Orgovyx

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: QT/QTc Interval Prolongation [see Warnings and Precautions (5.1) ] . The most common adverse reactions (≥ 10%) and laboratory abnormalities (≥ 15%) were hot flush, glucose increased, triglycerides increased, musculoskeletal pain, hemoglobin decreased, alanine aminotransferase (ALT) increased, fatigue, aspartate aminotransferase (AST) increased, constipation, and diarrhea ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Myovant Sciences, Inc., at 1-833-MYOVANT (1-833-696-8268) 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 ORGOVYX was evaluated in HERO, a randomized (2:1), open-label, clinical study in patients with advanced prostate cancer [see Clinical Studies (14) ] . Patients received orally administered ORGOVYX as a loading dose of 360 mg on the first day followed by 120 mg taken orally once daily (n = 622) or received leuprolide acetate administered by depot injection at doses of 22.5 mg (n = 264) or 11.25 mg (n = 44) per local guidelines every 12 weeks (n = 308). Leuprolide acetate 11.25 mg is a dosage regimen that is not recommended for this indication in the US. Among patients who received ORGOVYX, 91% were exposed for at least 48 weeks. Ninety-nine (16%) patients received concomitant radiotherapy and 17 (3%) patients received concomitant enzalutamide with ORGOVYX. Serious adverse reactions occurred in 12% of patients receiving ORGOVYX. Serious adverse reactions in ≥ 0.5% of patients included myocardial infarction (0.8%), acute kidney injury (0.6%), arrhythmia (0.6%), hemorrhage (0.6%), and urinary tract infection (0.5%). Fatal adverse reactions occurred in 0.8% of patients receiving ORGOVYX including metastatic lung cancer (0.3%), myocardial infarction (0.3%), and acute kidney injury (0.2%). Fatal and non-fatal myocardial infarction and stroke were reported in 2.7% of patients receiving ORGOVYX. Permanent discontinuation of ORGOVYX due to an adverse reaction occurred in 3.5% of patients. Adverse reactions which resulted in permanent discontinuation of ORGOVYX in ≥ 0.3 % of patients included atrioventricular block (0.3%), cardiac failure (0.3%), hemorrhage (0.3%), increased transaminases (0.3%), abdominal pain (0.3%), and pneumonia (0.3%). Dosage interruptions of ORGOVYX due to an adverse reaction occurred in 2.7% of patients. Adverse reactions which required dosage interruption in ≥ 0.3% of patients included fracture (0.3%). The most common adverse reactions (≥ 10%) and laboratory abnormalities (≥ 15%), were hot flush (54%), glucose increased (44%), triglycerides increased (35%), musculoskeletal pain (30%), hemoglobin decreased (28%), alanine aminotransferase increased (ALT) (27%), fatigue (26%), aspartate aminotransferase increased (AST) (18%), constipation (12%), and diarrhea (12%). Table 1 summarizes the adverse reactions in HERO. Table 1: Adverse Reactions ( ≥ 10%) of Patients with Advanced Prostate Cancer Who Received ORGOVYX in HERO Adverse Reaction ORGOVYX N = 622 Leuprolide Acetate N = 308 All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Vascular disorders Hot flush 54 0.6 52 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, back pain, pain in extremity, musculoskeletal pain, myalgia, bone pain, neck pain, arthritis, musculoskeletal stiffness, non-cardiac chest pain, musculoskeletal chest pain, spinal pain, and musculoskeletal discomfort. 30 1.1 29 1.6 General Fatigue Includes fatigue and asthenia. 26 0.3 24 0 Gastrointestinal disorders Diarrhea Includes diarrhea and colitis. 12 0.2 7 0 Constipation 12 0 10 0 Clinically relevant adverse reactions in < 10% of patients who received ORGOVYX included increased weight, insomnia, gynecomastia, hyperhidrosis, depression, decreased libido, and angioedema. Table 2 summarizes the laboratory abnormalities in HERO. Table 2: Select Laboratory Abnormalities ( ≥ 15%) That Worsened from Baseline in Patients with Advanced Prostate Cancer Who Received ORGOVYX in HERO ORGOVYX The denominator used to calculate the rate varied from 611 to 619 in the ORGOVYX arm and from 301 to 306 in the leuprolide arm based on the number of patients with a baseline value and at least one post-treatment value. Leuprolide Acetate Laboratory Test All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Glucose increased 44 2.9 54 6 Triglycerides increased 35 2 36 0.7 ALT increased 27 0.3 28 0 AST increased 18 0 19 0.3 Hematology Hemoglobin decreased 28 0.5 29 0.7 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of ORGOVYX. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune system disorders: hypersensitivity, including angioedema and urticaria.

