Darolutamide

5 WARNINGS AND PRECAUTIONS Ischemic Heart Disease : Optimize management of cardiovascular risk factors. Monitor for signs and symptoms of coronary artery disease. Discontinue NUBEQA for Grade 3-4 events. ( 5.1 ) Seizure : Consider discontinuation of NUBEQA in patients who develop a seizure during treatment. ( 5.2 ) Embryo-Fetal Toxicity : NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 Ischemic Heart Disease Ischemic heart disease, including fatal cases, occurred in patients receiving NUBEQA. In a pooled analysis of ARAMIS and ARANOTE, ischemic heart disease occurred in 3.4% of patients receiving NUBEQA and 2.2% receiving placebo, including Grade 3-4 events in 1.4% and 0.3%, respectively. Ischemic events led to death in 0.4% of patients receiving NUBEQA and 0.4% receiving placebo. In ARASENS, ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel and 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% and 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel and 0% receiving placebo with docetaxel. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue NUBEQA for Grade 3-4 ischemic heart disease. 5.2 Seizure Seizure occurred in patients receiving NUBEQA. In a pooled analysis of ARAMIS and ARANOTE, Grade 1-3 seizure occurred in 0.2% of patients receiving NUBEQA. Seizure occurred from 261 to 665 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.8% of patients receiving NUBEQA with docetaxel, including two Grade 3 events. Seizure occurred from 38 to 1754 days after initiation of NUBEQA. It is unknown whether anti-epileptic medications will prevent seizures with NUBEQA. Advise patients of the risk of developing a seizure while receiving NUBEQA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others. Consider discontinuation of NUBEQA in patients who develop a seizure during treatment. 5.3 Embryo-Fetal Toxicity The safety and efficacy of NUBEQA have not been established in females. Based on its mechanism of action, NUBEQA can cause fetal harm and loss of pregnancy when administered to a pregnant female [see Clinical Pharmacology (12.1) ] . Advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose of NUBEQA [see Use in Specific Populations (8.1 , 8.3) ] .

6 ADVERSE REACTIONS In nmCRPC and mCSPC : The most common adverse reactions (>10% with a ≥2% increase over placebo), including laboratory test abnormalities, are increased AST, decreased neutrophil count, increased bilirubin, fatigue, and increased ALT. ( 6.1 ) In mCSPC in combination with docetaxel : The most common adverse reactions (≥10% with a ≥2% increase over placebo) are constipation, rash, decreased appetite, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) are anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 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 pooled data in WARNINGS and PRECAUTIONS reflect two randomized clinical trials [ARAMIS, ARANOTE] in patients with nmCRPC (N = 954) and mCSPC (N = 445) treated with NUBEQA. In these trials, the median duration of treatment was 18.2 months (range 0.03 to 44.3) for patients who received NUBEQA [ see Clinical Studies (14) ]. In this pooled safety population, the most common adverse reactions (>10% with a ≥2% increase over placebo), including laboratory test abnormalities were increased AST, decreased neutrophil count, increased bilirubin, fatigue and increased ALT. The safety of NUBEQA in combination with docetaxel in mCSPC is based on data from 1302 patients of whom 652 received at least one dose of NUBEQA in the ARASENS study [ see Clinical Studies (14) ]. Non-Metastatic Castration Resistant Prostate Cancer ARAMIS The safety of NUBEQA in nmCRPC patients was evaluated in ARAMIS, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study [see Clinical Studies (14) ] . Patients received either NUBEQA at a dose of 600 mg, or a placebo, twice a day. All patients in the ARAMIS study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. Among patients who received NUBEQA, the median duration of exposure was 14.8 months (range: 0 to 44.3 months). Serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in ≥1% of patients who received NUBEQA included urinary retention, pneumonia and hematuria. Fatal adverse reactions occurred in 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo. Fatal adverse reactions that occurred in ≥2 patients who received NUBEQA included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%). Permanent discontinuation of NUBEQA due to adverse reactions occurred in 9% of patients receiving NUBEQA. The most common adverse reactions requiring permanent discontinuation in patients who received NUBEQA included cardiac failure (0.4%), and death (0.4%). Dosage interruptions due to adverse reactions occurred in 13% of patients treated with NUBEQA. The most common adverse reactions requiring dosage interruption in patients who received NUBEQA included hypertension (0.6%), diarrhea (0.5%), and pneumonia (0.5%). Dosage reductions due to adverse reactions occurred in 6% of patients treated with NUBEQA. The most common adverse reactions requiring dosage reduction in patients treated with NUBEQA included fatigue (0.7%), hypertension (0.3%), and nausea (0.3%). The most common (>2% with a ≥2% increase compared to placebo) adverse reactions, including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity, and rash. Table 1 summarizes the adverse reactions in ARAMIS. Table 1: Adverse Reactions (>2% with a ≥2% increase compared to placebo) in Patients with nmCRPC in ARAMIS Adverse Reaction NUBEQA (N=954) Placebo (N=554) All Grades % Grades 3 or 4 % All Grades % Grade 3 or 4 % Fatigue Includes fatigue and asthenia 16 0.6 11 1.1 Pain in extremity 6 0 3 0.2 Rash Includes rash, eczema, rash maculo-papular, dermatitis, erythema multiforme, rash macular, rash papular, rash pustular, skin exfoliation 4 0.1 1.4 0 Clinically relevant adverse reactions occurring in 2% or more of patients treated with NUBEQA included ischemic heart disease (4%) and heart failure (2.1%). Table 2 summarizes the laboratory test abnormalities in ARAMIS. Table 2: Laboratory Test Abnormalities in ARAMIS Laboratory Abnormality NUBEQA (N=954) The denominator used to calculate the rate varied based on the number of patients with a baseline value and at least one post-treatment value. Placebo (N=554) All Grades % Grade 3 or 4 % All Grades % Grade 3 or 4 % AST increased 23 0.5 14 0.2 Neutrophil count decreased 20 4 9 0.6 Bilirubin increased 16 0.1 7 0 Metastatic Castration-Sensitive Prostate Cancer ARANOTE The safety of NUBEQA in mCSPC patients was evaluated in ARANOTE, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study [see Clinical Studies (14) ]. Patients received either NUBEQA at a dose of 600 mg, or a placebo, twice a day. All patients in the ARANOTE study received a concomitant gonadotropin-releasing hormone (GnRH) agonist or antagonist or had a bilateral orchiectomy. Among patients who received NUBEQA, the median duration of exposure was 24 months (range: 0.03 to 39 months). Serious adverse reactions occurred in 24% of patients receiving NUBEQA. Serious adverse reactions in ≥1% of patients who received NUBEQA included pneumonia (2%), urinary tract infection (1.8%), musculoskeletal pain (1.6%), hemorrhage (1.6%), arrhythmias (1.3%), and spinal cord compression (1.1%). Fatal adverse reactions occurred in 4.7% of patients receiving NUBEQA and those that occurred in ≥2 patients included sepsis (1.1%), craniocerebral injury (0.4%), and myocardial infarction (0.4%). Permanent discontinuation of NUBEQA due to adverse reactions occurred in 6% of patients treated in the NUBEQA arm. The most common adverse reactions which resulted in permanent discontinuation of NUBEQA were increased ALT, increased AST, craniocerebral injury, myocardial infarction, and rash (all with 0.4%). Dosage interruptions of NUBEQA due to adverse reactions occurred in 14% of patients treated in the NUBEQA arm. The most common adverse reactions requiring dosage interruption of NUBEQA were increased AST (1.6%), increased ALT (1.3%), and