PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The steady-state mean (%CV) maximum concentration (Cmax) of elacestrant is 119 ng/mL (43.6%) and the area under the concentration-time curve (AUC0-24h) is 2440 ngh/mL (44.3%) after administration of the recommended dosage of 345 mg once daily. The Cmax and AUC of elacestrant increase more than proportionally over dosage range from 43 mg to 862 mg once daily (0.125 to 2.5 times the approved recommended dosage). Steady state is reached by Day and the mean accumulation ratio based on AUC0-24h is 2-fold.AbsorptionThe time to achieve peak plasma concentration (tmax) ranges from to hours. The elacestrant oral bioavailability is approximately 10%.Effect of FoodAdministration of ORSERDU 345 mg with high-fat meal (800 to 1000 calories, 50% fat) increased Cmax by 42% and AUC by 22% compared to fasted administration.DistributionThe estimated apparent volume of distribution is 5800L. Plasma protein binding of elacestrant is >99% and independent of concentration.Elimination The elimination half-life of elacestrant is 30 to 50 hours. The estimated mean (% CV) clearance of elacestrant is 186 L/hr (43.5%) and renal clearance is <= 0.14 L/hr.MetabolismElacestrant is primarily metabolized by CYP3A4 and to lesser extent by CYP2A6 and CYP2C9.ExcretionFollowing single radiolabeled oral dose of 345 mg, 82% was recovered in feces (34% unchanged) and 7.5% was recovered in urine (< 1% unchanged).Specific PopulationsThere were no clinically significant differences in the pharmacokinetics of elacestrant based on age (24 to 89 years), sex, and body weight (41 to 143 kg).Patients with Hepatic Impairment There were no clinically significant differences in the Cmax and AUC of elacestrant in subjects with mild hepatic impairment (Child-Pugh A). The AUC of elacestrant increased in subjects with moderate hepatic impairment (Child-Pugh B) by 83%.Elacestrant has not been studied in subjects with severe hepatic impairment (Child-Pugh C).Drug Interaction StudiesClinical StudiesThere were no clinically significant differences in the pharmacokinetics of elacestrant when used concomitantly with cimetidine (weak CYP3A inhibitor), omeprazole (gastric acid-reducing agent), or warfarin (highly protein-bound drug).Table describes the effect of other drugs on the pharmacokinetics of elacestrant and Table describes the effect of elacestrant on the pharmacokinetics of other drugs.Table 5: Effect of Other Drugs on ElacestrantaPredicted changes in Cmax and AUC of elacestrant.Concomitant DrugElacestrant DoseFold Increased or Percent Decrease of Elacestrant With Concomitant DrugCmax AUCCYP3A InhibitorsStrong InhibitorItraconazole 172 mg once daily4.45.3Moderate InhibitorFluconazolea345 mg single dose1.62.3CYP3A InducersStrong InducerRifampin345 mg single dose73%86%Moderate InducerEfavirenza345 mg single dose44-63%55-73%Table 6: Effect of Elacestrant on Other DrugsConcomitant DrugElacestrant DoseFold Increase of Concomitant Drug With ElacestrantCmax AUCSubstrate of P-gpDigoxin345 mg single dose1.31.1Substrate of BCRPRosuvastatin 345 mg single dose1.51.2In Vitro StudiesCytochrome P450 (CYP) Enzymes: Elacestrant is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.Elacestrant is not an inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A.Transporter Systems: Elacestrant is substrate for OATP2B1, but not P-gp. Elacestrant is not an inhibitor of OAT1, OAT3, OCT2, MATE1, MATE2-K, OCT1, OATP1B1, OATP1B3 or OATP2B1.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Dyslipidemia [see Warnings and Precautions (5.1)] Dyslipidemia [see Warnings and Precautions (5.1)] The most common (>10%) adverse reactions, including laboratory abnormalities, of ORSERDU were musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased ALT, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 ORSERDU was evaluated in 467 patients with ER+/HER2- advanced breast cancer following CDK4/6 inhibitor therapy in EMERALD, randomized, open-label, multicenter study [see Clinical Studies (14)]. Patients received ORSERDU 345 mg orally once daily (n=237) or standard of care (SOC) consisting of fulvestrant or an aromatase inhibitor (n=230). Among patients who received ORSERDU, 22% were exposed for months or longer and 9% were exposed for greater than one year.Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each).Permanent discontinuation of ORSERDU due to an adverse reaction occurred in 6% of patients. Adverse reactions which resulted in permanent discontinuation of ORSERDU in >1% of patients were musculoskeletal pain (1.7%) and nausea (1.3%).Dosage interruptions of ORSERDU due to an adverse reaction occurred in 15% of patients. Adverse reactions which resulted in dosage interruption of ORSERDU in >1% of patients were nausea (3.4%), musculoskeletal pain (1.7%), and increased ALT (1.3%).Dosage reductions of ORSERDU due to an adverse reaction occurred in 3% of patients. Adverse reactions which required dosage reductions of ORSERDU in >1% of patients were nausea (1.7%).The most common (>=10%) adverse reactions, including laboratory abnormalities, of ORSERDU were musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting, increased ALT, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia.Table summarizes the adverse reactions in EMERALD.Table 3: Adverse Reactions (>10%) in Patients with ER-positive, HER2-negative, Advanced or Metastatic Breast Cancer Who Received ORSERDU in EMERALDa aAdverse reactions were graded using NCI CTCAE version 5.0.bIncludes other related termscOnly includes Grade adverse reactions.Adverse ReactionORSERDU(n=237)Fulvestrant or an Aromatase Inhibitor (n=230)All Grades (%)Grade or c (%)All Grades (%)Grade or c (%)Musculoskeletal and connective tissue disordersMusculoskeletal painb 417391Gastrointestinal disordersNausea352.5190.9Vomitingb 190.890Diarrhea130101Constipation12060Abdominal painb 111100.9Dyspepsia1002.60General disordersFatigueb 262271Metabolism and nutrition disordersDecreased appetite150.8100.4Nervous systemHeadache122120Vascular disordersHot flush11080Clinically relevant adverse reactions in 10% of patients who received ORSERDU included rash, insomnia, dyspnea, cough, dizziness, stomatitis and gastroesophageal reflux disease.Table summarizes the laboratory abnormalities in EMERALD.Table 4: Select Laboratory Abnormalities (>10%) That Worsened from Baseline in Patients with ER-positive, HER2-negative, Advanced or Metastatic Breast Cancer Who Received ORSERDU in EMERALDa aThe denominator used to calculate the rate varied from 29 to 236 for ORSERDU and from 37 to 225 for fulvestrant or an aromatase inhibitor based on the number of patients with baseline value and at least one post-treatment value.Laboratory AbnormalityORSERDUa Fulvestrant or an Aromatase Inhibitora All Grades (%)Grade or (%)All Grades (%)Grade or (%)Chemistry Cholesterol increased301170 Aspartate aminotransferase increased290341 Triglycerides increased272151 Alanine aminotransferase increased170241 Sodium decreased161150 Creatinine increased16060Hematology Hemoglobin decreased261202.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Elacestrant is an estrogen receptor antagonist that binds to estrogen receptor-alpha (ER). In ER-positive (ER+) HER2-negative (HER2-) breast cancer cells, elacestrant inhibited 17-estradiol mediated cell proliferation at concentrations inducing degradation of ER protein mediated through proteasomal pathway. Elacestrant demonstrated in vitro and in vivo antitumor activity including in ER+ HER2- breast cancer models resistant to fulvestrant and cyclin-dependent kinase 4/6 inhibitors and those harboring estrogen receptor gene (ESR1) mutations.. 12.2 Pharmacodynamics. Elacestrant exposure-response relationships and the time course of pharmacodynamics have not been fully characterized.Cardiac ElectrophysiologyORSERDU does not cause mean increase in QTc interval 20 msec at the approved recommended dose.. 12.3 Pharmacokinetics. The steady-state mean (%CV) maximum concentration (Cmax) of elacestrant is 119 ng/mL (43.6%) and the area under the concentration-time curve (AUC0-24h) is 2440 ngh/mL (44.3%) after administration of the recommended dosage of 345 mg once daily. The Cmax and AUC of elacestrant increase more than proportionally over dosage range from 43 mg to 862 mg once daily (0.125 to 2.5 times the approved recommended dosage). Steady state is reached by Day and the mean accumulation ratio based on AUC0-24h is 2-fold.AbsorptionThe time to achieve peak plasma concentration (tmax) ranges from to hours. The elacestrant oral bioavailability is approximately 10%.Effect of FoodAdministration of ORSERDU 345 mg with high-fat meal (800 to 1000 calories, 50% fat) increased Cmax by 42% and AUC by 22% compared to fasted administration.DistributionThe estimated apparent volume of distribution is 5800L. Plasma protein binding of elacestrant is >99% and