ORSERDU 345mg film-coated tablets medication leaflet

ORSERDU 86 mg film-coated tablets

ORSERDU 345 mg film-coated tablets

ORSERDU 86 mg film-coated tablets

Each film-coated tablet contains elacestrant dihydrochloride equivalent to elacestrant 86.3 mg.

ORSERDU 345 mg film-coated tablets

Each film-coated tablet contains elacestrant dihydrochloride equivalent to elacestrant 345 mg.

For the full list of excipients, see section 6.1.

Film-coated tablet

ORSERDU 86 mg film-coated tablets

Blue to light blue biconvex round shaped film-coated tablet with ME debossed on one side and plainface on the opposite side. Approximate diameter: 8.8 mm.

ORSERDU 345 mg film-coated tablets

Blue to light blue biconvex oval shaped film-coated tablet with MH debossed on one side and plainface on the opposite side. Approximate size: 19.2 mm (length), 10.8 mm (width).

ORSERDU monotherapy is indicated for the treatment of postmenopausal women, and men, withestrogen receptor (ER)-positive, HER2-negative, locally advanced or metastatic breast cancer with anactivating ESR1 mutation who have disease progression following at least one line of endocrinetherapy including a CDK 4/6 inhibitor.

Treatment with ORSERDU should be initiated by a physician experienced in the use of anticancertherapies.

Patients with ER-positive, HER2-negative advanced breast cancer should be selected for treatmentwith ORSERDU based on the presence of an activating ESR1 mutation in plasma specimens, using a

CE marked in vitro diagnostic (IVD) with the corresponding intended purpose. If the CE-marked IVDis not available, the presence of an activating ESR1 mutation in plasma specimens should be assessedby an alternative validated test.

The recommended dose is 345 mg (one 345 mg film-coated tablet), once daily.

The maximum recommended daily dose of ORSERDU is 345 mg.

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

If a dose is missed, it can be taken immediately within 6 hours after the time it is usually taken. Aftermore than 6 hours, the dose should be skipped for that day. On the next day, ORSERDU should betaken at the usual time.

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

The recommended elacestrant dose modifications for patients with adverse reactions (see section 4.8)are provided in Tables 1 and 2:

Table 1: ORSERDU dose reduction for adverse reactions

ORSERDU dose level Dose and schedule Number and strength of tablets

Dose reduction 258 mg once daily Three 86 mg tablets

If further dose reduction below 258 mg once daily is required, discontinue ORSERDU.

Table 2: ORSERDU dose modification guidelines for adverse reactions

Severity Dose modification

Grade 2 Consider interruption of ORSERDU until recovery to Grade ≤ 1 orbaseline. Then resume ORSERDU at the same dose level.

Grade 3 Interrupt ORSERDU until recovery to Grade ≤ 1 or baseline. The doseshould be reduced to 258 mg when resuming therapy.

If the Grade 3 toxicity recurs, interrupt ORSERDU until recovery to

Grade ≤ 1 or baseline. The reduced dose of 258 mg may be resumed atthe discretion of the treating physician if the patient is benefiting fromtreatment. If a Grade 3 or intolerable adverse reaction recurs,permanently discontinue ORSERDU.

Grade 4 Interrupt ORSERDU until recovery to Grade ≤ 1 or baseline. The doseshould be reduced to 258 mg when resuming therapy.

If a Grade 4 or intolerable adverse reaction recurs, permanentlydiscontinue ORSERDU.

Use of ORSERDU with CYP3A4 inhibitors

Concomitant use of strong or moderate CYP3A4 inhibitors should be avoided and an alternativeconcomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered.

If a strong CYP3A4 inhibitor must be used, the elacestrant dose should be reduced to 86 mg oncedaily with careful monitoring of tolerability. If a moderate CYP3A4 inhibitor must be used, theelacestrant dose should be reduced to 172 mg once daily with careful monitoring of tolerability.

Subsequent dose reduction to 86 mg once daily may be considered with moderate CYP3A4 inhibitorsbased on tolerability.

If the CYP3A4 inhibitor is discontinued, the elacestrant dose should be increased to the dose usedprior to the initiation of the CYP3A4 inhibitor (after 5 half-lives of the CYP3A4 inhibitor) (seesections 4.4, 4.5 and 5.2).

No dose adjustments are required for coadministration of ORSERDU with mild CYP3A4 inhibitors(see section 4.5).

