VEOZA Film-coated tablet Ref.[107086] Active ingredients: Fezolinetant

Medical examination/consultation

Prior to the initiation or reinstitution of Veoza, a careful diagnosis should be made, and complete medical history (including family history) must be taken. During treatment, periodic check-ups must be carried out according to standard clinical practice.

Liver disease

Veoza is not recommended for use in individuals with Child-Pugh Class B (moderate) or C (severe) chronic hepatic impairment. Women with active liver disease or Child-Pugh Class B (moderate) or C (severe) chronic hepatic impairment have not been included in the clinical efficacy and safety studies with fezolinetant (see section 4.2) and this information cannot be reliably extrapolated. The pharmacokinetics of fezolinetant has been studied in women with Child-Pugh Class A (mild) and B (moderate) chronic hepatic impairment (see section 5.2). Monitoring of liver function in women with known or suspected hepatic disorder is advised during treatment.

ALT and AST elevations

Elevations in serum alanine aminotransferase (ALT) levels at least 3 times the upper limit of normal (ULN) occurred in 2.1% of women receiving fezolinetant compared to 0.8% of women receiving placebo. Elevations in serum aspartate aminotransferase (AST) levels at least 3 times the ULN occurred in 1.0% of women receiving fezolinetant compared to 0.4% of women receiving placebo (see section 4.8). ALT and/or AST elevations were not accompanied by an increase in bilirubin (greater than two times the ULN, i.e., there were no cases of Hy’s law) with fezolinetant. Women with ALT or AST elevations were generally asymptomatic. Transaminase levels returned to pre-treatment levels (or close to these) without sequelae with dose continuation, and upon dose interruption, or discontinuation. Acute liver test abnormalities may necessitate the discontinuation of Veoza use until the liver tests return to normal.

Known or previous breast cancer or oestrogen-dependent malignancies

Women undergoing oncologic treatment (e.g., chemotherapy, radiation therapy, anti-hormone therapy) for breast cancer or other oestrogen-dependent malignancies have not been included in the clinical studies. Therefore, Veoza is not recommended for use in this population as the safety and efficacy are unknown.

Women with previous breast cancer or other oestrogen-dependent malignancies and no longer on any oncologic treatment have not been included in the clinical studies. A decision to treat these women with Veoza should be based on a benefit-risk consideration for the individual.

Concomitant use of hormone replacement therapy with oestrogens (local vaginal preparations excluded)

Concomitant use of fezolinetant and hormone replacement therapy with oestrogens has not been studied, and therefore concomitant use is not recommended.

Seizures or other convulsive disorders

Fezolinetant has not been studied in women with a history of seizures or other convulsive disorders. There were no cases of seizures or convulsive disorders during clinical studies. A decision to treat these women with Veoza should be based on a benefit-risk consideration for the individual.

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 C_max 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 C_max and 9.4-fold increase in AUC; no change in t_max 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 C_max 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 × C_max,u) and 27.5 µmol/l (44 × C_max,u), respectively. ES259564 does not inhibit OAT1 and OAT3 (IC₅₀ >70 µmol/l).

Pregnancy

Veoza is contraindicated during pregnancy (see section 4.3). If pregnancy occurs during use with Veoza, treatment should be withdrawn immediately.

There are no or limited data from the use of fezolinetant in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Perimenopausal women of childbearing potential should use effective contraception. Non-hormonal contraceptives are recommended for this population.

Breast-feeding

Veoza is not indicated during lactation.

It is unknown whether fezolinetant and its metabolites are excreted in human milk. Available pharmacokinetic data in animals showed excretion of fezolinetant and/or its metabolites in animal milk (see section 5.3). A risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Veoza therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of fezolinetant on human fertility. In the fertility study in female rats, fezolinetant did not affect fertility (see section 5.3).

Fezolinetant has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

The most frequent adverse reactions with fezolinetant 45 mg were diarrhoea (3.2%) and insomnia (3.0%).

There were no serious adverse reactions reported at an incidence greater than 1% across the total study population. On fezolinetant 45 mg, four serious adverse reactions were reported. The most serious adverse reaction was an event of endometrial adenocarcinoma (0.1%).

The most frequent adverse reactions leading to dose discontinuation with fezolinetant 45 mg were alanine aminotransferase (ALT) increased (0.3%) and insomnia (0.2%).

Tabulated list of adverse reactions

The safety of fezolinetant has been studied in 2203 women with VMS associated with menopause receiving fezolinetant once daily in phase 3 clinical studies.

Adverse reactions observed during clinical studies are listed below by frequency category in each system organ class. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000); and not known (cannot be estimated from the available data).

Table 1. Adverse reactions for fezolinetant 45 mg:

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.