Elacestrant

Co-administration of elacestrant (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 elacestrant 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.

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 elacestrant with OATP2B1 inhibitors.

Elacestrant is metabolised by the liver, and impaired hepatic function can increase the risk for adverse reactions. Therefore, elacestrant 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. In the absence of clinical data, elacestrant is not recommended in patients with severe hepatic impairment (Child-Pugh C).

Co-administration of elacestrant (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 elacestrant 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.

Concomitant use of strong or moderate CYP3A4 inhibitors should be avoided and an alternative concomitant 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 once daily with careful monitoring of tolerability. If a moderate CYP3A4 inhibitor must be used, the elacestrant 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 inhibitors based on tolerability.

If the CYP3A4 inhibitor is discontinued, the elacestrant dose should be increased to the dose used prior to the initiation of the CYP3A4 inhibitor (after 5 half-lives of the CYP3A4 inhibitor).

Concomitant use of strong or moderate CYP3A4 inducers should be avoided and an alternative concomitant 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) or intermittently (i.e. treatment periods ≤ 3 days separated by at least 2 weeks or 1 week + 5 half-lives of the CYP3A4 inducer, whichever is longer), continue elacestrant without increasing the dose.

Based on findings from animal studies and its mechanism of action, elacestrant may impair fertility in females and males of reproductive potential.

There are no data from the use of elacestrant in pregnant women. Studies in animals have shown reproductive toxicity. Elacestrant 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 elacestrant. If pregnancy occurs while taking elacestrant, the patient must be informed of the potential hazard to the foetus and potential risk of miscarriage.

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 elacestrant and one week after the last dose of elacestrant.

Women of childbearing potential/Contraception in males and females

Elacestrant 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, elacestrant can cause foetal harm when administered to pregnant women. Females of reproductive potential should be advised to use effective contraception during treatment with elacestrant and one week after the last dose.

Fertility

Based on findings from animal studies and its mechanism of action, elacestrant may impair fertility in females and males of reproductive potential.

Elacestrant 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, 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 elacestrant 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).

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.