independent of concentration.Elimination The elimination half-life of elacestrant is 30 to 50 hours. The estimated mean (% CV) clearance of elacestrant is 186 L/hr (43.5%) and renal clearance is <= 0.14 L/hr.MetabolismElacestrant is primarily metabolized by CYP3A4 and to lesser extent by CYP2A6 and CYP2C9.ExcretionFollowing single radiolabeled oral dose of 345 mg, 82% was recovered in feces (34% unchanged) and 7.5% was recovered in urine (< 1% unchanged).Specific PopulationsThere were no clinically significant differences in the pharmacokinetics of elacestrant based on age (24 to 89 years), sex, and body weight (41 to 143 kg).Patients with Hepatic Impairment There were no clinically significant differences in the Cmax and AUC of elacestrant in subjects with mild hepatic impairment (Child-Pugh A). The AUC of elacestrant increased in subjects with moderate hepatic impairment (Child-Pugh B) by 83%.Elacestrant has not been studied in subjects with severe hepatic impairment (Child-Pugh C).Drug Interaction StudiesClinical StudiesThere were no clinically significant differences in the pharmacokinetics of elacestrant when used concomitantly with cimetidine (weak CYP3A inhibitor), omeprazole (gastric acid-reducing agent), or warfarin (highly protein-bound drug).Table describes the effect of other drugs on the pharmacokinetics of elacestrant and Table describes the effect of elacestrant on the pharmacokinetics of other drugs.Table 5: Effect of Other Drugs on ElacestrantaPredicted changes in Cmax and AUC of elacestrant.Concomitant DrugElacestrant DoseFold Increased or Percent Decrease of Elacestrant With Concomitant DrugCmax AUCCYP3A InhibitorsStrong InhibitorItraconazole 172 mg once daily4.45.3Moderate InhibitorFluconazolea345 mg single dose1.62.3CYP3A InducersStrong InducerRifampin345 mg single dose73%86%Moderate InducerEfavirenza345 mg single dose44-63%55-73%Table 6: Effect of Elacestrant on Other DrugsConcomitant DrugElacestrant DoseFold Increase of Concomitant Drug With ElacestrantCmax AUCSubstrate of P-gpDigoxin345 mg single dose1.31.1Substrate of BCRPRosuvastatin 345 mg single dose1.51.2In Vitro StudiesCytochrome P450 (CYP) Enzymes: Elacestrant is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A.Elacestrant is not an inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A.Transporter Systems: Elacestrant is substrate for OATP2B1, but not P-gp. Elacestrant is not an inhibitor of OAT1, OAT3, OCT2, MATE1, MATE2-K, OCT1, OATP1B1, OATP1B3 or OATP2B1.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of ORSERDU was evaluated in EMERALD (NCT03778931), randomized, open-label, active-controlled, multicenter trial that enrolled 478 postmenopausal women and men with ER+/HER2- advanced or metastatic breast cancer of which 228 patients had ESR1 mutations. Patients were required to have disease progression on one or two prior lines of endocrine therapy, including one line containing CDK4/6 inhibitor. Eligible patients could have received up to one prior line of chemotherapy in the advanced or metastatic setting.Patients were randomized (1:1) to receive ORSERDU 345 mg orally once daily (n=239), or investigators choice of endocrine therapy (n=239), which included fulvestrant (n=166), or an aromatase inhibitor (n=73; anastrozole, letrozole or exemestane). Randomization was stratified by ESR1 mutation status (detected vs not detected), prior treatment with fulvestrant (yes vs no), and visceral metastasis (yes vs no). 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 ligand binding domain (between codons 310 to 547). Patients were treated until disease progression or unacceptable toxicity.The major efficacy outcome was progression-free survival (PFS), assessed by blinded imaging review committee (BIRC). An additional efficacy outcome measure was overall survival (OS).A statistically significant difference in PFS was observed in the intention to treat (ITT) population and in the subgroup of patients with ESR1 mutations. An exploratory analysis of PFS in the 250 (52%) patients without ESR1 mutations showed HR 0.86 (95% CI: 0.63, 1.19) indicating that the improvement in the ITT population was primarily attributed to the results seen in the ESR1 mutated population.Among the patients with ESR1 mutations (n=228), the median age was 63 years (range: 28-89); 100% were female; 72% were White, 5.7% Asian, 3.5% Black, 0.4% Other, 18.4% unknown/not reported; 8.8% were Hispanic/Latino; and