LYNKUET Soft capsule Ref.[116026] Active ingredients: Elinzanetant

Concomitant use with other medicinal products

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 (see section 4.5).

Elinzanetant in combination with other breast cancer treatments

The use of elinzanetant has been evaluated in combination with AET consisting of aromatase inhibitors or tamoxifen, with or without GnRH agonists. A decision to treat women with elinzanetant who receive medication other than those evaluated in the clinical studies should be based on an individual benefit-risk consideration.

Concomitant use of hormone replacement therapy (HRT) with oestrogens to treat VMS associated with menopause

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.

Excipient with known effect

Sorbitol

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use when administered concomitantly.

Effects of other medicinal products on elinzanetant

Elinzanetant is metabolised via CYP3A4 and is a substrate for the P-glycoprotein (P-gp) transporter protein.

CYP3A4 inhibitors (substances increasing exposure to elinzanetant)

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) (see section 4.4).

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 (see section 4.2).

No dose adjustment is required for weak CYP3A4 inhibitors.

Effects of elinzanetant on other medicinal products

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.

Pregnancy

Lynkuet is contraindicated during pregnancy (see section 4.3). If pregnancy occurs during treatment with Lynkuet, 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 (see section 5.3). Women of child-bearing potential have to use effective contraception during treatment. Non-hormonal contraceptives are recommended for this population.

Breast-feeding

It is unknown whether elinzanetant/metabolites are excreted in human milk. Available pharmacokinetic data in animals have shown excretion of elinzanetant/metabolites in milk (see section 5.3). A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Lynkuet 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 (see section 5.3).

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 (see section 4.8).

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 1. 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).

Table 1. 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.

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.