Interactions : אינטראקציות

4.5     Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on fezolinetant
CYP1A2 inhibitors
Fezolinetant is primarily metabolised by CYP1A2 and to a lesser extent by CYP2C9 and CYP2C19.
Concomitant use of fezolinetant with medicinal products that are moderate or strong inhibitors of CYP1A2 (e.g., ethinyl oestradiol containing contraceptives, mexiletine, enoxacin, fluvoxamine) increase the plasma Cmax and AUC of fezolinetant.

Concomitant use of moderate or strong CYP1A2 inhibitors with Veoza is contraindicated (see section 4.3).

Co-administration with fluvoxamine, a strong CYP1A2 inhibitor, resulted in an overall 1.8-fold increase in fezolinetant Cmax and 9.4-fold increase in AUC; no change in tmax was observed. Given the large effect of a strong CYP1A2 inhibitor and supportive modelling, the increase in fezolinetant concentrations is expected to be of clinical concern also following concomitant use with moderate CYP1A2 inhibitors (see section 4.3). The increase in fezolinetant exposure was however not predicted to be clinically relevant following concomitant use with weak CYP1A2 inhibitors.

CYP1A2 inducers
In vivo data
Smoking (moderate inducer of CYP1A2) decreased fezolinetant Cmax to a geometric LS mean ratio of 71.74%, while AUC decreased to a geometric LS mean ratio of 48.29%. The efficacy data did not point to relevant differences between smokers and non-smokers. No dose modification is recommended for smokers.

Transporters
In vitro data
Fezolinetant is not a substrate of P-glycoprotein (P-gp). Major metabolite ES259564 is a substrate of P-gp.


Effect of fezolinetant on other medicinal products

Cytochrome P450 (CYP) enzymes
In vitro data
Fezolinetant and ES259564 are not inhibitors of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Fezolinetant and ES259564 are not inducers of CYP1A2, CYP2B6, and CYP3A4.

Transporters
In vitro data
Fezolinetant and ES259564 are not inhibitors of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, MATE1, and MATE2-K (IC50 >70 µmol/l). Fezolinetant inhibited OAT1 and OAT3 with IC50 values of 18.9 µmol/l (30 × Cmax,u) and 27.5 µmol/l (44 × Cmax,u), respectively. ES259564 does not inhibit OAT1 and OAT3 (IC50 >70 µmol/l).