baseline ECOG performance status was (57%) or (43%). Most patients had visceral disease (71%); 62% had received line of endocrine therapy and 39% had received lines of endocrine therapy in the advanced or metastatic setting. All patients had received prior treatment with CDK4/6 inhibitor, 24% had received prior fulvestrant, and 25% had received prior chemotherapy in the advanced or metastatic setting.Efficacy results are presented in Table and Figure for patients with ESR1 mutations.Table 7: Efficacy Results for EMERALD (Patients with ESR1 Mutations)CI=confidence interval; ESR1=estrogen receptor aPFS results based on blinded imaging review committee.bKaplan-Meier estimate; 95% CI based on the Brookmeyer-Crowley method using linear transformation.cCox proportional hazards model stratified by prior treatment with fulvestrant (yes vs no) and visceral metastasis (yes vs no).dStratified log-rank test two-sided p-value.eNS Not statistically significant.ORSERDU(N 115)Fulvestrant or an Aromatase Inhibitor (N=113)Progression-free Survival (PFS)a Number of PFS Events, (%)62 (54)78 (69) Median PFS monthsb (95% CI)3.8 (2.2, 7.3)1.9 (1.9, 2.1) Hazard ratioc (95% CI)0.55 (0.39, 0.77) p-valued 0.0005Overall Survival (OS)Number of OS Events, (%)61 (53)60 (53) Hazard ratioc (95% CI)0.90 (0.63, 1.30) p-valued NSe Figure 1: Kaplan-Meier Curve for PFS in EMERALD (Patients with ESR1 Mutations, BIRC Assessment)+ Censored times. Figure 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Select patients for treatment with ORSERDU based on the presence of ESR1 mutations. (2.1)The recommended dosage of ORSERDU is one 345 mg tablet taken orally, once daily, with food (2.2)Dose interruption, reduction, or permanent discontinuation may be required due to adverse reactions. (2.3). Select patients for treatment with ORSERDU based on the presence of ESR1 mutations. (2.1). The recommended dosage of ORSERDU is one 345 mg tablet taken orally, once daily, with food (2.2). Dose interruption, reduction, or permanent discontinuation may be required due to adverse reactions. (2.3). 2.1 Patient Selection. Select patients for treatment of ER-positive, HER2-negative advanced or metastatic breast cancer with ORSERDU based on the presence of ESR1 mutation(s) in plasma specimen using an FDA-approved test [see Indications and Usage (1) and Clinical Studies (14)].Information on FDA-approved tests for detection of ESR1 mutations in breast cancer is available at: http://www.fda.gov/CompanionDiagnostics.. 2.2 Recommended Dosage. The recommended dosage of ORSERDU is 345 mg taken orally with food once daily until disease progression or unacceptable toxicity occurs.Take ORSERDU at approximately the same time each day. Take with food to reduce nausea and vomiting [see Adverse Reactions (6.1)].Swallow ORSERDU tablet(s) whole. Do not chew, crush, or split prior to swallowing. Do not take any ORSERDU tablets that are broken, cracked, or that look damaged.If dose is missed for more than hours or vomiting occurs, skip the dose and take the next dose the following day at its regularly scheduled time.. 2.3 Dosage Modifications for Adverse Reactions. The recommended dose reduction levels for adverse reactions are listed in Table 1:Table 1: ORSERDU Dose Reduction Levels for Adverse Reactions1 If further dose reduction below 172 mg once daily is required, permanently discontinue ORSERDU.Dose ReductionDosageNumber and Strength of TabletsFirst-dose reduction258 mg once dailyThree 86 mg tabletsSecond-dose reduction172 mg once daily1 Two 86 mg tabletsRecommended dosage modifications of ORSERDU for adverse reactions are provided in Table [see Adverse Reactions (6.1)].Table 2: ORSERDU Dosage Modification Guidelines for Adverse ReactionsSeverityDosage ModificationGrade 1Continue ORSERDU at current dose level.Grade 2Consider interruption of ORSERDU until recovery to Grade <= or baseline. Then resume ORSERDU at the same dose level.Grade 3Interrupt ORSERDU until recovery to Grade <= or baseline. Then resume ORSERDU at the next lower dose level. If the Grade toxicity recurs, interrupt ORSERDU until recovery to Grade <= or baseline. Then resume ORSERDU reduced by another dose level.Grade 4Interrupt ORSERDU until recovery to Grade <= or baseline. Then resume ORSERDU reduced by one dose level. If Grade or intolerable adverse reaction recurs, permanently discontinue ORSERDU.. 