VEPPANU

1 INDICATIONS AND USAGE VEPPANU is indicated for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 (ESR1) -mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy. VEPPANU is a heterobifunctional protein degrader indicated for the treatment of adults with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, estrogen receptor-1 ( ESR1) -mutated advanced or metastatic breast cancer, as detected by an FDA-authorized test, with disease progression following at least one line of endocrine therapy. ( 1 )

2 DOSAGE AND ADMINISTRATION Select patients for treatment with VEPPANU based on the presence of ESR1 mutation. ( 2.1 ) Recommended Dosage: 200 mg orally once daily with food. ( 2.2 ) Interruption, dose 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 VEPPANU based on the presence of ESR1 mutation(s) in plasma specimen using an FDA-authorized test [see Indications and Usage ( 1 ) and Clinical Studies ( 14 )] . Information on FDA-authorized tests for detection of ESR1 mutations in breast cancer is available at: http://www.fda.gov/CompanionDiagnostics. 2.2 Recommended Dosage and Administration The recommended dosage of VEPPANU is 200 mg taken orally once daily with food [see Clinical Pharmacology ( 12.3 )] until disease progression or unacceptable toxicity. Swallow VEPPANU tablet(s) whole. Do not chew, crush, dissolve, or split prior to swallowing. Do not take VEPPANU tablets that are broken, cracked, or look damaged. If a patient misses a dose or vomits after taking a dose, the patient should take the next dose at the regularly scheduled time. 2.3 Dosage Modifications for Adverse Reactions The recommended dose reduction for adverse reactions is 100 mg orally once daily. Permanently discontinue VEPPANU in patients who are unable to tolerate 100 mg orally once daily. The recommended dosage modifications for VEPPANU for adverse reactions are provided in Table 1 and Table 2 . Table 1: Dosage Modifications for Adverse Reactions (Except QTc Prolongation) CTCAE Severity Grade Dosage Modification Abbreviations: CTCAE=National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Grade 1 No dose modification is required. Grade 2 Consider interruption of VEPPANU until recovery to Grade ≤1 or baseline. Then resume VEPPANU at the same dose. Grade 3 First occurrence: Interrupt VEPPANU until recovery to Grade ≤1 or baseline. Then resume VEPPANU at the same dose or at the reduced dose at the discretion of the physician. If the Grade 3 toxicity recurs, interrupt VEPPANU until recovery to Grade ≤1 or baseline. Then resume VEPPANU at the reduced dose or discontinue VEPPANU at the discretion of the physician. Grade 4 First occurrence: Interrupt VEPPANU until recovery to Grade ≤1 or baseline. Then resume VEPPANU at the reduced dose. If a Grade 4 or intolerable adverse reaction recurs, permanently discontinue VEPPANU. Table 2: Dosage Modification and Management for QTc Prolongation QTc Prolongation Heart-rate corrected QTc using Fridericia's method. [see Warnings and Precautions ( 5.1 )] Dosage Modification and Management QTc >480 ms or >60 ms increase from baseline (and QTc ≤500 ms) Withhold until QTc resolves to ≤480 ms and ≤60 ms above baseline, then resume VEPPANU at the same dose. Identify and treat reversible causes (e.g., hypokalemia and hypomagnesemia). Initiate more frequent ECG monitoring. QTc >500 ms Withhold until QTc resolves to ≤480 ms and ≤60 ms above baseline, then: resume VEPPANU at the same dose if reversible cause is identified and corrected (e.g., hypokalemia and hypomagnesemia). resume VEPPANU at the reduced dose if no reversible cause is identified. Initiate more frequent ECG monitoring. Permanently discontinue if QTc >500 ms recurs. Torsade de Pointes, polymorphic ventricular tachycardia, or signs/symptoms of serious arrhythmia Permanently discontinue VEPPANU. 2.4 Dosage Modifications for Drug Interactions Strong CYP3A Inhibitors Avoid concomitant use with strong CYP3A inhibitors in patients receiving VEPPANU 200 mg once daily. If concomitant use cannot be avoided, reduce VEPPANU from 200 mg once daily to 100 mg once daily [see Drug Interactions ( 7.1 )] . After a CYP3A inhibitor has been discontinued for 3 to 5 elimination half-lives, resume VEPPANU 200 mg once daily. Avoid concomitant use with strong CYP3A inhibitors in patients receiving VEPPANU …

