Erbitux

Cetuximab.

Each mL of solution for infusion contains cetuximab 5 mg. Each vial of 20 mL contains cetuximab 100 mg. Cetuximab is a chimeric monoclonal IgG1 antibody produced in a mammalian cell line (Sp2/0) by recombinant DNA technology.

Pharmacotherapeutic Group: Antineoplastic agents, monoclonal antibodies. ATC Code: L01XC06.
Pharmacology: Pharmacodynamics: Mechanism of Action: Cetuximab is a chimeric monoclonal IgG₁ antibody that is specifically directed against the epidermal growth factor receptor (EGFR).
EGFR signalling pathways are involved in the control of cell survival, cell cycle progression, angiogenesis, cell migration and cellular invasion/metastasis.
Cetuximab binds to the EGFR with an affinity that is approximately 5- to 10-fold higher than that of endogenous ligands. Cetuximab blocks binding of endogenous EGFR ligands resulting in inhibition of the function of the receptor. It further induces the internalisation of EGFR, which can lead to down-regulation of EGFR. Cetuximab also targets cytotoxic immune effector cells towards EGFR-expressing tumour cells [antibody dependent cell-mediated cytotoxicity (ADCC)].
Cetuximab does not bind to other receptors belonging to the hydroxyethylrutosides (HER) family.
The protein product of the proto-oncogene Kirsten rat sarcoma 2 viral oncogene homologue (KRAS) is a central down-stream signal-transducer of EGFR. In tumours, activation of KRAS by EGFR contributes to EGFR-mediated increased proliferation, survival and the production of proangiogenic factors.
KRAS is one of the most frequently activated oncogenes in human cancers. Mutations of the KRAS gene at certain hot-spots (mainly codons 12 and 13) result in constitutive activation of the KRAS protein independently of EGFR signalling.
Pharmacodynamic Effects: In both in vitro and in vivo assays, cetuximab inhibits the proliferation and induces apoptosis of human tumour cells that express EGFR. In vitro cetuximab inhibits the production of angiogenic factors by tumour cells and blocks endothelial cell migration. In vivo cetuximab inhibits expression of angiogenic factors by tumour cells and causes a reduction in tumour neovascularisation and metastasis.
Immunogenicity: The development of human anti-chimeric antibodies (HACA) is a class effect of monoclonal chimeric antibodies. Current data on the development of HACAs is limited. Overall, measurable HACA titres were noted in 3.4% of the patients studied, with incidences ranging from 0-9.6% in the target indication studies. No conclusive data on the neutralising effect of HACAs on cetuximab is available to date. The appearance of HACA did not correlate with the occurrence of hypersensitivity reactions or any other undesirable effect to cetuximab.
Colorectal Cancer: A diagnostic assay (EGFR pharmDx) was used for immunohistochemical detection of EGFR expression in tumour material. A tumour was considered to be EGFR-expressing if 1 stained cell could be identified. Approximately 75% of the patients with metastatic colorectal cancer screened for clinical studies had an EGFR-expressing tumour and were therefore considered eligible for cetuximab treatment. The efficacy and safety of cetuximab have not been documented in patients with tumours where EGFR was not detected.
In metastatic colorectal cancer, the incidence of KRAS mutations is in the range of 30-50%. Recent data demonstrate that patients with KRAS wild-type metastatic colorectal cancer have a significantly higher chance to benefit from treatment with cetuximab or a combination of cetuximab and chemotherapy.
Cetuximab, as a single agent or in combination with chemotherapy, was investigated in 5 randomised controlled clinical studies and several supportive studies. The 5 randomised studies investigated a total of 3734 patients with metastatic colorectal cancer, in whom EGFR expression was detectable and who had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. The majority of patients included had an ECOG performance status of ≤1. In all studies, cetuximab was administered as described in Dosage & Administration.
The KRAS status was recognised as predictive factor for the treatment with cetuximab in 4 of the randomised controlled studies. KRAS mutational status was available for 2072 patients. An analysis was not possible in study EMR 62 202-207 alone.
Cetuximab in Combination with Chemotherapy: EMR 62 202-013: This randomised study in patients with metastatic colorectal cancer who had not received prior treatment for metastatic disease compared the combination of cetuximab and irinotecan plus infusional 5-fluorouracil/folinic acid (FOLFIRI) (599 patients) to the same chemotherapy alone (599 patients). The proportion of patients with KRAS wild-type tumours from the patient population evaluable for KRAS status comprised 63%.
The efficacy data generated in this study are summarised in Table 1.


