4.1. Therapeutic indications

Lynkuet is indicated for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause (see sections 4.4 and 5.1).

4.2. Posology and method of administration

Posology

The recommended dose is 120 mg elinzanetant (two 60 mg capsules) taken orally once daily at bedtime.

Missed dose

If a dose is missed, the next dose should be taken as scheduled on the following day at bedtime.

Patients should not take two doses on the same day to make up for a missed dose.

The benefit of long-term treatment should be periodically assessed since the duration of VMS can vary by individual.

Special populations

Elderly

The safety and efficacy of Lynkuet has not been established in women over 65 years of age. No dose recommendation can be made for this population.

Hepatic impairment

No clinically relevant increase in elinzanetant exposure was observed in patients with mild chronic hepatic impairment. In a clinical pharmacokinetic study, moderate chronic hepatic impairment increased the exposure of elinzanetant. Elinzanetant has not been studied in individuals with severe chronic hepatic impairment (see section 5.2).

No dose modification is required for individuals with mild (Child‑Pugh A) chronic hepatic impairment.

Elinzanetant is not recommended for use in individuals with moderate (Child-Pugh B) chronic hepatic impairment (see section 5.2).

Elinzanetant is contraindicated in individuals with severe (Child-Pugh C) chronic hepatic impairment (see sections 4.3 and 5.2).

Renal impairment

Population pharmacokinetic analysis of the clinical study data indicates similar total exposure of elinzanetant in patients with mild or moderate renal impairment compared to patients with normal renal function. The available data on elinzanetant pharmacokinetics in patients with severe renal impairment is limited (see section 5.2).

The pharmacokinetics of elinzanetant has not been studied in patients with end stage renal disease (estimated Glomerular Filtration Rate [eGFR] less than 15 mL/min/1.73 m2).

No dose modification is required for individuals with mild to moderate (eGFR 30 - 89 mL/min/1.73 m2) renal impairment.

Elinzanetant is not recommended for use in individuals with severe (eGFR less than 30 mL/min/1.73 m2) renal impairment (see section 5.2).

Other special populations

Co-administration with moderate CYP3A4 inhibitors

The recommended daily dose when used with moderate CYP3A4 inhibitors is 60 mg elinzanetant (one 60 mg capsule) taken orally once daily at bedtime (see section 4.5). 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.

No dose adjustment is necessary based on race (see section 5.2).

Paediatric population

The safety and efficacy of elinzanetant in children and adolescents below 18 years of age has not been established. No data are available.

There is no relevant use of Lynkuet in the paediatric population in the indication of treatment of moderate to severe VMS associated with menopause.

Method of administration

Lynkuet should be administered orally once daily at bedtime with or without food (see sections 4.5 and 5.2).

The capsules are to be swallowed whole with water and not cut, chewed or crushed.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Severe hepatic impairment.

Concomitant use of strong CYP3A4 inhibitors (see sections 4.4 and 4.5).

Known or suspected pregnancy (see section 4.6).

4.4. Special warnings and precautions for use

Medical examination/consultation

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

Concomitant use with other medicinal products

Cytochrome P450 isoform 3A4 (CYP3A4) inhibitors may decrease the clearance of elinzanetant, resulting in higher exposure.

Concomitant use of elinzanetant with strong CYP3A4 inhibitors is contraindicated (see sections 4.3 and 4.5). Reduce elinzanetant dosage when co-administered with moderate CYP3A4 inhibitors (see sections 4.2 and 4.5).

Concomitant use of elinzanetant with moderate to strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenobarbital, St. John´s Wort) reduces elinzanetant exposure and efficacy may be reduced. Monitor elinzanetant efficacy when co-administered with moderate to strong CYP3A4 inducers (see section 4.5).

Oestrogen-dependent tumours and other types of pharmacologically induced menopause

Efficacy and safety of elinzanetant in patients with breast cancer or other oestrogen dependent tumours or patients with a history of such malignancies has not been established so far. This applies, in particular, to patients receiving anti-oestrogen treatment (which is associated with severe VMS and/or other symptoms of oestrogen deficiency). No data for other types of pharmacologically induced menopause (e.g., in those treated with GnRH analogues) are available.

The decision to use elinzanetant in such patients should be based on individual benefit-risk considerations.

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

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

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

Drug-induced liver injury (DILI)

Elevations in serum alanine aminotransferase (ALT) levels and serum aspartate aminotransferase (AST) at least 3 times the upper limit of normal (ULN) were observed in women treated with products from a similar class. Liver function testing is recommended before starting treatment with elinzanetant.

Liver function testing should be performed if symptoms suggestive of liver injury occur.

Information about excipients

This medicinal product contains 71 mg sorbitol in each capsule.

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 administered concomitantly.

