Cetuximab
(US Adopted Name, rINN)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Adverse Effects, Treatment, and Precautions
For general discussions see Antineoplastics.
Adverse effects associated with cetuximab include skin reactions, asthenia, and gastrointestinal disturbances. Skin reactions present mainly as an acneform rash, and, if severe, require dosage adjustment (see Uses and Administration, below). Infusion reactions suggestive of a cytokine release syndrome can occur, usually with the first dose. Mild reactions include chills, fever, and dyspnoea; severe reactions include bronchospasm, urticaria, hypotension, and loss of consciousness, and fatalities have occurred. Premedication with a histamine H1-antagonist is recommended, and dose adjustment may be necessary (see below). Cardiopulmonary arrest and/or sudden death has been reported in patients treated with cetuximab and radiation therapy, and cetuximab should be given with caution to head and neck cancer patients with coronary artery disease, congestive cardiac failure, or arrhythmias. Hypomagnesaemia can occur; patients should be monitored for this and accompanying hypocalcaemia and hypokalaemia both during, and for up to 8 weeks after stopping, cetuximab therapy. Interstitial lung disease and pneumonitis have been reported rarely.
Effects on the skin, hair, and nails. Acneformfollicular rashes have been reported with cetuximab therapy; lesions were pustular and papular, and commonly occurred on the face, scalp, chest, and upper back. It has been suggested that there is a relationship between rash and response to therapy or survival, i.e. that rash might be a surrogate marker of cetuximab activity; doubling the cetuximab dose in patients without severe initial skin reactions is reported to increase their response rate to therapy. A few cases of lengthening eyelash and eyebrow hair and abnormal growth of chest hair have been described. Paronychia has also been reported, as have intraoral aphthous ulcers. Treatment with oral isotretinoin 500 micrograms/kg daily has been reported to successfully clear acneform skin lesions in 2 patients; topical therapy with metronidazole 0.75% gel or erythromycin 1% was also used. Prophylactic oral minocycline 100 mg daily, started on the same day as cetuximab and given for 8 weeks, significantly reduced total facial lesion counts in the first 4 weeks when compared with placebo; this difference tapered by the end of 8 weeks of treatment. Topical tazarotene showed no clinical benefit and caused local irritation that forced tazarotene to be stopped in many patients.
Some have suggested that the clinical findings of papulopustular rash, nail and periungual abnormalities, alterations in hair texture and growth, and dry skin and pruritus, constitute a syndrome unique to the epidermal growth factor receptor (EGFR) inhibitors, believed to be due to EGFR inhibition in the epidermis, hair follicle, and nail matrix.
Erythema and focal epidermolysis, progressing to severe radiation dermatitis with necrosis, has been reported in patients given radiation therapy with cetuximab.
Hypomagnesaemia. A patient given cetuximab developed profound hypomagnesaemia, requiring intravenous supplementation with up to 10 g magnesium sulfate daily, throughout the duration of cetuximab therapy. This case prompted a review of 154 patients treated with cetuximab, of whom 34 had their magnesium concentrations measured at least once. Among these 34 patients, 6 had grade 3 and 2 had grade 4 hypomagnesaemia; this equated to an incidence of 24% of grade 3/4 hypomagnesaemia. In each of these cases the need for supplementation subsided after stopping cetuximab, with resolution of the hypomagnesaemia within several weeks. However, it was not clear whether all patients had a normal magnesium concentration before treatment, nor was there any indication of the median time to development of hypomagnesaemia.
