proximately equivalent to the vascular space (2.9 l/m2 with a range of 1.5 to 6.2 l/m2). The mean Cmax (± standard deviation) was 185±55 microgram per ml. The mean clearance was 0.022 l/h per m² body surface area. Cetuximab has a long elimination half-life with values ranging from 70 to 100 hours at the target dose.
Cetuximab serum concentrations reached stable levels after three weeks of cetuximab monotherapy. Mean peak cetuximab concentrations were 155.8 microgram per ml in week 3 and 151.6 microgram per ml in week 8, whereas the corresponding mean trough concentrations were 41.3 and 55.4 microgram per ml, respectively. In a study of cetuximab administered in combination with irinotecan, the mean cetuximab trough levels were 50.0 microgram per ml in week 12 and 49.4 microgram per 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, i.e. small peptides or amino acids.
Pharmacokinetics in 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 1.5fold, transaminases 5fold and bilirubin 1.5fold the upper limit of normal).
Paediatric population
In a phase-I study in paediatric patients (1-18 years) with refractory solid tumours, cetuximab was administered in combination with irinotecan. The pharmacokinetic results were comparable to those in adults.
5.3 Preclinical safety data
Dose-dependent skin alterations, starting at dose levels equivalent to those used in humans, 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.
Non-clinical 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 non-clinical 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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium chloride
Glycine
Polysorbate 80
Citric acid monohydrate
Sodium hydroxide
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
3 years.
Chemical and physical in-use stability of Erbitux 5 mg/ml has been demonstrated for 48 hours at 25ºC, if the solution is prepared as described in section 6.6.
Erbitux does not contain any antimicrobial preservative or bacteriostatic agent. From a microb