4.5. Interaction with other medicinal products and other forms of interaction

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 and P-gp inducers (substances increasing the clearance of elinzanetant)

Co-administration of multiple daily doses of carbamazepine (600 mg), a strong CYP3A4 and P-gp inducer, and elinzanetant 120 mg resulted in a decrease of Cmax by 44% and AUC by 64% of elinzanetant.

CYP3A4 and P‑gp inhibitors (substances decreasing the clearance of 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 Cmax and between 4.6‑fold and 6.3‑fold in AUC of elinzanetant.

Physiologically Based Pharmacokinetic (PBPK) modelling predictions after co‑administration of 120 mg elinzanetant with the moderate CYP3A4 inhibitor erythromycin showed a 3.0‑fold increase of AUC and 2.0‑fold increase for Cmax 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 for Cmax 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 Cmax of elinzanetant.

No clinically relevant interaction with P‑gp inhibitors is expected due to high permeability of elinzanetant through membranes and its main elimination through metabolism.

Elinzanetant should not be used together with strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir or cobicistat) (see sections 4.3 and 4.4).

In patients taking moderate CYP3A4 inhibitors (e.g., erythromycin, ciprofloxacin, fluconazole, verapamil) the recommended daily dose of elinzanetant is 60 mg.

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

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 Cmax and 1.8‑fold in AUC of midazolam.

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

Co-administration of multiple daily doses of tamoxifen 20 mg and elinzanetant 120 mg resulted in no clinically relevant changes in the pharmacokinetics of tamoxifen and its metabolites, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data on the use of elinzanetant in pregnant women.

Studies in animals have shown reproductive toxicity (see section 5.3).

Pregnancy should be prevented in women of child-bearing potential by using effective contraception during treatment with Lynkuet. If pregnancy occurs during use of Lynkuet, treatment should be withdrawn.

Breast‑feeding

There are no data on the presence of elinzanetant or its metabolites in human milk.

Excretion of elinzanetant and its metabolites in milk has been demonstrated in rats (see section 5.3). Use of Lynkuet in lactating women is not recommended.

Fertility

No human data on the effect of elinzanetant on fertility are available.

In female rats an impairment of fertility was observed at exposures markedly exceeding the exposure of humans at the therapeutic dose (see section 5.3).

4.7. Effects on ability to drive and use machines

Elinzanetant may cause undesirable effects like fatigue, dizziness or somnolence (see section 4.8). Women should be advised to be careful when driving or using machines if such symptoms occur during treatment with Lynkuet (see section 5.1).

4.8. Undesirable effects

Summary of the safety profile

The most frequently observed adverse reactions (≥5%) with elinzanetant 120 mg during clinical studies were headache (7.8%) and fatigue (5%).

Tabulated list of adverse reactions

The following information is based on data from 1113 treated postmenopausal women with VMS, who received at least one dose of elinzanetant 120 mg, in phase III (OASIS 1, OASIS 2, OASIS 3) or phase II (SWITCH-1) clinical studies.

The adverse reactions observed during clinical studies in women treated with elinzanetant are listed in Table 1.

These are classified according to the MedDRA System Organ Class (SOC).

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 the available data).

Table 1: Adverse reactions observed with elinzanetant

System Organ Class

(MedDRA)

Common

Nervous system disorders

Dizziness

Headache a

Somnolence b

Gastrointestinal disorders

Abdominal pain c

Diarrhoea d

Skin and subcutaneous tissue disorders

Rash e

Musculoskeletal and connective tissue disorders

Muscle spasms f

General disorders and administration site conditions

Fatigue g

a Including sinus headache, tension headache

b Including hypersomnia

c Including abdominal discomfort, abdominal pain lower/upper, gastrointestinal pain

d Including frequent bowel movements, intestinal transit time decreased

e Including rash maculo-papular, rash popular, rash pruritic

f Including muscle tension, musculoskeletal stiffness

g Including asthenia

Seizures or other convulsive disorders

A total of 7 patients with a history of seizures were included in the clinical trials. One of these patients reported generalized tonic-clonic seizure 46 days after initiating treatment with Lynkuet. The patient had not experienced seizures or required anti-seizure medications for at least eight years prior to starting Lynkuet. A causal relationship between Lynkuet and a risk for seizures has not been established.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There were no cases of overdose reported in clinical studies.

Single doses of elinzanetant up to 600 mg have been tested in clinical studies in healthy volunteers. Adverse reactions at higher doses were similar to those observed with the therapeutic dose, but occurred slightly more often and with moderately higher intensity. Multiple once daily doses up to 240 mg over 5 days were well tolerated. No dose limiting toxicities were observed with tested doses.

In the case of overdose, the individual should be closely monitored, and supportive treatment should be considered based on signs and symptoms.

There is no specific antidote for Lynkuet.