3 DOSAGE FORMS AND STRENGTHS Tablets: 100 mg blue film-coated, immediate release, round tablet debossed with "VEP" on one side and "100" on the other side. 200 mg blue film-coated, immediate release, oval tablet debossed with "VEP" on one side and "200" on the other side. Tablets: 100 mg and 200 mg ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reaction is described elsewhere in the labeling: QTc Interval Prolongation [see Warnings and Precautions ( 5.1 )] Most common ( > 10%) adverse reactions with VEPPANU, including laboratory abnormalities, were decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rigel Pharmaceuticals, Inc. at 1-800-983-1329 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 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 VEPPANU was evaluated in patients with ER-positive, HER2-negative, advanced or metastatic breast cancer following endocrine therapy in VERITAC-2 [see Clinical Studies ( 14 )] . Patients received VEPPANU 200 mg orally once daily (N=312) or fulvestrant 500 mg intramuscularly on Days 1 and 15 of Cycle 1 and then on Day 1 of each subsequent 28-day cycle (N=307). Among patients who received VEPPANU, 33% were exposed for 6 months or longer and 6% were exposed for greater than one year. Serious adverse reactions occurred in 9% of patients who received VEPPANU. The serious adverse reactions included any fracture (1.3%), fall, hypercalcemia, hepatic injury, pneumonia, musculoskeletal pain (0.6% each), and QTc prolonged (0.3%). Fatal adverse reactions occurred in 1.0% of patients who received VEPPANU, including dyspnea, cerebral ischemia, and unknown cause (one patient each). Permanent discontinuation of VEPPANU due to an adverse reaction occurred in 2.9% of patients. Adverse reactions that resulted in permanent discontinuation of VEPPANU included increased alanine aminotransferase (ALT) and dyspnea (0.6% each). Dosage interruptions of VEPPANU due to an adverse reaction occurred in 14% of patients. Adverse reactions which required dosage interruption in >1% of patients included neutropenia (1.9%), anemia, hepatic injury, nausea, fatigue, and musculoskeletal pain (1.3% each). Dosage reductions of VEPPANU due to an adverse reaction occurred in 1.9% of patients. Adverse reactions which required dosage reductions of VEPPANU included electrocardiogram QT prolonged, fatigue and musculoskeletal pain (0.3% each). The most common (≥10%) adverse reactions, including laboratory abnormalities, were decreased white blood cells, increased AST, musculoskeletal pain, fatigue, decreased hemoglobin, decreased neutrophils, increased ALT, increased alkaline phosphatase, nausea, decreased blood potassium, increased bilirubin, decreased appetite, electrocardiogram QT prolonged, decreased platelets, and constipation. Table 3 and Table 4 summarize adverse reactions and laboratory abnormalities in VERITAC-2, respectively. Table 3: Adverse Reactions (≥10%) in Patients with ER+, HER2-, Advanced or Metastatic Breast Cancer Who Received VEPPANU in VERITAC-2 Adverse reactions were graded using NCI CTCAE version 5.0. Adverse Reaction VEPPANU N=312 Fulvestrant N=307 All Grades % Grade 3 No Grade 4 events were reported. % All Grades % Grade 3 % Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain Includes multiple related terms. 30 2.6 23 1 General Disorders and Administration Site Conditions Fatigue 29 1 16 1.3 Gastrointestinal Disorders Nausea 14 0 9 1 Constipation 10 0 3.3 0 Metabolism and Nutrition Disorders Decreased appetite 11 0.3 5 0 Investigations Electrocardiogram QT prolonged 10 1.6 1.3 0.3 Clinically relevant adverse reactions in <10% of patients who received VEPPANU included headache, hot flush, diarrhea, vomiting …