2.4 Dosage Modifications for Use with Concomitant CYP3A4 Inducers and Inhibitors. Avoid concomitant use of ORSERDU with strong or moderate CYP3A4 inducers and inhibitors [see Drug Interactions (7.1)].. 2.5 Dosage Modifications for Hepatic Impairment. Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the ORSERDU dosage to 258 mg once daily for patients with moderate hepatic impairment (Child-Pugh B). No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A) [see Clinical Pharmacology (12.3)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong and Moderate CYP3A4 Inducers: Avoid concomitant use with ORSERDU (7.1)Strong and Moderate CYP3A4 Inhibitors: Avoid concomitant use with ORSERDU (7.1). Strong and Moderate CYP3A4 Inducers: Avoid concomitant use with ORSERDU (7.1). Strong and Moderate CYP3A4 Inhibitors: Avoid concomitant use with ORSERDU (7.1). 7.1 Effect of Other Drugs on ORSERDU. Strong and Moderate CYP3A4 InhibitorsAvoid concomitant use of strong or moderate CYP3A inhibitors with ORSERDU.Elacestrant is CYP3A4 substrate. Concomitant use of strong or moderate CYP3A4 inhibitor increase elacestrant exposure [see Clinical Pharmacology (12.3)], which may increase the risk of adverse reactions of ORSERDU.Strong and Moderate CYP3A4 InducersAvoid concomitant use of strong or moderate CYP3A inducers with ORSERDU.Elacestrant is CYP3A4 substrate. Concomitant use of strong or moderate CYP3A4 inducer decreases elacestrant exposure [see Clinical Pharmacology (12.3)], which may decrease effectiveness of ORSERDU.. 7.2 Effect of ORSERDU on Other Drugs. P-gp SubstratesReduce the dosage of P-gp substrates per their Prescribing Information when minimal concentration changes may lead to serious or life-threatening adverse reactions.Elacestrant is P-gp inhibitor. Concomitant use of ORSERDU with P-gp substrate increased the concentrations of P-gp substrate [see Clinical Pharmacology (12.3)], which may increase the adverse reactions associated with P-gp substrate.BCRP SubstratesReduce the dosage of BCRP substrates per their Prescribing Information when minimal concentration changes may lead to serious or life-threatening adverse reactions.Elacestrant is BCRP inhibitor. Concomitant use of ORSERDU with BCRP substrate increased the plasma concentrations of BCRP substrate [see Clinical Pharmacology (12.3)], which may increase the adverse reactions associated with BCRP substrate.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).DyslipidemiaAdvise patients that hypercholesterolemia and hypertriglyceridemia may occur while taking ORSERDU. Inform patients that lipid profile monitoring will be performed prior to starting and periodically while taking ORSERDU [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Embryo-Fetal ToxicityAdvise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1)].Advise females of reproductive potential to use effective contraception during treatment with ORSERDU and for week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for week after the last dose [see Use in Specific Populations (8.3)].LactationAdvise women not to breastfeed during treatment with ORSERDU and for week after the last dose [see Use in Specific Populations (8.2)]. InfertilityAdvise males and females of reproductive potential that ORSERDU may impair fertility [see Use in Specific Populations (8.3)]. Drug InteractionsAdvise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, and herbal products [see Drug Interactions (7.1, 7.2)].Other Common Adverse ReactionsAdvise patients that other adverse reactions with ORSERDU treatment may include musculoskeletal pain, nausea, fatigue, vomiting, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia, [see Adverse Reactions (6.1)].Dosing InstructionsInstruct patients to take ORSERDU at approximately the same time each day and to swallow the tablet(s) whole. Tablets should not be chewed, crushed, or split prior to swallowing [see Dosage and Administration (2.2)].Advise patients to take ORSERDU with food to reduce nausea and vomiting [see Dosage and Administration (2.2) and Adverse Reactions (6.1)].Instruct patients that if dose of ORSERDU is missed for more than hours or vomiting occurs, skip the dose and take the next dose the following day at its regularly scheduled time [see Dosage and Administration (2.2)].ORSERDU is trademark of the Menarini Group.(C)Stemline Therapeutics, Inc., Menarini Group company Manufactured for: Stemline Therapeutics, Inc., New York, NY 10022.