vepdegestrant 100 MG Oral Tablet

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 )

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 Grade1 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. Abbreviations: CTCAE=National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Table 2: Dosage Modification and Management for QTc Prolongation QTc Prolongation1 [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. 1 Heart-rate corrected QTc using Fridericia's method. 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 100 mg once daily. Strong CYP3A Inducers Avoid concomitant use with strong CYP3A inducers in patients receiving VEPPANU 200 mg once daily. If concomitant use cannot be avoided, increase VEPPANU from 200 mg once daily to 300 mg once daily [see Drug Interactions ( 7.1 )] . After a CYP3A inducer has been discontinued for 7 to 14 days, resume VEPPANU 200 mg once daily. Avoid concomitant use with strong CYP3A inducers in patients receiving VEPPANU 100 mg once daily.

WARNINGS AND PRECAUTIONS QTc Interval Prolongation : Monitor electrocardiograms (ECGs) and electrolytes prior to initiation of treatment with VEPPANU. Correct hypokalemia and hypomagnesemia prior to and during treatment. Repeat ECGs as clinically indicated. Withhold, reduce dose, or permanently discontinue VEPPANU based on severity. (5.1) Embryo-Fetal Toxicity : VEPPANU can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. (5.2, 8.1, 8.3) 5.1 QTc Interval Prolongation VEPPANU can cause QT (QTc) interval prolongation [see Clinical Pharmacology ( 12.2 )] . In VERITAC-2, QTc interval prolongation was reported in 10% of patients; Grade 3 occurred in 1.6% of patients. The heart-rate corrected QTc interval using Fridericia’s method was greater than 500 msec in 1.6% of patients, and the increase from baseline QTc was greater than 60 msec in 2.6% of patients. VEPPANU dose reduction was required for 0.3% of patients due to QTc interval prolongation [see Adverse Reactions ( 6.1 )] . Correct electrolyte abnormalities, including hypokalemia and hypomagnesemia, prior to and during treatment with VEPPANU. Perform an ECG prior to initiation of treatment with VEPPANU, and do not initiate VEPPANU in patients with QTc > 470 msec. Repeat ECG approximately 4 weeks after initiating treatment and as clinically indicated. In patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval, additional ECG monitoring may be necessary. Avoid concomitant use of VEPPANU with strong CYP3A inhibitors or drugs known to prolong the QTc interval. Reduce VEPPANU dose when concomitant use with strong CYP3A inhibitors cannot be avoided [see Dosage and Administration ( 2.4 ), Drug Interactions ( 7.1 , 7.3 ), and Clinical Pharmacology ( 12.2 )] . If concomitant use with other QTc-prolonging agents cannot be avoided, increase the frequency of ECG monitoring. Withhold, reduce dose, or permanently discontinue based on severity [see Dosage and Administration ( 2.3 )] . 5.2 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, VEPPANU can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, oral administration of vepdegestrant to pregnant rats during the period of organogenesis 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 VEPPANU and for 2 weeks after the last dose. 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 [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )] .

