dy with axitinib for the treatment of patients with RCC that excluded patients with untreated brain metastasis, haemorrhagic adverse reactions were reported in 10.6% of patients receiving axitinib. The most common haemorrhagic adverse reactions in patients treated with axitinib were epistaxis (5.3%), haematuria (1.4%), rectal haemorrhage (1.1%) and gingival bleeding (1.1%). Grade ≥ 3 haemorrhagic adverse reactions were reported in 0.8% of patients receiving axitinib (including cerebral haemorrhage, gastric haemorrhage and lower gastrointestinal haemorrhage). Fatal haemorrhage was reported in one patient (0.3%) receiving axitinib (gastric haemorrhage). In monotherapy studies with axitinib (N=699), haemoptysis was reported as an adverse reaction in 1.6% of patients, including one case (0.1%) of a Grade ≥ 3 event.
Gastrointestinal perforation and fistula formation (see section 4.4)
In a controlled clinical study with axitinib for the treatment of patients with RCC, gastrointestinal perforation was reported in one patient (0.3%, all-causality incidence) receiving axitinib. In monotherapy studies with axitinib (N=699), fistulas were reported in 0.7% of patients (all-causality incidence) and fatal gastrointestinal perforation was reported in one patient (0.1%).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
There is no specific treatment for axitinib overdose.
In a controlled clinical study with axitinib for the treatment of patients with RCC, one patient inadvertently received a dose of 20 mg twice daily for 4 days and experienced dizziness (Grade 1).
n a clinical dose finding study with axitinib, subjects who received starting doses of 10 mg twice daily or 20 mg twice daily experienced adverse reactions which included hypertension, seizures associated with hypertension, and fatal haemoptysis.
In cases of suspected overdose, axitinib should be withheld and supportive care instituted.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group:Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE17
Mechanism of action
Axitinib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2 and VEGFR-3. These receptors are implicated in pathologic angiogenesis, tumour growth, and metastatic progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-2 in xenograft tumour vasculature that expressed the target in vivo and produced tumour growth delay, regression, and inhibition of metastases in many experimental models of cancer.
Effect on QTc interval
In a randomised, 2-way crossover study, 35 healthy subjects were administered a single oral dose of axitinib (5 mg) in the absence and presence of 400 mg ketoconazole for 7 days. Results of this study indicated that axitinib plasma exposures up to two-fold greater than therapeutic levels expected following a 5 mg dose, did not produce clinically-significant QT interval prolongation.
Clinical efficacy
The saf |