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on ORSERDU use in pregnant women to inform the drug-associated risk. In an animal reproduction study, oral administration of elacestrant to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities at maternal exposures below the recommended dose based on AUC (see Data). Advise pregnant women and females of reproductive potential of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.DataAnimal DataIn an embryo-fetal development study in pregnant rats, administration of oral doses of elacestrant up to 30 mg/kg/day during the period of organogenesis resulted in maternal toxicity (reduced body weight gain, low food consumption, red vulvar discharge) and embryo-fetal mortality (increased resorptions, post-implantation loss, and reduced number of live fetuses) at >= mg/kg/day (approximately 0.1 times the human AUC at the recommended dose). Additional adverse effects included reduced fetal weight and external malformations of the limbs (hyperflexion, malrotation) and head (domed, misshapen, flattened) with corresponding skeletal malformations of the skull at doses >= 10 mg/kg/day (approximately 0.5 times the human AUC at the recommended dose).

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 01/2023PATIENT INFORMATIONORSERDU(TM) (or-SER-doo)(elacestrant)tabletsWhat is ORSERDUORSERDU is prescription medicine to treat women who have gone through menopause and adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor (HER2)-negative, ESR1-mutated advanced breast cancer or breast cancer that has spread to other parts of the body (metastatic), and whose disease has progressed after endocrine therapy.Your healthcare provider will perform test to make sure that ORSERDU is right for you.It is not known if ORSERDU is safe and effective in children.Before taking ORSERDU, tell your healthcare provider about all of your medical conditions, including if you:have liver problemsare pregnant or plan to become pregnant. ORSERDU can harm your unborn baby.Females who are able to become pregnant: Your healthcare provider may do pregnancy test before you start treatment with ORSERDU.You should use effective (contraception) birth control during treatment with ORSERDU and for week after the last dose.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ORSERDU. Males with female partners who are able to become pregnant: You should use effective (contraception) birth control during treatment with ORSERDU and for week after the last dose. are breastfeeding or plan to breastfeed. It is not known if ORSERDU passes into your breast milk. Do not breastfeed during treatment with ORSERDU and for week after the last dose.Tell your healthcare provider about all of the medicines you take, including prescription and over-the counter medicines, vitamins, and herbal supplements. ORSERDU and other medicines may affect each other causing side effects. Know the medicines you take. Keep list of them to show your healthcare provider or pharmacist when you get new medicine.How should take ORSERDUTake ORSERDU exactly as your healthcare provider tells you.Do not change your dose or stop taking ORSERDU unless your healthcare provider tells you.Take ORSERDU time each day, at about the same time each day.Take ORSERDU with food. Taking ORSERDU with food may help reduce nausea and vomiting.Swallow ORSERDU tablets whole. Do not chew, crush or split the tablets before swallowing.Do not take any ORSERDU tablets that are broken, cracked, or that look damaged.If you miss dose of ORSERDU or vomit after taking dose of ORSERDU, do not take another dose of ORSERDU on that day. Skip the dose and take your next dose the following day at your regularly scheduled time.What are the possible side effects of ORSERDUORSERDU may cause serious side effects, including:Increased fat (lipid) levels in your blood (hypercholesterolemia and hypertriglyceridemia). Your healthcare provider will do blood tests to check your lipid levels before and during your treatment with ORSERDU.The most common side effects of ORSERDU include:muscle and joint (musculoskeletal) painnauseaincreased cholesterol and triglyceride levels in your bloodincreased liver function teststirednessdecreased red blood cell countsvomitingdecreased salt (sodium) levels in your bloodincreased kidney function testdecreased appetitediarrheaheadacheconstipationstomach-area (abdominal) painhot flushindigestion or heartburnYour healthcare provider may decrease your dose, temporarily stop, or completely stop treatment with ODSERDU, if you develop certain side effects.ORSERDU may affect fertility in males and in females who are able to become pregnant. Talk to your healthcare provider if this is concern for you.These are not all of the possible side effects of ORSERDU.