Erbitux 5 mg/ml solution for infusion

Each ml of solution for infusion contains 5 mg cetuximab.

Each vial of 10 ml contains 50 mg cetuximab.

Each vial of 20 ml contains 100 mg cetuximab.

Each vial of 50 ml contains 250 mg cetuximab.

Each vial of 100 ml contains 500 mg cetuximab.

Cetuximab is a chimeric monoclonal IgG₁ antibody produced in a mammalian cell line (Sp2/0) by recombinant DNA technology.

For a full list of excipients, see section 6.1.

Solution for infusion.

Colourless solution.

Erbitux is indicated for the treatment of patients with epidermal growth factor receptor (EGFR)-expressing, KRAS wild-type metastatic colorectal cancer

• in combination with irinotecan-based chemotherapy or FOLFOX4 (for details, see section 5.1),

• as a single agent in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.

Erbitux is indicated for the treatment of patients with squamous cell cancer of the head and neck

• in combination with radiation therapy for locally advanced disease,

• in combination with platinum-based chemotherapy for recurrent and/or metastatic disease.

Erbitux must be administered under the supervision of a physician experienced in the use of antineoplastic medicinal products. Close monitoring is required during the infusion and for at least 1 hour after the end of the infusion. Availability of resuscitation equipment must be ensured.

Posology

Prior to the first infusion, patients must receive premedication with an antihistamine and a corticosteroid. This premedication is recommended prior to all subsequent infusions.

In all indications, Erbitux is administered once a week. The initial dose is 400 mg cetuximab per m² body surface area. All subsequent weekly doses are 250 mg cetuximab per m² each.

Colorectal cancer

In patients with metastatic colorectal cancer, cetuximab is used in combination with chemotherapy or as a single agent (see section 5.1). Detection of KRAS mutational status must be performed prior to the first cetuximab infusion. It is important that a validated test method is used by an experienced laboratory (see section 4.4 and 5.1).

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

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

Squamous cell cancer of the head and neck

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

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

Method of administration

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

For the initial dose, the recommended infusion period is 120 minutes. For the subsequent weekly doses, the recommended infusion period is 60 minutes. The maximum infusion rate must not exceed 10 mg/min.

Special populations

Only patients with adequate renal and hepatic function have been investigated to date (see section 4.4).

Cetuximab has not been studied in patients with pre-existing haematological disorders (see section 4.4).

No dose adjustment is required in the elderly, but the experience is limited in patients 75 years of age and above.

Paediatric population

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.

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

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

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

If a patient experiences a severe skin reaction ( grade 3; US National Cancer Institute - Common Terminology Criteria for Adverse Events, CTCAE), cetuximab therapy must be interrupted. Treatment may only be resumed if the reaction has resolved to grade 2.

If the severe skin reaction occurred for the first time, treatment may be resumed without any change in dose level.

With the second and third occurrences of severe skin reactions, cetuximab therapy must again be interrupted. Treatment may only be resumed at a lower dose level (200 mg/m² after the second occurrence and 150 mg/m² after the third occurrence), if the reaction has resolved to grade 2.

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

Electrolyte disturbances

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

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

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 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 survival (OS) was 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 1.5fold, transaminases 5fold and bilirubin 1.5fold the upper limit of normal).

Cetuximab has not been studied in patients presenting with one or more of the following laboratory parameters:

• haemoglobin < 9 g/dl

• leukocyte count < 3000/mm³

• absolute neutrophil count < 1500/mm³

• platelet count < 100000/mm³

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

Paediatric population

The 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 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.

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.

Breastfeeding

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 eva luated 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 patients experience treatment-related symptoms affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

The main undesirable effects of cetuximab are skin reactions, which occur in more than 80% of patients, hypomagnesaemia which occurs in more than 10% of patients and infusion-related reactions, which occur with mild to moderate symptoms in more than 10% of patients and with severe symptoms in more than 1% of patients.

The following definitions apply to the frequency terminology used hereafter:

Very common ( 1/10)

Common ( 1/100 to < 1/10)

Uncommon ( 1/1,000 to < 1/100)

Rare ( 1/10,000 to < 1/1,000)

Very rare (< 1/10,000)

Frequency not known (cannot be estimated from the available data)

An asterisk (*) indicates that additional information on the respective undesirable effect is provided below the table.