4 CONTRAINDICATIONS ORGOVYX is contraindicated in patients with severe hypersensitivity to relugolix or to any of the product components. Known severe hypersensitivity to relugolix or to any of the product components( 4 ).

11 DESCRIPTION Relugolix is a nonpeptide small molecule, GnRH receptor antagonist. The chemical name is N-(4-{1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl}phenyl)-N'-methoxyurea. The molecular weight is 623.63 daltons and the molecular formula is C 29 H 27 F 2 N 7 O 5 S. The structural formula is: Relugolix is a white to off-white to slightly yellow solid with a solubility of 0.04 mg per mL in water at 25°C. ORGOVYX is provided as film-coated tablets for oral administration. Each tablet contains 120 mg of relugolix. The inactive ingredients are mannitol, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hypromellose, titanium dioxide, ferric oxide red, and carnauba wax. Chemical Structure

2 DOSAGE AND ADMINISTRATION Recommended Dosage: A loading dose of 360 mg on the first day of treatment followed by 120 mg taken orally once daily, at approximately the same time each day ( 2.1 ). ORGOVYX can be taken with or without food ( 2.1 , 12.3 ). Instruct patients to swallow tablets whole and not to crush or chew tablets ( 2.1 ). 2.1 Recommended Dosage Initiate treatment of ORGOVYX with a loading dose of 360 mg on the first day and continue treatment with a 120 mg dose taken orally once daily at approximately the same time each day. ORGOVYX can be taken with or without food [see Clinical Pharmacology (12.3) ] . Instruct patients to swallow tablets whole and not to crush or chew tablets. Advise patients to take a missed dose of ORGOVYX as soon as they remember. If the dose was missed by more than 12 hours, patients should not take the missed dose and resume with the next scheduled dose. If treatment with ORGOVYX is interrupted for greater than 7 days, restart ORGOVYX with a loading dose of 360 mg on the first day, and continue with a dose of 120 mg once daily. In patients treated with GnRH receptor agonists and antagonists for prostate cancer, treatment is usually continued upon development of nonmetastatic or metastatic castration-resistant prostate cancer. 2.2 Dose Modification for Use with P-gp Inhibitors Avoid co-administration of ORGOVYX with oral P-gp inhibitors. If co-administration is unavoidable, take ORGOVYX first and separate dosing by at least 6 hours [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . Treatment with ORGOVYX may be interrupted for up to two weeks if a short course of treatment with a P-gp inhibitor is required. 2.3 Dose Modification for Use with Combined P-gp and Strong CYP3A Inducers Avoid co-administration of ORGOVYX with combined P-gp and strong CYP3A inducers. If co-administration is unavoidable, increase the ORGOVYX dose to 240 mg once daily. After discontinuation of the combined P-gp and strong CYP3A inducer, resume the recommended ORGOVYX dose of 120 mg once daily [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .

1 INDICATIONS AND USAGE ORGOVYX is indicated for the treatment of adult patients with advanced prostate cancer. ORGOVYX is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the treatment of adult patients with advanced prostate cancer ( 1 ).

