.5fold the upper limit of normal).

In a phase-I study in paediatric patients (1-18 years) with refractory solid tumours, cetuximab wasadministered in combination with irinotecan. The pharmacokinetic results were comparable to those inadults.

Dose-dependent skin alterations, starting at dose levels equivalent to those used in humans, were themajor findings observed in toxicity studies with Cynomolgus monkeys (a chronic repeat-dose toxicitystudy 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 routesother than the intended infusion revealed no special hazard for humans.

No formal animal studies have been performed to establish the carcinogenic potential of cetuximab orto determine its effects on male and female fertility.

Toxicity studies with co-administration of cetuximab and chemotherapeutic agents have not beenperformed.

No non-clinical data on the effect of cetuximab on wound healing are available to date. However, inpreclinical wound healing models EGFR selective tyrosine kinase inhibitors were shown to retardwound healing.

Sodium chloride

Glycine

Polysorbate 80

Citric acid monohydrate

Sodium hydroxide

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

4 years.

Chemical and physical in-use stability of Erbitux 5 mg/mL has been demonstrated for 48 hours at25ºC, if the solution is prepared as described in section 6.6.

Erbitux does not contain any antimicrobial preservative or bacteriostatic agent. From amicrobiological point of view, the product shall be used immediately after opening. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8ºC, unless opening has taken place in controlledand validated aseptic conditions.

Store in a refrigerator (2°C - 8°C).

For storage conditions after opening, see section 6.3.

20 mL or 100 mL of solution in a vial (Type I glass) with a stopper (halobutyl rubber) and a seal(aluminium/polypropylen).

Pack size of 1 vial.

Not all vial sizes may be marketed.

Erbitux may be administered via a gravity drip, an infusion pump or a syringe pump. A separateinfusion line must be used for the infusion, and the line must be flushed with sterile sodium chloride9 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), polyolefinethermoplastic (TP) or polyvinyl chloride (PVC) infusion sets,

* with polypropylene (PP) syringes for syringe pump.

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 chloride9 mg/mL (0.9%) solution): Take an infusion bag of adequate size of sterile sodium chloride9 mg/mL (0.9%) solution. Calculate the required volume of Erbitux. Remove an adequatevolume of the sodium chloride solution from the infusion bag, using an appropriate sterilesyringe 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 preparedinfusion bag. Repeat this procedure until the calculated volume has been reached. Connect theinfusion line and prime it with the diluted Erbitux before starting the infusion. Use a gravity dripor 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 requiredvolume of Erbitux. Take an appropriate sterile syringe (minimum 50 mL) and attach a suitableneedle. Draw up the required volume of Erbitux from a vial. Transfer the Erbitux into a sterileevacuated 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 controlthe rate as explained in section 4.2.

* For administration with a syringe pump: Calculate the required volume of Erbitux. Take anappropriate sterile syringe and attach a suitable needle. Draw up the required volume of Erbituxfrom a vial. Remove the needle and put the syringe into the syringe pump. Connect the infusionline to the syringe, set and control the rate as explained in section 4.2 and start the infusion afterpriming 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 Europe B.V.

Gustav Mahlerplein 1021082 MA Amsterdam

The Netherlands

EU/1/04/281/003

EU/1/04/281/005

Date of first authorisation: 29/06/2004

Date of latest renewal: 17/06/2009

MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.