ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS 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.ARAMIS, randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had non-metastatic, castration-resistant prostate cancer (nmCRPC). In this study, patients received either NUBEQA at dose of 600 mg, or placebo, twice day. All patients in the ARAMIS study received concomitant gonadotropin-releasing hormone (GnRH) analog or had bilateral orchiectomy. The median duration of exposure was 14.8 months (range: to 44.3 months) in patients who received NUBEQA. Overall, serious adverse reactions occurred in 25% of patients receiving NUBEQA and in 20% of patients receiving placebo. Serious adverse reactions in >= % of patients who received NUBEQA included urinary retention, pneumonia and hematuria. Overall 3.9% of patients receiving NUBEQA and 3.2% of patients receiving placebo died from adverse reactions, which included death (0.4%), cardiac failure (0.3%), cardiac arrest (0.2%), general physical health deterioration (0.2%), and pulmonary embolism (0.2%) for NUBEQA.Permanent discontinuation due to adverse reactions occurred in 9% of patients receiving NUBEQA or placebo. The most frequent 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 frequent 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 frequent adverse reactions requiring dosage reduction in patients treated with NUBEQA included fatigue (0.7%), hypertension (0.3%), and nausea (0.3%). Table shows adverse reactions in ARAMIS reported in the NUBEQA arm with >=2% absolute increase in frequency compared to placebo. Table shows laboratory test abnormalities related to NUBEQA treatment and reported more frequently in NUBEQA-treated patients compared to placebo-treated patients in the ARAMIS study. Table 1: Adverse Reactions in ARAMISAdverse ReactionCommon Terminology Criteria for Adverse Events (CTCAE) version 4.03 NUBEQA (n=954)Placebo (n=554)All Grades%Grades 3%All Grades%Grade 3% FatigueIncludes fatigue and asthenia 160.6111.1 Pain in extremity6030.2 Rash30.110Additionally, clinically significant adverse reactions occurring in 2% or more of patients treated with NUBEQA included ischemic heart disease (4.0% versus 3.4% on placebo) and heart failure (2.1% versus 0.9% on placebo).Table 2: Laboratory Test Abnormalities in ARAMISLaboratory Abnormality NUBEQA(N=954)The denominator used to calculate the rate varied based on the number of patients with baseline value and at least one post-treatment value. Placebo(N=554) All GradesCommon Terminology Criteria for Adverse Events (CTCAE) version 4.03. %Grade 3-4 %All Grades %Grade 3-4 Neutrophil count decreased 20490.6 AST increased230.5140.2 Bilirubin increased 160.170. The most common adverse reactions (>=2%) are fatigue, pain in extremity, and rash. (6) 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.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies to evaluate the carcinogenic potential of darolutamide have not been conducted. Darolutamide was clastogenic in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Darolutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in the in vivo combined bone marrow micronucleus assay and the Comet assay in the liver and duodenum of the rat. Fertility studies in animals have not been conducted with darolutamide. In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), tubular dilatation of testes, hypospermia, and atrophy of seminal vesicles, testes, prostate gland and epididymides were observed at doses >= 100 mg/kg/day in rats (0.6 times the human exposure based on AUC) and >= 50 mg/kg/day in dogs (approximately times the human exposure based on AUC).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Darolutamide is an androgen receptor (AR) inhibitor. Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. major metabolite, keto-darolutamide, exhibited similar in vitro activity to darolutamide. In addition, darolutamide functioned as progesterone receptor (PR) antagonist in vitro (approximately 1% activity compared to AR). Darolutamide decreased prostate cancer cell proliferation in vitro and tumor volume in mouse xenograft models of prostate cancer. 12.2 Pharmacodynamics Darolutamide exposure at 600 mg twice daily results in PSA mean reduction of more than 90% from baseline.. Cardiac Electrophysiology The effect of darolutamide (600 mg twice daily) on the QTc interval was evaluated in subgroup of 500 patients in the ARAMIS study. No large mean increase in QTc (i.e., 20 ms) was detected. 