rash (1.3%). Dosage reductions of NUBEQA due to adverse reactions occurred in 3.6% of patients treated in the NUBEQA arm. The most common adverse reactions requiring dosage reduction of NUBEQA were increased AST (0.7%), rash (0.7%), increased ALT (0.4%), and hypertension (0.4%). Table 3 summarizes the adverse reactions in ARANOTE. Table 3: Adverse Reactions (≥10% with a ≥2% increase compared to placebo) in Patients with mCSPC in ARANOTE Adverse Reaction NUBEQA (N=445) Placebo (N=221) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Urinary Tract Infection 12 1.8 8 0.5 Clinically relevant adverse reactions in 2%) adverse reactions requiring dosage interruption of NUBEQA were increased alanine aminotransferase (ALT) (3.2%), increased AST (3.1%) and febrile neutropenia (2.1%). Dosage reductions of NUBEQA due to adverse reactions occurred in 9% of patients treated in the NUBEQA with docetaxel arm. The most common (>2%) adverse reactions requiring dosage reduction of NUBEQA were increased ALT (2.8%) and increased AST (2.5%). The most common ( > 10% with a ≥2% increase over placebo with docetaxel) adverse reactions are constipation, rash, decreased appetite, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) are anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Table 5 summarizes the adverse reactions in ARASENS. Table 5: Adverse Reactions (≥10% with a ≥2% increase compared to placebo with docetaxel) in ARASENS Adverse Reaction NUBEQA with docetaxel (N=652) Placebo with docetaxel (N=650) All Grades % Grades 3 or 4 % All Grades % Grades 3 or 4 % Constipation 23 0.3 20 0.3 Rash Rash includes rash, rash maculo-papular, palmar-plantar erythrodysesthesia syndrome, eczema, dermatitis, skin exfoliation, dermatitis acneiform, drug eruption, rash pruritic, rash erythematous, erythema multiforme, rash macular, dermatitis exfoliative generalized, penile rash, dyshidrotic eczema, rash papular, dermatitis bullous, rash follicular, rash pustular, rash vesicular, toxic skin eruption 20 1.8 15 0.2 Decreased Appetite 19 0.2 13 0.6 Hemorrhage Hemorrhage includes hematuria, epistaxis, anal hemorrhage, hemorrhoidal hemorrhage, rectal hemorrhage, upper gastrointestinal hemorrhage, hemoptysis, hemorrhage urinary tract, hemorrhagic stroke, subarachnoid hemorrhage, lower gastrointestinal hemorrhage, cystitis hemorrhagic, gastrointestinal hemorrhage, hemorrhage subcutaneous, intra-abdominal hemorrhage, nail bed bleeding, subdural hemorrhage 18 1.4 13 1.4 Weight Increased 18 2.1 16 1.2 Hypertension Hypertension includes hypertension, blood pressure increased, hypertensive emergency and hypertensive crisis. 14 7 10 3.6 Clinically relevant adverse reactions in < 10% of patients who received NUBEQA with docetaxel included fractures (8%), ischemic heart disease (3.2%), seizures (0.6%), and drug-induced liver injury (0.3%). Table 6 summarizes laboratory test abnormalities in the ARASENS study. Table 6: Laboratory Test Abnormalities (≥30%) in ARASENS Laboratory Abnormality NUBEQA with docetaxel The denominator used to calculate the rate varied from 470 to 648 based on the number of patients with a baseline value and at least one post-treatment value. (N=652) Placebo with docetaxel (N=650) All Grades % Grade 3-4 % All Grades % Grade 3-4 % Anemia 72 6 71 7 Hyperglycemia 57 7 53 10 Lymphocyte count decreased 52 12 49 13 Neutrophil count decreased 49 33 44 31 AST increased ALT or AST increases to ≥5 × upper limit of normal (ULN) occurred in 5.3% of patients who received NUBEQA with docetaxel. ALT or AST increases to ≥20 × ULN occurred in 0.3% of patients who received NUBEQA with docetaxel. The median time to onset of any grade ALT or AST increases was 2.8 months (range: 0.03 to 46.9). 40 3.6 35 2.3 ALT increased 37 3.7 31 2.9 Hypocalcemia 31 2.8 28 1.9 Clinically relevant laboratory test abnormalities in < 30% of patients who received NUBEQA with docetaxel included blood bilirubin increased (all grades 20%, Grade 3-4 0.5%) compared to placebo with docetaxel (all grades 10%, grades 3-4 0.3%).