CONTRAINDICATIONS None. None. ( 4 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Vepdegestrant is a heterobifunctional protein degrader that binds to estrogen receptor (ER) and the E3 ligase cereblon (CRBN). This interaction results in the degradation cascade through CRBN-mediated polyubiquitination and degradation of ER by the proteasome, leading to reduction of ER protein levels in breast cancer cells. Vepdegestrant induced degradation of wild-type (WT) and mutant ER, inhibited ER-dependent breast cancer cell line proliferation in vitro and demonstrated antitumor activity in vivo in both WT and mutant ESR1 breast cancer models. 12.2 Pharmacodynamics The exposure-response relationship and time-course of pharmacodynamic response of vepdegestrant have not been fully characterized. Cardiac Electrophysiology The largest mean increase in QTc interval was 12 ms (upper confidence interval = 15 ms) after administration of vepdegestrant at the recommended dosage of 200 mg once daily in patients with ESR1 mutation-positive breast cancer. 12.3 Pharmacokinetics Vepdegestrant pharmacokinetics were observed at steady state in patients with ER+/HER2- breast cancer at the approved recommended dosage of 200 mg once daily and are presented as mean (coefficient of variation (CV%)) unless otherwise specified. Vepdegestrant maximum concentration (C max ) is 926 ng/mL (39%), and the total systemic exposure (AUC) is 17155 ng•hr/mL (36%). Vepdegestrant AUC and C max increase in an approximately dose proportional manner over the dose range of 100 mg (0.5 times the approved recommended dose) to 500 mg (2.5 times the approved recommended dose). Vepdegestrant accumulation is approximately 1.4-fold for AUC and 1.3-fold for C max . Vepdegestrant steady state is reached in approximately 7 days. Absorption Vepdegestrant median (min, max) time to maximum plasma concentration (T max ) is approximately 6 (4, 8) hours. Effect of Food Vepdegestrant AUC increased 2.9-fold and C max 3.2-fold following administration with a high-fat meal (approximately 800 to 1,000 calories; ≥50% fat). Distribution Vepdegestrant plasma protein binding is >99%. The apparent (oral) volume of distribution is 764 L (26%) following a single 200 mg dose. Elimination Vepdegestrant effective elimination half-life is 19 hours (50%) with an apparent (oral) clearance of 12 L/h (36%). Metabolism Vepdegestrant is primarily metabolized through direct sulfation via multiple SULT isoforms and oxidation via CYP3A4 and to a lesser extent by CYP2C8, CYP2C9 and CYP3A5. Unchanged total vepdegestrant represented 92% of total radioactivity in plasma. Excretion Following a single oral dose of radiolabeled vepdegestrant 200 mg to healthy subjects, approximately 68% of the dose was recovered in feces (18% unchanged) and 1.5% in urine (<0.02% unchanged). Specific Populations No clinically significant differences in the pharmacokinetics of vepdegestrant were observed based on age (26 to 89 years), sex, body weight (37 to 181 kg), race (60% White, 27% Asian, 2.2% Black or African American, and 10% other), CLcr 30 mL/min to 90 mL/min (estimated by Cockcroft Gault equation) or mild hepatic impairment (total bilirubin ≤ULN and AST>ULN or total bilirubin >1 to 1.5 × ULN and any AST). The effect of moderate hepatic impairment (total bilirubin >1.5 to 3 × ULN and any AST), severe hepatic impairment (total bilirubin > 3 x ULN and any AST), CLcr 15 to < 30 mL/min, and end-stage renal disease (CLcr < 15 mL/min) on the pharmacokinetics of vepdegestrant is unknown. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Strong CYP3A Inhibitors : Vepdegestrant AUC increased 1.7-fold and C max 1.5-fold following concomitant use of itraconazole (strong CYP3A inhibitor) 200 mg once daily. Strong CYP3A Inducers: Vepdegestrant AUC decreased to 64% and C max to 80% following concomitant use of carbamazepine (strong CYP3A inducer) 200 mg three times daily. Acid Reducing Agents: Vepdegestrant AUC decreased to 84% and C max to 74% following concomitant use of esomeprazole (proton-pump inhibitor) 40 mg once daily. CYP3A Substrates : Midazolam (CYP3A substrate) AUC increased 1.7-fold and C max 1.2-fold following concomitant use of VEPPANU 200 mg once daily. P-gp Substrates : Dabigatran etexilate (P-gp substrate) AUC increased 2-fold and C max 1.9-fold following concomitant use of a single dose of VEPPANU 200 mg. Breast Cancer Resistance Protein (BCRP) Substrates : Rosuvastatin (BCRP substrate) AUC increased 1.2-fold and C max 1.2-fold following concomitant use of a single dose of VEPPANU 200 mg. UGT1A9 Substrates : Dapagliflozin (UGT1A9 index substrate) AUC is predicted to increase approximately 2‑fold following multiple doses of VEPPANU. In vitro studies: CYP450 Enzymes: Vepdegestrant does not inhibit CYP1A2, CYP2C8, CYP2C9, CYP2C19 or CYP2D6 and does not induce CYP1A2, CYP2C8, CYP2C9, or CYP2C19.Vepdegestrant is an inhibitor of CYP2B6. UDP-Glucuronosyltransferases (UGT): Vepdegestrant does not inhibit UGT1A1, UGT1A4, UGT1A6, UGT2B7, or UGT2B15. Transporter Systems: Vepdegestrant is not a substrate of P-gp, BCRP, OATP1B1, or OATP1B3. Vepdegestrant does not inhibit MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, or OCT2.