7 DRUG INTERACTIONS P-gp Inhibitors: Avoid co-administration. If unavoidable, take ORGOVYX first, separate dosing by at least 6 hours, and monitor patients more frequently for adverse reactions ( 2.2 , 7.1 ). Combined P-gp and Strong CYP3A Inducers: Avoid co-administration. If unavoidable, increase the ORGOVYX dose to 240 mg once daily ( 2.3 , 7.1 ). 7.1 Effect of Other Drugs on ORGOVYX P-gp Inhibitors Co-administration of ORGOVYX with a P-gp inhibitor increases the AUC and the maximum concentration (C max ) of relugolix [see Clinical Pharmacology (12.3) ], which may increase the risk of adverse reactions associated with ORGOVYX. Avoid co-administration of ORGOVYX with oral P-gp inhibitors. If co-administration is unavoidable, take ORGOVYX first, separate dosing by at least 6 hours, and monitor patients more frequently for adverse reactions [see Dosage and Administration (2.2) ] . Treatment with ORGOVYX may be interrupted for up to 2 weeks for a short course of treatment with certain P-gp inhibitors. If treatment with ORGOVYX is interrupted for more than 7 days, resume administration of ORGOVYX with a 360 mg loading dose on the first day, followed by 120 mg once daily. Combined P-gp and Strong CYP3A Inducers Co-administration of ORGOVYX with a combined P-gp and a strong CYP3A inducer decreases the AUC and C max of relugolix [see Clinical Pharmacology (12.3) ], which may reduce the effects of ORGOVYX. Avoid co-administration of ORGOVYX with combined P-gp and strong CYP3A inducers. If co-administration is unavoidable, increase the ORGOVYX dose [see Dosage and Administration (2.3) ] . After discontinuation of the combined P-gp and strong CYP3A inducer, resume the recommended dose of ORGOVYX once daily.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, thereby, reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and consequently testosterone. 12.2 Pharmacodynamics Pituitary and Gonadal Hormones Relugolix reduced LH, FSH (Figure 1), and testosterone concentrations after oral administration of the recommended loading dose of 360 mg and a 120 mg dose once daily. Out of 622 patients, 56% had testosterone concentrations at castrate levels (< 50 ng/dL) by the first sampling timepoint at Day 4, and 97% maintained castrate levels of testosterone through 48 weeks. In a substudy of 137 patients who did not receive subsequent androgen deprivation therapy for at least 90 days after discontinuation of relugolix, the cumulative incidence rate of achieving testosterone concentrations above the lower limit of the normal range (> 280 ng/dL) or baseline at 90 days was 55% [see Clinical Studies (14) ] . Figure 1: Mean (± 95% CI) Follicle-Stimulating Hormone and Luteinizing Hormone Concentrations over Time in HERO Figure 1 Cardiac Electrophysiology In a randomized, double-blind, placebo- and positive-controlled (open-label moxifloxacin), parallel-group thorough QT/QTc study, no increase in mean QTc interval > 10 ms was identified after administration of single 60 or 360 mg doses of relugolix (0.2 or 1 times the recommended loading dose, respectively). 12.3 Pharmacokinetics After administration of single doses ranging from 60 mg to 360 mg (0.17 to 1 times the recommended loading dose), the AUC from time zero extrapolated to infinity (AUC 0-inf ) and the maximum observed plasma concentration (C max ) of relugolix increase approximately proportionally with dose. After administration of multiple 20 mg to 180 mg doses of relugolix once daily (0.17 to 1.5 times the recommended once daily dose), the AUC tau of relugolix increases approximately proportionally with dose and the C max increases greater than proportionally to dose. After administration of a single 360 mg loading dose in patients, the mean (± standard deviation [± SD]) of AUC 0-24 and C max of relugolix were 985 (± 742) ng.hr/mL and 215 (± 184) ng/mL, respectively. After administration of a 120 mg dose once daily in patients, the mean (± SD) of AUC 0-24 and C max of relugolix at steady-state were 407 (± 168) ng.hr/mL and 70 (± 65) ng/mL, respectively. The accumulation of relugolix upon once daily administration is approximately 2-fold. Absorption Relugolix is a substrate for intestinal P-gp. The mean (CV%) absolute bioavailability of relugolix is approximately 12% (62%). The median (range) T max of relugolix is 2.25 hours (0.5 to 5.0 hours). Effect of Food No clinically meaningful differences in the pharmacokinetics of relugolix were observed following consumption of a high-calorie, high-fat meal (approximately 800 to 1000 calories with 500, 220, and 124 from fat, carbohydrate, and protein, respectively). Distribution Plasma protein binding of relugolix is 68 to 71%, primarily to albumin and to a lesser extent to α 1 -acid glycoprotein. The mean blood-to-plasma ratio is 0.78. Elimination The mean effective half-life of relugolix is 25 hours and the mean (CV%) terminal elimination half-life is 60.8 (11%) hours. The mean (CV%) total clearance of relugolix is 29.4 (15%) L/h and the renal clearance is 8 L/h. Metabolism Relugolix is metabolized primarily by CYP3A and to a lesser extent by CYP2C8 in vitro. Excretion After oral administration of a single 80-mg radiolabeled dose of relugolix, approximately 81% of the radioactivity was recovered in feces (4.2% as unchanged) and 4.1% in urine (2.2% as unchanged). Specific Populations No clinically meaningful differences in the pharmacokinetics of relugolix were observed based on age (45 to 91 years), race/ethnicity (Asian [19%], White [71%], Black/African American [6%]), body weight (41 to 193 kg), mild to severe renal impairment (creatinine clearance [CLcr] 15 to 89 mL/min, as estimated by the Cockcroft-Gault equation), or mild to moderate hepatic impairment (Child-Pugh A or B). The effect of end-stage renal disease with or without hemodialysis or severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of relugolix has not been evaluated. Drug Interactions Studies Clinical Studies Combined P-gp and Moderate CYP3A Inhibitor: Co-administration with erythromycin (P-gp and moderate CYP3A inhibitor) increased the AUC and C max of relugolix by 6.2-fold. Combined P-gp and Strong CYP3A Inducer: Co-administration with rifampin (P-gp and strong CYP3A inducer) decreased the AUC and C max of relugolix by 55% and 23%, respectively. Other Drugs: No clinically significant differences in the pharmacokinetics of relugolix were observed when co-administered with voriconazole (strong CYP3A inhibitor), atorvastatin, enzalutamide, or acid-reducing agents. No clinically significant differences in the pharmacokinetics of midazolam (sensitive CYP3A substrate) or rosuvastatin (BCRP substrate) were observed upon co-administration with relugolix. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Relugolix is a substrate of CYP3A and CYP2C8. Relugolix is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Relugolix is an inducer of CYP3A and CYP2B6, but not an inducer of CYP1A2. Transporter Systems: Relugolix is a substrate of P-gp, but not a substrate of BCRP. Relugolix is an inhibitor of BCRP and P-gp, but not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, or BSEP.

