DRUG INTERACTIONS

 • Combined P-gp and Strong or Moderate CYP3A Inducers: Avoid concomitant use. 

• Combined P-gp and Strong CYP3A Inhibitors: Monitor patients more frequently for NUBEQA adverse reactions. 

• 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. 

 DRUG INTERACTIONS

1. Effect 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 

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]which may increase the risk of NUBEQA adverse reactions. 

Monitor patients more frequently for NUBEQA adverse reactions and modify NUBEQA dosage as needed 

2 Effects of NUBEQA on Other Drugs

Breast Cancer Resistance Protein (BCRP) Substrates NUBEQA is an inhibitor of BCRP transporter. Concomitant use of NUBEQA increases the AUC and Cmax of BCRP substrates , 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. 

Consult the approved product labeling of the BCRP substrate when used concomitantly with NUBEQA. 

                      To treat adult patients with non-metastatic castration resistent cancer

ADVERSE REACTIONS

­ The most common adverse reactions (=2%) are fatigue, pain in extremity, and rash.

 PATIENT COUNSELING 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 a 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 a missed dose.

Embryo-Fetal Toxicity

Inform patients that NUBEQA can be harmful to a developing fetus and can cause loss of pregnancy 

Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose of NUBEQA

Infertility

Advise male patients that NUBEQA may impair fertility

Manufactured by: Orion Corporation, Orion Pharma, FI-02101 Espoo, Finland

Manufactured for: Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ 07981 USA © 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

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Darolutamide is an androgen receptor (AR) inhibitor.

Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. A major metabolite, keto-darolutamide, exhibited similar in vitro activity to darolutamide.

In addition, darolutamide functioned as a 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.

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 a subgroup of 500 patients in the ARAMIS study. No large mean increase in QTc (i.e., > 20 ms) was detected. 

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 0 to 12 hours (AUC12h) is 52.82 h•µg/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 a 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 4 hours after administration of a single 600 mg oral dose.

The absolute bioavailability is approximately 30% following oral administration of a NUBEQA tablet containing 300 mg darolutamide under fasted conditions.

Food

Effect Bioavailability of darolutamide increased by 2.0 to 2.5-fold when administered with food. A 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.

Elimination

The 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 a single radiolabeled dose as an oral solution, a 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 7 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 Inducers Concomitant 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 significant differences in the pharmacokinetics of midazolam were observed when used concomitantly with darolutamide.

BCRP Substrates Concomitant use of darolutamide increased the mean AUC and Cmax of rosuvastatin (BCRP substrate) by approximately 5-fold. P-gp Substrates

No clinically significant differences in the pharmacokinetics of dabigatran (P-gp substrate) were observed when used concomitantly with darolutamide. In Vitro Studies In vitro, darolutamide inhibits OATP1B1 and OATP1B3.

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.

  USE IN SPECIFIC POPULATIONS

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 

Animal embryo-fetal developmental toxicology studies were not conducted with darolutamide. There are no human data on the use of NUBEQA in pregnant females.

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.

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.

Infertility Males

Based on animal studies, NUBEQA may impair fertility in males of reproductive potential 

4. Pediatric Use

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

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.

6. Renal Impairment

Patients with severe renal impairment (eGFR 15–29 mL/min/1.73 m2 ) who are not receiving hemodialysis have a higher exposure to NUBEQA and reduction of the dose is recommended.

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.

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.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.

 OVERDOSAGE

There is no known specific antidote for darolutamide overdose. The highest dose of NUBEQA studied clinically was 900 mg twice daily, equivalent to a 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 a higher than recommended dose of darolutamide is not expected to lead to systemic toxicity in patients with intact hepatic and renal function.

In the event of intake of a 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.