Use of ORSERDU with CYP3A4 inducers

Concomitant use of strong or moderate CYP3A4 inducers should be avoided and an alternativeconcomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered.

If a strong or moderate CYP3A4 inducer must be used for a short duration of time (i.e. ≤ 3 days) orintermittently (i.e. treatment periods ≤ 3 days separated by at least 2 weeks or 1 week + 5 half-lives ofthe CYP3A4 inducer, whichever is longer), continue elacestrant without increasing the dose.

No dose adjustments are required for coadministration of ORSERDU with mild CYP3A4 inducers(see sections 4.4, 4.5 and 5.2).

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

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). Inpatients with moderate hepatic impairment (Child-Pugh B), ORSERDU dose should be reduced to258 mg. Elacestrant has not been studied in patients with severe hepatic impairment (Child-Pugh C),therefore no dose recommendation can be made for patients with severe hepatic impairment (seesection 4.4).

No dose adjustment in subjects with renal impairment is necessary. Elacestrant has not been studied inpatients with severe renal impairment, therefore no dose recommendation can be made for patientswith severe renal impairment (see section 5.2).

The safety and efficacy of ORSERDU in children from birth to 18 years of age has not beenestablished. No data are available.

ORSERDU is for oral use.

The tablets should be swallowed whole. They should not be chewed, crushed or split prior toswallowing. Patients should take their dose of ORSERDU at approximately the same time each day.

ORSERDU should be administered with a light meal. Administration with food may also reducenausea and vomiting (see section 5.2).

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

ORSERDU is metabolised by the liver, and impaired hepatic function can increase the risk for adversereactions. Therefore, ORSERDU should be used cautiously in patients with hepatic impairment andpatients should be regularly and closely monitored for adverse reactions. Administration of elacestrantshould be undertaken with caution at a dose of 258 mg once daily in patients with moderate hepaticimpairment (see section 4.2). In the absence of clinical data, elacestrant is not recommended inpatients with severe hepatic impairment (Child-Pugh C) (see section 4.2).

Concomitant use with CYP3A4 inhibitors

Concomitant administration of ORSERDU with strong CYP3A4 inhibitors including, but not limitedto: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir,posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juiceshould be avoided. An alternative concomitant medicinal product with no or minimal potential toinhibit CYP3A4 should be considered. If the strong CYP3A4 inhibitor cannot be avoided, ORSERDUdose adjustment should be applied (see sections 4.2 and 4.5).

Concomitant administration of ORSERDU with moderate CYP3A4 inhibitors including, but notlimited to: aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone,erythromycin, fluconazole, fluvoxamine, grapefruit juice, imatinib, isavuconazole, tofisopam andverapamil should be avoided. An alternative concomitant medicinal product with no or minimalpotential to inhibit CYP3A4 should be considered. If the moderate CYP3A4 inhibitor cannot beavoided, ORSERDU dose adjustment should be applied (see sections 4.2 and 4.5).

Concomitant use with CYP3A4 inducers

Concomitant administration of ORSERDU with strong CYP3A4 inducers including, but not limitedto: phenytoin, rifampicin, carbamazepine and St John’s Wort (Hypericum perforatum) should beavoided. An alternative concomitant medicinal product with no or minimal potential to induce

CYP3A4 should be considered. If the strong CYP3A4 inducer cannot be avoided, ORSERDU doseadjustment should be applied (see sections 4.2 and 4.5).

Concomitant administration of ORSERDU with moderate CYP3A4 inducers including, but not limitedto: bosentan, cenobamate, dabrafenib, efavirenz, etravirine, lorlatinib, phenobarbital, primidone andsotorasib should be avoided. An alternative concomitant medicinal product with no or minimalpotential to induce CYP3A4 should be considered. If the moderate CYP3A4 inducer cannot beavoided, ORSERDU dose adjustment should be applied (see sections 4.2 and 4.5).

Thromboembolic events are commonly observed in patients with advanced breast cancer and havebeen observed in clinical studies with ORSERDU (see section 4.8). This should be taken intoconsideration when prescribing ORSERDU to patients at risk.

ORSERDU is primarily metabolised by CYP3A4 and is a substrate of the Organic Anion Transporting

Polypeptide 2B1 (OATP2B1). ORSERDU is an inhibitor of P-glycoprotein (P-gp) and Breast Cancer

Resistance Protein (BCRP) efflux transporters.