12.1 Mechanism of Action Relugolix is a nonpeptide GnRH receptor antagonist that competitively binds to pituitary GnRH receptors, thereby, reducing the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and consequently testosterone.

12.2 Pharmacodynamics Pituitary and Gonadal Hormones Relugolix reduced LH, FSH (Figure 1), and testosterone concentrations after oral administration of the recommended loading dose of 360 mg and a 120 mg dose once daily. Out of 622 patients, 56% had testosterone concentrations at castrate levels (< 50 ng/dL) by the first sampling timepoint at Day 4, and 97% maintained castrate levels of testosterone through 48 weeks. In a substudy of 137 patients who did not receive subsequent androgen deprivation therapy for at least 90 days after discontinuation of relugolix, the cumulative incidence rate of achieving testosterone concentrations above the lower limit of the normal range (> 280 ng/dL) or baseline at 90 days was 55% [see Clinical Studies (14) ] . Figure 1: Mean (± 95% CI) Follicle-Stimulating Hormone and Luteinizing Hormone Concentrations over Time in HERO Figure 1 Cardiac Electrophysiology In a randomized, double-blind, placebo- and positive-controlled (open-label moxifloxacin), parallel-group thorough QT/QTc study, no increase in mean QTc interval > 10 ms was identified after administration of single 60 or 360 mg doses of relugolix (0.2 or 1 times the recommended loading dose, respectively).