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EMR 62 202-047: This randomised study in patients with metastatic colorectal cancer who had not received prior treatment for metastatic disease compared the combination of cetuximab and oxaliplatin plus infusional 5-fluorouracil/folinic acid (FOLFOX4) (169 patients) to the same chemotherapy alone (168 patients). The proportion of patients with KRAS wild-type tumours from the patient population evaluable for KRAS status comprised 57%.
The efficacy data generated in this study are summarised in Table 2.


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CA225006: This randomised study in patients with metastatic colorectal cancer who had received initial combination treatment with oxaliplatin plus fluoropyrimidine for metastatic disease compared the combination of cetuximab and irinotecan (648 patients) with irinotecan alone (650 patients). The proportion of patients with KRAS wild-type tumours from the patient population evaluable for KRAS status comprised 64%.
A significant difference in overall survival time could not be shown in this study. Following disease progression, treatment with EGFR-targeting agents was initiated in 50% of patients in the irinotecan-alone arm, which most likely impacted survival results. Objective response rate and progression free survival time were significantly improved with cetuximab. However, as no independent review of imaging data was conducted, these results have to be interpreted with caution.
EMR 62 202-007: This randomised study in patients with metastatic colorectal cancer after failure of irinotecan-based treatment for metastatic disease as the last treatment before study entry compared the combination of cetuximab and irinotecan (218 patients) with cetuximab monotherapy (111 patients).
The combination of cetuximab with irinotecan compared to cetuximab alone reduced the overall risk of disease progression by 46% and significantly increased objective response rate. In the randomised trial, the improvement in overall survival time did not reach statistical significance; however, in the follow-up treatment, nearly 50% of the patients of the cetuximab-alone arm received a combination of cetuximab and irinotecan after progression of disease, which may have influenced overall survival time.
Cetuximab as a Single Agent: CA225025: This randomised study in patients with metastatic colorectal cancer who had received prior oxaliplatin-, irinotecan- and fluoropyrimidine-based treatment for metastatic disease compared the addition of cetuximab as a single agent to best supportive care (BSC) (287 patients) with best supportive care (285 patients). The proportion of patients with KRAS wild-type tumours from the patient population evaluable for KRAS status comprised 58%.
The efficacy data generated in this study are summarised in Table 3.


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Squamous Cell Cancer of the Head and Neck: Immunohistochemical detection of EGFR expression was not performed since >90% of patients with squamous cell cancer of the head and neck have tumours that express EGFR.
Cetuximab in Combination with Radiation Therapy for Locally Advanced Disease: EMR 62 202-006: This randomised study compared the combination of cetuximab and radiation therapy (211 patients) with radiation therapy alone (213 patients) in patients with locally advanced squamous cell cancer of the head and neck. Cetuximab was started 1 week before radiation therapy and administered at the doses described in Dosage & Administration until the end of the radiation therapy period.
The efficacy data generated in this study are summarised in Table 4.


