Elinzanetant

Elinzanetant is a weak inhibitor of CYP3A4. Co-administration of midazolam, a sensitive substrate of CYP3A4, and multiple daily doses of elinzanetant 120 mg resulted in an increase of 1.5-fold in C_max and 1.8-fold in AUC of midazolam.

Caution is required when co-administering elinzanetant with sensitive CYP3A4 substrates with a narrow therapeutic window (e.g. cyclosporine, fentanyl or tacrolimus). The related recommendation in the product information of these CYP3A4 substrates should be followed.

Cytochrome P450 isoform 3A4 (CYP3A4) inhibitors may decrease the clearance of elinzanetant, resulting in higher exposure. The concomitant use of elinzanetant with strong CYP3A4 inhibitors is not recommended. For concomitant use with moderate CYP3A4 inhibitors reduce the dose of elinzanetant.

The recommended daily dose when used with moderate CYP3A4 inhibitors is 60 mg elinzanetant at bedtime. After discontinuation of the moderate inhibitor (after 3 to 5 half-lives of the inhibitor), elinzanetant should be used at the usual dose of 120 mg once daily.

Co-administration of multiple daily doses of itraconazole (200 mg), a strong CYP3A4 and P-gp inhibitor, and elinzanetant 120 mg resulted in an increase of approximately 3.3-fold in C_max and between 4.6-fold and 6.3-fold in area under the curve (AUC) of elinzanetant. Physiologically based pharmacokinetic (PBPK) modelling predictions after co-administration of 120 mg elinzanetant with the moderate CYP3A4 inhibitor erythromycin showed a 3-fold increase of AUC and 2-fold increase for C_max of elinzanetant. PBPK predictions after co-administration of 60 mg elinzanetant with the moderate CYP3A4 inhibitor erythromycin showed a 1.4-fold increase of AUC and no increase in C_max compared to 120 mg elinzanetant alone. PBPK predictions after co-administration of 120 mg elinzanetant with the weak CYP3A4 inhibitor cimetidine showed a 1.5-fold increase of AUC and 1.3-fold increase for C_max of elinzanetant.

Elinzanetant should not be used together with strong CYP3A4 inhibitors (e.g. itraconazole, clarithromycin, ritonavir, cobicistat or ribociclib).

The concomitant use of elinzanetant with grapefruit (juice) is not recommended.

If used concomitantly with moderate CYP3A4 inhibitors (e.g. erythromycin, ciprofloxacin, fluconazole, verapamil) the daily dose of elinzanetant is 60 mg.

For patients with moderate to severe (eGFR less than 60 mL/min/1.73 m²) renal impairment the recommended daily dose is 60 mg elinzanetant at bedtime.

Elinzanetant is not recommended for use in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) chronic hepatic impairment.

Concomitant use of elinzanetant and HRT with oestrogens has not been studied, and therefore concomitant use is not recommended. Local vaginal preparations can be used.

Elinzanetant is contraindicated during pregnancy. If pregnancy occurs during treatment with elinzanetant, the treatment should be withdrawn.

There are no or limited data from the use of elinzanetant in pregnant women. Studies in animals have shown reproductive toxicity. Women of child-bearing potential have to use effective contraception during treatment. Non-hormonal contraceptives are recommended for this population.

It is unknown whether elinzanetant/metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of elinzanetant/metabolites in milk. A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from elinzanetant therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No human data on the effect of elinzanetant on fertility are available. In the fertility study in female rats, elinzanetant did not affect fertility.

Elinzanetant has minor influence on the ability to drive and use machines. Somnolence and fatigue are potential adverse reactions to elinzanetant. Therefore, women should be advised to be careful when driving or using machines if they experience such reactions during treatment with elinzanetant.

Summary of the safety profile

The most frequent adverse reactions (≥5%) with elinzanetant are:

• for VMS associated with menopause: headache (7.8%) and fatigue (5.0%)
• for VMS caused by AET: fatigue (14.2%), somnolence (9.5%), diarrhoea (7.1%), depression (6.2%), and muscle spasm (5.2%).

Tabulated list of adverse reactions

The safety profile of elinzanetant is based on data from women who received at least 1 dose of 120 mg elinzanetant:

• 1 113 treated women with VMS associated with menopause in 3 phase III (OASIS 1, OASIS 2, OASIS 3) and 1 phase II (SWITCH-1) clinical studies and
• 465 treated women with VMS caused by AET in a separate phase III clinical study (OASIS 4).

The adverse reactions are listed in table below. They are classified according to MedDRA System Organ Class. Adverse reactions are grouped according to their frequencies. Frequency groups are defined by the following convention: 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), not known (cannot be estimated from available data).

Adverse reactions:

^* see 'description of selected adverse reactions'

Description of selected adverse reactions

Photosensitivity reactions

In the pooled safety data up to 52 weeks, photosensitivity reactions were reported in 0.4% of patients treated with elinzanetant and in 0.1% of patients treated with placebo. In OASIS 4 up to 52 weeks, photosensitivity reactions were reported in 0.9% of patients treated with elinzanetant and in 0.6% of patients treated with placebo.

ALT and AST increased

In the pooled safety data up to 52 weeks, the term ALT increased was reported in 0.6% of patients treated with elinzanetant and in 0.5% of patients treated with placebo. The term AST increased was reported in 0.4% of patients treated with elinzanetant and in 0.5% of patients treated with placebo. In OASIS 4 up to 52 weeks, the term ALT increased was reported in 1.1% of patients treated with elinzanetant and in 0.6% of patients treated with placebo. The term AST increased was reported in 0.6% of patients treated with elinzanetant and in none of the patients treated with placebo.