12.3 Pharmacokinetics After administration of single doses ranging from 60 mg to 360 mg (0.17 to 1 times the recommended loading dose), the AUC from time zero extrapolated to infinity (AUC 0-inf ) and the maximum observed plasma concentration (C max ) of relugolix increase approximately proportionally with dose. After administration of multiple 20 mg to 180 mg doses of relugolix once daily (0.17 to 1.5 times the recommended once daily dose), the AUC tau of relugolix increases approximately proportionally with dose and the C max increases greater than proportionally to dose. After administration of a single 360 mg loading dose in patients, the mean (± standard deviation [± SD]) of AUC 0-24 and C max of relugolix were 985 (± 742) ng.hr/mL and 215 (± 184) ng/mL, respectively. After administration of a 120 mg dose once daily in patients, the mean (± SD) of AUC 0-24 and C max of relugolix at steady-state were 407 (± 168) ng.hr/mL and 70 (± 65) ng/mL, respectively. The accumulation of relugolix upon once daily administration is approximately 2-fold. Absorption Relugolix is a substrate for intestinal P-gp. The mean (CV%) absolute bioavailability of relugolix is approximately 12% (62%). The median (range) T max of relugolix is 2.25 hours (0.5 to 5.0 hours). Effect of Food No clinically meaningful differences in the pharmacokinetics of relugolix were observed following consumption of a high-calorie, high-fat meal (approximately 800 to 1000 calories with 500, 220, and 124 from fat, carbohydrate, and protein, respectively). Distribution Plasma protein binding of relugolix is 68 to 71%, primarily to albumin and to a lesser extent to α 1 -acid glycoprotein. The mean blood-to-plasma ratio is 0.78. Elimination The mean effective half-life of relugolix is 25 hours and the mean (CV%) terminal elimination half-life is 60.8 (11%) hours. The mean (CV%) total clearance of relugolix is 29.4 (15%) L/h and the renal clearance is 8 L/h. Metabolism Relugolix is metabolized primarily by CYP3A and to a lesser extent by CYP2C8 in vitro. Excretion After oral administration of a single 80-mg radiolabeled dose of relugolix, approximately 81% of the radioactivity was recovered in feces (4.2% as unchanged) and 4.1% in urine (2.2% as unchanged). Specific Populations No clinically meaningful differences in the pharmacokinetics of relugolix were observed based on age (45 to 91 years), race/ethnicity (Asian [19%], White [71%], Black/African American [6%]), body weight (41 to 193 kg), mild to severe renal impairment (creatinine clearance [CLcr] 15 to 89 mL/min, as estimated by the Cockcroft-Gault equation), or mild to moderate hepatic impairment (Child-Pugh A or B). The effect of end-stage renal disease with or without hemodialysis or severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of relugolix has not been evaluated. Drug Interactions Studies Clinical Studies Combined P-gp and Moderate CYP3A Inhibitor: Co-administration with erythromycin (P-gp and moderate CYP3A inhibitor) increased the AUC and C max of relugolix by 6.2-fold. Combined P-gp and Strong CYP3A Inducer: Co-administration with rifampin (P-gp and strong CYP3A inducer) decreased the AUC and C max of relugolix by 55% and 23%, respectively. Other Drugs: No clinically significant differences in the pharmacokinetics of relugolix were observed when co-administered with voriconazole (strong CYP3A inhibitor), atorvastatin, enzalutamide, or acid-reducing agents. No clinically significant differences in the pharmacokinetics of midazolam (sensitive CYP3A substrate) or rosuvastatin (BCRP substrate) were observed upon co-administration with relugolix. In Vitro Studies Cytochrome P450 (CYP) Enzymes: Relugolix is a substrate of CYP3A and CYP2C8. Relugolix is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Relugolix is an inducer of CYP3A and CYP2B6, but not an inducer of CYP1A2. Transporter Systems: Relugolix is a substrate of P-gp, but not a substrate of BCRP. Relugolix is an inhibitor of BCRP and P-gp, but not an inhibitor of OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, or BSEP.

20230404

8

3 DOSAGE FORMS AND STRENGTHS Tablets: 120 mg, light red, almond-shaped, film-coated, and debossed with "R" on one side and "120" on the other side. Tablets: 120 mg ( 3 ).

Orgovyx relugolix RELUGOLIX RELUGOLIX MANNITOL SODIUM STARCH GLYCOLATE TYPE A HYDROXYPROPYL CELLULOSE (90000 WAMW) MAGNESIUM STEARATE HYPROMELLOSE 2910 (6 MPA.S) TITANIUM DIOXIDE FERRIC OXIDE RED CARNAUBA WAX light red almond R;120

