Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction
Effects of vemurafenib on Drug Metabolizing Enzymes
Results from an in vivo drug-drug interaction study in metastatic melanoma patients demonstrated that vemurafenib is a moderate CYP1A2 inhibitor and a CYP3A4 inducer.

Concomitant use of vemurafenib with agents metabolized by CYP1A2 with narrow therapeutic windows (e.g. agomelatine, alosetron, duloxetine, melatonin, ramelteon, tacrine, tizanidine, theophylline) is not recommended. If co-administration cannot be avoided, exercise caution, as vemurafenib may increase plasma exposure of CYP1A2 substrate drugs. Dose reduction of the concomitant CYP1A2 substrate drug may be considered, if clinically indicated.
Co-administration of vemurafenib increased the plasma exposure (AUC) of caffeine (CYP1A2 substrate) 2.6-fold. In another clinical trial, vemurafenib increased Cmax and AUC of a single 2 mg dose of tizanidine (CYP1A2 substrate) approximately 2.2-fold and 4.7-fold, respectively.

Concomitant use of vemurafenib with agents metabolized by CYP3A4 with narrow therapeutic windows is not recommended. If co-administration cannot be avoided, it needs to be considered that vemurafenib may decrease plasma concentrations of CYP3A4 substrates and thereby their efficacy may be impaired. On this basis, the efficacy of contraceptive pills metabolized by CYP3A4 used concomitantly with vemurafenib might be decreased. Dose adjustments for CYP3A4 substrates with narrow therapeutic window may be considered, if clinically indicated (see sections 4.4 and 4.6).
In a clinical trial, co-administration of vemurafenib decreased the AUC of midazolam (CYP3A4 substrate) by an average 39% (maximum decrease up to 80%).

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 µ g/ml) may decrease plasma concentrations of concomitantly administered CYP2B6 substrates, such as bupropion.

Co-administration of vemurafenib resulted in an 18% increase in AUC of S-warfarin (CYP2C9 substrate). Exercise caution and consider additional INR (international normalized ratio) monitoring when vemurafenib is used concomitantly with warfarin (see section 4.4).

Vemurafenib moderately 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. Concomitant administration of CYP2C8 substrates with a narrow therapeutic window should be made with caution since vemurafenib may increase their concentrations.

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.

Radiation treatment
Potentiation of radiation treatment toxicity has been reported in patients receiving vemurafenib (see sections 4.4 and 4.8). In the majority of cases, patients received radiotherapy regimens greater than or equal to 2 Gy/day (hypofractionated regimens).

Effects of vemurafenib on drug transport systems
In vitro studies have demonstrated that vemurafenib is an inhibitor of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

A clinical drug interaction study demonstrated that multiple oral doses of vemurafenib (960 mg twice daily) increased the exposure of a single oral dose of the P-gp substrate digoxin, approximately 1.8 and 1.5 fold for digoxin AUClast and Cmax, respectively.

Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates (e.g.
aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, everolimus, fexofenadine, lapatinib, maraviroc, nilotinib, posaconazole, ranolazine, sirolimus, sitagliptin, talinolol, topotecan) and dose reduction of the concomitant medicinal product may be considered, if clinically indicated. Consider additional drug level monitoring for P-gp substrate medicinal products with a narrow therapeutic index (NTI) (e.g. digoxin, dabigatran etexilate, aliskiren) (see section 4.4).

The effects of vemurafenib on medicinal products that are substrates of BCRP are unknown. It cannot be excluded that vemurafenib may increase the exposure of medicines transported by BCRP (e.g.
methotrexate, mitoxantrone, rosuvastatin).
Many anticancer medicinal products are substrates of 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. In vitro studies have demonstrated that vemurafenib is a substrate of the efflux transporters P-gp and BCRP. It is currently unknown whether vemurafenib is a substrate also to other transport proteins.
Concomitant administration of strong CYP3A4 inhibitors or inducers or inhibitors/inducer of transport protein activity may alter vemurafenib concentrations.

Co-administration of itraconazole, a strong CYP3A4/Pgp inhibitor, increased steady state vemurafenib AUC by approximately 40%. Vemurafenib should be used with caution in combination with strong inhibitors of CYP3A4, glucuronidation and/or transport proteins (e.g. ritonavir, saquinavir, telithromycin, ketoconazole, itraconazole, voriconazole, posaconazole, nefazodone, atazanavir).
Patients co-treated with such agents should be carefully monitored for safety and dose modifications applied if clinically indicated (see Table 1 in section 4.2).

In a clinical study, co-administration of a single dose 960 mg of vemurafenib with rifampicin, significantly decreased the plasma exposure of vemurafenib by approximately 40%.
Concomitant administration of strong inducers of P-gp, glucuronidation, and/or CYP3A4 (e.g.
rifampicin, rifabutin, carbamazepine, phenytoin or St John’s Wort [Hypericum perforatum]) may lead to suboptimal exposure to vemurafenib and should be avoided.

The effects of P-gp and BCRP inhibitors that are not also strong CYP3A4 inhibitors are unknown. It cannot be excluded that vemurafenib pharmacokinetics could be affected by such medicines through influence on P-gp (e.g. verapamil, cyclosporine, quinidine) or BCRP (e.g. cyclosporine, gefitinib).