elinzanetant: prescribing information – dosing, contraindications, interactions, side effects

Lynkuet is indicated for the treatment of moderate to severe vasomotor symptoms (VMS):
- associated with menopause (see section 5.1)
- caused by adjuvant endocrine therapy (AET) related to breast cancer (see section 5.1).

Posology

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

Benefits of symptomatic treatment should be periodically assessed (e.g. during routine and/or cancer follow-up care) as the need for treatment can vary by individual or change over time.

Co-administration with moderate CYP3A4 inhibitors
The recommended daily dose when used with moderate CYP3A4 inhibitors is 60 mg (one 60 mg capsule) elinzanetant 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.

Missed dose
If a dose is missed, the next dose should be taken as scheduled on the following day.
Patients should not take 2 doses on the same day to make up for a missed dose.

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

Hepatic impairment
No dose modification is required for patients with mild (Child-Pugh A) chronic hepatic impairment.

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

Renal impairment
For patients with moderate to severe (eGFR less than 60 mL/min/1.73 m2) renal impairment the recommended daily dose is 60 mg (one 60 mg capsule) elinzanetant at bedtime (see section 5.2).

No dose modification is required for patients with mild (eGFR 60 - 89 mL/min/1.73 m2) renal impairment.

Paediatric population
There is no relevant use of elinzanetant in the paediatric population in the indications moderate to severe VMS associated with menopause or caused by AET.

Method of administration

Lynkuet is for oral use.

The capsules should be taken orally once daily at bedtime.
The capsules should be swallowed whole with water. The capsules should not be cut, chewed or crushed as they contain an oily solution.

The capsules can be taken with or without food (see section 5.2) but should not be taken with grapefruit or grapefruit juice (see section 4.5).

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Known or suspected pregnancy (see section 4.6).

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
System organ class
Frequency
VMS associated with menopause
VMS caused by AET
Psychiatric disorders
Common

Depression
Depressive mood
Nervous system disorders
Common
Dizziness
Headache
Somnolence
Dizziness
Somnolence
Vertigo
Gastrointestinal disorders
Common
Abdominal pain
Diarrhoea
Diarrhoea
Hepatobiliary disorders
Common

Alanine aminotransferase (ALT) increased*
Uncommon
Alanine aminotransferase (ALT) increased*
Aspartate aminotransferase (AST) increased*
Aspartate aminotransferase (AST) increased*
Skin and subcutaneous tissue disorders
Common
Rash
Alopecia
Uncommon
Photosensitivity reactions*
Photosensitivity reactions*
Musculoskeletal and connective tissue disorders
Common
Muscle spasms
Muscle spasms
General disorders and administration site conditions
Very common

Fatigue
Common
Fatigue

* 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.

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 Cmax 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 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 in 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.

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 Cmax 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).

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. Safety and tolerability of multiple once daily doses up to 240 mg over 5 days were similar compared to the recommended daily dose of 120 mg elinzanetant.

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

There is no specific antidote for Lynkuet.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Other gynaecologicals, other gynaecologicals, ATC code: G02CX07

Mechanism of action

Elinzanetant is a non-hormonal, selective neurokinin 1 (NK-1) and 3 (NK-3) receptors antagonist. It blocks NK-1 and NK-3 receptors signalling on kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which is postulated to normalise neuronal activity involved in thermo- and sleep regulation.

Pharmacodynamic effects

No clinically relevant prolongation of the QTc interval was observed after single oral administration of elinzanetant at doses up to 5 times the maximum recommended dose.

In healthy premenopausal women having received elinzanetant over 21 days, results showed changes of plasma concentrations of sexual hormones (i.e. dose-related reductions of LH, oestradiol, and progesterone) and prolongation of the menstrual cycle. Changes in female sex hormones that were observed, are consistent with the anticipated pharmacological effects of elinzanetant on hypothalamic kisspeptin/neurokinin B/dynorphin neurons.

In postmenopausal women treated with elinzanetant, a transient decrease in luteinizing hormone (LH) levels was observed. No significant changes were noted in oestrogen, follicle-stimulating hormone (FSH), and testosterone levels in this population. These effects are not clinically relevant.

Clinical efficacy and safety

Treatment of moderate to severe VMS associated with menopause (OASIS 1-3)
The efficacy and safety of elinzanetant for the treatment of moderate to severe VMS associated with menopause were studied in 3 randomised, double-blind, placebo-controlled, multicentre phase III studies (OASIS 1, 2 and 3).
In OASIS 1 and 2 a total of 796 postmenopausal women were randomised 1:1 to receive 120 mg elinzanetant or placebo once daily at bedtime for 12 weeks, followed by elinzanetant for 14 weeks, for a total treatment of up to 26 weeks. Women who had at least 50 moderate to severe VMS, including VMS at night, per week were enrolled in OASIS 1 and 2.
In OASIS 3 a total of 628 postmenopausal women were randomised 1:1 to receive 120 mg elinzanetant or placebo once daily at bedtime for 52 weeks. Inclusion did not require minimum number of VMS.

In OASIS 1 and 2 studies, the following patient demographics were balanced between treatment groups. The mean age of women was 54.6 years (range 40-65 years). Most women were White (80.4%), 17.1% Black or African American, 0.5% Asian, and 8.5% with Hispanic or Latino ethnicity.
The study population included postmenopausal women with spontaneous amenorrhoea for ≥ 12 consecutive months (62.1%), spontaneous amenorrhoea/hysterectomy for ≥ 6 months with FSH > 40 IU/L (29.4%), or uni-/bilateral oophorectomy (20.6%). 31.4% had used prior hormone replacement therapy (HRT).

The primary efficacy endpoints in OASIS 1 and 2 were the mean change in frequency of moderate to severe VMS from baseline to weeks 4 and 12, including day and night VMS measured using hot flash daily diary (HFDD).

Elinzanetant soft gel capsules show a dose-proportional increase in Cmax in the dose range 25 mg to 600 mg. The AUC increases dose-proportional in the dose range 25 mg to 120 mg and greater than dose proportional in the dose range 160 mg to 600 mg.
Steady state plasma concentrations of elinzanetant were reached 5 – 7 days after daily dosing, with < 2-fold accumulation.

Absorption

The absolute bioavailability of elinzanetant is 52%.
Administering 120 mg elinzanetant with food reduces Cmax with 60-70% and the AUC(0-24) with 20-40%, but no effect on the AUC was observed. The tmax shifted from 1-1.5 hours under fasted conditions to 3-4 hours under fed conditions. The food effect is not expected to be of clinical relevance for efficacy. Lynkuet may be administered with or without food (see section 4.2).

Distribution

The plasma protein binding of elinzanetant is high (> 99%) and is affected by circadian fluctuation.
The blood-to-plasma ratio is between 0.6 and 0.7. The mean volume of distribution after intravenous administration at steady state (Vss) of elinzanetant is 137 L, indicating extensive extravascular distribution. Exposure of elinzanetant in human brain was shown by clinical positron emission tomography (PET) studies.

Biotransformation

Elinzanetant is primarily metabolised by CYP3A4 to yield 3 active metabolites (M30/34 [13.7%], M27 [7.6%], M18/21 [4.9%]). Elinzanetant is also metabolised to a minor extend by CYP3A5 and UGTs. The active metabolites have similar potency for the human NK-1 and NK-3 receptors as compared to elinzanetant and contribute for < 50% to the pharmacological effect. The ratio of these metabolites to parent in plasma is approximately 0.39.

Elimination