Effect of other medicinal products on ORSERDU

CYP3A4 Inhibitors

Co-administration of the strong CYP3A4 inhibitor itraconazole (200 mg once daily for 7 days) with

ORSERDU (172 mg once daily for 7 days) increased elacestrant plasma exposure (AUCinf) and thepeak concentration (Cmax) in healthy subjects 5.3 and 4.4-fold, respectively.

Physiologically based pharmacokinetic (PBPK) simulations in cancer patients suggested that theconcomitant administration of multiple daily doses of elacestrant 345 mg and itraconazole 200 mgmay increase elacestrant steady-state AUC and Cmax 5.5- and 3.9-fold, respectively, which mayincrease the risk of adverse reactions.

PBPK simulations in cancer patients suggested that concomitant administration of multiple daily dosesof elacestrant 345 mg with moderate CYP3A4 inhibitors may increase elacestrant steady-state AUCand Cmax by 2.3- and 1.9-folds, respectively, with fluconazole (200 mg once daily), and by 3.9- and3.0-folds, respectively, with erythromycin (500 mg four times a day), which may increase the risk ofadverse reaction.

CYP3A4 Inducers

Co-administration of the strong CYP3A4 inducer rifampicin (600 mg once daily for 7 days) with asingle dose of ORSERDU 345 mg decreased elacestrant plasma exposure (AUCinf) and the peakconcentration (Cmax) in healthy subjects by 86% and 73%, respectively, which may decreaseelacestrant activity.

PBPK simulations in cancer patients suggested that the concomitant administration of multiple dailydoses of elacestrant 345 mg and rifampicin 600 mg may decrease elacestrant steady-state AUC and

Cmax by 84% and 77%, respectively, which may decrease elacestrant activity.

PBPK simulations in cancer patients suggested that the concomitant administration of multiple dailydoses of elacestrant 345 mg and the moderate CYP3A4 inducer efavirenz (600 mg) may decreaseelacestrant steady-state AUC and Cmax by 57% and 52%, respectively, which may decrease elacestrantactivity.

OATP2B1 inhibitors

Elacestrant is a substrate of OATP2B1 in vitro. As it cannot be excluded that the coadministration of

OATP2B1 inhibitors may increase the exposure of elacestrant, which may increase the risk of adversereactions, caution is recommended in case of concomitant use of ORSERDU with OATP2B1inhibitors.

Effect of ORSERDU on other medicinal products

Co-administration of ORSERDU (345 mg, single dose) with digoxin (0.5 mg, single dose) increaseddigoxin exposure by 27% for Cmax and 13% for AUC. Digoxin administration should be monitored andits dose reduced as necessary.

Concomitant use of ORSERDU with other P-gp substrates may increase their concentrations, whichmay increase the adverse reactions associated with the P-gp substrates. The dose of coadministered

P-gp substrates should be reduced according to their Summary of Product Characteristics.

Co-administration of ORSERDU (345 mg, single dose) with rosuvastatin (20 mg, single dose)increased rosuvastatin exposure by 45% for Cmax and 23% for AUC. Rosuvastatin administrationshould be monitored and its dose reduced as necessary.

Concomitant use of ORSERDU with other BCRP substrates may increase their concentrations, whichmay increase the adverse reactions associated with the BCRP substrates. The dose of coadministered

BCRP substrates should be reduced according to their Summary of Product Characteristics.

ORSERDU should not be used during pregnancy or in women of childbearing potential not usingcontraception. Based on the mechanism of action of elacestrant and findings from reproductivetoxicity studies in animals, ORSERDU can cause foetal harm when administered to pregnant women.

Females of reproductive potential should be advised to use effective contraception during treatmentwith ORSERDU and one week after the last dose.

There are no data from the use of elacestrant in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). ORSERDU should not be used during pregnancy or in womenof childbearing potential not using contraception. The pregnancy status of females of reproductivepotential should be verified prior to starting treatment with ORSERDU. If pregnancy occurs whiletaking ORSERDU, the patient must be informed of the potential hazard to the foetus and potential riskof miscarriage.

It is unknown whether elacestrant/metabolites are excreted in human milk. Because of the potential forserious adverse reactions in the breast-fed infant, it is recommended that lactating women should notbreast-feed during treatment with ORSERDU and one week after the last dose of ORSERDU.