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Patients with a good prognosis as indicated by tumour stage, Karnofsky performance status (KPS) and age had a more pronounced benefit, when cetuximab was added to radiation therapy. No clinical benefit could be demonstrated in patients with KPS ≤80 who were ≥65 years.
The use of cetuximab in combination with chemoradiotherapy has so far not been adequately investigated. Thus, a benefit-risk ratio for this combination has not yet been established.
Cetuximab in Combination with Platinum-Based Chemotherapy in Recurrent and/or Metastatic Disease: EMR 62 202-002: This randomised study in patients with recurrent and/or metastatic squamous cell cancer of the head and neck who had not received prior chemotherapy for this disease compared the combination of cetuximab and cisplatin or carboplatin plus infusional 5-fluorouracil (222 patients) to the same chemotherapy alone (220 patients). Treatment in the cetuximab arm consisted of up to 6 cycles of platinum-based chemotherapy in combination with cetuximab followed by cetuximab as maintenance therapy until disease progression.
The efficacy data generated in this study are summarised in Table 5.


Click on icon to see table/diagram/image


Patients with a good prognosis as indicated by tumour stage, Karnofsky performance status (KPS) and age had a more pronounced benefit, when cetuximab was added to platinum-based chemotherapy. In contrast to progression free survival time, no benefit in overall survival time could be demonstrated in patients with KPS ≤80 who were ≤65 years.
Pharmacokinetics: Cetuximab pharmacokinetics were studied when cetuximab was administered as monotherapy or in combination with concomitant chemotherapy or radiation therapy in clinical studies. Intravenous infusions of cetuximab exhibited dose-dependent pharmacokinetics at weekly doses ranging from 5-500 mg/m² body surface area.
When cetuximab was administered at an initial dose of 400 mg/m² body surface area, the mean volume of distribution was approximately equivalent to the vascular space (2.9 L/m² with a range of 1.5-6.2 L/m²). The mean C_max (±standard deviation) was 185±55 mcg/mL. The mean clearance was 0.022 L/hr/m² body surface area.
Cetuximab has a long elimination half-life with values ranging from 70-100 hrs at the target dose.
Cetuximab serum concentrations reached stable levels after 3 weeks of cetuximab monotherapy. Mean peak cetuximab concentrations were 155.8 mcg/mL in week 3 and 151.6 mcg/mL in week 8, whereas the corresponding mean trough concentrations were 41.3 mcg/mL and 55.4 mcg/mL, respectively. In a study of cetuximab administered in combination with irinotecan, the mean cetuximab trough levels were 50 mcg/mL in week 12 and 49.4 mcg/mL in week 36.
Several pathways have been described that may contribute to the metabolism of antibodies. All of these pathways involve the biodegradation of the antibody to smaller molecules eg, small peptides or amino acids.
Special Populations: An integrated analysis across all clinical studies showed that the pharmacokinetic characteristics of cetuximab are not influenced by race, age, gender, renal or hepatic status.
Only patients with adequate renal and hepatic function have been investigated to date (serum creatinine ≤1.5-fold, transaminases ≤5-fold and bilirubin ≤1.5-fold the upper limit of normal).
Toxicology: Preclinical Safety Data: Starting at dose levels equivalent to those used in humans, dose-dependent skin alterations were the major findings observed in toxicity studies with cynomolgus monkeys (a chronic repeat-dose toxicity study and an embryo-foetal development study).
An embryo-foetal toxicity study in cynomolgus monkeys revealed no signs of teratogenicity. However, dependent on the dose, an increased incidence of abortion was observed.
Nonclinical data on genotoxicity and local tolerance including accidental administration by routes other than the intended infusion revealed no special hazard for humans.
No formal animal studies have been performed to establish the carcinogenic potential of cetuximab or to determine its effects on male and female fertility.
Toxicity studies with co-administration of cetuximab and chemotherapeutic agents have not been performed.
No nonclinical data on the effect of cetuximab on wound healing are available to date. However, in preclinical wound healing models, EGFR-selective tyrosine kinase inhibitors were shown to retard wound healing.

Treatment of patients with epidermal growth factor receptor(EGFR)-expressing, KRAS wild-type metastatic colorectal cancer in combination with chemotherapy and in patients who have failed oxaliplatin- and irinotecan-based therapy and who are intolerant to irinotecan.
Treatment of patients with squamous cell cancer of the head and neck in combination with radiation therapy for locally advanced disease and with platinum-based chemotherapy for recurrent and/or metastatic disease.

