Orserdu

ORSERDU is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)‑negative,

• Select patients for treatment with ORSERDU based on the presence of
  ESR1
  mutations. (
  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 and Clinical Studies ]

  .

  Information on FDA-approved tests for detection of

  ESR1

  mutations in breast cancer is available at: http://www.fda.gov/CompanionDiagnostics.
  )
• The recommended dosage of ORSERDU is one 345 mg tablet taken orally, once daily, with food (
  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 ]

  .

  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 a dose 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.
  )
• Dose interruption, reduction, or permanent discontinuation may be required due to adverse reactions. (
  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 Reactions

  1If further dose reduction below 172 mg once daily is required, permanently discontinue ORSERDU.
  Dose Reduction	Dosage	Number and Strength of Tablets
  First-dose reduction	258 mg once daily	Three 86 mg tablets
  Second-dose reduction	172 mg once daily1	Two 86 mg tablets

  Recommended dosage modifications of ORSERDU for adverse reactions are provided in Table 2

  [see Adverse Reactions ]

  .

  Table 2: ORSERDU Dosage Modification Guidelines for Adverse Reactions

  Severity	Dosage Modification
  Grade 1	Continue ORSERDU at current dose level.
  Grade 2	Consider interruption of ORSERDU until recovery to Grade ≤ 1 or baseline. Then resume ORSERDU at the same dose level.
  Grade 3	Interrupt ORSERDU until recovery to Grade ≤ 1 or baseline. Then resume ORSERDU at the next lower dose level. If the Grade 3 toxicity recurs, interrupt ORSERDU until recovery to Grade ≤ 1 or baseline. Then resume ORSERDU reduced by another dose level.
  Grade 4	Interrupt ORSERDU until recovery to Grade ≤ 1 or baseline. Then resume ORSERDU reduced by one dose level. If a Grade 4 or intolerable adverse reaction recurs, permanently discontinue ORSERDU.
  )

Tablets: Elacestrant 345 mg (equivalent to 400 mg elacestrant hydrochloride) and 86 mg (equivalent to 100 mg elacestrant hydrochloride):

• 345 mg: light blue, unscored, oval film-coated biconvex tablet, imprinted with “MH” on one side and plain on the other side.
• 86 mg: light blue, unscored, round film-coated biconvex tablet, imprinted with “ME” on one side and plain on the other side.

• Lactation
  : Advise not to breastfeed. (
  8.2 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.
  )
• 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 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 ]

  .
  ,
  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 and Clinical Pharmacology ]

  .
  )

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

  Hypercholesterolemia and hypertriglyceridemia occurred in patients taking ORSERDU at an incidence of 30% and 27%, respectively. The incidence of Grade 3 and 4 hypercholesterolemia and hypertriglyceridemia were 0.9% and 2.2%, respectively

  [see Adverse Reactions ]

  .

  Monitor lipid profile prior to starting and periodically while taking ORSERDU.
  )
• Embryo-Fetal Toxicity: ORSERDU can cause fetal harm. Advise of the potential risk to a fetus and to use effective contraception. (
  5.2 Embryo-Fetal Toxicity

  Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a 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 a fetus. 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 and Clinical Pharmacology ]

  .
  ,
  8.1 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 ]

  . 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.

  Data

  Animal Data

  In 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 ≥ 3 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).
  ,
  8.3 Females and Males of Reproductive Potential

  ORSERDU can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ]

  .

  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 ]

  .
  )