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.

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.

Breastfeeding

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