Cetuximab

Patients with mild (CRCL ≥60 and <90 mL/min) and moderate (CRCL ≥30 and <60 mL/min) renal impairment, as well as mild hepatic impairment according to National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria, have been investigated to date. The effect of moderate or severe hepatic impairment, as defined by NCI-ODWG criteria, on cetuximab pharmacokinetics has not been assessed. The pharmacokinetics of cetuximab in patients with severe (CRCL ≥15 and <30 mL/min) renal impairment or end-stage renal disease have not been evaluated.

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 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.

Cetuximab in combination with capecitabine and oxaliplatin (XELOX) the frequency of severe diarrhoea may be increased.

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.

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.

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.

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. Sufficient data from pregnant or lactating women are not available.

It is strongly recommended that cetuximab 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.

It is recommended that women do not breast-feed during treatment with cetuximab 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.

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 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)

Table. Adverse reactions:

^* composite terms which included more than one preferred term
^a includes but not limited to extrasystoles, supraventricular tachycardia, atrial tachycardia and sinus tachycardia
^b includes, but not limited to, angioedema, anaphylactic reaction, drug hypersensitivity, hypersensitivity, hypersensitivity vasculitis and urticaria
^c includes but not limited to urinary tract infection, gastroenteritis, peritonitis, cellulitis, abdominal infection, gastrointestinal infection, infection, lower respiratory tract infection, viral and bacterial pneumonia, viral infection
^d includes, but not limited to, myalgia, muscular weakness, muscle spasm, muscle injury, myopathy, myositis
^e includes keratoacanthoma, squamous cell carcinoma and squamous cell carcinoma of skin
^f includes but not limited to cold dysaesthesia, dysaesthesia, hyperaesthesia, hypoaesthesia, neuralgia, neuropathy peripheral, neurotoxicity, paraesthesia, peripheral sensory neuropathy, polyneuropathy
^g includes erythema, generalised erythema, plantar erythema
^h includes dermatitis exfoliative, skin exfoliation, exfoliative rash
ⁱ includes haemorrhage at various sites including, but not limited to, cerebral haemorrhage, intracranial haemorrhage, vaginal haemorrhage, heavy menstrual bleeding, intermenstrual bleeding, haematochezia, epistaxis, haemoptysis, haemothorax, gastrointestinal haemorrhage and haematuria

Description of selected adverse reactions

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.

Superinfection of skin lesions

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 chemotherapeutic agents, also refer to their respective 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.

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 encorafenib and FOLFOX or encorafenib, no new adverse reactions other than those currently known to occur with cetuximab, encorafenib or FOLFOX were identified. There was no meaningful increase in frequency or severity of known adverse reactions. Please refer to the product information of encorafenib and individual product components of FOLFOX.

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.