ADVERSE REACTIONS SECTION.

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)] . 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.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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, randomized (2:1), open-label, clinical study in patients with advanced prostate cancer [see Clinical Studies (14)] Patients received orally administered ORGOVYX as 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 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 summarizes the adverse reactions in HERO.Table 1:Adverse Reactions >= 10%) of Patients with Advanced Prostate Cancer Who Received ORGOVYX in HEROAdverse ReactionORGOVYX = 622 Leuprolide Acetate = 308 All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Vascular disorders Hot flush540.6520Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, back pain, pain in extremity, musculoskeletal pain, myalgia, bone pain, neck pain, arthritis, muculoskeletal stiffness, non-cardiac chest pain, musculoskeletal chest pain, spinal pain, and musculoskeletal discomfort. 301.1291.6General Fatigue Includes fatigue and asthenia. 260.3240Gastrointestinal disorders Diarrhea Includes diarrhea and colitis. 120.270 Constipation120100Clinically relevant adverse reactions in 10% of patients who received ORGOVYX included increased weight, insomnia, gynecomastia, hyperhidrosis, depression, and decreased libido.Table 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 HEROORGOVYX 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 baseline value and at least one post-treatment value. Leuprolide Acetate Laboratory TestAll Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Glucose increased442.9546 Triglycerides increased352360.7 ALT increased270.3280 AST increased180190.3Hematology Hemoglobin decreased280.5290.7.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

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 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 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 >= 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 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Relugolix is 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 HormonesRelugolix reduced LH, FSH (Figure 1), and testosterone concentrations after oral administration of the recommended loading dose of 360 mg and 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 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 ElectrophysiologyIn 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 times the recommended loading dose, respectively).. 12.3 Pharmacokinetics. After administration of single doses ranging from 60 mg to 360 mg (0.17 to 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 max increases greater than proportionally to dose. After administration of single 360 mg loading dose in patients, the mean (+- standard deviation [+- SD]) of AUC 0-24 and max of relugolix were 985 (+- 742) ng.hr/mL and 215 (+- 184) ng/mL, respectively. After administration of 120 mg dose once daily in patients, the mean (+- SD) of AUC 0-24 and 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. AbsorptionRelugolix is substrate for intestinal P-gp. The mean (CV%) absolute bioavailability of relugolix is approximately 12% (62%). The median (range) max of relugolix is 2.25 hours (0.5 to 5.0 hours). Effect of FoodNo clinically meaningful differences in the pharmacokinetics of relugolix were observed following consumption of high-calorie, high-fat meal (approximately 800 to 1000 calories with 500, 220, and 124 from fat, carbohydrate, and protein, respectively).. DistributionPlasma protein binding of relugolix is 68 to 71%, primarily to albumin and to lesser extent to 1-acid glycoprotein. The mean blood-to-plasma ratio is 0.78. EliminationThe 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 L/h.. MetabolismRelugolix is metabolized primarily by CYP3A and to lesser extent by CYP2C8 in vitro.. ExcretionAfter oral administration of 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 PopulationsNo 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 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 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 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 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 substrate of P-gp, but not 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. HERO StudyThe safety and efficacy of ORGOVYX was evaluated in HERO (NCT03085095), randomized, open label study in men with advanced prostate cancer requiring at least 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 2:1 ratio for 48 weeks:ORGOVYX at 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 months. Leuprolide acetate 11.25 mg is 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 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 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 and 15 and castration rates with testosterone 20 ng/dL at Day 15.The efficacy results are shown in Table and the timecourse 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 HEROORGOVYX 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 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 HEROThe 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 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/dLTestosterone 20 ng/dLORGOVYX (N 622) Leuprolide Acetate (N 308) ORGOVYX (N 622) Leuprolide Acetate (N 308) Day 456%0%7%0%Day 891%0%27%0%Day 1599%12%78%1%Day 2999%82%95%57%Figure 3:Cumulative Incidence of Time to Testosterone 50 ng/dL and 20 ng/dL in HEROIn the clinical trial, PSA levels were monitored and were lowered on average by 65% two weeks after administration of ORGOVYX, 83% after weeks, 92% after 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 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.. ORGOVYX at 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 months. Leuprolide acetate 11.25 mg is dosage regimen that is not recommended for this indication in the US. Figure 2. Figure 3. Figure 3.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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, randomized (2:1), open-label, clinical study in patients with advanced prostate cancer [see Clinical Studies (14)] Patients received orally administered ORGOVYX as 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 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 summarizes the adverse reactions in HERO.Table 1:Adverse Reactions >= 10%) of Patients with Advanced Prostate Cancer Who Received ORGOVYX in HEROAdverse ReactionORGOVYX = 622 Leuprolide Acetate = 308 All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Vascular disorders Hot flush540.6520Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes arthralgia, back pain, pain in extremity, musculoskeletal pain, myalgia, bone pain, neck pain, arthritis, muculoskeletal stiffness, non-cardiac chest pain, musculoskeletal chest pain, spinal pain, and musculoskeletal discomfort. 301.1291.6General Fatigue Includes fatigue and asthenia. 260.3240Gastrointestinal disorders Diarrhea Includes diarrhea and colitis. 120.270 Constipation120100Clinically relevant adverse reactions in 10% of patients who received ORGOVYX included increased weight, insomnia, gynecomastia, hyperhidrosis, depression, and decreased libido.Table 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 HEROORGOVYX 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 baseline value and at least one post-treatment value. Leuprolide Acetate Laboratory TestAll Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) Chemistry Glucose increased442.9546 Triglycerides increased352360.7 ALT increased270.3280 AST increased180190.3Hematology Hemoglobin decreased280.5290.7.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None 4). None 4).