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

ORSERDU has no or negligible influence on the ability to drive and use machines. However, sincefatigue, asthenia, and insomnia have been reported in some patients taking elacestrant (seesection 4.8), caution should be observed by patients who experience those adverse reactions whendriving or operating machinery.

The most common (≥ 10%) adverse reactions with ORSERDU were nausea, triglycerides increased,cholesterol increased, vomiting, fatigue, dyspepsia, diarrhoea, calcium decreased, back pain, creatinineincreased, arthralgia, sodium decreased, constipation, headache, hot flush, abdominal pain, anaemia,potassium decreased, and alanine aminotransferase increased. The most common Grade ≥3 (≥2%)adverse reactions of elacestrant were nausea (2.7%), AST increased (2.7%), ALT increased (2.3%),anaemia (2%), back pain (2%), and bone pain (2%).

Serious adverse reactions reported in ≥ 1% of patients included nausea, dyspnoea, andthromboembolism (venous).

Adverse reactions leading to discontinuation in ≥ 1% of patients included nausea and decreasedappetite.

Adverse reactions leading to dose reduction in ≥ 1% of patients included nausea.

Adverse reactions leading to dose interruption in ≥ 1% of patients were nausea, abdominal pain,alanine aminotransferase increased, vomiting, rash, bone pain, decreased appetite, aspartateaminotransferase increased, and diarrhoea.

Adverse reactions described in the list below reflect exposure to elacestrant in 301 patients with breastcancer in three open label studies (RAD1901-005, RAD1901-106, and RAD1901-308) in whichpatients received elacestrant 400 mg once daily as a single agent. The frequencies of adverse reactionsare based on all-cause adverse event frequencies identified in patients exposed to elacestrant at therecommended dose in the target indication, whereas frequencies for changes in laboratory parametersare based on worsening from baseline by at least 1 grade and shifts to ≥ grade 3. The median durationof treatment was 85 days (range 5 to 1288).

The adverse reaction frequencies from clinical trials are based on all-cause adverse event frequencies,where a proportion of the events for an adverse reaction may have other causes than the drug, such asthe disease, other medication or unrelated causes.

The following convention is used for the classification of the frequency of an adverse drug reaction(ADR) and is based on the Council for International Organizations of Medical Sciences (CIOMS)guidelines: 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 theavailable data).

Table 3. Adverse reactions in patients treated with elacestrant monotherapy 345 mg inmetastatic breast cancer

Elacestrant

N= 301

Infections and Common Urinary tract infectioninfestations

Blood and lymphatic Very common Anaemiasystem disorders Common Lymphocyte count decreased

Metabolism and nutrition Very common Decreased appetitedisorders

Psychiatric disorders Common Insomnia

Nervous system disorder Very common Headache

Common Dizziness, Syncope

Vascular disorders Very common Hot flush*

Uncommon Thromboembolism (venous)*

Respiratory, thoracic and Common Dyspnoea, Cough*mediastinal disorders

Gastrointestinal disorders Very common Nausea, Vomiting, Diarrhoea, Constipation,

Abdominal pain*, Dyspepsia*

Common Stomatitis

Hepatobiliary disorders Uncommon Acute hepatic failure

Skin and subcutaneous Common Rash*tissue disorders

Musculoskeletal and Very common Arthralgia, Back painconnective tissues Common Pain in extremity, Musculoskeletal chest pain *,disorders Bone pain

General disorders and Very common Fatigueadministration site Common Astheniaconditions

Elacestrant

N= 301

Investigations Very common Aspartate aminotransferase increased,

Triglycerides increased, Cholesterol increased,

Alanine aminotransferase increased, Calciumdecreased, Creatinine increased, Sodiumdecreased, Potassium decreased

Common Blood alkaline phosphatase increased

*Incidence represents a grouping of similar terms.

ADRs listed by system organ class and by decreasing frequency..

Nausea

Nausea was reported in 35% of patients. Grade 3-4 nausea events were reported in 2.5% of patients.

Nausea was generally reported early, with a median time to the first onset 14 days (range: 1 to 490days). Nausea occurred more frequently in the first cycle and from Cycle 2 onward, the incidence ofnausea was generally lower in subsequent cycles (i.e., over time). Prophylactic treatment for nauseawas prescribed for 12 (5%) subjects in the elacestrant arm and 28 (11.8%) received an antiemetic forthe treatment of nausea during the on-treatment period.

