4.1. Therapeutic indications

Inluriyo is indicated as monotherapy for the treatment of adult patients with oestrogen receptor (ER)-positive, HER2-negative, locally advanced or metastatic breast cancer with an activating ESR1-mutation, who have disease progression following prior treatment with an endocrine based regimen (for biomarker-based patient selection, see section 4.2).

In pre- or perimenopausal women, or men, Inluriyo should be combined with a luteinising hormone-releasing hormone (LHRH) agonist.

4.2. Posology and method of administration

Treatment should be initiated and supervised by a physician experienced in the use of anticancer therapies.

Patient selection

Patients with ER-positive, HER2-negative advanced breast cancer should be selected for treatment based on the presence of an activating ESR1-mutation in tumour or in plasma specimens, using a CE-marked in vitro diagnostic (IVD) with the corresponding intended purpose. If the CE-marked IVD is not available, the presence of an activating ESR1-mutation should be assessed by an alternative validated test.

Posology

The recommended dose of imlunestrant is 400 mg orally (two 200 mg film-coated tablets), once daily.

It is recommended that treatment is continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.

Missed dose

If a dose is missed, it can be taken up to 6 hours after the time it is usually taken. After more than 6 hours, the dose should be skipped for that day. An additional dose should not be taken. On the next day, the dose should be taken at the usual time.

Vomiting

If the patient vomits after taking the dose, the patient should not take an additional dose on that day and should resume the usual dosing schedule the next day at the usual time.

Dose adjustments

If dose reduction is necessary, the dose should be decreased by 200 mg. Management of some adverse reactions may require dose interruption and/or dose reduction as shown in Tables 1 and 2. The treatment should be discontinued for patients unable to tolerate 200 mg once daily.

Table 1: Recommended dose modification for increased ALT and AST

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be monitored during treatment, and as clinically indicated.

Toxicitya

Dose modification

Persistent or Recurrent Grade 2 AST or ALT, if baseline was normal

Suspend until toxicity resolves to baseline or Grade 1 if baseline was normal.

Dose reduction is not required.

Grade 3 AST or ALT if baseline was normal

Or

Grade 2 or above AST or ALT if baseline was abnormal

Or

AST or ALT > 8 × ULN

(whichever is the lower threshold)

Suspend until toxicity resolves to baseline or Grade 1 if baseline was normal.

Resume at 200 mg dose level or discontinue if receiving 200 mg daily.

Grade 4 AST or ALT if baseline was normal

Discontinue dosing.

AST or ALT ≥ 3 × ULN concurrent with total bilirubin (TBL) ≥ 2 × ULN if baseline was normal in the absence of cholestasis

Or

AST or ALT ≥ 2 × baseline concurrent with TBL ≥ 2 × ULN if baseline was abnormal, in the absence of cholestasis

Discontinue dosing.

aNCI CTCAE v5.0

ULN: upper limit of normal

Table 2: Recommended dose modification for adverse reactions (except increased ALT and AST)

Toxicitya

Dose modifications

Persistent or recurrent Grade 2 that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1

Suspend until toxicity resolves to baseline or ≤ Grade 1.

Dose reduction is not required.

Grade 3 (except non-hepatic asymptomatic laboratory changes)

Suspend until toxicity resolves to baseline or ≤ Grade 1.

Resume at next lower dose level or discontinue if receiving 200 mg daily.

Grade 4 (except non-hepatic asymptomatic laboratory changes)

Suspend until toxicity resolves to baseline or ≤ Grade 1.

Resume at next lower dose level or discontinue if receiving 200 mg daily.

Closely monitor on resuming treatment.

a NCI CTCAE 5.0

Strong CYP3A inducers

Concomitant use of strong CYP3A inducers should be avoided. If strong CYP3A inducers cannot be avoided, the imlunestrant dose should be increased by 200 mg once daily (see section 4.5).

Strong CYP3A inhibitors

Concomitant use of strong CYP3A inhibitors should be avoided. If strong CYP3A inhibitors cannot be avoided, the imlunestrant dose should be decreased by 200 mg once daily (see section 4.5).

Special populations

Elderly

No dose adjustment is required on the basis of patient age (see section 5.2). Limited data are available in patients ≥ 75 years of age (see section 5.2).

Hepatic impairment

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A).

The dose should be reduced to 200 mg once daily in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment.

Renal impairment

No dose adjustment is necessary in patients with mild or moderate renal impairment. Limited data indicates that the exposure of imlunestrant may be increased in patients with severe renal impairment, end stage renal disease, or in patients on dialysis (see section 5.2). Treatment should be administered with caution in patients with severe renal impairment, with close monitoring for signs of toxicity.

Paediatric population

There is no relevant use of imlunestrant in the paediatric population in the indication of locally advanced breast cancer.

Method of administration

Inluriyo is for oral use.

Patients should take their dose at approximately the same time each day.

The tablets should be taken on an empty stomach at least 2 hours before or 1 hour after food (see section 5.2). The tablets should be swallowed whole (patients should not split, crush, or chew the tablets before swallowing). The effects of splitting, crushing, or chewing the tablets have not been investigated and may impact the safety, efficacy, or stability of the product. Exposure to the active substance could be harmful for caregivers.

4.3. Contraindications

Lactation (see section 4.6).

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

4.4. Special warnings and precautions for use

Food effect

Imlunestrant exposures in the presence of a high-fat meal are unknown. The dose should be taken in the fasted state as higher exposures may occur with food.

Excipients

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”.

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

Imlunestrant is metabolized by sulfation, CYP3A4 oxidation and direct glucuronidation.

Potential for other medicinal products to effect imlunestrant

Strong CYP3A inducers

Coadministration of imlunestrant with carbamazepine (a strong CYP3A inducer) decreased the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of imlunestrant by 42 % and 29 %, respectively. Concomitant use of strong CYP3A inducers should be avoided. If strong CYP3A inducers cannot be avoided, the imlunestrant dose should be increased by 200 mg once daily (see section 4.2).

Strong CYP3A inhibitors

Coadministration of imlunestrant with itraconazole (a strong CYP3A inhibitor) increased the AUC and Cmax of imlunestrant by 2.11-fold and 1.87-fold, respectively. Concomitant use of strong CYP3A inhibitors should be avoided. If strong CYP3A inhibitors cannot be avoided, the imlunestrant dose should be decreased by 200 mg once daily (see section 4.2).

Gastric acid reducing agents

Coadministration of imlunestrant with omeprazole (a proton pump inhibitor) had no clinically meaningful effect on the pharmacokinetics of imlunestrant.

Potential for imlunestrant to effect other medicinal products

CYP2D6 substrates

Imlunestrant increased the AUC and Cmax of dextromethorphan (a CYP2D6 substrate) by 1.33-fold and 1.43-fold, respectively. Caution should be used when coadministering imlunestrant with CYP2D6 substrates for which a small increase in concentration leads to significant adverse events.

P-glycoprotein (P-gp) substrates

Imlunestrant increased the AUC and Cmax of digoxin (a P-gp substrate) by 1.39-fold and 1.60-fold, respectively. Caution should be used when coadministering imlunestrant with P-gp substrates for which a small increase in concentration leads to significant adverse events.

BCRP substrates

Imlunestrant increased the AUC and Cmax of rosuvastatin (a BCRP substrate) by 1.49-fold and 1.65-fold, respectively. Caution should be used when coadministering imlunestrant with BCRP substrates for which a small increase in concentration leads to significant adverse events.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

The pregnancy status of females of reproductive potential should be verified prior to starting treatment.

Females and males of reproductive potential should be advised to use highly effective contraception during treatment and for at least 1 week after the last dose (see section 5.3).

Pregnancy

There are no data from the use of imlunestrant in pregnant women. Based on the mechanism of action of imlunestrant and findings from embryofoetal toxicity studies in animals, imlunestrant can cause foetal harm when administered to pregnant women (see section 5.3). Imlunestrant should not be used during pregnancy and in women of childbearing potential not using contraception. If pregnancy occurs during treatment, the patient must be informed of the potential hazard to the foetus and potential risk of miscarriage.

Breast-feeding

It is unknown whether imlunestrant or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in the breast-fed infant, use during lactation is contraindicated (see section 4.3).

Fertility

Based on findings from animal studies (see section 5.3) and its mechanism of action, imlunestrant may impair fertility in females and males of reproductive potential.

4.7. Effects on ability to drive and use machines

Imlunestrant has no or negligible influence on the ability to drive and use machines. However, since fatigue and asthenia have been reported with imlunestrant, caution should be observed by those patients who experience this adverse reaction when driving or operating machinery.

4.8. Undesirable effects

Summary of the safety profile

The most common and clinically relevant adverse reactions were ALT increased (34.3 %), AST increased (33.2 %), fatigue (25.7 %), diarrhoea (22.5 %), nausea (20.1 %), and vomiting (9.0 %).

Adverse reactions leading to discontinuations of treatment in more than 1 patient included ALT increased (0.8 %) only.

Tabulated list of adverse reactions

The frequencies of adverse drug reactions (ADRs) displayed below are based on pooled data in 378 patients, treated with 400 mg imlunestrant once daily from a randomised, open-label, multicenter Phase 3 study (EMBER-3) and an open-label, multicenter, dose escalation and dose expansion phase 1a/1b study (EMBER).

In the following tables, adverse reactions are listed in order of MedDRA body system organ class and frequency. Frequency gradings are: 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3: Adverse drug reactions in patients receiving imlunestrant

System organ class

Very common

Common

Metabolism and Nutrition Disorders

Decreased appetite a

Nervous System Disorders

Headache

Vascular Disorders

Venous thromboembolism a

Hot flush a

Respiratory, Thoracic and Mediastinal Disorders

Cough a

Gastrointestinal Disorders

Diarrhoea

Nausea

Vomiting

Constipation

Abdominal pain a

Musculoskeletal Disorders

Joint and muscular skeletal pain b

Back pain

General Disorders and Administration Site Conditions

Fatigue a

Investigations c

ALT increased

AST increased

Triglycerides increased

a Consolidated term consisting of analogous preferred terms.

b Consolidated term consisting of preferred terms: arthralgia, myalgia, musculoskeletal discomfort, musculoskeletal chest pain, musculoskeletal pain, pain in extremity, neck pain.

c Based on laboratory assessments.

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

4.9. Overdose

Symptoms of overdose have not been established. The ADRs reported in association with doses higher than the recommended dose were consistent with the established safety profile (see section 4.8). The most frequent ADRs at higher doses were diarrhoea, nausea, fatigue and arthralgia. There is no known antidote for an overdose of imlunestrant. Patients should be closely monitored, and supportive care should be provided.