DESCRIPTION SECTION.

11 DESCRIPTION. Relugolix is 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-ylphenyl)-N-methoxyurea.The molecular weight is 623.63 daltons and the molecular formula is 29H 27F 2N 7O 5S. The structural formula is: Relugolix is white to off-white to slightly yellow solid with solubility of 0.04 mg per mL in water at 25C.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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Recommended Dosage: 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). Recommended Dosage: 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 loading dose of 360 mg on the first day and continue treatment with 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 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 days, restart ORGOVYX with loading dose of 360 mg on the first day, and continue with 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 hours [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)] Treatment with ORGOVYX may be interrupted for up to two weeks if short course of treatment with 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)].

DOSAGE FORMS & STRENGTHS SECTION.

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). Tablets: 120 mg 3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. P-gp Inhibitors: Avoid co-administration. If unavoidable, take ORGOVYX first, separate dosing by at least 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 InhibitorsCo-administration of ORGOVYX with 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 hours, and monitor patients more frequently for adverse reactions [see Dosage and Administration (2.2)] Treatment with ORGOVYX may be interrupted for up to weeks for short course of treatment with certain P-gp inhibitors.If treatment with ORGOVYX is interrupted for more than days, resume administration of ORGOVYX with 360 mg loading dose on the first day, followed by 120 mg once daily.. Combined P-gp and Strong CYP3A InducersCo-administration of ORGOVYX with combined P-gp and strong CYP3A inducer decreases the AUC and 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Contraception. MalesBased 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 weeks after the last dose of ORGOVYX [see Use in Specific Populations (8.1)]. Infertility. MalesBased 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)].

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 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 desiccant and is closed with child-resistant induction seal cap. The blister cards contain nine tablets packaged in carton (NDC 72974-120-02). Each ORGOVYX tablet contains 120 mg of relugolix.. Store ORGOVYX at room temperature. Do not store above 30C (86F).Dispense to patients in original container only.For bottles, keep container tightly closed after first opening.Keep out of reach of children.. Store ORGOVYX at room temperature. Do not store above 30C (86F).. Dispense to patients in original container only.. For bottles, keep container tightly closed after first opening.. Keep out of reach of children.

INDICATIONS & USAGE SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. QT/QTc Interval ProlongationAdvise 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)] . 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)] . Androgen DeprivationInform 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)] . 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 ToxicityInform patients that ORGOVYX can be harmful to 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 weeks after the last dose of ORGOVYX [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)]. Inform patients that ORGOVYX can be harmful to 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 weeks after the last dose of ORGOVYX [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)]. InfertilityInform patients that ORGOVYX may cause infertility [see Use in Specific Populations (8.3)] . Inform patients that ORGOVYX may cause infertility [see Use in Specific Populations (8.3)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryThe 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 DataIn lactating rats administered 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 hours post-dose.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Relugolix is 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.

NONCLINICAL TOXICOLOGY SECTION.

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 >= 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 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 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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 120 mg Tablet Bottle Label. NDC 72974-120-01 Rx only ORGOVYX (TM) (relugolix) tablets 120 mg30 tablets. PRINCIPAL DISPLAY PANEL 120 mg Tablet Bottle Label.

PEDIATRIC USE SECTION.