12.3 Pharmacokinetics Following administration of 600 mg twice daily, darolutamide mean (%CV) steady-state peak plasma concentration (Cmax) is 4.79 mg/L (30.9%) and area under the plasma concentration-time curve from time to 12 hours (AUC12h) is 52.82 houg/mL (33.9%). Steady-state is reached 2-5 days after repeated dosing with food, with an approximate 2-fold accumulation. The exposure (Cmax and AUC12) of the darolutamide and the active metabolite keto-darolutamide increase in nearly dose-proportional manner in the dose range of 100 to 700 mg (0.17 to 1.17 times the approved recommended dosage). No further increase in darolutamide exposure was observed at 900 mg twice daily (1.5 times the approved recommended dosage). Absorption Darolutamide Cmax is reached approximately hours after administration of single 600 mg oral dose. The absolute bioavailability is approximately 30% following oral administration of NUBEQA tablet containing 300 mg darolutamide under fasted conditions. Food EffectBioavailability of darolutamide increased by 2.0 to 2.5-fold when administered with food. similar increase of exposure was observed for the active metabolite keto-darolutamide. Distribution The apparent volume of distribution of darolutamide after intravenous administration is 119 L. Protein binding is 92% for darolutamide and 99.8% for the active metabolite, keto-darolutamide. Serum albumin is the main binding protein for darolutamide and keto-darolutamide. EliminationThe effective half-life of darolutamide and keto-darolutamide is approximately 20 hours in patients. The clearance (%CV) of darolutamide following intravenous administration is 116 mL/min (39.7%).. Metabolism Darolutamide is primarily metabolized by CYP3A4, as well as by UGT1A9 and UGT1A1. Keto-darolutamide total exposure in plasma is 1.7-fold higher compared to darolutamide. Excretion After single radiolabeled dose as an oral solution, total of 63.4% of darolutamide-related material is excreted in the urine (approximately 7% unchanged) and 32.4% (approximately 30% unchanged) in the feces. More than 95% of the dose was recovered within days after administration. Specific Populations In nmCRPC patients, no clinically significant differences in the pharmacokinetics of darolutamide were observed based on age (48-95 years), race (White, Japanese, non-Japanese Asian, Black or African American), mild to moderate renal impairment (eGFR 30-89 mL/min/1.73m2), or mild hepatic impairment. In non-cancer subjects with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) not receiving dialysis or with moderate hepatic impairment (Child-Pugh Class B), NUBEQA exposure increased by about 2.5- and 1.9-fold, respectively, compared to healthy subjects. The effect of end-stage renal disease (eGFR <15 mL/min/1.73 m2) or severe hepatic impairment (Child-Pugh C) on darolutamide pharmacokinetics has not been studied.. Drug Interaction Studies Clinical Studies Combined P-gp and Strong CYP3A4 InducersConcomitant use of rifampicin (a combined P-gp and strong CYP3A4 inducer) decreased mean darolutamide AUC0-72 by 72% and Cmax by 52%. The decrease of darolutamide exposure by moderate CYP3A4 inducers is expected to be in the range of 36% 58%.. Combined P-gp and Strong CYP3A4 Inhibitors Itraconazole (a strong combined CYP3A4 and P-gp inhibitor) increased mean darolutamide AUC0-72 by 1.7- and Cmax by 1.4-fold. CYP3A4 substrates Concomitant use of darolutamide decreased the mean AUC and Cmax of midazolam (CYP3A4 substrate) by 29% and 32%, respectively. No clinically relevant differences in the pharmacokinetics of midazolam were observed when used concomitantly with darolutamide.. BCRP, OATP1B1 and OATP1B3 Substrates Concomitant use of darolutamide increased the mean AUC and Cmax of rosuvastatin (BCRP, OATP1B1 and OATP1B3 substrate) by approximately 5-fold.. P-gp Substrates No clinically relevant differences in the pharmacokinetics of dabigatran (P-gp substrate) were observed when used concomitantly with darolutamide. In Vitro Studies In vitro, darolutamide did not inhibit the major CYP enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) or transporters (MRP2, BSEP, OATs, OCTs, MATEs, OATP2B1, and NTCP) at clinically relevant concentrations.

