Erbitux

/ Merck

This medicinal product 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 at least 1 hour prior to administration of cetuximab. This premedication is recommended prior to all subsequent infusions.
In all indications, this product 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. Evidence of wild-type RAS (KRAS and NRAS) status is required before initiating the treatment. Mutational status should be determined by an experienced laboratory using validated test methods for detection of KRAS and NRAS (exons 2, 3, and 4) mutations.
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. Chemotherapy must not be administered earlier than 1 hour after the end of the cetuximab infusion.
In patients with recurrent and/or metastatic squamous cell cancer of the head and neck, cetuximab is used as monotherapy. It is recommended that treatment be continued until progression of the underlying disease.
Special populations: Only patients with adequate renal and hepatic function have been investigated to date.
Cetuximab has not been studied in patients with pre-existing haematological disorders.
No dose adjustment is required in older people, but the experience is limited in patients 75 years of age and above.
Paediatric population: There is no relevant use of cetuximab in the paediatric population in the granted indications.
Method of administration: This medicinal product is administered intravenously with an infusion pump, gravity drip or a syringe pump. The initial dose should be given slowly and speed of infusion must not exceed 5 mg/min. The recommended infusion period is 120 minutes. For the subsequent weekly doses, the recommended infusion period is 60 minutes. The infusion rate must not exceed 10 mg/min.
See prescribing information for full details.

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.
See prescribing information for full details.
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,
• as a single agent after failure of platinum-based chemotherapy for recurrent and/or metastatic disease.

Severe (grade 3 or 4)  hypersensitivity  reactions to Cetuximab. Combination with Oxaliplatin-containing chemotherapy is contraindicated for patients with mutant RAS metastatic colorectal cancer (mCRC) or for whom RAS mCRC status is unknown.
Before initiation of combination treatment, contraindications for concomitantly used chemotherapeutic agents or radiation therapy must be considered.

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 and the speed must not exceed 5 mg/min 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. See prescribing information for full details.
A cytokine release syndrome (CRS) typically occurs within one hour after infusion and is less commonly associated with bronchospasm and urticaria. CRS is normally most severe in relation to the first infusion.
Mild or moderate infusion-related reactions are very common comprising symptoms such as fever, chills, dizziness, or dyspnoea that occur in a close temporal relationship mainly to the first cetuximab infusion. 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.
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.
Respiratory disorders: 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.
Skin reactions: 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.
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.
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 RAS mutated tumours: Cetuximab should not be used in the treatment of colorectal cancer patients whose tumours have RAS mutations or for whom RAS tumour status is
unknown. Results from clinical studies show a negative benefit-risk balance in tumours with RAS mutations. In particular, in these patients negative effects on progression-free survival (PFS) and overall survival (OS) were seen as add-on to FOLFOX4 (see prescribing information for full details).
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 ≤ 1.5 fold, 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.
See prescribing information for full details.

Very common: Hypomagnesaemia, increase in liver enzyme levels (ASAT, ALAT, AP), skin reactions, mild or moderate infusion-related reactions, mucositis (in some cases severe. May lead to epistaxis).
Common: Dehydration, in particular secondary to diarrhoea or mucositis; hypocalcaemia; anorexia which may lead to weight decrease, headache, conjunctivitis, diarrhoea, nausea, vomiting, severe infusion-related reactions (in some cases with fatal outcome), fatigue.
See prescribing information for full details.

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 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.
See prescribing information for full details.

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. 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.

There is limited experience with single doses higher than 400 mg/m2 body surface area to date or weekly administrations of doses higher than 250 mg/m2 body surface area.
See prescribing information for full details.  

Compatibilities: This medicinal product may be administered via a gravity drip, an infusion pump or a syringe pump. A separate infusion line must be used for the infusion, and the line must be used with sterile sodium chloride 9 mg/mL (0.9%) solution for injection at the end of infusion.
This medicinal product is compatible with:
• polyethylene (PE), ethyl vinyl acetate (EVA) or polyvinyl chloride (PVC) bags,
• polyethylene (PE), polyurethane (PUR), ethyl vinyl acetate (EVA), polyolefine thermoplastic (TP) or polyvinyl chloride (PVC) infusion sets,
• polypropylene (PP) syringes for syringe pump.
Care must be taken to ensure aseptic handling when preparing the infusion.
Storage: Store in a refrigerator (2°C – 8°C). Chemical and physical in-use stability of this drug has been demonstrated for 48 hours at 25°C, if the solution is prepared as described in prescribing information.
This drug does not contain any antimicrobial preservative or bacteriostatic agent. From a microbiological point of view, the product shall be used immediately after opening. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless opening has taken place in controlled and validated aseptic conditions.