13.2 Animal Toxicology and/or Pharmacology Phospholipidosis (intracellular phospholipid accumulation) was observed in multiple organs and tissues (e.g., liver, pancreas, spleen, kidney, lymph nodes, lung, bone marrow, gastrointestinal tract or testes) after repeated oral administration of relugolix in rats and monkeys. In a rat 26-week toxicity study, phospholipidosis was observed at doses ≥ 100 mg/kg (approximately 18 times the human exposure at the recommended dose based on AUC). In a monkey 39-week toxicity study, this effect was observed at doses ≥ 1.5 mg/kg (approximately 0.6 times the human exposure at the recommended dose based on AUC) and demonstrated evidence of reversibility after cessation of treatment. The significance of this finding in humans is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day. Relugolix was not carcinogenic in mice or rats at exposures up to approximately 75 or 224 times, respectively, the human exposure at the recommended dose of 120 mg daily based on AUC. Relugolix was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells or the in vivo rat bone marrow micronucleus assay. In human GnRH-receptor knock-in male mice, oral administration of relugolix decreased prostate and seminal vesicle weights at doses ≥ 3 mg/kg twice daily for 28 days. The effects of relugolix were reversible, except for testis weight, which did not fully recover within 28 days after drug withdrawal. In a 39-week repeat-dose toxicity study in monkeys, there were no significant effects on male reproductive organs at oral relugolix doses up to 50 mg/kg/day (approximately 53 times the human exposure at the recommended dose of 120 mg daily based on AUC).

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies were conducted in mice at oral relugolix doses up to 100 mg/kg/day and in rats at doses up to 600 mg/kg/day. Relugolix was not carcinogenic in mice or rats at exposures up to approximately 75 or 224 times, respectively, the human exposure at the recommended dose of 120 mg daily based on AUC. Relugolix was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or clastogenic in the in vitro chromosomal aberration assay in Chinese hamster lung cells or the in vivo rat bone marrow micronucleus assay. In human GnRH-receptor knock-in male mice, oral administration of relugolix decreased prostate and seminal vesicle weights at doses ≥ 3 mg/kg twice daily for 28 days. The effects of relugolix were reversible, except for testis weight, which did not fully recover within 28 days after drug withdrawal. In a 39-week repeat-dose toxicity study in monkeys, there were no significant effects on male reproductive organs at oral relugolix doses up to 50 mg/kg/day (approximately 53 times the human exposure at the recommended dose of 120 mg daily based on AUC). 13.2 Animal Toxicology and/or Pharmacology Phospholipidosis (intracellular phospholipid accumulation) was observed in multiple organs and tissues (e.g., liver, pancreas, spleen, kidney, lymph nodes, lung, bone marrow, gastrointestinal tract or testes) after repeated oral administration of relugolix in rats and monkeys. In a rat 26-week toxicity study, phospholipidosis was observed at doses ≥ 100 mg/kg (approximately 18 times the human exposure at the recommended dose based on AUC). In a monkey 39-week toxicity study, this effect was observed at doses ≥ 1.5 mg/kg (approximately 0.6 times the human exposure at the recommended dose based on AUC) and demonstrated evidence of reversibility after cessation of treatment. The significance of this finding in humans is unknown.

NDA214621

Orgovyx

relugolix

72974-120

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 120 mg Tablet Bottle Label NDC 72974-120-01 Rx only ORGOVYX ® (relugolix) tablets 120 mg 30 tablets PRINCIPAL DISPLAY PANEL - 120 mg Tablet Bottle Label

Contraindications, Hypersensitivity ( 4 ). 03/2023 Warnings and Precautions, Hypersensitivity ( 5.2 ). 03/2023

Manufactured for Myovant Sciences, Inc., Brisbane, CA 94005 214621-MS-003

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). QT/QTc Interval Prolongation Advise patients that androgen deprivation therapy treatment with ORGOVYX may prolong the QT interval. Inform patients of the signs and symptoms of QT prolongation. Advise patients to contact their healthcare provider immediately for signs or symptoms of QT prolongation [see Warnings and Precautions (5.1) ] . Hypersensitivity Inform patients that if they have experienced severe hypersensitivity with relugolix or to any of the product components, ORGOVYX is contraindicated [see Contraindications (4) ] . Inform patients that ORGOVYX can cause severe hypersensitivity reactions that include angioedema [see Warnings and Precautions (5.2) ]. Advise patients who experience hypersensitivity symptoms to discontinue ORGOVYX and promptly contact their healthcare provider. Androgen Deprivation Inform patients about adverse reactions related to androgen deprivation therapy with ORGOVYX, including hot flashes, flushing of the skin, increased weight, decreased sex drive, and difficulties with erectile function [see Adverse Reactions (6.1) ] . Embryo-Fetal Toxicity Inform patients that ORGOVYX can be harmful to a developing fetus and can cause loss of pregnancy. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose of ORGOVYX [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1 , 8.3) ]. Infertility Inform patients that ORGOVYX may cause infertility [see Use in Specific Populations (8.3) ] .