CLINICAL STUDIES SECTION.

Clinical Studies Combined P-gp and Strong CYP3A4 InducersConcomitant use of rifampicin (a combined P-gp and strong CYP3A4 inducer) decreased mean darolutamide AUC0-72 by 72% and Cmax by 52%. The decrease of darolutamide exposure by moderate CYP3A4 inducers is expected to be in the range of 36% 58%.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION NUBEQA is an androgen receptor inhibitor. The chemical name is N-(2S)-1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide. The molecular weight is 398.85 and the molecular formula is C19H19Cl N6O2. The structural formula is:Darolutamide is an optically active with specific rotation value []20 D= 72.2 omL/(dmg), white to greyish- or yellowish white crystalline powder, that is soluble in tetrahydrofuran, but practically insoluble in aqueous medium. Darolutamide has pKa of 11.75.NUBEQA (darolutamide) is supplied as film-coated tablets containing 300 mg of darolutamide for oral use. The inactive ingredients of the tablet are: calcium hydrogen phosphate, croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone 30, hypromellose 15 cP, macrogol 3350, and titanium dioxide.. The molecular weight is 398.85 and the molecular formula is C19H19Cl N6O2. The structural formula is:. chemical structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION NUBEQA 600 mg, (two 300 mg tablets) administered orally twice daily. Swallow tablets whole. Take NUBEQA with food. (2.1) Patients should also receive gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. (2.3) 2.1 Recommended Dosage The recommended dose of NUBEQA is 600 mg (two 300 mg film-coated tablets) taken orally, twice daily, equivalent to total daily dose of 1200 mg. Swallow tablets whole with food [see Clinical Pharmacology (12.3)]. Patients receiving NUBEQA should also receive gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Advise patients to take any missed dose as soon as they remember prior to the next scheduled dose, and not to take two doses together to make up for missed dose. 2.2 Dosage Modification If patient experiences greater than or equal to Grade toxicity or an intolerable adverse reaction, withhold dosing or reduce to 300 mg twice daily until symptoms improve. Then the treatment may be resumed at dose of 600 mg twice daily. Dose reduction below 300 mg twice daily is not recommended. 2.3 Recommended Dosage in Patients with Severe Renal Impairment For patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) not receiving hemodialysis, the recommended dose of NUBEQA is 300 mg twice daily [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].. 2.4 Recommended Dosage in Patients with Moderate Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh Class B), the recommended dose of NUBEQA is 300 mg twice daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Tablets (300 mg): white to off-white oval film-coated tablets marked with 300 on one side and Bayer on the other. Tablets: 300 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oCombined P-gp and Strong or Moderate CYP3A Inducers: Avoid concomitant use. (7.1)oCombined P-gp and Strong CYP3A Inhibitors: Monitor patients more frequently for NUBEQA adverse reactions. (7.1)oBCRP 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).oOATP1B1 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). oCombined P-gp and Strong or Moderate CYP3A Inducers: Avoid concomitant use. (7.1). oCombined P-gp and Strong CYP3A Inhibitors: Monitor patients more frequently for NUBEQA adverse reactions. (7.1). oBCRP 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).. oOATP1B1 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 Effect of Other Drugs on NUBEQA Combined P-gp and Strong or Moderate CYP3A4 Inducer Concomitant use of NUBEQA with 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 clinical combined P-gp and strong or moderate CYP3A4 inducers. Combined P-gp and Strong CYP3A4 Inhibitors Concomitant use of NUBEQA with 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 Cmax 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.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

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 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)].

GERIATRIC USE SECTION.

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. No overall differences in safety or efficacy were observed between these patients and younger patients.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied NUBEQA (darolutamide) 300 mg film-coated tablets are white to off-white, oval shaped tablets, marked with 300 on one side, and BAYER on the other side. NUBEQA 300 mg tablets are available in bottles of 120 tablets.NDC 50419-395-01. 16.2 Storage and Handling Store at 20C to 25C (68F to 77F); excursions permitted between 15C and 30C (59F and 86F) [see USP Controlled Room Temperature]. Keep the bottle tightly closed after first opening.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE NUBEQA is indicated for the treatment of patients with non-metastatic castration resistant prostate cancer (nmCRPC). NUBEQA is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic castration-resistant prostate cancer. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information)Dosage and Administration Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with NUBEQA.Instruct patients to take their dose of two tablets (twice daily). NUBEQA should be taken with food. Each tablet should be swallowed whole.Inform patients that in the event of missed daily dose of NUBEQA, to take any missed dose, as soon as they remember prior to the next scheduled dose, and not to take two doses together to make up for missed dose [see Dosage and Administration (2.1)]. Embryo-Fetal Toxicity Inform patients that NUBEQA can be harmful to developing fetus and can cause loss of pregnancy [see Use in Specific Populations (8.1)].Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for week after the last dose of NUBEQA [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1, 8.3)]. Infertility Advise male patients that NUBEQA may impair fertility [see Use in Specific Populations (8.3)]. Manufactured by: Orion Corporation, Orion Pharma, FI-02101 Espoo, FinlandManufactured for: Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981 USA(C) 2019 Bayer HealthCare Pharmaceuticals Inc.For more information, call Bayer HealthCare Pharmaceuticals Inc. at Bayer at 1-888-842-2937 or go to www.NUBEQA-us.com.

