DRUG INTERACTIONS- (Summary)

 • Strong and Moderate CYP3A4 Inducers: Avoid concomitant use with ORSERDU 

• Strong and Moderate CYP3A4 Inhibitors: Avoid concomitant use with ORSERDU 

DRUG INTERACTIONS-(Details)

1. Effect of Other Drugs on ORSERDU Strong and Moderate CYP3A4 Inhibitors- Avoid concomitant use of strong or moderate CYP3A inhibitors with ORSERDU. Elacestrant is a CYP3A4 substrate. Concomitant use of a 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 Inducers

Avoid concomitant use of strong or moderate CYP3A inducers with ORSERDU. Elacestrant is a CYP3A4 substrate. Concomitant use of a strong or moderate CYP3A4 inducer decreases elacestrant exposure [see Clinical Pharmacology (12.3)], which may decrease effectiveness of ORSERDU.

2. Effect of ORSERDU on Other Drugs P-gp Substrates-                                         Reduce the dosage of P-gp substrates per their Prescribing Information when minimal concentration changes may lead to serious or life-threatening adverse reactions. 5 Reference ID: 5119185

Elacestrant is a P-gp inhibitor. Concomitant use of ORSERDU with a P-gp substrate increased the concentrations of P-gp substrate [see Clinical Pharmacology (12.3)], which may increase the adverse reactions associated with a P-gp substrate. BCRP Substrates Reduce the dosage of BCRP substrates per their Prescribing Information when minimal concentration changes may lead to serious or life-threatening adverse reactions. Elacestrant is a BCRP inhibitor. Concomitant use of ORSERDU with a BCRP substrate increased the plasma concentrations of BCRP substrate [see Clinical Pharmacology (12.3)], which may increase the adverse reactions associated with a BCRP substrate.

BRIEF SUMMARY-

ELACESTRANT- (Jan 2023)-

 Indcn- To  treat estrogen receptor-positive,human   epidermal growth factor2- negative ,ESRI -    mutated, advanced or metastatic breast cancer with disease progression following at   least one on line endocrine therapy                                                                                                                     

Dosage-  • Tablets: 345 mg and 86 mg   The recommended dosage of is one 345 mg tablet taken orally, once daily, with food.

ADR- The most common  adverse reactions, including laboratory abnormalities, of  were musculoskeletal pain, nausea, increased cholesterol, increased AST, increased triglycerides, fatigue, decreased hemoglobin, vomiting.

CI- • None .

 WARNINGS - • Dyslipidemia:  may cause hypercholesterolemia and hypertriglyceridemia. Monitor lipid profile prior to starting treatment and periodically thereafter. 

 • Embryo-Fetal Toxicity: ORSERDU can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception.

Pat Inform

Dyslipidemia- Advise 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 the drug

Embryo-Fetal Toxicity- Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a known or suspected pregnancy.].

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

Lactation Advise women not to breastfeed during treatment and for 1 week after the last dose.                                                                                                                         .

Infertility- Advise males and females of reproductive potential that ORSERDU may impair fertility 

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U.S.  APPROVED DRUGS DURING 2023                                        

Serial No 4

Name-        ORSERDU

Acive  Ingredient -  Elacestrant

Pharmacological clssificiation-        To  treat estrogen receptor-positive,human                                                                     epidermal growth factor2- negative ,ESRI -                                                                     mutated, advanced or metastatic breast                                                                          cancer with disease orogression following at                                                                least one on line endocrine therapy                                                                                                                        

 Date of Approval-         1/27/2023

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                        ORSERDU safely and effectively. See full prescribing information for ORSERDU. ORSERDU™ (elacestrant) tablets, for oral use.

Initial U.S. Approval: 2023

INDICATIONS AND USAGE

 ORSERDU is an estrogen receptor antagonist indicated for:                                            • treatment of postmenopausal women or adult men, with ERpositive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy.

 ADVERSE REACTIONS-

 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.