Another retrospective review of 114 patients did address these issues. It found 48 patients had normal baseline magnesium concentrations before starting cetuximab. Of these 48 evaluable patients, 13 developed grade 3 or grade 4 hypomagnesaemia (27%); median time to onset of grade 3/4 hypomagnesaemia was 5.5 months. There was a significant association between duration of cetuximab therapy and grade of hypomagnesaemia. Magnesium replacement therapy was given to those patients with grade 3/4 toxicity. Initial attempts at oral replacement with up to 1.6 g magnesium oxide three times daily were ineffective, and intravenous supplementation was needed. However, the effects of infusion did not extend beyond 48 to 72 hours, with some patients requiring daily magnesium sulfate infusions of up to 10 g daily. Furthermore, in some patients, magnesium supplementation became less effective with continued cetuximab treatment. Of 3 patients evaluable for recovery from hypomagnesaemia after stopping cetuximab, 2 were found to correct their magnesium concentrations without supplementation after 1 month. However, 1 patient required prolonged and ongoing supplementation for more than 5 months, at 4 g infused 3 times weekly (having received 8 g daily while on cetuximab). A prospective study found that a progressive decrease in serum magnesium concentrations was seen in 97% of patients after treatment with cetuximab, panitumumab, or matuzumab. The authors concluded that magnesium wasting was specifically due to inhibition of the epidermal growth factor receptor (EGFR), and suggested hypomagnesaemia might be a class effect of the monoclonal antibodies directed against EGFR. However, incidence and severity may vary between products. There was also high interindividual variability; increasing age was associated with more severe hypomagnesaemia.
Pharmacokinetics
The pharmacokinetics of cetuximab have been reported to be non-linear and dose-dependent. Steady-state concentrations are reached after 3 weeks. Cetuximab has a long elimination half-life of about 70 to 100 hours.
Uses and Administration
Cetuximab is a monoclonal antibody that binds to the epidermal growth factor receptor (EGFR). It is used in the treatment of EGFR-expressing metastatic colorectal cancer, either with irinotecan in patients refractory to irinotecan-based chemotherapy, or as monotherapy in patients intolerant to irinotecan. Cetuximab with radiotherapy is also used for the treatment of locally advanced squamous cell cancer of the head and neck. It is also approved as monotherapy for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. It is under investigation for non-small cell lung cancer and other solid tumours.
Cetuximab 400 mg/m is given as a loading dose by intravenous infusion over 2 hours. This is followed by once weekly maintenance doses of 250 mg/m given over 1 hour. Premedication with a histamine H1-antagonist is recommended, and patients should be closely monitored for at least 1 hour after the end of the cetuximab infusion. A low-protein-binding 0.22-micrometre in-line filter should be used, and the infusion given via an infusion or syringe pump. In combined therapy for colorectal cancer, irinotecan should not be given for at least 1 hour after the end of cetuximab infusion. In head and neck carcinoma, cetuximab therapy is started one week before radiation therapy and continued until the end of the radiation therapy period. Cetuximab is usually given 1 hour before radiation therapy. When used as monotherapy, cetuximab is continued until disease progression or unacceptable toxicity occurs.
Cetuximab doses should be permanently halved in patients who have experienced a mild to moderate infusion reaction, and stopped permanently if a severe reaction has occurred (see Adverse Effects and Precautions, above). When a severe acneform rash has occurred, the next dose should be delayed by 1 to 2 weeks. After the first occurrence, the full maintenance dose may be given if there has been improvement in the rash; after a second occurrence the next dose should be delayed and reduced to 200 mg/m; after a third occurrence the next dose should be delayed and reduced to 150 mg/m. If there is no improvement in the rash when therapy has been delayed, or if the rash has occurred 4 times, cetuximab should be stopped.
Proprietary Preparations
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Chile: Erbitux;
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Finland: Erbitux;
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Hong Kong; Erbitux;
Hungary: Erbitux;
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Israel: Erbitux;
Italy: Erbitux;
Malaysia: Erbitux;
The Netherlands: Erbitux;
Norway: Erbitux;
New Zealand: Erbitux;
Philippines: Erbitux;
Portugal: Erbitux;
Singapore: Erbitux;
Spain: Erbitux;
Sweden: Erbitux;
Switzerland: Erbitux;
United Kingdom (UK): Erbitux;
United States of America (US and USA): Erbitux.
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