Orgovyx

5 WARNINGS AND PRECAUTIONS QT/QTc Interval Prolongation: Androgen deprivation therapy may prolong the QT interval ( 5.1 ). Hypersensitivity: ORGOVYX can cause hypersensitivity reactions, including angioedema. Withhold ORGOVYX in patients who experience symptoms of hypersensitivity. Discontinue ORGOVYX for severe hypersensitivity reactions and manage as clinically indicated ( 5.2 ). Embryo-Fetal Toxicity: ORGOVYX can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception ( 5.3 , 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 Hypersensitivity Reactions ORGOVYX is contraindicated in patients with severe hypersensitivity to relugolix or any of the product components [see Contraindications ( 4 )] . Hypersensitivity reactions, including pharyngeal edema and other serious cases of angioedema, have been reported postmarketing in patients treated with ORGOVYX. In HERO, patients treated with relugolix reported angioedema (0.2%) [see Clinical Trials Experience ( 6.1 )] . Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue ORGOVYX and promptly seek medical care. Discontinue ORGOVYX for severe hypersensitivity reactions and manage as clinically indicated. 5.3 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 a 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 2 weeks after the last dose of ORGOVYX [see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.1 )] . 5.4 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.

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 Sumitomo Pharma America, at 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 dosing 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 a 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. b Includes fatigue and asthenia. c Includes diarrhea and colitis. 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 a 30 1.1 29 1.6 General Fatigue b 26 0.3 24 0 Gastrointestinal disorders Diarrhea c 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 Laboratory Test ORGOVYX a Leuprolide Acetate a All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%) a 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. 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.

<table ID="t1" width="100%"><caption>Table 1: Adverse Reactions ( &#x2265; 10%) of Patients with Advanced Prostate Cancer Who Received ORGOVYX in HERO </caption><col width="45.020%" align="left"/><col width="13.780%" align="left"/><col width="13.500%" align="left"/><col width="13.400%" align="left"/><col width="14.300%" align="left"/><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^a 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. </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^b Includes fatigue and asthenia. </paragraph></td></tr><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^c Includes diarrhea and colitis. </paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="center" valign="middle" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Adverse Reaction</content></td><td colspan="2" align="center" valign="bottom" styleCode="Toprule Botrule Rrule"><content styleCode="bold">ORGOVYX N = 622</content></td><td colspan="2" align="center" valign="bottom" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Leuprolide Acetate</content> <content styleCode="bold">N = 308</content></td></tr><tr><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">All Grades</content> <content styleCode="bold">(%)</content></td><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Grade 3-4</content> <content styleCode="bold">(%)</content></td><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">All Grades</content> <content styleCode="bold">(%)</content></td><td align="center" valign="top" styleCode="Botrule Rrule"><content styleCode="bold">Grade 3-4</content> <content styleCode="bold">(%)</content></td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Vascular disorders</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Hot flush </td><td align="center" valign="middle" styleCode="Botrule Rrule">54 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.6 </td><td align="center" valign="middle" styleCode="Botrule Rrule">52 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Musculoskeletal and connective tissue disorders</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Musculoskeletal pain^a</td><td align="center" valign="middle" styleCode="Botrule Rrule">30 </td><td align="center" valign="middle" styleCode="Botrule Rrule">1.1 </td><td align="center" valign="middle" styleCode="Botrule Rrule">29 </td><td align="center" valign="middle" styleCode="Botrule Rrule">1.6 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">General</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Fatigue^b</td><td align="center" valign="top" styleCode="Botrule Rrule">26 </td><td align="center" valign="top" styleCode="Botrule Rrule">0.3 </td><td align="center" valign="top" styleCode="Botrule Rrule">24 </td><td align="center" valign="top" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Gastrointestinal disorders</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Diarrhea^c</td><td align="center" valign="middle" styleCode="Botrule Rrule">12 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.2 </td><td align="center" valign="middle" styleCode="Botrule Rrule">7 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="top" styleCode="Botrule Lrule Rrule"> Constipation </td><td align="center" valign="middle" styleCode="Botrule Rrule">12 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">10 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td></tr></tbody></table>

<table ID="t2" width="100%"><caption>Table 2: Select Laboratory Abnormalities ( &#x2265; 15%) That Worsened from Baseline in Patients with Advanced Prostate Cancer Who Received ORGOVYX in HERO </caption><col width="22.244%" align="left"/><col width="19.384%" align="left"/><col width="20.004%" align="left"/><col width="16.923%" align="left"/><col width="21.444%" align="left"/><thead><tr><th rowspan="2" align="center" valign="middle" styleCode="Toprule Botrule Lrule Rrule"><content styleCode="bold">Laboratory Test</content></th><th colspan="2" align="center" valign="middle" styleCode="Toprule Botrule Rrule"><content styleCode="bold">ORGOVYX</content><content styleCode="bold">^a</content></th><th colspan="2" align="center" valign="middle" styleCode="Toprule Botrule Rrule"><content styleCode="bold">Leuprolide Acetate</content><content styleCode="bold">^a</content></th></tr><tr><th align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">All Grades</content> <content styleCode="bold">(%)</content></th><th align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">Grade 3-4</content> <content styleCode="bold">(%)</content></th><th align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">All Grades</content> <content styleCode="bold">(%)</content></th><th align="center" valign="middle" styleCode="Botrule Rrule"><content styleCode="bold">Grade 3-4</content> <content styleCode="bold">(%)</content></th></tr></thead><tfoot><tr><td colspan="5" align="left" valign="top"><paragraph styleCode="footnote">^a 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. </paragraph></td></tr></tfoot><tbody><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Chemistry</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Glucose increased </td><td align="center" valign="middle" styleCode="Botrule Rrule">44 </td><td align="center" valign="middle" styleCode="Botrule Rrule">2.9 </td><td align="center" valign="middle" styleCode="Botrule Rrule">54 </td><td align="center" valign="middle" styleCode="Botrule Rrule">6 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Triglycerides increased </td><td align="center" valign="middle" styleCode="Botrule Rrule">35 </td><td align="center" valign="middle" styleCode="Botrule Rrule">2 </td><td align="center" valign="middle" styleCode="Botrule Rrule">36 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.7 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> ALT increased </td><td align="center" valign="middle" styleCode="Botrule Rrule">27 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.3 </td><td align="center" valign="middle" styleCode="Botrule Rrule">28 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold"> </content>AST increased </td><td align="center" valign="middle" styleCode="Botrule Rrule">18 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0 </td><td align="center" valign="middle" styleCode="Botrule Rrule">19 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.3 </td></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"><content styleCode="bold">Hematology</content></td><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/><td align="center" valign="middle" styleCode="Botrule Rrule"/></tr><tr><td align="left" valign="middle" styleCode="Botrule Lrule Rrule"> Hemoglobin decreased </td><td align="center" valign="middle" styleCode="Botrule Rrule">28 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.5 </td><td align="center" valign="middle" styleCode="Botrule Rrule">29 </td><td align="center" valign="middle" styleCode="Botrule Rrule">0.7 </td></tr></tbody></table>