Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction

Effects of concomitant medicinal products on vismodegib
Clinically significant pharmacokinetic (PK) interactions between vismodegib and pH elevating agents are not expected. Results from a clinical study demonstrated a 33% decrease in vismodegib unbound drug concentrations after 7 days co-treatment with 20 mg rabeprazole (a proton pump inhibitor) given 2 hours before each vismodegib administration. This interaction is not expected to be clinically significant.

Clinically significant PK interactions between vismodegib and CYP450 inhibitors are not expected.
Results from a clinical study demonstrated a 57% increase in vismodegib unbound drug concentrations on day 7 after co-treatment with 400 mg fluconazole (a moderate CYP2C9 inhibitor) daily, but this interaction is not expected to be clinically significant. Itraconazole (a strong CYP3A4 inhibitor) 200 mg daily did not influence vismodegib AUC0-24h after 7 days co-treament in healthy volunteers.

Clinically significant PK interactions between vismodegib and P-gp inhibitors are not expected.
Results from a clinical study demonstrated no clinically significant PK interaction between vismodegib and itraconazole (a strong P-glycoprotein inhibitor) in healthy volunteers.

When vismodegib is administered with CYP inducers (rifampicin, carbamazepine, phenytoin, St. John´s wort), exposure to vismodegib may be decreased (see sections 4.3 and 4.4).

Effects of vismodegib on concomitant medicinal products

Contraceptive steroids
Results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of ethinyl estradiol and norethindrone is not altered when co-administered with vismodegib.
However, the interaction study was of only 7 days duration and it cannot be excluded that vismodegib upon longer treatment is an inducer of enzymes which metabolise contraceptive steroids. Induction could lead to decreases in systemic exposure of the contraceptive steroids and thereby reduced contraceptive efficacy.

Effects on specific enzymes and transporters
In vitro studies indicate that vismodegib has the potential to act as an inhibitor of breast cancer resistance protein (BCRP). In vivo interaction data is not available. It may not be excluded that vismodegib may give rise to increased exposure of medicinal products transported by this protein, such as rosuvastatin, topotecan, and sulfasalazin. Concomitant administration should be performed with caution and a dose adjustment may be necessary.

Clinically significant PK interactions between vismodegib and CYP450 substrates are not expected. In vitro, CYP2C8 was the most sensitive CYP isoform for vismodegib inhibition. However, results of a drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of 
rosiglitazone (a CYP2C8 substrate) is not altered when co-administered with vismodegib. Thus inhibition of CYP enzymes by vismodegib in vivo may be excluded.

In vitro, vismodegib is an inhibitor of OATP1B1. It cannot be excluded that vismodegib may increase the exposure to substrates of OATP1B1, e.g. bosentan, ezetimibe, glibenclamide, repaglinide, valsartan and statins. In particular, caution should be exercised if vismodegib is administered in combination with any statin.