14 CLINICAL STUDIES HERO Study The safety and efficacy of ORGOVYX was evaluated in HERO (NCT03085095), a randomized, open label study in men with advanced prostate cancer requiring at least 1 year of androgen deprivation therapy and defined as biochemical (PSA) or clinical relapse following local primary intervention, newly diagnosed castration-sensitive metastatic disease, or advanced localized disease. A total of 934 patients were randomized to receive ORGOVYX or leuprolide in a 2:1 ratio for 48 weeks: ORGOVYX at a loading dose of 360 mg on the first day followed by daily doses of 120 mg orally. Leuprolide acetate 22.5 mg injection (or 11.25 mg in Japan and Taiwan) subcutaneously every 3 months. Leuprolide acetate 11.25 mg is a dosage regimen that is not recommended for this indication in the US. Serum testosterone concentrations were measured at screening; on Days 1, 4, 8, 15, and 29 in the first month; then monthly until the end of the study. The population (N = 930) across both treatment groups had a median age of 71 years (range 47 to 97 years). The ethnic/racial distribution was 68% White, 21% Asian, 4.9% Black, and 5% other. Disease stage was distributed as follows: 32% metastatic (M1), 31% locally advanced (T3/4 NX M0 or any T N1 M0), 28% localized (T1 or T2 N0 M0), and 10% not classifiable. The median testosterone concentration at baseline across the treatment groups was 408 ng/dL. The major efficacy outcome measure was medical castration rate defined as achieving and maintaining serum testosterone suppression to castrate levels (< 50 ng/dL) by Day 29 through 48 weeks of treatment. Other endpoints included castration rates on Day 4 and 15 and castration rates with testosterone < 20 ng/dL at Day 15. The efficacy results are shown in Table 3 and the time course of percent change from baseline in testosterone suppression by ORGOVYX and leuprolide during the 48 week treatment period are shown in Figure 2. Table 3: Medical Castration Rates (Testosterone Concentrations < 50 ng/dL) from Day 29 through Week 48 in HERO ORGOVYX 360/120 mg (N = 622) Two patients in each arm did not receive the study treatment and were not included. Leuprolide Acetate 22.5 or 11.25 mg 11.25 mg is a dosage regimen that is not recommended for this indication in the US. The castration rate of the subgroup of patients receiving 22.5 mg leuprolide (n = 264) was 88.0% (95% CI: 83.4%, 91.4%). (N = 308) Castration Rate (95% CI) Kaplan-Meier estimates within group. 96.7% (94.9%, 97.9%) 88.8% (84.6%, 91.8%) Figure 2: Mean (95% CI) Percent Change from Baseline in Testosterone Concentrations from Baseline to Week 49 by Treatment Group in HERO The percentages of patients who attained the medical castration levels of testosterone < 50 ng/dL and < 20 ng/dL within the first 29 days of treatment are summarized in Table 4 and the cumulative incidences of time to testosterone < 50 ng/dL or < 20 ng/dL are shown in Figure 3. Table 4: Percentage of Patients Attaining Testosterone Decreases within the First 29 Days in HERO Kaplan-Meier estimates within group. Testosterone < 50 ng/dL Testosterone < 20 ng/dL ORGOVYX (N = 622) Leuprolide Acetate (N = 308) ORGOVYX (N = 622) Leuprolide Acetate (N = 308) Day 4 56% 0% 7% 0% Day 8 91% 0% 27% 0% Day 15 99% 12% 78% 1% Day 29 99% 82% 95% 57% Figure 3: Cumulative Incidence of Time to Testosterone < 50 ng/dL and < 20 ng/dL in HERO In the clinical trial, PSA levels were monitored and were lowered on average by 65% two weeks after administration of ORGOVYX, 83% after 4 weeks, 92% after 3 months and remained suppressed throughout the 48 weeks of treatment. These PSA results should be interpreted with caution because of the heterogeneity of the patient population studied. No evidence has shown that the rapidity of PSA decline is related to a clinical benefit. A substudy was conducted in 137 patients who did not receive subsequent androgen deprivation therapy for at least 90 days after discontinuation of ORGOVYX. Based on Kaplan-Meier analyses, 55% of patients achieved testosterone levels above the lower limit of the normal range (> 280 ng/dL) or baseline at 90 days after discontinuation of ORGOVYX. Figure 2 Figure 3 Figure 3

8.5 Geriatric Use Of the 622 patients who received ORGOVYX in the HERO study, 81% were 65 years of age or older, while 35% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. There was no clinically relevant impact of age on the pharmacokinetics of ORGOVYX or testosterone response based on population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses in men 45 to 91 years of age.

