Cetuximab interacts in the following cases:
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.
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.
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.
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. 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.
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.
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.
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 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.
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.
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 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.
Very common: Hypomagnesaemia.
Common: Dehydration, in particular secondary to diarrhoea or mucositis; hypocalcaemia; anorexia which may lead to weight decrease.
Common: Headache.
Frequency not known: Aseptic meningitis.
Common: Conjunctivitis.
Uncommon: Blepharitis; keratitis.
Uncommon: Deep vein thrombosis.
Uncommon: Pulmonary embolism; interstitial lung disease, which may be fatal.
Common: Diarrhoea; nausea; vomiting.
Very common: Increase in liver enzyme levels (ASAT, ALAT, AP).
Very common: Skin reactions*.
Very rare: Stevens-Johnson syndrome/toxic epidermal necrolysis.
Frequency not known: Superinfection of skin lesions*.
Very common: Mild or moderate infusion-related reactions; mucositis, in some cases severe. Mucositis may lead to epistaxis.
Common: Severe infusion-related reactions, in some cases with fatal outcome; fatigue.
Overall, no clinically relevant difference between genders was observed.
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.
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.
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 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.
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