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

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Pituitary and Gonadal HormonesRelugolix reduced LH, FSH (Figure 1), and testosterone concentrations after oral administration of the recommended loading dose of 360 mg and 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 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 ElectrophysiologyIn 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 times the recommended loading dose, respectively).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. After administration of single doses ranging from 60 mg to 360 mg (0.17 to 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 max increases greater than proportionally to dose. After administration of single 360 mg loading dose in patients, the mean (+- standard deviation [+- SD]) of AUC 0-24 and max of relugolix were 985 (+- 742) ng.hr/mL and 215 (+- 184) ng/mL, respectively. After administration of 120 mg dose once daily in patients, the mean (+- SD) of AUC 0-24 and 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. AbsorptionRelugolix is substrate for intestinal P-gp. The mean (CV%) absolute bioavailability of relugolix is approximately 12% (62%). The median (range) max of relugolix is 2.25 hours (0.5 to 5.0 hours). Effect of FoodNo clinically meaningful differences in the pharmacokinetics of relugolix were observed following consumption of high-calorie, high-fat meal (approximately 800 to 1000 calories with 500, 220, and 124 from fat, carbohydrate, and protein, respectively).. DistributionPlasma protein binding of relugolix is 68 to 71%, primarily to albumin and to lesser extent to 1-acid glycoprotein. The mean blood-to-plasma ratio is 0.78. EliminationThe 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 L/h.. MetabolismRelugolix is metabolized primarily by CYP3A and to lesser extent by CYP2C8 in vitro.. ExcretionAfter oral administration of 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 PopulationsNo 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 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 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 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 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 substrate of P-gp, but not 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe 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 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 DataIn 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 dose of mg/kg/day (approximately 0.3 times the human exposure at the recommended dose of 120 mg daily based on AUC).

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: December 2020PATIENT INFORMATION ORGOVYX (or-GO-vix) (relugolix) Tablets What is ORGOVYXORGOVYX is prescription medicine used in adults for the treatment of advanced prostate cancer.It is not known if ORGOVYX is safe or effective in females.It is not known if ORGOVYX is safe or effective in children.Before taking ORGOVYX, tell your healthcare provider about all of your medical conditions, including if you:have any heart problems, including condition called long QT syndrome.are pregnant or plan to become pregnant. ORGOVYX can harm your unborn baby and cause loss of pregnancy (miscarriage).have partner who is pregnant or may become pregnant. Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ORGOVYX and for weeks after the last dose of ORGOVYX. are breastfeeding or plan to breastfeed. It is not known if ORGOVYX passes into your breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking ORGOVYX with certain other medicines can affect how ORGOVYX works or may cause side effects. You should not start or stop any medicine before you talk with your healthcare provider who prescribed ORGOVYX. Know the medicines you take. Keep list of them with you to show to your healthcare provider and pharmacist when you get new medicine. How should take ORGOVYXTake ORGOVYX exactly as your healthcare provider tells you.Take ORGOVYX tablets on your first day of treatment. After that, take ORGOVYX tablet each day.Take ORGOVYX at about the same time each day.Take ORGOVYX with or without food.Swallow ORGOVYX tablets whole. Do not crush or chew tablets.Your healthcare provider may change your dose if needed.Do not change your dose or stop taking ORGOVYX without talking with your healthcare provider first.If you miss dose of ORGOVYX, take it as soon as you remember. If the dose was missed by more than 12 hours, the missed dose should not be taken. Take your next dose at your regular time the next day.What are the possible side effects of ORGOVYXORGOVYX may cause serious side effects, including:Changes in the electrical activity of your heart (QT prolongation). Your healthcare provider may check your body salts (electrolytes) and the electrical activity of your heart during treatment with ORGOVYX. Tell your healthcare provider right away if you get any signs or symptoms of QT prolongation, including: dizzinessfaintingfeeling that your heart is pounding or racing (palpitations)chest painThe most common side effects of ORGOVYX include:hot flushesincreased blood sugar levelsincreased blood fat (triglyceride) levelsmuscle and joint paindecreased blood hemoglobin levelsincreased liver enzymestirednessconstipationdiarrheaOther side effects include weight gain, decreased sex drive, and erectile function problems.ORGOVYX may cause fertility problems in males, which may affect your ability to father children. Talk to your healthcare provider if this is concern for you.These are not all the possible side effects of ORGOVYX.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ORGOVYXStore ORGOVYX at room temperature. Do not store ORGOVYX above 86F (30C).Keep the bottle tightly closed after you first open it.The ORGOVYX bottle contains desiccant to help keep your medicine dry (protect it from moisture). Do not remove the desiccant from the bottle.Keep ORGOVYX and all medicines out of the reach of children.General information about the safe and effective use of ORGOVYX.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ORGOVYX for condition for which it was not prescribed. Do not give ORGOVYX to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about ORGOVYX that is written for health professionals.What are the ingredients in ORGOVYXActive ingredient: relugolix Inactive ingredients: mannitol, sodium starch glycolate, hydroxypropyl cellulose, magnesium stearate, hypromellose, titanium dioxide, ferric oxide red, and carnauba wax. Manufactured by: Bushu Pharmaceuticals, Ltd, Kawagoe, Saitama, Japan Manufactured for: Myovant Sciences, Inc., Brisbane, CA 94005 For more information, go to www.orgovyx.com or call 1-833-MYOVANT (1-833-696-8268).214621-MS-000. have any heart problems, including condition called long QT syndrome.. are pregnant or plan to become pregnant. ORGOVYX can harm your unborn baby and cause loss of pregnancy (miscarriage).. have partner who is pregnant or may become pregnant. Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ORGOVYX and for weeks after the last dose of ORGOVYX. Males who have female partners who are able to become pregnant should use effective birth control (contraception) during treatment with ORGOVYX and for weeks after the last dose of ORGOVYX.. are breastfeeding or plan to breastfeed. It is not known if ORGOVYX passes into your breast milk.. Take ORGOVYX exactly as your healthcare provider tells you.. Take ORGOVYX tablets on your first day of treatment. After that, take ORGOVYX tablet each day.. Take ORGOVYX at about the same time each day.. Take ORGOVYX with or without food.. Swallow ORGOVYX tablets whole. Do not crush or chew tablets.. Your healthcare provider may change your dose if needed.. Do not change your dose or stop taking ORGOVYX without talking with your healthcare provider first.. If you miss dose of ORGOVYX, take it as soon as you remember. If the dose was missed by more than 12 hours, the missed dose should not be taken. Take your next dose at your regular time the next day.. Changes in the electrical activity of your heart (QT prolongation). Your healthcare provider may check your body salts (electrolytes) and the electrical activity of your heart during treatment with ORGOVYX. Tell your healthcare provider right away if you get any signs or symptoms of QT prolongation, including: dizziness. fainting. feeling that your heart is pounding or racing (palpitations). chest pain. hot flushes. increased blood sugar levels. increased blood fat (triglyceride) levels. muscle and joint pain. decreased blood hemoglobin levels. increased liver enzymes. tiredness. constipation. diarrhea. Store ORGOVYX at room temperature. Do not store ORGOVYX above 86F (30C).. Keep the bottle tightly closed after you first open it.. The ORGOVYX bottle contains desiccant to help keep your medicine dry (protect it from moisture). Do not remove the desiccant from the bottle.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage. Initiate treatment of ORGOVYX with loading dose of 360 mg on the first day and continue treatment with 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 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 days, restart ORGOVYX with loading dose of 360 mg on the first day, and continue with 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.

