CYP3A4 induction was observed when a single dose of midazolam was co-administered after repeat dosing with vemurafenib for 15 days. This resulted in an average 32% decrease (maximum up to 80%) in midazolam plasma exposure after vemurafenib treatment. Vemurafenib may decrease the plasma exposure of substances predominantly metabolised by CYP3A4. On this basis, the efficacy of contraceptive pills metabolised by CYP3A4 used concomitantly with vemurafenib might be decreased. Dose adjustments for CYP3A4 substrates with narrow therapeutic window should be considered (see sections 4.4 and 4.6).

Mild induction of CYP2B6 by vemurafenib was noted in vitro at a vemurafenib concentration of 10 µM. It is currently unknown whether vemurafenib at a plasma level of 100 µM observed in patients at steady state (approximately 50 µg/ml) may decrease plasma concentrations of concomitantly administered CYP2B6 substrates, such as bupropion.

When a single dose of warfarin was co-administered after repeat dosing with vemurafenib for 15 days, some patients exhibited increased warfarin exposure (mean 20%) (see section 4.4). Caution should be exercised when vemurafenib is co-administered with warfarin (CYP2C9) in patients with melanoma.

Vemurafenib inhibited CYP2C8 in vitro. The in vivo relevance of this finding is unknown, but a risk for a clinically relevant effect on concomitantly administered CYP2C8 substrates cannot be excluded.

Due to the long half-life of vemurafenib, the full inhibitory effect of vemurafenib on a concomitant medicinal product might not be observed before 8 days of vemurafenib treatment.

After cessation of vemurafenib treatment, a washout of 8 days might be necessary to avoid an interaction with a subsequent treatment.

Effects of vemurafenib on substance transport systems

In vitro studies have demonstrated that vemurafenib is an inhibitor of the efflux transporters P-gp and BCRP. The clinical relevance of this finding is unknown. It cannot be excluded that vemurafenib may increase the exposure of other medicines transported by P-gp (e.g. aliskiren, colchicine, digoxin, everolimus, fexofenadine) or BCRP (e.g. methotrexate, mitoxantrone, rosuvastatin).

Many anticancer drugs are substrates of P-gp and/or BCRP and therefore there is a theoretical risk for an interaction with vemurafenib.

The possible effect of vemurafenib on other transporters is currently unknown.

Effects of concomitant medicines on vemurafenib

In vitro studies suggest that CYP3A4 metabolism and glucuronidation are responsible for the metabolism of vemurafenib. Biliary excretion appears to be another important elimination pathway. There are no clinical data available showing the effect of strong inducers or inhibitors of CYP3A4 and/or transport protein activity on vemurafenib exposure. Vemurafenib should be used with caution in combination with potent inhibitors of CYP3A4, glucuronidation and/or transport proteins (e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir).

Concomitant administration of potent inducers of P-gp, glucuronidation, and/or CYP3A4 (e.g. rifampicin, rifabutin, carbamazepine, phenytoin or St John's Wort [Hypericum perfo