In the RAD1901-308 study, 104 patients who received elacestrant were ≥ 65 years and 40 patientswere ≥ 75 years. Gastrointestinal disorders were reported more frequently in patients aged ≥ 75 years.

Monitoring of treatment emergent adverse reactions by the treating physician, should includeconsideration of the patient’s age and comorbidities, when selecting personalised interventions.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The highest dose of ORSERDU administered in clinical studies was 1000 mg per day. The adversedrug reactions reported in association with doses higher than the recommended dose were consistentwith the established safety profile (see section 4.8). The frequency and severity of gastrointestinaldisorders (abdominal pain, nausea, dyspepsia and vomiting) appeared to be dose-related. There is noknown antidote for an overdose of ORSERDU. Patients should be closely monitored and treatment ofoverdose should consist of supportive treatment.

Pharmacotherapeutic group: Endocrine therapy, anti estrogen, ATC code: L02BA04

Elacestrant, a tetrahydronaphthalene compound, is a potent, selective and orally active estrogenreceptor-α (ERα) antagonist and degrader.

Elacestrant inhibits the estradiol-dependent and independent growth of ERα-positive breast cancercells, including models harbouring estrogen receptor 1 (ESR1) gene mutations. Elacestrant displayedpotent antitumor activity in patient derived xenograft models previously exposed to multiple endocrinetherapies, harbouring wild type ESR1 or ESR1 gene mutations in the ligand binding domain.

In patients with ER+ advanced breast cancer with a median of 2.5 prior lines of endocrine therapy,dosed with elacestrant dihydrochloride 400 mg (345 mg of elacestrant) daily, median reduction intumour 16α-18F-fluoro-17β-estradiol (FES) uptake from baseline to Day 14 was 88.7%demonstrating reduced ER availability and antitumor activity measured by FES-PET/CT in patientswith prior endocrine therapies.

The efficacy and safety of ORSERDU in patients with ER+/HER2- advanced breast cancer followingprior endocrine therapy in combination with a CDK4/6 inhibitor was evaluated in RAD1901-308, arandomised, open-label, active-controlled, multicenter trial which compared ORSERDU with standardof care (SOC) (fulvestrant for patients who received prior aromatase inhibitors in the metastatic settingor aromatase inhibitors for patients who received fulvestrant in the metastatic setting). Eligible patientsincluded post-menopausal women and men whose disease had relapsed or progressed on at least 1 andno more than 2 prior lines of endocrine therapy. All patients were required to have Eastern Cooperative

Oncology Group (ECOG)performance status of 0 or 1, and evaluable lesions per Response Evaluation

Criteria in Solid Tumors (RECIST) version 1.1, i.e., measurable disease or bone only disease withevaluable lesions. Prior endocrine therapy must have included a combination with CDK4/6 inhibitortherapy and no more than 1 prior line of cytotoxic chemotherapy for metastatic breast cancer. Patientswere required to be appropriate candidates for endocrine monotherapy. Patients with presence ofsymptomatic metastatic visceral disease, patients with cardiac comorbidity, and patients with severehepatic impairment were excluded.

A total of 478 patients were randomised 1:1 to daily oral administration of 400 mg of elacestrantdihydrochloride (345 mg of elacestrant) or standard of care (SOC) (239 on elacestrant and 239 on

SOC), including a total of 228 patients (47.7%) with ESR1 mutations at baseline (115 patients onelacestrant and 113 patients on SOC). Among the 239 patients randomised to the SOC arm, 166received fulvestrant, and 73 received an aromatase inhibitor that included anastrozole, letrozole orexemestane. Randomisation was stratified by ESR1 mutations status (ESR1-mut vs ESR1-mut-nd [no

ESR1 mutations detected]), prior treatment with fulvestrant (yes vs no), and visceral metastasis (yes vsno). ESR1 mutational status was determined by blood circulating tumor deoxyribonucleic acid(ctDNA) using the Guardant360 CDx assay and was limited to ESR1 missense mutations in the ligandbinding domain (between codons 310 to 547).

The median age of patients (ORSERDU vs standard of care) at baseline was 63.0 years (range of 24-89) vs 63.0 (range of 32-83) and 45.0% were over 65 (43.5 vs 46.4). Most patients were women(97.5% vs 99.6%) and most patients were white (88.4% vs 87.2%), followed by Asian (8.4% vs 8.2%),

Black or African American (2.6% vs 4.1%), and Other/Unknown (0.5% vs 0.5%). Baseline ECOGperformance status was 0 (59.8% vs 56.5%), 1 (40.2% vs 43.1%) or > 1 (0% vs 0.4%). Patientdemographics for those with ESR1-mutated tumors were generally representative of the broader studypopulation. The median duration of exposure to ORSERDU was 2.8 months (range: 0.4 to 24.8).