7 DRUG INTERACTIONS Strong CYP3A Inhibitors : Avoid concomitant use with strong CYP3A inhibitors. If concomitant use cannot be avoided, reduce VEPPANU dosage. ( 2.4 , 7.1 ) Strong CYP3A Inducers : Avoid concomitant use with strong CYP3A inducers. If concomitant use cannot be avoided, increase VEPPANU dosage. ( 2.4 , 7.1 ) Certain P-gp Substrates : Avoid concomitant use with certain P-gp substrates where minimal increases in concentration may lead to serious adverse reactions. ( 7.2 ) Certain UGT1A9 Substrates : Refer to the Prescribing Information for UGT1A9 substrates where minimal increases in concentration may lead to serious adverse reactions. ( 7.2 ) 7.1 Effect of Other Drugs on VEPPANU Table 5 describes drug interactions where concomitant use of another drug affects VEPPANU. Table 5: Drug Interactions that Affect VEPPANU Strong CYP3A Inhibitors Prevention or Management Strong CYP3A Inhibitors: Avoid concomitant use of VEPPANU with strong CYP3A inhibitors in patients receiving VEPPANU 200 mg once daily. If concomitant use cannot be avoided, reduce VEPPANU dosage [see Dosage and Administration ( 2.4 )] . Avoid concomitant use with strong CYP3A inhibitors in patients receiving VEPPANU 100 mg once daily. Mechanism and Clinical Effect(s) Vepdegestrant is a CYP3A substrate. Concomitant use with a strong CYP3A inhibitor may increase vepdegestrant plasma concentration [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of VEPPANU-associated adverse reactions. Strong CYP3A Inducers Prevention or Management Avoid concomitant use with strong CYP3A inducers in patients receiving VEPPANU 200 mg once daily. If concomitant use cannot be avoided, increase VEPPANU dosage [see Dosage and Administration ( 2.4 )] . Avoid concomitant use with strong CYP3A inducers in patients receiving VEPPANU 100 mg once daily. Mechanism and Clinical Effect(s) Vepdegestrant is a CYP3A substrate. Concomitant use with a strong CYP3A inducer may decrease vepdegestrant plasma concentration [see Clinical Pharmacology ( 12.3 )] , which may reduce the effectiveness of VEPPANU. 7.2 Effect of VEPPANU on Other Drugs Table 6 describes drug interactions where concomitant use of VEPPANU affects another drug. Table 6: VEPPANU Drug Interactions that Affect Other Drugs Certain P-gp Substrates Prevention or Management Avoid concomitant use with certain P-gp substrates where minimal increases in concentration may lead to serious adverse reactions. Mechanism and Clinical Effect(s) Vepdegestrant is a P-gp inhibitor. Vepdegestrant increases exposure of P-gp substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. Certain UGT1A9 Substrates Prevention or Management Refer to the Prescribing Information for UGT1A9 substrates where minimal increases in the concentration may lead to serious adverse reactions. Mechanism and Clinical Effect(s) Vepdegestrant is a UGT1A9 inhibitor. Vepdegestrant increases exposure of UGT1A9 substrates [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of adverse reactions related to these substrates. 7.3 Drugs that Prolong QTc Interval Avoid concomitant use of VEPPANU with other drugs with a known potential to prolong the QTc interval. If concomitant use cannot be avoided: Obtain ECGs when initiating and during concomitant use, and as clinically indicated [see Warnings and Precautions ( 5.1 )] . Withhold VEPPANU if the QTc interval is >480 ms or the change from baseline is >60 ms [see Dosage and Administration ( 2.3 )] . Vepdegestrant causes QTc interval prolongation [see Clinical Pharmacology ( 12.2 )] . Concomitant use of VEPPANU with other drugs that prolong the QTc interval may result in a greater increase in the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de Pointes, other serious arrhythmias, and sudden death [see Warnings and Precautions ( 5.1 )] .

