INLURIYO Film-coated tablet Ref.[116076] Active ingredients: Imlunestrant

5.1 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, INLURIYO can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of imlunestrant to pregnant rats during the period of organogenesis led to embryo-fetal mortality and structural abnormalities at maternal exposures that were below the human exposure at the recommended dose based on AUC.

Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with INLURIYO and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with INLURIYO and for 1 week after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of INLURIYO was evaluated in 651 patients with ER+, HER2- locally advanced or metastatic breast cancer previously treated with endocrine therapy with or without a prior CDK4/6 inhibitor in EMBER-3 [see Clinical Studies (14.1)]. Patients received INLURIYO 400 mg orally, once daily (n=327), or standard of care (n=324) consisting of either fulvestrant (n=292) or exemestane (n=32). Among patients who were treated with INLURIYO, the median duration of exposure was 5.6 months (range: 0.2 to 28.6 months) in EMBER-3.

Serious adverse reactions occurred in 10% of patients who received INLURIYO. Serious adverse reactions in >1% of patients included pleural effusion (1.2%). Fatal adverse reactions occurred in 1.8% of patients who received INLURIYO, including cardiac arrest, acute myocardial infarction, right ventricular failure, hypovolemic shock, and upper gastrointestinal hemorrhage (each 0.3%).

Permanent treatment discontinuation of INLURIYO due to an adverse reaction occurred in 4.6% of patients. Adverse reactions which resulted in permanent discontinuation of INLURIYO included increased alanine aminotransferase (0.9%), abdominal pain, fatigue, fractured sacrum, hepatotoxicity, neuropathy peripheral, and pyrexia (each 0.3%).

Dosage interruption of INLURIYO due to an adverse reaction occurred in 10% of patients. Adverse reactions which required dosage interruption in >0.5% were vomiting (1.5%); increased aspartate aminotransferase and COVID-19 (each 0.9%); and increased alanine aminotransferase, anemia, diarrhea, decreased neutrophil count, and pyrexia (each 0.6%).

Dose reductions of INLURIYO due to an adverse reaction occurred in 2.4% of patients. Adverse reactions which required dose reductions were increased aspartate aminotransferase (0.6%); and increased alanine aminotransferase, anemia, fatigue, interstitial lung disease, nausea, neutropenia, and vomiting (each 0.3%).

The most common (≥10%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, musculoskeletal pain, calcium decreased, neutrophils decreased, AST increased, fatigue, diarrhea, ALT increased, triglycerides increased, nausea, platelets decreased, constipation, cholesterol increased, and abdominal pain.

Table 3 summarizes the adverse reactions in EMBER-3.

Table 3. Adverse Reactions (≥10%) in Patients Who Received INLURIYO in EMBER-3:

^a Adverse reactions were graded using NCI CTCAE version 5.0.
^b Includes other related terms

Clinically relevant adverse reactions (<10%) in patients who received INLURIYO included: vomiting (9%), headache (9%), cough (9%), decreased appetite (8%), hot flush (7%), pruritus (3.7%), dyspepsia (2.8%), and stomatitis (2.4%).

Table 4 summarizes the laboratory abnormalities in EMBER-3.

Table 4. Select Laboratory Abnormalities (≥10%) That Worsened from Baseline in Patients Who Received INLURIYO in EMBER-3:

^a Graded according to NCI CTCAE version 5.
^b The denominator used to calculate the rate varied from 252 to 325 based on the number of patients with a baseline value and at least one post-treatment value.

7.1 Effects of Other Drugs on INLURIYO

Strong CYP3A Inhibitors

Avoid concomitant use of INLURIYO with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce the dosage of INLURIYO [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

Imlunestrant is a CYP3A substrate. Concomitant use of a strong CYP3A inhibitor increases imlunestrant exposure [see Clinical Pharmacology (12.3)], which may increase the risk of INLURIYO-associated adverse reactions.

Strong CYP3A Inducers

Avoid concomitant use of INLURIYO with strong CYP3A inducers. If concomitant use cannot be avoided, increase the dosage of INLURIYO [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].

Imlunestrant is a CYP3A substrate. Concomitant use of a strong CYP3A inducer decreases imlunestrant exposure [see Clinical Pharmacology (12.3)], which may reduce effectiveness of INLURIYO.

7.2 Effects of INLURIYO on Other Drugs

P-gp or BCRP Substrates

Avoid concomitant use unless otherwise recommended in the Prescribing Information for P-gp or BCRP substrates where minimal concentration changes may lead to serious adverse reactions.

Imlunestrant inhibits both P-gp and BCRP. Imlunestrant increases exposure of P-gp and BCRP substrates, which may increase the risk of adverse reactions related to these substrates [see Clinical Pharmacology (12.3)].

Risk Summary

Based on findings in animals and its mechanism of action, INLURIYO can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on INLURIYO use in pregnant women to inform the drug-associated risk. In an animal reproduction study, oral administration of imlunestrant to pregnant rats during the period of organogenesis led to embryo-fetal mortality and structural abnormalities at maternal exposures below the human exposure at the recommended dose based on AUC (see Data). Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

Data

Animal Data

In an embryo-fetal development study, imlunestrant was administered orally to pregnant rats during the period of organogenesis from gestation day 6 to 17 at doses of 0.3, 3, and 30 mg/kg/day. Imlunestrant caused embryo-fetal mortality (increased resorption, reduced number of live fetuses) at ≥0.3 mg/kg/day, approximately 0.1 times the human AUC at the recommended dose. Early delivery, fetal malformations (including small jaw, protruding tongue, malrotated, and hyperextended hindlimb) and fetal variations (edema localized subcutis) were observed at ≥3 mg/kg/day, approximately 1 time the human AUC at the recommended dose.

Risk Summary

There are no data on the presence of imlunestrant or its metabolites in human milk, its effects on the breastfed child, or on milk production. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with INLURIYO and for 1 week after the last dose.

INLURIYO can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status in females of reproductive potential prior to initiating INLURIYO.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with INLURIYO and for 1 week after the last dose.

Males

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with INLURIYO and for 1 week after the last dose.

Infertility

Based on findings in animals, INLURIYO may impair fertility in females and males of reproductive potential. Findings in animals were reversible [see Nonclinical Toxicology (13.1)].

The safety and effectiveness of INLURIYO have not been established in pediatric patients.

Of 327 patients who received INLURIYO in the EMBER-3 study, 118 patients were ≥ 65 years of age and 37 patients were ≥75 years of age. No overall differences in safety or effectiveness of INLURIYO have been observed between patients 65 years of age and older and younger adult patients.

Reduce the dose of INLURIYO in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. No dosage modification is recommended for patients with mild hepatic impairment (Child-Pugh A) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].