STORAGE AND HANDLING SECTION.

Store ORGOVYX at room temperature. Do not store above 30C (86F).Dispense to patients in original container only.For bottles, keep container tightly closed after first opening.Keep out of reach of children.. Store ORGOVYX at room temperature. Do not store above 30C (86F).. Dispense to patients in original container only.. For bottles, keep container tightly closed after first opening.. Keep out of reach of children.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThe 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 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 DataIn 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 dose of 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 SummaryThe 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 DataIn lactating rats administered 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 hours post-dose.. 8.3 Females and Males of Reproductive Potential. Contraception. MalesBased 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 weeks after the last dose of ORGOVYX [see Use in Specific Populations (8.1)]. Infertility. MalesBased 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. QT/QTc Interval Prolongation: Androgen deprivation therapy may prolong the QT interval 5.1). Embryo-Fetal Toxicity: ORGOVYX can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception 5.2, 8.1, 8.3). QT/QTc Interval Prolongation: Androgen deprivation therapy may prolong the QT interval 5.1). Embryo-Fetal Toxicity: ORGOVYX can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception 5.2, 8.1, 8.3). 5.1 QT/QTc Interval Prolongation. Androgen deprivation therapy, such as ORGOVYX may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, or frequent electrolyte abnormalities and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes [see Clinical Pharmacology (12.2)]. 5.2 Embryo-Fetal Toxicity 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 pregnant female. In an animal reproduction study, oral administration of relugolix to pregnant rabbits during the period of 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 area under the curve (AUC). Advise males with female partners of reproductive potential to use effective contraception during treatment and for weeks after the last dose of ORGOVYX [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)] . 5.3 Laboratory Testing. Therapy with ORGOVYX results in suppression of the pituitary gonadal system. Results of diagnostic tests of the pituitary gonadotropic and gonadal functions conducted during and after ORGOVYX may be affected. The therapeutic effect of ORGOVYX should be monitored by measuring serum concentrations of prostate specific antigen (PSA) periodically. If PSA increases, serum concentrations of testosterone should be measured.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Orgovyx. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Skin and subcutaneous tissue disorders: angioedema, urticaria.

RECENT MAJOR CHANGES SECTION.

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