LACTATION SECTION.

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.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Darolutamide is an androgen receptor (AR) inhibitor. Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. major metabolite, keto-darolutamide, exhibited similar in vitro activity to darolutamide. In addition, darolutamide functioned as progesterone receptor (PR) antagonist in vitro (approximately 1% activity compared to AR). Darolutamide decreased prostate cancer cell proliferation in vitro and tumor volume in mouse xenograft models of prostate cancer.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies to evaluate the carcinogenic potential of darolutamide have not been conducted. Darolutamide was clastogenic in an in vitro chromosome aberration assay in human peripheral blood lymphocytes. Darolutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in the in vivo combined bone marrow micronucleus assay and the Comet assay in the liver and duodenum of the rat. Fertility studies in animals have not been conducted with darolutamide. In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), tubular dilatation of testes, hypospermia, and atrophy of seminal vesicles, testes, prostate gland and epididymides were observed at doses >= 100 mg/kg/day in rats (0.6 times the human exposure based on AUC) and >= 50 mg/kg/day in dogs (approximately times the human exposure based on AUC).

OVERDOSAGE SECTION.

10 OVERDOSAGE There is no known specific antidote for darolutamide overdose. The highest dose of NUBEQA studied clinically was 900 mg twice daily, equivalent to total daily dose of 1800 mg. No dose limiting toxicities were observed with this dose. Considering the saturable absorption and the absence of evidence for acute toxicity, an intake of higher than recommended dose of darolutamide is not expected to lead to systemic toxicity in patients with intact hepatic and renal function [see Clinical Pharmacology (12.3)]. In the event of intake of higher than recommended dose in patients with severe renal impairment or moderate hepatic impairment, if there is suspicion of toxicity, interrupt NUBEQA treatment and undertake general supportive measures until clinical toxicity has been diminished or resolved. If there is no suspicion of toxicity, NUBEQA treatment can be continued with the next dose as scheduled.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL 50419-395-01Rx OnlyNUBEQA(darolutamide) tablets300 mg120 film-coated tablets. NUBEQA 300 mg label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use Safety and effectiveness of NUBEQA in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics Darolutamide exposure at 600 mg twice daily results in PSA mean reduction of more than 90% from baseline.. Cardiac Electrophysiology The effect of darolutamide (600 mg twice daily) on the QTc interval was evaluated in subgroup of 500 patients in the ARAMIS study. No large mean increase in QTc (i.e., 20 ms) was detected.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Following administration of 600 mg twice daily, darolutamide mean (%CV) steady-state peak plasma concentration (Cmax) is 4.79 mg/L (30.9%) and area under the plasma concentration-time curve from time to 12 hours (AUC12h) is 52.82 houg/mL (33.9%). Steady-state is reached 2-5 days after repeated dosing with food, with an approximate 2-fold accumulation. The exposure (Cmax and AUC12) of the darolutamide and the active metabolite keto-darolutamide increase in nearly dose-proportional manner in the dose range of 100 to 700 mg (0.17 to 1.17 times the approved recommended dosage). No