th chemotherapy on PFS in patients with wild-type KRAS tumours. Studies investigating this effect are currently ongoing. The European Medicines Agency (EMA) will review new information on the product every year and this SPC will be updated as necessary.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Vectibix in all subsets of the paediatric population in colorectal cancer. See section 4.2 for information on paediatric use.
5.2 Pharmacokinetic properties
Vectibix administered as a single agent or in combination with chemotherapy exhibits nonlinear pharmacokinetics.
Following a single-dose administration of panitumumab as a 1-hour infusion, the area under the concentration-time curve (AUC) increased in a greater than dose-proportional manner and clearance (CL) of panitumumab decreased from 30.6 to 4.6 ml/day/kg as the dose increased from 0.75 to 9 mg/kg. However, at doses above 2 mg/kg, the AUC of panitumumab increases in an approximately dose-proportional manner.
Following the recommended dose regimen (6 mg/kg given once every 2 weeks as a 1-hour infusion), panitumumab concentrations reached steady-state levels by the third infusion with mean (± SD) peak and trough concentrations of 213 ± 59 and 39 ± 14 mcg/ml, respectively. The mean (± SD) AUC0-tau and CL were 1306 ± 374 mcg•day/ml and 4.9 ± 1.4 ml/kg/day, respectively. The elimination half-life was approximately 7.5 days (range: 3.6 to 10.9 days).
A population pharmacokinetic analysis was performed to explore the potential effects of selected covariates on panitumumab pharmacokinetics. Results suggest that age (21-88), gender, race, hepatic function, renal function, chemotherapeutic agents, and EGFR membrane staining intensity (1+, 2+, 3+) in tumour cells had no apparent impact on the pharmacokinetics of panitumumab.
No clinical studies have been conducted to examine the pharmacokinetics of panitumumab in patients with renal or hepatic impairment.
5.3 Preclinical safety data
Adverse reactions seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:
Skin rash and diarrhoea were the major findings observed in repeat-dose toxicity studies of up to 26 weeks duration in cynomolgus monkeys. These findings were observed at doses approximately equivalent to the recommended human dose and were reversible upon termination of administration of panitumumab. The skin rash and diarrhoea observed in monkeys are considered related to the pharmacological action of panitumumab and are consistent with the toxicities observed with other anti-EGFR inhibitors.
Studies to eva luate the mutagenic and carcinogenic potential of panitumumab have not been performed.
Animal studies are insufficient with respect to embryo-foetal development since foetal panitumumab exposure levels were not examined. Panitumumab has been shown to cause foetal abortions and/or foetal deaths in cynomolgus monkeys when administered during the period of organogenesis at doses approximately equivalent to the recommended human dose.
Formal male fertility studies have not been conducted; however, microscopic eva luation of male reproductive organs from repeat-dose toxicity studies in cynomolgus monkeys at doses up to approximately 5-fold the human dose on a mg/kg basis, revealed no differences compared to c |
