4.1. Therapeutic indications

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 who are intolerant to irinotecan.

For details, see section 5.1.

Erbitux is indicated in combination with encorafenib, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, who have received prior systemic therapy.

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 at least 1 hour prior to administration of cetuximab. This premedication is recommended prior to all subsequent infusions.

Colorectal cancer

As a single-agent or in combination with chemotherapy

In patients with metastatic colorectal cancer, cetuximab is used in combination with chemotherapy or as a single agent (see section 5.1). Evidence of wild-type RAS (KRAS and NRAS) status is required before initiating treatment with Erbitux. Mutational status should be determined by an experienced laboratory 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 surface area.

For the dosage or recommended dose modifications of concomitantly used antineoplastic medicinal products, refer to the product information for these medicinal products. Intravenously administered antineoplastic medicinal products must not be administered earlier than 1 hour after the end of the cetuximab infusion.

In combination with encorafenib

Evidence of BRAF V600E mutation status is required before initiating treatment with Erbitux in combination with encorafenib. Mutational status should be determined by an experienced laboratory using validated test methods for detection BRAF V600E mutations.

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.

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

Squamous cell cancer of the head and neck

In combination with radiation therapy

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.

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 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.

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 surface area.

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 older people, but the experience is limited in patients 75 years of age and above.

Paediatric population

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).

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 the infusion rate must not exceed 10 mg/min. If initial infusion is well tolerated the recommended infusion period for weekly dose regimen of 250 mg/m2 is 60 minutes and recommended infusion period for biweekly dose regimen of 500 mg/m2 is 120 minutes.

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 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 chemotherapeutic agents or radiation therapy must be considered.

4.4. Special warnings and precautions for use

Traceability

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

Infusion-related, including anaphylactic, reactions

Severe infusion-related reactions, including anaphylactic reactions, may commonly occur, in some cases with fatal outcome. Occurrence of a severe infusion-related reaction requires immediate and permanent discontinuation of cetuximab therapy and may necessitate emergency treatment. Some of these reactions may be anaphylactic or anaphylactoid in nature or represent a cytokine release syndrome (CRS). Symptoms may occur during the first infusion and for up to several hours afterwards 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 or signs of an infusion-related reaction occur. Symptoms may include 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.

Anaphylactic reactions may occur as early as within a few minutes of the first infusion e.g. due to preformed IgE antibodies cross-reacting with cetuximab. These reactions are commonly associated with 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 meat or tick bites or positive results of tests for IgE antibodies against cetuximab (α-1-3-galactose). In these patients cetuximab should be administered only after a careful assessment of benefit/risk, including alternative treatments, and only under close supervision of well trained personnel with resuscitation equipment ready.

The first dose should be administered slowly whilst all vital signs are closely monitored for at least two 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 including consideration whether the patient may have preformed IgE antibodies before a subsequent infusion is given.

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

a) Grade 1:

b) Grade 2:

c) Grade 3 and 4:

continue slow infusion under close supervision

continue slow infusion and immediately administer treatment for symptoms

stop infusion immediately, treat symptoms vigorously and contraindicate further use of cetuximab

A cytokine release syndrome (CRS) typically occurs within one hour after infusion and is less commonly associated with bronchospasm and urticaria. CRS is normally most severe in relation to the first 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 cetuximab infusion. 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.

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

Respiratory disorders

Cases of interstitial lung disease (ILD), including fatal cases, have been reported, with the majority of patients 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 closely monitored. In the event of symptoms (such as dyspnoea, cough, fever) or radiographic findings suggestive of ILD, prompt diagnostic investigation should occur.

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

Skin reactions

Main adverse reactions of cetuximab are skin reactions which may become severe, especially in combination with chemotherapy. The risk for secondary infections (mainly bacterial) is increased and cases of staphylococcal scalded skin syndrome, necrotising fasciitis and sepsis, in some cases with fatal 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) 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 an intolerable or severe skin reaction (≥ grade 3; 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. 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 dosing regimen, 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 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 ≥ 65 years or performance status has been observed. When prescribing cetuximab, the cardiovascular and performance status of the patients and concomitant administration of cardiotoxic compounds such as fluoropyrimidines should be taken into account.

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 RAS mutated tumours

Cetuximab should not be used in the treatment of colorectal cancer patients whose tumours have RAS mutations or for whom RAS tumour status is unknown. Results from clinical studies show a negative benefit-risk balance in tumours with RAS 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.

Colorectal cancer patients with BRAF mutated tumours

Before taking cetuximab in combination with encorafenib patients must have metastatic colorectal cancer with BRAF V600E mutation confirmed by a validated test. The efficacy and safety of cetuximab in combination with encorafenib have been established only in patients with colorectal tumours expressing BRAF V600E mutation. Cetuximab in combination with encorafenib should not be used in patients with other than BRAF V600E mutated colorectal cancer or for whom BRAF V600E mutation status is unknown.

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 < 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 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. Fertility, 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 (≥ 1/10)

Common (≥ 1/100 to < 1/10)

Uncommon (≥ 1/1000 to < 1/100)

Rare (≥ 1/10 000 to < 1/1000)

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

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.

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; interstitial lung disease, which may be fatal (see section 4.4).

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*.

Very rare:

Stevens-Johnson syndrome/toxic epidermal necrolysis.

Frequency not known:

Superinfection of skin lesions*.

General disorders and administration site conditions

Very common:

Mild or moderate infusion-related reactions (see section 4.4); mucositis, in some cases severe. Mucositis may lead to epistaxis.

Common:

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

Additional information

Overall, no clinically relevant difference between genders was observed.

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, necrotising fasciitis or sepsis.

Combination treatment

When cetuximab is used in combination with antineoplastic medicinal products also refer to their respective product information.

In combination with encorafenib, most adverse reactions were similar in frequency and severity to those known to occur with cetuximab or encorafenib administered as single agents. In addition, the following adverse reactions were reported in the combination trial: haemorrhage, abdominal pain, myopathy/muscular disorder (very common); dizziness (common). For more information on the combination with encorafenib, refer to encorafenib 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or

search for MHRA Yellow Card in the Google

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4.9. Overdose

There is limited experience with weekly administrations of doses higher than 250 mg/m2 body surface area or biweekly administrations of doses higher than 500 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.