CONTRAINDICATIONS-

 • None .

 WARNINGS AND PRECAUTIONS-

 • Dyslipidemia: ORSERDU may cause hypercholesterolemia and hypertriglyceridemia. Monitor lipid profile prior to starting treatment and periodically thereafter. 

 • Embryo-Fetal Toxicity: ORSERDU can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception.

-------------------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)

----------------------- 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) See 17 for PATIENT COUNSELING INFORMATION and FDA approved patient labeling.

DOSAGE AND ADMINISTRATION-

 • Select patients for treatment with ORSERDU based on the presence of ESR1 mutations.

 • The recommended dosage of ORSERDU is one 345 mg tablet taken orally, once daily, with food.

 • Dose interruption, reduction, or permanent discontinuation may be required due to adverse reactions.

 DOSAGE FORMS AND STRENGTHS.

 • Tablets: 345 mg and 86 mg

PATIENT COUNSELING INFORMATION- 

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Dyslipidemia- Advise 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 Toxicity Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females to inform their healthcare provider of a 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 1 week after the last dose.

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose [see Use in Specific Populations (8.3)].

Lactation Advise women not to breastfeed during treatment with ORSERDU and for 1 week after the last dose [see Use in Specific Populations (8.2)]. Infertility Advise males and females of reproductive potential that ORSERDU may impair fertility [see Use in

Specific Populations (8.3)].

Drug Interactions Advise 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 Reactions- 12 Reference ID: 5119185 Advise 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 Instructions Instruct 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 a dose of ORSERDU is missed for more than 6 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 a trademark of the Menarini Group. ©Stemline Therapeutics, Inc., a Menarini Group company Manufactured for: Stemline Therapeutics, Inc., New York, NY 10022

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                          Elacestrant is an estrogen receptor antagonist that binds to estrogen receptor-alpha (ERa). In ERpositive (ER+) HER2-negative (HER2-) breast cancer cells, elacestrant inhibited 17ß-estradiol mediated cell proliferation at concentrations inducing degradation of ERa 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 1 gene (ESR1) mutations.

2 Pharmacodynamics- Elacestrant exposure-response relationships and the time course of pharmacodynamics have not been fully characterized.

Cardiac Electrophysiology-                                                                                       ORSERDU does not cause a mean increase in QTc interval > 20 msec at the approved recommended dose.

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 ng*h/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 a 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 6 and the mean accumulation ratio based on AUC0-24h is 2-fold. Absorption The time to achieve peak plasma concentration (tmax) ranges from 1 to 4 hours. The elacestrant oral bioavailability is approximately 10%.

Effect of Food Administration of ORSERDU- 345 mg with a high-fat meal (800 to 1000 calories, 50% fat) increased Cmax by 42% and AUC by 22% compared to fasted administration.

Distribution- The 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.

Metabolism- Elacestrant is primarily metabolized by CYP3A4 and to a lesser extent by CYP2A6 and CYP2C9.

Excretion- 8 Reference ID: 5119185 Following a single radiolabeled oral dose of 345 mg, 82% was recovered in feces (34% unchanged) and 7.5% was recovered in urine (< 1% unchanged).

Specific Populations- There 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 Studies- Clinical Studies There 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 5 describes the effect of other drugs on the pharmacokinetics of elacestrant and Table 6 describes the effect of elacestrant on the pharmacokinetics of other drugs. Table 5: Effect of Other Drugs on Elacestran

USE IN SPECIFIC POPULATIONS

1 Pregnancy Risk Summary -                                                                                    Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a 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 a 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.

2. Lactation Risk Summary- There 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 1 week after the last dose.

3. Females and Males of Reproductive Potential -                                                 ORSERDU 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 ORSERDU treatment.

Contraception Females-                                                                                                  Advise females of reproductive potential to use effective contraception during treatment with ORSERDU 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 ORSERDU and for 1 week after the last dose. Infertility Based 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)].