further increase in darolutamide exposure was observed at 900 mg twice daily (1.5 times the approved recommended dosage). Absorption Darolutamide Cmax is reached approximately hours after administration of single 600 mg oral dose. The absolute bioavailability is approximately 30% following oral administration of NUBEQA tablet containing 300 mg darolutamide under fasted conditions. Food EffectBioavailability of darolutamide increased by 2.0 to 2.5-fold when administered with food. similar increase of exposure was observed for the active metabolite keto-darolutamide. Distribution The apparent volume of distribution of darolutamide after intravenous administration is 119 L. Protein binding is 92% for darolutamide and 99.8% for the active metabolite, keto-darolutamide. Serum albumin is the main binding protein for darolutamide and keto-darolutamide. EliminationThe effective half-life of darolutamide and keto-darolutamide is approximately 20 hours in patients. The clearance (%CV) of darolutamide following intravenous administration is 116 mL/min (39.7%).. Metabolism Darolutamide is primarily metabolized by CYP3A4, as well as by UGT1A9 and UGT1A1. Keto-darolutamide total exposure in plasma is 1.7-fold higher compared to darolutamide. Excretion After single radiolabeled dose as an oral solution, total of 63.4% of darolutamide-related material is excreted in the urine (approximately 7% unchanged) and 32.4% (approximately 30% unchanged) in the feces. More than 95% of the dose was recovered within days after administration. Specific Populations In nmCRPC patients, no clinically significant differences in the pharmacokinetics of darolutamide were observed based on age (48-95 years), race (White, Japanese, non-Japanese Asian, Black or African American), mild to moderate renal impairment (eGFR 30-89 mL/min/1.73m2), or mild hepatic impairment. In non-cancer subjects with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) not receiving dialysis or with moderate hepatic impairment (Child-Pugh Class B), NUBEQA exposure increased by about 2.5- and 1.9-fold, respectively, compared to healthy subjects. The effect of end-stage renal disease (eGFR <15 mL/min/1.73 m2) or severe hepatic impairment (Child-Pugh C) on darolutamide pharmacokinetics has not been studied.. Drug Interaction Studies Clinical Studies Combined P-gp and Strong CYP3A4 InducersConcomitant use of rifampicin (a combined P-gp and strong CYP3A4 inducer) decreased mean darolutamide AUC0-72 by 72% and Cmax by 52%. The decrease of darolutamide exposure by moderate CYP3A4 inducers is expected to be in the range of 36% 58%.. Combined P-gp and Strong CYP3A4 Inhibitors Itraconazole (a strong combined CYP3A4 and P-gp inhibitor) increased mean darolutamide AUC0-72 by 1.7- and Cmax by 1.4-fold. CYP3A4 substrates Concomitant use of darolutamide decreased the mean AUC and Cmax of midazolam (CYP3A4 substrate) by 29% and 32%, respectively. No clinically relevant differences in the pharmacokinetics of midazolam were observed when used concomitantly with darolutamide.. BCRP, OATP1B1 and OATP1B3 Substrates Concomitant use of darolutamide increased the mean AUC and Cmax of rosuvastatin (BCRP, OATP1B1 and OATP1B3 substrate) by approximately 5-fold.. P-gp Substrates No clinically relevant differences in the pharmacokinetics of dabigatran (P-gp substrate) were observed when used concomitantly with darolutamide. In Vitro Studies In vitro, darolutamide did not inhibit the major CYP enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) or transporters (MRP2, BSEP, OATs, OCTs, MATEs, OATP2B1, and NTCP) at clinically relevant concentrations.