The primary efficacy endpoint was progression-free survival (PFS) as assessed by IRC (Independent

Review Committee) in all patients, i.e., including patients with an ESR1 mutation, and in patients with

ESR1 mutations. A statistically significant PFS benefit was observed in all patients with a median PFSof 2.79 months in the Orserdu arm as compared with 1.91 months in the standard of care arm (HR=0.70, 95% CI: 0.55, 0.88). Efficacy results are presented in Table 4 and Figure 1 for patients with

ESR1 mutations.

Table 4: Efficacy results among patients with ESR1 mutations (evaluated by a blinded imagingreview committee)

ORSERDU Standard of care

Progression-free survival (PFS) N = 115 N = 113

Number of PFS events, n (%) 62 (53.9) 78 (69.0)

Median PFS months* (95% CI) 3.78 (2.17, 7.26) 1.87 (1.87, 2.14)

Hazard ratio** (95% CI) 0.546 (0.387, 0.768)p-value (stratified log-rank) 0.0005

Overall survival (OS) N = 115 N = 113

Number of OS events, n (%) 61 (53) 60 (53.1)

Median OS months* (95% CI) 24.18 (20.53, 28.71) 23.49 (15.64, 29.90)

Hazard ratio** (95% CI) 0.903 (0.629, 1.298)

CI=confidence interval; ESR1=estrogen receptor 1; PFS=progression-free survival.

*Kaplan-Meir estimate; 95% CI based on the Brookmeyer-Crowley method using a lineartransformation.

**From a Cox proportional hazards model stratified by prior treatment with fulvestrant (yes vs no),and visceral metastasis (yes vs no).

Data cut-off dates are 06 September 2021 for PFS and 02 September 2022 for OS.

Figure 1: PFS in patients with an ESR1 mutation (evaluated by a blinded imaging reviewcommittee)

The European Medicines Agency has waived the obligation to submit the results of studies with

ORSERDU in all subsets of the paediatric population in breast cancer (see section 4.2).

The elacestrant oral bioavailability is approximately 10%. Steady state is reached by Day 6 followingonce daily dosing. Cmax and AUC increase slightly more than proportional to dose for doses ≥ 50 mg(salt form).

Following oral administration, elacestrant was rapidly absorbed, reaching Cmax within 1-4 hours. Thegeometric mean Cmax was 52.86 ng/mL (35.2% coefficient of variation [CV%]) and AUCinf was1566 ng*h/mL (38.4% CV) after single dose administration of 345 mg of elacestrant in fed conditions.

At steady state, the median [min, max] plasma concentration at 4h post-dose (C4h) and AUC arepredicted to be 108 ng/mL [27.5 - 351] and 2190 ng*h/mL [461 - 8470], respectively.

Administration of elacestrant 345 mg tablet with a high-fat high-calorie meal increased Cmax and AUCby 40% and 20%, respectively, as compared to fasted administration. When the tablet was co-administered with a light meal, Cmax and AUC increased in a similar fashion, i.e., by 30 and 20%,respectively. Ingestion with food may reduce gastrointestinal adverse effects.

Effect of P-gp transporter on Elacestrant

Elacestrant is a substrate of P-gp. The transport is saturated at the dosages of 258 mg and 345 mg.

As no clinical data is available when lower elacestrant dosages of 86 mg and 172 mg are co-administered with a P-gp inhibitor, it cannot be excluded that co-administration with a P-gp inhibitormay increase the absorption at lower elacestrant dosages.

Plasma protein binding of elacestrant is > 99% and independent of concentration and hepaticimpairment status. Elacestrant penetrates the blood brain barrier in a dose-dependent manner.

Following once daily administration of elacestrant for 7 consecutive days, median concentrations ofelacestrant in the cerebrospinal fluid were 0.0966 ng/mL and 0.155 ng/mL at the doses of 200 and500 mg, respectively.

Based on population pharmacokinetic analysis, elacestrant is extensively distributed in the tissues withan apparent peripheral volume of distribution of 5411 L. The apparent central volume of distributionof elacestrant at steady state is 422 L.

