Erbitux · 4.8 Undesirable effects · 1

HOS-093878 · has-adverse-reaction-information · PDF-Seite 9

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 safety of cetuximab in combination with encorafenib (300 mg orally once daily) (dosed as per its SmPC) was evaluated in 216 patients with BRAF V600E-mutant metastatic colorectal cancer, based on the phase III study ARRAY-818-302. The most common ADRs (>25%) reported in this population were: fatigue, nausea, diarrhoea, dermatitis acneiform, abdominal pain, arthralgia/musculoskeletal pain, decreased appetite, rash and vomiting. The rate of all study drug discontinuation due to any adverse reaction was 1.9 % in patients treated with cetuximab in combination with encorafenib. The safety of cetuximab in combination with encorafenib (300 mg orally once daily) and FOLFOX was evaluated in 259 patients with BRAF V600E-mutant metastatic colorectal cancer, based on the study C4221015 – BREAKWATER (hereafter referred to as the pooled EC+FOLFOX population, i.e all patients who received encorafenib and cetuximab (EC)+FOLFOX in the different portions of the study). The most common ADRs (>25%) reported in this population were: neuropathy peripheral, neutropenia, nausea, fatigue, anaemia, diarrhoea, vomiting, decreased appetite, rash, thrombocytopenia, abdominal pain, haemorrhage, arthralgia/musculoskeletal pain, pyrexia, constipation, mucosal inflammation and infection. The rate of all study drug discontinuation due to any adverse reaction was 3.5 % in patients treated with cetuximab in combination with encorafenib and FOLFOX. 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) 9 Table: Adverse reactions Cetuximab Cetuximab in Cetuximab in combination combination with with Encorafenib and Encorafenib FOLFOX (n = 216) (n = 259) Blood and lymphatic system disorders Very common

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HOS-093874 · has-contraindication-information · PDF-Seite 4

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

HOS-093873 · has-indication-information · PDF-Seite 2

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 for the treatment of adult patients with BRAF V600E mutant metastatic colorectal cancer • in combination with encorafenib and FOLFOX for the first line treatment. • in combination with encorafenib in patients who have received prior systemic therapy. For details, see section 5.1, for biomarker-based patient selection, see section 4.2. 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.

HOS-093876 · has-interaction-information · PDF-Seite 8

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.

HOS-093877 · has-pregnancy-information · PDF-Seite 8

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). 8

HOS-093875 · has-warning-information · PDF-Seite 5

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: continue slow infusion under close supervision b) Grade 2: conti

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