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ORSERDUStore ORSERDU at room temperature 68 to 77 (20 to 25).Keep ORSERDU and all medicines out of the reach of children.General information about the safe and effective use of ORSERDU.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ORSERDU for condition for which it was not prescribed. Do not give ORSERDU to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for more information about ORSERDU that is written for health professionals.What are the ingredients in ORSERDUActive ingredient: elacestrantInactive ingredients: colloidal silicon dioxide, crospovidone, magnesium stearate (non-bovine), microcrystalline cellulose, silicified microcrystalline cellulose and Opadry II Blue (polyvinyl alcohol, titanium dioxide, polyethylene glycol, FD&C Blue and talc).ORSERDU is trademark of the Menarini Group.(C)Stemline Therapeutics, Inc., Menarini Group CompanyManufactured for: Stemline Therapeutics, Inc., New York, NY 10022For more information, go to www.ORSERDU.com or call 1-877-332-7961. have liver problems. are pregnant or plan to become pregnant. ORSERDU can harm your unborn baby.Females who are able to become pregnant: Your healthcare provider may do pregnancy test before you start treatment with ORSERDU.You should use effective (contraception) birth control during treatment with ORSERDU and for week after the last dose.Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ORSERDU. Males with female partners who are able to become pregnant: You should use effective (contraception) birth control during treatment with ORSERDU and for week after the last dose. Your healthcare provider may do pregnancy test before you start treatment with ORSERDU.. You should use effective (contraception) birth control during treatment with ORSERDU and for week after the last dose.. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with ORSERDU.. You should use effective (contraception) birth control during treatment with ORSERDU and for week after the last dose.. are breastfeeding or plan to breastfeed. It is not known if ORSERDU passes into your breast milk. Do not breastfeed during treatment with ORSERDU and for week after the last dose.. Take ORSERDU exactly as your healthcare provider tells you.. Do not change your dose or stop taking ORSERDU unless your healthcare provider tells you.. Take ORSERDU time each day, at about the same time each day.. Take ORSERDU with food. Taking ORSERDU with food may help reduce nausea and vomiting.. Swallow ORSERDU tablets whole. Do not chew, crush or split the tablets before swallowing.. Do not take any ORSERDU tablets that are broken, cracked, or that look damaged.. If you miss dose of ORSERDU or vomit after taking dose of ORSERDU, do not take another dose of ORSERDU on that day. Skip the dose and take your next dose the following day at your regularly scheduled time.. Increased fat (lipid) levels in your blood (hypercholesterolemia and hypertriglyceridemia). Your healthcare provider will do blood tests to check your lipid levels before and during your treatment with ORSERDU.. muscle and joint (musculoskeletal) pain. nausea. increased cholesterol and triglyceride levels in your blood. increased liver function tests. tiredness. decreased red blood cell counts. vomiting. decreased salt (sodium) levels in your blood. increased kidney function test. decreased appetite. diarrhea. headache. constipation. stomach-area (abdominal) pain. hot flush. indigestion or heartburn. Store ORSERDU at room temperature 68 to 77 (20 to 25).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2)Hepatic impairment: Avoid use in patients with severe hepatic impairment (Child-Pugh C). Reduce the dosage for patients with moderate hepatic impairment (Child-Pugh B). (2.5, 8.6). Lactation: Advise not to breastfeed. (8.2). Hepatic impairment: Avoid use in patients with severe hepatic impairment (Child-Pugh C). Reduce the dosage for patients with moderate hepatic impairment (Child-Pugh B). (2.5, 8.6). 