8 USE IN SPECIFIC POPULATIONS Lactation : Advise not to breastfeed. ( 8.2 ) 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, VEPPANU can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 ) ]. There are no available human data on the use of VEPPANU in pregnant women to inform the drug-associated risk. In an animal reproduction study, oral administration of vepdegestrant to pregnant rats during the period of organogenesis caused adverse developmental outcomes, including 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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In an embryo-fetal development study in pregnant rats, administration of oral doses of vepdegestrant up to 300 mg/kg/day during the period of organogenesis resulted in embryo-fetal mortality (increased resorptions, post-implantation loss and reduced number of live fetuses) at ≥30 mg/kg/day (approximately 0.3 times the human AUC at the recommended dose). Additional adverse effects at ≥30 mg/kg/day included reduced fetal weight and skeletal abnormalities including delays in skeletal ossification (reduced number of ossification sites, incompletely ossified cervical arches or thoracic centra), skeletal malformations (fusion of sacral centra, hemivertebrae of the sacrum), and/or increased incidence of fetal variations (short cervical ribs, misaligned caudal vertebrae, misshapen cervical arches, and misaligned sacral vertebrae). 8.2 Lactation Risk Summary There are no data on the presence of vepdegestrant or its metabolites in human milk, or its effects on milk production or the breastfed child. Because of the potential for serious adverse reactions in the breastfed child, advise lactating women not to breastfeed during treatment with VEPPANU and for 2 weeks after the last dose. 8.3 Females and Males of Reproductive Potential VEPPANU 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 VEPPANU treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose. Males Advise male patients with female partners of reproductive potential to use effective contraception during treatment with VEPPANU and for 2 weeks after the last dose. Infertility Based on findings from animal studies, VEPPANU may impair fertility in females and males of reproductive potential. The effects of vepdegestrant on fertility were reversible in female animals [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use The safety and effectiveness of VEPPANU in pediatric patients have not been established. 8.5 Geriatric Use Of 313 patients who received VEPPANU in the VERITAC-2 study, 39% were 65 years of age or older and 13% were 75 years of age or older. No overall differences in safety or effectiveness of VEPPANU were observed between patients 65 years of age or older compared to younger patients. There is an insufficient number of patients 75 years of age or older to assess whether there are differences in safety or effectiveness.

11 DESCRIPTION Vepdegestrant is a heterobifunctional protein degrader. It is a small molecule comprised of an estrogen receptor binding domain joined by a linker to an E3 ligase binding domain. The chemical name of vepdegestrant is 2,6-piperidinedione, 3-[1,3-dihydro-1-oxo-5-[4-[[1-[4-[(1 R ,2 S )-1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthalenyl]phenyl]-4-piperidinyl]methyl]-1-piperazinyl]-2 H -isoindol-2-yl]-, (3 S )-. The chemical structure of vepdegestrant is: Vepdegestrant is white to off-white to pale yellow solid with the molecular formula of C 45 H 49 N 5 O 4 and a molecular weight of 723.90 Daltons. Vepdegestrant solubility is pH dependent. The solubility ranges from freely soluble under gastric pH conditions to slightly soluble under intestinal pH conditions. VEPPANU is supplied as blue film-coated, immediate release tablets containing either 100 mg or 200 mg vepdegestrant together with: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, microcrystalline cellulose, sodium stearyl fumarate, vitamin E-polyethylene glycol succinate, and Opadry ® QX Blue as inactive ingredients. Opadry ® QX Blue film-coating contains: FD&C Blue No. 2 (indigo carmine) aluminum lake, ferric oxide yellow (yellow iron oxide), ferrosoferric oxide (black iron oxide), glyceryl mono and dicaprylocaprate (glycerol monocaprylocaprate), polyvinyl alcohol, polyvinyl alcohol polyethylene glycol graft copolymer [macrogol poly (vinyl alcohol) grafted copolymer], talc, and titanium dioxide. chemstructure

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied VEPPANU (vepdegestrant) film-coated tablets for oral use are supplied in bottles of 30 tablets with child-resistant closures as follows: Strength Description NDC Number 100 mg Blue round tablet "VEP" debossed on one side and "100" on the other side. 71332-007-30 200 mg Blue oval tablet "VEP" debossed on one side and "200" on the other side. 71332-008-30 Storage Store at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C and 30°C (between 59°F and 86°F) [see USP controlled room temperature].