7 DRUG INTERACTIONS Combined P-gp and Strong or Moderate CYP3A Inducers : Avoid concomitant use. ( 7.1 ) Combined P-gp and Strong CYP3A Inhibitors : Monitor patients more frequently for NUBEQA adverse reactions. ( 7.1 ) BCRP Substrates : Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions and consider dose reduction of the BCRP substrate drug. ( 7.2 ) OATP1B1 and OATP1B3 Substrates : Concomitant use of NUBEQA may increase the plasma concentrations of OATP1B1 or OATP1B3 substrates. If used together, monitor patients more frequently for adverse reactions and consider dose reduction of these drugs. ( 7.2 ) 7.1 Effects of Other Drugs on NUBEQA Combined P-gp and Strong or Moderate CYP3A4 Inducer Concomitant use of NUBEQA with a combined P-gp and strong or moderate CYP3A4 inducer decreases darolutamide exposure which may decrease NUBEQA activity [see Clinical Pharmacology (12.3) ] . Avoid concomitant use of NUBEQA with combined P-gp and strong or moderate CYP3A4 inducers. Combined P-gp and Strong CYP3A4 Inhibitors Concomitant use of NUBEQA with a combined P-gp and strong CYP3A4 inhibitor increases darolutamide exposure [see Clinical Pharmacology (12.3) ] which may increase the risk of NUBEQA adverse reactions . Monitor patients more frequently for NUBEQA adverse reactions and modify NUBEQA dosage as needed [see Dosage and Administration (2.2) ] . 7.2 Effects of NUBEQA on Other Drugs Breast Cancer Resistance Protein (BCRP) and Organic Anion Transporting Polypeptides (OATP) 1B1 and 1B3 Substrates NUBEQA is an inhibitor of BCRP transporter. Concomitant use of NUBEQA increases the AUC and C max of BCRP substrates [see Clinical Pharmacology (12.3) ], which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions, and consider dose reduction of the BCRP substrate drug. NUBEQA is an inhibitor of OATP1B1 and OATP1B3 transporters. Concomitant use of NUBEQA may increase the plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor patients more frequently for adverse reactions of these drugs and consider dose reduction while patients are taking NUBEQA [see Clinical Pharmacology (12.3) ] , Review the prescribing information of the BCRP, OATP1B1 and OATP1B3 substrates when used concomitantly with NUBEQA.

8 USE IN SPECIFIC POPULATIONS Severe Renal Impairment (not on hemodialysis): Recommended dose is 300 mg twice daily. ( 8.6 ) Moderate Hepatic Impairment: Recommended dose is 300 mg twice daily. ( 8.7 ) 8.1 Pregnancy Risk Summary The safety and efficacy of NUBEQA have not been established in females. Based on its mechanism of action, NUBEQA can cause fetal harm and loss of pregnancy [see Clinical Pharmacology (12.1) ]. Animal embryo-fetal developmental toxicology studies were not conducted with darolutamide. There are no human data on the use of NUBEQA in pregnant females. 8.2 Lactation Risk Summary The safety and efficacy of NUBEQA have not been established in females. There are no data on the presence of darolutamide or its metabolites in human milk, the effect on the breastfed child, or the effect on milk production. 8.3 Females and Males of Reproductive Potential Contraception Males Based on the mechanism of action, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose of NUBEQA [see Use in Specific Populations (8.1) ]. Infertility Males Based on animal studies, NUBEQA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1) ] . 8.4 Pediatric Use Safety and effectiveness of NUBEQA in pediatric patients have not been established. 8.5 Geriatric Use Of the 954 patients who received NUBEQA in ARAMIS, 88% of patients were 65 years and over, and 49% were 75 years and over. Of the 445 patients who received NUBEQA in ARANOTE, 74% of patients were 65 years and over, and 30% were 75 years and over. Of the 652 patients who received NUBEQA in ARASENS, 63% of patients were 65 years and over, and 16% were 75 years and over. No overall differences in safety or efficacy were observed between these patients and younger patients in both studies. 8.6 Renal Impairment Patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m 2 ) who are not receiving hemodialysis have a higher exposure to NUBEQA and reduction of the dose is recommended [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]. No dose reduction is needed for patients with mild or moderate renal impairment (eGFR 30-89 mL/min/1.73 m 2 ) . The effect of end stage renal disease (eGFR ≤15 mL/min/1.73 m 2 ) on darolutamide pharmacokinetics is unknown. 8.7 Hepatic Impairment Patients with moderate hepatic impairment (Child-Pugh Class B) have a higher exposure to NUBEQA and reduction of the dose is recommended [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]. No dose reduction is needed for patients with mild hepatic impairment. The effect of severe hepatic impairment (Child-Pugh C) on darolutamide pharmacokinetics is unknown.