ORSERDU Film-coated tablet Ref.[51613] Active ingredients: Elacestrant

Hepatic impairment

ORSERDU is metabolised by the liver, and impaired hepatic function can increase the risk for adverse reactions. Therefore, ORSERDU should be used cautiously in patients with hepatic impairment and patients should be regularly and closely monitored for adverse reactions. Administration of elacestrant should be undertaken with caution at a dose of 258 mg once daily in patients with moderate hepatic impairment (see section 4.2). In the absence of clinical data, elacestrant is not recommended in patients 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 limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice should be avoided. An alternative concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. If the strong CYP3A4 inhibitor cannot be avoided, ORSERDU dose adjustment should be applied (see sections 4.2 and 4.5).

Concomitant administration of ORSERDU with moderate CYP3A4 inhibitors including, but not limited to: aprepitant, ciprofloxacin, conivaptan, crizotinib, cyclosporine, diltiazem, dronedarone, erythromycin, fluconazole, fluvoxamine, grapefruit juice, imatinib, isavuconazole, tofisopam and verapamil should be avoided. An alternative concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. If the moderate CYP3A4 inhibitor cannot be avoided, 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 limited to: phenytoin, rifampicin, carbamazepine and St John’s Wort (Hypericum perforatum) should be avoided. 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 dose adjustment should be applied (see sections 4.2 and 4.5).

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

Thromboembolic events

Thromboembolic events are commonly observed in patients with advanced breast cancer and have been observed in clinical studies with ORSERDU (see section 4.8). This should be taken into consideration 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 the peak concentration (C_max) in healthy subjects 5.3 and 4.4-fold, respectively.

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

PBPK simulations in cancer patients suggested that concomitant administration of multiple daily doses of elacestrant 345 mg with moderate CYP3A4 inhibitors may increase elacestrant steady-state AUC and C_max by 2.3- and 1.9-folds, respectively, with fluconazole (200 mg once daily), and by 3.9- and 3.0-folds, respectively, with erythromycin (500 mg four times a day), which may increase the risk of adverse reaction.

CYP3A4 Inducers

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

PBPK simulations in cancer patients suggested that the concomitant administration of multiple daily doses of elacestrant 345 mg and rifampicin 600 mg may decrease elacestrant steady-state AUC and C_max by 84% and 77%, respectively, which may decrease elacestrant activity.

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

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 adverse reactions, caution is recommended in case of concomitant use of ORSERDU with OATP2B1 inhibitors.

Effect of ORSERDU on other medicinal products

P-gp substrates

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

Concomitant use of ORSERDU with other P-gp substrates may increase their concentrations, which may 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.

BCRP substrates

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

Concomitant use of ORSERDU with other BCRP substrates may increase their concentrations, which may 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.

Women of childbearing potential/Contraception in males and females

ORSERDU should not be used during pregnancy or in women of childbearing potential not using contraception. Based on the mechanism of action of elacestrant and findings from reproductive toxicity 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 treatment with ORSERDU and one week after the last dose.

Pregnancy

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

Breast-feeding

It is unknown whether elacestrant/metabolites are excreted in human milk. Because of the potential for serious adverse reactions in the breast-fed infant, it is recommended that lactating women should not breast-feed during treatment with ORSERDU and one week after the last dose of ORSERDU.

Fertility

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

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

Summary of the safety profile

The most common (≥10%) adverse reactions with ORSERDU were nausea, triglycerides increased, cholesterol increased, vomiting, fatigue, dyspepsia, diarrhoea, calcium decreased, back pain, creatinine increased, 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, and thromboembolism (venous).

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

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, aspartate aminotransferase increased, and diarrhoea.

Tabulated list of adverse reactions

Adverse reactions described in the list below reflect exposure to elacestrant in 301 patients with breast cancer in three open label studies (RAD1901-105, RAD1901-106, and RAD1901-308) in which patients received elacestrant 400 mg once daily as a single agent. The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in patients exposed to elacestrant at the recommended dose in the target indication, whereas frequencies for changes in laboratory parameters are based on worsening from baseline by at least 1 grade and shifts to ≥ grade 3. The median duration of 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 as the 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 the available data).

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

^* Incidence represents a grouping of similar terms.
ADRs listed by system organ class and by decreasing frequency.

Description of selected adverse reactions

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 490 days). Nausea occurred more frequently in the first cycle and from Cycle 2 onward, the incidence of nausea was generally lower in subsequent cycles (i.e., over time). Prophylactic treatment for nausea was prescribed for 12 (5%) subjects in the elacestrant arm and 28 (11.8%) received an antiemetic for the treatment of nausea during the on-treatment period.

Elderly

In the RAD1901-308 study, 104 patients who received elacestrant were ≥65 years and 40 patients were ≥75 years. Gastrointestinal disorders were reported more frequently in patients aged ≥75 years. Monitoring of treatment emergent adverse reactions by the treating physician, should include consideration of the patient’s age and comorbidities, when selecting personalised interventions.

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.