Elacestrant was a minor (< 10% of plasma radioactivity) component in human plasma. 4-[2-(Ethylamino)ethyl]benzoic acid (EAEBA) glucuronide was a major human plasma metabolite (about41% of plasma radioactivity). Elacestrant is primarily metabolised by CYP3A4 with a potential smallcontribution by CYP2A6 and CYP2C9.

The half-life of elacestrant is predicted to be approximately 30 hours. After a single dose, the mean (%

CV) clearance of elacestrant was 220.3 L/hr (38.4%). At steady state, the mean (% CV) clearance ofelacestrant is predicted to be 186 L/hr (43.5%).

Following a single oral dose of 345 mg radiolabeled elacestrant, 81.5% (majority as unchanged) wasrecovered in feces and 7.53% (trace as unchanged) was recovered in urine. Elacestrant renal clearanceis very low (≤ 2.3 mL/min) and it was eliminated by oxidative metabolism and fecal excretion.

Effect of age, weight and gender

From analyses of population pharmacokinetic data in cancer patients, no dose adjustment is warrantedbased on body weight, age, and gender.

The Cmax and AUC values were similar between subjects in the mild hepatic impairment group (Child-

Pugh A) and the normal hepatic function group upon single dose administration of elacestrant 176 mg.

There were significant increases in AUC0-t (76%) and AUC0-∞ (83%) in the moderate hepaticimpairment group (Child-Pugh B) compared to the normal hepatic function group. The Cmax valueswere similar between the normal and moderate impairment groups.

The geometric mean elimination half-life (t1/2) tended to increase with increasing severity of hepaticimpairment. Elacestrant has not been studied in subjects with severe hepatic impairment (Child-

Pugh C).

In PBPK modeling simulation of elacestrant at 345 mg, the steady state AUC and Cmax were predictedto increase by 2.14- and 1.92-fold, respectively, in subjects with moderate hepatic impairmentcompared to patients with normal hepatic function.

Elacestrant displayed low acute toxicity. In repeated dose toxicity studies in rats and monkeys, theantiestrogenic activity of elacestrant was responsible for the effects seen, particularly in the femalereproductive system, but also in other organs sensitive to hormones such as mammary gland, pituitaryand testes. Sporadic emesis and diarrhoea were recorded in monkeys. In addition, in long-term studies(26 weeks in rats and 39 weeks in cynomolgus monkeys), increased vacuolation of the mucosalepithelium of the non-glandular stomach were observed in rats and vacuolated macrophage infiltratesin the small intestine were recorded in both rats and monkeys. In monkeys this effect occurred at alevel of systemic exposure of about 70% of the human exposure.

Elacestrant showed no genotoxic potential in the Ames test, chromosomal aberrations in humanlymphocytes and in the micronucleus assay in rats.

Fertility studies in animals have not been conducted. In repeated-dose toxicity studies effects related tofertility were observed in rat and monkey female reproductive tract; these effects occurred belowhuman exposures at MRHD (maximum recommended dose). Decreased cellularity of Leydig cells inrat testes was also observed at exposure levels 2.7-fold higher than in humans.

In embryo-foetal development studies in rats, oral administration of elacestrant resulted in maternaltoxicity (body weight loss, low food consumption, red vulvar discharge) and increased resorptions,increased post-implantation loss, and reduced number of live foetuses and foetal variations andmalformations below human exposures at MHRD.

Microcrystalline cellulose [E460]

Silicified microcrystalline cellulose

Crospovidone [E1202]

Magnesium stearate [E470b]

Colloidal silicon dioxide [E551]

Opadry II 85F105080 Blue containing polyvinyl alcohol [E1203], titanium dioxide [E171], macrogol[E1521], talc [E553b] and brilliant blue FCF aluminium lake [E133]

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

ORSERDU is packaged in aluminium-aluminium blisters packed into a cardboard box.

ORSERDU 86 mg film-coated tablets

Packs containing 28 film-coated tablets: 4 blisters with 7 tablets each

ORSERDU 345 mg film-coated tablets

Packs containing 28 film-coated tablets: 4 blisters with 7 tablets each

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Stemline Therapeutics B.V.

Basisweg 101043 AP Amsterdam

The Netherlands

EU/1/23/1757/001

EU/1/23/1757/002

Date of first authorisation:15 September 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu