5, or UGT1A1 at therapeutic plasma concentrations.
In vitro studies indicated that axitinib has a potential to inhibit CYP1A2. Therefore, co-administration of axitinib with CYP1A2 substrates may result in increased plasma concentrations of CYP1A2 substrates (e.g. theophylline).
In vitro studies also indicated that axitinib has the potential to inhibit CYP2C8. However, co-administration of axitinib with paclitaxel, a known CYP2C8 substrate, did not result in increased plasma concentrations of paclitaxel in patients with advanced cancer, indicating lack of clinical CYP2C8 inhibition.
In vitro studies in human hepatocytes also indicated that axitinib does not induce CYP1A1, CYP1A2, or CYP3A4/5. Therefore co-administration of axitinib is not expected to reduce the plasma concentration of co-administered CYP1A1, CYP1A2, or CYP3A4/5 substrates in vivo.
In vitro studies with P-glycoprotein
In vitro studies indicated that axitinib inhibits P-glycoprotein. However, axitinib is not expected to inhibit P-glycoprotein at therapeutic plasma concentrations. Therefore, co-administration of axitinib is not expected to increase the plasma concentration of digoxin, or other P-glycoprotein substrates, in vivo.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no data regarding the use of axitinib in pregnant women. Based on the pharmacological properties of axitinib, it may cause foetal harm when administered to a pregnant woman. Studies in animals have shown reproductive toxicity including malformations (see section 5.3). Axitinib should not be used during pregnancy unless the clinical condition of the woman requires treatment with this medicinal product.
Women of childbearing potential must use effective contraception during and up to 1 week after treatment.
Breast-feeding
It is unknown whether axitinib is excreted in human milk. A risk to the suckling child cannot be excluded. Axitinib should not be used during breast-feeding.
Fertility
Based on non-clinical findings, axitinib has the potential to impair reproductive function and fertility in humans (see section 5.3).
4.7 Effects on ability to drive and use machines
Axitinib has a minor influence on the ability to drive and use machines. Patients should be advised that they may experience events such as dizziness and/or fatigue during treatment with axitinib.
4.8 Undesirable effects
Summary of the safety profile
The most important serious adverse reactions reported in patients receiving axitinib were arterial embolic and thrombotic events, venous embolic and thrombotic events, haemorrhage (including gastrointestinal haemorrhage, cerebral haemorrhage and haemoptysis), gastrointestinal perforation and fistula formation, hypertensive crisis, and posterior reversible encephalopathy syndrome. These risks, including appropriate action to be taken, are discussed in section 4.4.
The most common (≥ 20%) adverse reactions observed following treatment with axitinib were diarrhoea, hypertension, fatigue, dysphonia, nausea, decreased appetite, and palmar-plantar erythrodysaesthesia (hand-foot) syndrome.
Tabulated list of adverse reactions
Table 1 presents adverse reactions reported in patients who received axitinib in a pivotal clinical study for the treatment of patients with RCC (see section 5.1).
The adverse reactions are listed by system organ class, frequency category and grade of severity. Frequency ca |