Erbitux 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 hr after the end of the infusion. Availability of resuscitation equipment must be ensured.
Prior to the 1st infusion, patients must receive premedication with an antihistamine and a corticosteroid. This premedication is recommended prior to all subsequent infusions.
In all indications, Erbitux is administered once a week. The very 1st dose is cetuximab 400 mg/m² body surface area. All subsequent weekly doses are 250 mg/m² each.
Colorectal Cancer: In patients with metastatic colorectal cancer, cetuximab is used in combination with chemotherapy or as a single agent (see Pharmacology under Actions). Detection of KRAS mutational status must be performed prior to the 1st cetuximab infusion. It is important that a validated test method is used by an experienced laboratory (see Pharmacology under Actions and Precautions).
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 hr 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 1 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 (see Pharmacology under Actions). Chemotherapy must not be administered earlier than 1 hr after the end of the cetuximab infusion.
Special Populations: Only patients with adequate renal and hepatic function have been investigated to date (see Precautions).
Cetuximab has not been studied in patients with preexisting haematological disorders (see Precautions).
No dose adjustment is required in the elderly, but the experience is limited in patients ≥75 years.
Paediatric Population: There is no experience in children (see Precautions).
Administration: Erbitux 5 mg/mL is administered IV with an infusion pump, gravity drip or a syringe pump (for handling instructions, see Cautions For Usage).
For the initial dose, the recommended infusion period is 120 min.
For the subsequent weekly doses, the recommended infusion period is 60 min. The maximum infusion rate must not exceed 10 mg/min.

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. In clinical studies with doses up to 700 mg/m² given every 2 weeks, the safety profile was consistent with that described in Adverse Reactions.

Patients with known severe (grade 3 or 4) hypersensitivity reactions to cetuximab.
Before initiation of combination treatment, contraindications for concomitantly used chemotherapeutic agents or radiation therapy must be considered.

Infusion-Related Reactions: 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.
Severe infusion-related reactions have been reported in patients treated with cetuximab (see Adverse Reactions). Symptoms usually occurred during the 1st infusion and up to 1 hr after the end of infusion, but may occur after several hrs 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 of an infusion-related reaction occur. Occurrence of a severe infusion-related reaction requires immediate and permanent discontinuation of cetuximab therapy and may necessitate emergency treatment.
Special attention is recommended for patients with reduced performance status and preexisting cardiopulmonary disease.
Respiratory Disorders: Cases of interstitial lung disease have been reported, with the majority of patients from the japanese population. If interstitial lung disease is diagnosed, cetuximab must be discontinued and the patient be treated appropriately.
Skin Reactions: 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 a severe skin reaction [≥grade 3; US National Cancer Institute-Common Toxicity Criteria (NCI-CTC)], cetuximab therapy must be interrupted. Treatment may only be resumed if the reaction has resolved to grade 2 (see Adverse Reactions).
If the severe skin reaction occurred for the 1st time, treatment may be resumed without any change in dose level.
With the 2nd and 3rd occurrences of severe skin reactions, cetuximab therapy must again be interrupted. Treatment may only be resumed at a lower dose level (200 mg/m² body surface area after the 2nd occurrence and 150 mg/m² after the 3rd occurrence) if the reaction has resolved to grade 2.
If severe skin reactions occur for the 4th 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; the frequency of severe hypocalcaemia may be increased particularly when combined with platinum-based chemotherapy.
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 eg, 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 (see Adverse Reactions).
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 eg, fluoropyrimidines should be taken into account.
Eye Disorders: Patients presenting with signs and symptoms suggestive of keratitis eg, 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 KRAS Mutated Tumours: 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 combination with continuous infusional 5-fluorouracil/folinic acid plus oxaliplatin (see Pharmacology under Actions).
Special Populations: Only patients with adequate renal and hepatic function have been investigated to date (serum creatinine ≤1.5-fold, transaminases ≤5-fold and bilirubin ≤1.5-fold the upper limit of normal).
Cetuximab has not been studied in patients presenting with 1 or more of the following laboratory parameters: Haemoglobin <9 g/dL, leukocyte count <3000/mm³, absolute neutrophil count <1500/mm³ and platelet count <100,000/mm³.
There is limited experience in the use of cetuximab in combination with radiation therapy in colorectal cancer.
Effects on the Ability to Drive or Operate Machinery: 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.
Use in pregnancy & lactation: The epidermal growth factor receptor (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 Toxicology under Actions). 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 justifies a potential risk to the foetus.
It is recommended that women do not breastfeed during treatment with Erbitux and for 2 months after the last dose, because it is not known whether cetuximab is excreted in breast milk.
Use in children: The safety and effectiveness of cetuximab in paediatric patients <18 years have not been established.

The epidermal growth factor receptor (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 Toxicology under Actions). 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 justifies a potential risk to the foetus.
It is recommended that women do not breastfeed during treatment with Erbitux and for 2 months after the last dose, because it is not known whether cetuximab is excreted in breast milk.

The primary undesirable effects of cetuximab are skin reactions, which occur in >80% of patients, hypomagnesaemia which occurs in >10% of patients and infusion-related reactions, which occur with mild to moderate symptoms in >10% of patients and with severe symptoms in >1% of patients.
The following definitions apply to the frequency terminology used hereafter: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000) and frequency not known (cannot be estimated from the available data).
An asterisk (*) indicates that additional information on the respective adverse reactions is provided as follows: Nervous System Disorders: Common: Headache. Frequency Not Known: Aseptic meningitis.
Eye Disorders: Common: Conjunctivitis. Uncommon: Blepharitis, keratitis.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Pulmonary embolism, interstitial lung disease.
Gastrointestinal Disorders: Common: Diarrhoea, nausea, vomiting.
Skin and Subcutaneous Tissue Disorders: Very Common: Skin reactions^*. Frequency Not Known: Superinfection of skin lesions^*.
Metabolism and Nutritional Disorders: Very Common: Hypomagnesaemia (see Precautions). Common: Dehydration, in particular secondary to diarrhoea or mucositis; hypocalcaemia (see Precautions); anorexia which may lead to decrease in weight.
Vascular Disorders: Uncommon: Deep vein thrombosis.
General Disorders and Administration Site Conditions: Very Common: Mild or moderate infusion-related reactions^*; mild to moderate mucositis which may lead to epistaxis. Common: Severe infusion-related reactions^*, fatigue.
Hepatobiliary Disorders: Very Common: Increase in liver enzyme levels (ASAT, ALAT, AP).
Additional Information^*: Overall, no clinically relevant difference between genders was observed.
Infusion-Related Reactions: Mild or moderate infusion-related reactions are very common comprising symptoms eg, fever, chills, dizziness, or dyspnoea that occur in a close temporal relationship mainly to the 1st cetuximab infusion.
Severe infusion-related reactions may commonly occur, in rare cases with fatal outcome. They usually develop during or within 1 hr of the initial cetuximab infusion, but may occur after several hrs or with subsequent infusions. Although the underlying mechanism has not been identified, some of these reactions may be anaphylactoid/anaphylactic in nature and may include symptoms eg, bronchospasm, urticaria, increase/decrease of blood pressure, loss of consciousness or shock. In rare cases, angina pectoris, myocardial infarction or cardiac arrest have been observed.
For clinical management of infusion-related reactions, see Precautions.
Skin Reactions: Skin reactions may develop in >80% of patients and mainly present as acne-like rash and/or less frequently, as pruritus, dry skin, desquamation, hypertrichosis, or nail disorders (eg, paronychia).
Approximately 15% of the skin reactions are severe, including single cases of skin necrosis. The majority of skin reactions develop within the first 3 weeks of therapy. They generally resolve, without sequelae, over time following cessation of treatment if the recommended adjustments in dose regimen are followed (see Precautions).
Skin lesions induced by cetuximab may predispose patients to superinfections (eg, with Staphylococcus aureus), which may lead to subsequent complications eg, cellulitis, erysipelas, or potentially with fatal outcome, staphylococcal scalded skin syndrome 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 eg, febrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (see Precautions).
In combination with infusional 5-fluorouracil, 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 infusional 5-fluorouracil.
In combination with local radiation therapy of the head and neck area, additional undesirable effects were those typical of radiation therapy (eg, 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.