PREGNANCY SECTION.

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.

RISKS.

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.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Package Insert PATIENT INFORMATIONNUBEQA(R) (NOO-b-k) (darolutamide) tablets What is NUBEQANUBEQA is prescription medicine used to treat men with prostate cancer that has not spread to other parts of the body and no longer responds to medical or surgical treatment that lowers testosterone.It is not known if NUBEQA is safe and effective in females. It is not known if NUBEQA is safe and effective in children.Before taking NUBEQA, tell your healthcare provider about all your medical conditions, including if you:ohave kidney or liver problemsoare pregnant or plan to become pregnant. NUBEQA can cause harm to your unborn baby and loss of pregnancy (miscarriage).ohave partner who may become pregnant. Males who have female partners who may become pregnant should use effective birth control (contraception) during treatment and for week after the last dose of NUBEQA. Talk with your healthcare provider about birth control methods.oare breastfeeding or plan to breastfeed. It is not known if NUBEQA passes into breast milk.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. NUBEQA may affect the way other medicines work and other medicines may affect how NUBEQA works.You should not start or stop any medicine before you talk with the healthcare provider that prescribed NUBEQA.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 NUBEQAoTake NUBEQA exactly as your healthcare provider tells you.oYour healthcare provider may change your dose if needed.oTake your prescribed dose of NUBEQA times day with food.oSwallow NUBEQA tablets whole.oIf you are receiving gonadotropin-releasing hormone (GnRH) analog therapy, you should continue with this treatment during your treatment with NUBEQA unless you have had surgery to lower the amount of testosterone in your body (surgical castration).oIf you miss dose of NUBEQA, take your prescribed dose as soon as you remember before the next scheduled dose. Do not take doses together to make up for missed dose.oIf you take more NUBEQA than prescribed, call your healthcare provider right away.What are the possible side effects of NUBEQAThe most common side effects of NUBEQA include:ofeeling more tired than usualoarm, leg, hand or foot painorashodecreased white blood cells (neutropenia)ochanges in liver function testsNUBEQA may cause fertility problems in males, which may affect the ability to father children. Talk to your healthcare provider if you have concerns about fertility. These are not all the possible side effects of NUBEQA.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store NUBEQAoStore NUBEQA at room temperature between 68F to 77F (20C to 25C).oKeep the bottle tightly closed after you first open it.Keep NUBEQA and all medicines out of the reach of children.General information about the safe and effective use of NUBEQA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use NUBEQA for condition for which it was not prescribed. Do not give NUBEQA to other people, even if they have the same symptoms that you have. It may harm them.You can ask your healthcare provider or pharmacist for information about NUBEQA that is written for health professionals.What are the ingredients in NUBEQAActive ingredient:darolutamideInactive ingredients:calcium hydrogen phosphate, croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone 30, hypromellose 15 cP, macrogol 3350, and titanium dioxide.Manufactured by: Orion Corporation, Orion Pharma, FI-02101 Espoo, FinlandManufactured for: Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981 USA(C) 2019 Bayer HealthCare Pharmaceuticals Inc. For more information, call Bayer HealthCare Pharmaceuticals Inc. at Bayer at 1-888-842-2937 or go to www.NUBEQA-us.com This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 1/2021. ohave kidney or liver problems. oare pregnant or plan to become pregnant. NUBEQA can cause harm to your unborn baby and loss of pregnancy (miscarriage).. ohave partner who may become pregnant. Males who have female partners who may become pregnant should use effective birth control (contraception) during treatment and for week after the last dose of NUBEQA. Talk with your healthcare provider about birth control methods.. oare breastfeeding or plan to breastfeed. It is not known if NUBEQA passes into breast milk.. oTake NUBEQA exactly as your healthcare provider tells you.. oYour healthcare provider may change your dose if needed.. oTake your prescribed dose of NUBEQA times day with food.. oSwallow NUBEQA tablets whole.. oIf you are receiving gonadotropin-releasing hormone (GnRH) analog therapy, you should continue with this treatment during your treatment with NUBEQA unless you have had surgery to lower the amount of testosterone in your body (surgical castration).. oIf you miss dose of NUBEQA, take your prescribed dose as soon as you remember before the next scheduled dose. Do not take doses together to make up for missed dose.. oIf you take more NUBEQA than prescribed, call your healthcare provider right away.. ofeeling more tired than usual. oarm, leg, hand or foot pain. orash. odecreased white blood cells (neutropenia). ochanges in liver function tests. oStore NUBEQA at room temperature between 68F to 77F (20C to 25C).. oKeep the bottle tightly closed after you first open it.. This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: 1/2021.

SPL UNCLASSIFIED SECTION.

2.1 Recommended Dosage The recommended dose of NUBEQA is 600 mg (two 300 mg film-coated tablets) taken orally, twice daily, equivalent to total daily dose of 1200 mg. Swallow tablets whole with food [see Clinical Pharmacology (12.3)]. Patients receiving NUBEQA should also receive gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Advise patients to take any missed dose as soon as they remember prior to the next scheduled dose, and not to take two doses together to make up for missed dose.

USE IN SPECIFIC POPULATIONS SECTION.

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 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. No overall differences in safety or efficacy were observed between these patients and younger patients.. 8.6 Renal Impairment Patients with severe renal impairment (eGFR 15-29 mL/min/1.73 m2) who are not receiving hemodialysis have 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 m2). The effect of end stage renal disease (eGFR <=15 mL/min/1.73 m2) on darolutamide pharmacokinetics is unknown.. 8.7 Hepatic Impairment Patients with moderate hepatic impairment (Child-Pugh Class B) have 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception. (5.1, 8.1, 8.3). 5.1 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 pregnant female [see Clinical Pharmacology (12.1)]. Advise males with female partners of reproductive potential to use effective contraception during treatment and for week after the last dose of NUBEQA [see Use in Specific Populations (8.1, 8.3)].

RECENT MAJOR CHANGES SECTION.

Indications and Usage (1)8/2022 Dosage and Administration (2.1)8/2022 Warnings and Precautions (5.1, 5.2)8/2022. Indications and Usage (1)8/2022 Dosage and Administration (2.1)8/2022 Dosage and Administration (2.1)8/2022. Warnings and Precautions (5.1, 5.2)8/2022.