8.1 Pregnancy. Risk SummaryBased on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to pregnant woman [see Clinical Pharmacology (12.1)]. There are no available human data on ORSERDU use in pregnant women to inform the drug-associated risk. In an animal reproduction study, oral administration of elacestrant to pregnant rats during organogenesis caused embryo-fetal mortality and structural abnormalities at maternal exposures below the recommended dose based on AUC (see Data). Advise pregnant women and females of reproductive potential of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.DataAnimal DataIn an embryo-fetal development study in pregnant rats, administration of oral doses of elacestrant up to 30 mg/kg/day during the period of organogenesis resulted in maternal toxicity (reduced body weight gain, low food consumption, red vulvar discharge) and embryo-fetal mortality (increased resorptions, post-implantation loss, and reduced number of live fetuses) at >= mg/kg/day (approximately 0.1 times the human AUC at the recommended dose). Additional adverse effects included reduced fetal weight and external malformations of the limbs (hyperflexion, malrotation) and head (domed, misshapen, flattened) with corresponding skeletal malformations of the skull at doses >= 10 mg/kg/day (approximately 0.5 times the human AUC at the recommended dose).. 8.2 Lactation. Risk SummaryThere are no data on the presence of elacestrant in human milk, its effects on milk production, or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women to not breastfeed during treatment with ORSERDU and for week after the last dose.. 8.3 Females and Males of Reproductive Potential. ORSERDU can cause fetal harm when administered to pregnant woman [see Use in Specific Populations (8.1)].Pregnancy TestingVerify the pregnancy status in females of reproductive potential prior to initiating ORSERDU treatment.ContraceptionFemalesAdvise females of reproductive potential to use effective contraception during treatment with ORSERDU and for week after the last dose.MalesAdvise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for week after the last dose.InfertilityBased on findings from animal studies, ORSERDU may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)].. 8.4 Pediatric Use. The safety and effectiveness of ORSERDU in pediatric patients have not been established.. 8.5 Geriatric Use. Of 237 patients who received ORSERDU in the EMERALD trial, 43% were 65 years of age or older and 17% were 75 years of age or older. No overall differences in safety or effectiveness of ORSERDU were observed between patients 65 years or older of age compared to younger patients. There are an insufficient number of patients 75 years of age or older to assess whether there are differences in safety or effectiveness.. 8.6 Hepatic Impairment. Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of ORSERDU in patients with moderate hepatic impairment (Child-Pugh B). No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A) [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Dyslipidemia: ORSERDU may cause hypercholesterolemia and hypertriglyceridemia. Monitor lipid profile prior to starting treatment and periodically thereafter. (5.1)Embryo-Fetal Toxicity: ORSERDU can cause fetal harm. Advise of the potential risk to fetus and to use effective contraception. (5.2, 8.1, 8.3). Dyslipidemia: ORSERDU may cause hypercholesterolemia and hypertriglyceridemia. Monitor lipid profile prior to starting treatment and periodically thereafter. (5.1). Embryo-Fetal Toxicity: ORSERDU can cause fetal harm. Advise of the potential risk to fetus and to use effective contraception. (5.2, 8.1, 8.3). 5.1 Dyslipidemia. Hypercholesterolemia and hypertriglyceridemia occurred in patients taking ORSERDU at an incidence of 30% and 27%, respectively. The incidence of Grade and hypercholesterolemia and hypertriglyceridemia were 0.9% and 2.2%, respectively [see Adverse Reactions (6.1)].Monitor lipid profile prior to starting and periodically while taking ORSERDU.. 5.2 Embryo-Fetal Toxicity. Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to pregnant woman. Administration of elacestrant to pregnant rats resulted in adverse developmental outcomes, including embryo-fetal mortality and structural abnormalities, at maternal exposures below the recommended dose based on area under the curve (AUC).Advise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with ORSERDU and for week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for week after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].