8.4 Pediatric Use The safety and efficacy of ORGOVYX in pediatric patients have not been established.

8.1 Pregnancy Risk Summary The safety and efficacy of ORGOVYX have not been established in females. Based on findings in animals and mechanism of action, ORGOVYX can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1) ] . There are no human data on the use of ORGOVYX in pregnant females to inform the drug-associated risk. In an animal reproduction study, oral administration of relugolix to pregnant rabbits during organogenesis caused embryo-fetal lethality at maternal exposures that were 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC ( see Data ). Advise patients of the potential risk to the fetus. Data Animal Data In an embryo-fetal development study, oral administration of relugolix to pregnant rabbits during the period of organogenesis resulted in abortion, total litter loss, or decreased number of live fetuses at a dose of 9 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The safety and efficacy of ORGOVYX have not been established in females. Based on findings in animals and mechanism of action, ORGOVYX can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1) ] . There are no human data on the use of ORGOVYX in pregnant females to inform the drug-associated risk. In an animal reproduction study, oral administration of relugolix to pregnant rabbits during organogenesis caused embryo-fetal lethality at maternal exposures that were 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC ( see Data ). Advise patients of the potential risk to the fetus. Data Animal Data In an embryo-fetal development study, oral administration of relugolix to pregnant rabbits during the period of organogenesis resulted in abortion, total litter loss, or decreased number of live fetuses at a dose of 9 mg/kg/day (approximately 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC). 8.2 Lactation Risk Summary The safety and efficacy of ORGOVYX at the recommended dose of 120 mg daily have not been established in females. There are no data on the presence of relugolix in human milk, the effects on the breastfed child, or the effects on milk production. Relugolix and/or its metabolites were present in milk of lactating rats (see Data ) . Data Animal Data In lactating rats administered a single oral dose of 30 mg/kg radiolabeled relugolix on post-partum day 14, relugolix and/or its metabolites were present in milk at concentrations up to 10-fold higher than in plasma at 2 hours post-dose. 8.3 Females and Males of Reproductive Potential Contraception Males Based on findings in animals and mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 2 weeks after the last dose of ORGOVYX [see Use in Specific Populations (8.1) ]. Infertility Males Based on findings in animals and mechanism of action, ORGOVYX may impair fertility in males of reproductive potential [see Clinical Pharmacology (12.1) and Nonclinical Toxicology (13.1) ]. 8.4 Pediatric Use The safety and efficacy of ORGOVYX in pediatric patients have not been established. 8.5 Geriatric Use Of the 622 patients who received ORGOVYX in the HERO study, 81% were 65 years of age or older, while 35% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. There was no clinically relevant impact of age on the pharmacokinetics of ORGOVYX or testosterone response based on population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses in men 45 to 91 years of age.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied The 120 mg tablets are film-coated, light red, almond shaped, and debossed with "R" on one side and "120" on the other side and are supplied in two configurations, bottles and blister packs. Each bottle (NDC 72974-120-01) contains 30 tablets and a desiccant and is closed with a child-resistant induction seal cap. The blister cards contain nine tablets packaged in a carton (NDC 72974-120-02). Each ORGOVYX tablet contains 120 mg of relugolix. Storage and Handling Store ORGOVYX at room temperature. Do not store above 30°C (86°F). Dispense to patients in original container only. For bottles, keep container tightly closed after first opening. Keep out of reach of children. Dispose unused medication via a take-back option if available. Otherwise, follow FDA instructions for disposing medication in the household trash, www.fda.gov/drugdisposal. Do NOT flush down the toilet.

Storage and Handling Store ORGOVYX at room temperature. Do not store above 30°C (86°F). Dispense to patients in original container only. For bottles, keep container tightly closed after first opening. Keep out of reach of children. Dispose unused medication via a take-back option if available. Otherwise, follow FDA instructions for disposing medication in the household trash, www.fda.gov/drugdisposal. Do NOT flush down the toilet.