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 eg, febrile neutropenia, pneumonia and sepsis compared to platinum-based chemotherapy alone (see Precautions).
In combination with infusional 5-fluorouracil, 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 infusional 5-fluorouracil.
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.
Incompatibilities: Erbitux must not be mixed with other medicinal products except those mentioned in Cautions For Usage.

Special Precautions for Disposal and Other Handling: Erbitux 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 flushed with sterile sodium chloride 9 mg/mL (0.9%) solution for injection at the end of infusion.
Erbitux 5 mg/mL is compatible with: Polyethylene (PE), ethyl vinyl acetate (EVA) or polyvinyl chloride (PVC) bags; with PE, polyurethane (PUR), EVA, polyolefine thermoplastic (TP) or PVC infusion sets; with polypropylene (PP) syringes for syringe pump.
Care must be taken to ensure aseptic handling when preparing the infusion.
Preparation as Follows: For Administration with Infusion Pump or Gravity Drip [Diluted with Sterile Sodium Chloride 9 mg/mL (0.9%) Solution]: Take an infusion bag of adequate size of sterile sodium chloride 9 mg/mL (0.9%) solution. Calculate the required volume of Erbitux. Remove an adequate volume of the sodium chloride solution from the infusion bag, using an appropriate sterile syringe with a suitable needle.
Take an appropriate sterile syringe and attach a suitable needle.
Draw up the required volume of Erbitux from a vial. Transfer the Erbitux into the prepared infusion bag. Repeat this procedure until the calculated volume has been reached. Connect the infusion line and prime it with the diluted Erbitux before starting the infusion.
Use a gravity drip or an infusion pump for administration. Set and control the rate as explained in Dosage & Administration.
For Administration with Infusion Pump or Gravity Drip (Undiluted): Calculate the required volume of Erbitux. Take an appropriate sterile syringe (minimum 50 mL) and attach a suitable needle. Draw up the required volume of Erbitux from a vial. Transfer the Erbitux into a sterile evacuated container or bag. Repeat this procedure until the calculated volume has been reached. Connect the infusion line and prime it with Erbitux before starting the infusion. Set and control the rate as explained in Dosage & Administration.
For Administration with a Syringe Pump: Calculate the required volume of Erbitux. Take an appropriate sterile syringe and attach a suitable needle. Draw up the required volume of Erbitux from a vial. Remove the needle and put the syringe into the syringe pump.
Connect the infusion line to the syringe, set and control the rate as explained in Dosage & Administration and start the infusion after priming the line with Erbitux or sterile sodium chloride 9 mg/mL (0.9%) solution. If necessary, repeat this procedure until the calculated volume has been infused.

Store in a refrigerator (2°-8°C). Do not freeze.
For storage conditions after opening: Chemical and physical in-use stability of Erbitux 5 mg/mL has been demonstrated for 48 hrs at 25°C, if the solution is prepared as described in Cautions For Usage.
Erbitux does not contain any antimicrobial preservative or bacteriostatic agent. From a microbiological point of view, Erbitux 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 hrs at 2°-8°C, unless opening has taken place in controlled and validated aseptic conditions.

Targeted Cancer Therapy

L01FE01 - cetuximab ; Belongs to the class of EGFR (Epidermal Growth Factor Receptor) inhibitors. Used in the treatment of cancer.

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