LIMITED DDIs WITH NUBEQA
Drug interactions with concomitant use of NUBEQA
- Administration of NUBEQA in combination with docetaxel resulted in no clinically relevant changes in the pharmacokinetics of docetaxel in patients with mHSPC. There were also no clinically relevant changes in the pharmacokinetics of NUBEQA when used in combination with docetaxel1
Review the prescribing information of the BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.1
NEARLY ALL PATIENTS WITH mHSPC OR nmCRPC ARE ON CONCOMITANT MEDICATIONS, SO CHOOSE AN ARI WITH LIMITED DDIs8
100% of PATIENTS WITH mHSPC IN THE ARASENS TRIAL WERE ON ≥1 CONCOMITANT MEDICATIONS8
98.7% OF PATIENTS WITH nmCRPC IN THE ARAMIS TRIAL WERE ON
≥1 CONCOMITANT MEDICATIONS8
NO POTENTIAL DDIs EXPECTED BETWEEN NUBEQA AND ANTICOAGULANTS, BASED ON PRECLINICAL, PHARMACOKINETIC STUDIES1,9-21
NUBEQA is a CYP3A4, UGT1A9, UGT1A1 substrate and BCRP, OATP1B1/1B3 inhibitor1,9
Anticoagulants that are substrates with no inducer/inhibitor activity, and therefore have no expected interaction with NUBEQA10-16:
- Warfarin (substrate of CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4)
- Apixaban (substrate of CYP3A4, 1A2, 2C8, 2C9, 2C19, and 2J2)
- Rivaroxaban (substrate of CYP3A4/5 and 2J2)
- Edoxaban (substrate of CYP3A4, 1A2)
- Argatroban (substrate of CYP3A4/5)
Anticoagulants that are not substrates, inhibitors, or inducers of CYP450 enzymes, P-gp, BCRP, or OATP1B1, and therefore have no expected interaction with NUBEQA17-21:
- Dabigatran, dalteparin, enoxaparin, fondaparinux, and unfractioned heparin
*Decreases darolutamide exposure, which may decrease NUBEQA activity.1
†Increases darolutamide exposure, which may increase the risk of NUBEQA adverse reactions.1
‡Increases BCRP substrate exposure, which may increase the risk of related toxicities. Consult the approved product labeling of the BCRP substrate when used concomitantly with NUBEQA.1
§Concomitant use of NUBEQA may increase the plasma concentrations of OATP1B1 or OATP1B3 substrates.1
ARI=androgen receptor inhibitor; DDI=drug-drug interaction; mHSPC=metastatic hormone-sensitive prostate cancer; nmCRPC=non-metastatic castration-resistant prostate cancer.
Indications
NUBEQA® (darolutamide) is an androgen receptor inhibitor indicated for the treatment of adult patients with:
- Non-metastatic castration-resistant prostate cancer (nmCRPC)
- Metastatic hormone-sensitive prostate cancer (mHSPC) in combination with docetaxel
Important Safety Information
Warnings & Precautions
Ischemic Heart Disease – In a study of patients with nmCRPC (ARAMIS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA versus 2.5% receiving placebo, including Grade 3-4 events in 1.7% vs. 0.4%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA vs. 0.2% receiving placebo. In a study of patients with mHSPC (ARASENS), ischemic heart disease occurred in 3.2% of patients receiving NUBEQA with docetaxel vs. 2% receiving placebo with docetaxel, including Grade 3-4 events in 1.3% vs. 1.1%, respectively. Ischemic events led to death in 0.3% of patients receiving NUBEQA with docetaxel vs. 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.
Seizure – In ARAMIS, Grade 1-2 seizure occurred in 0.2% of patients receiving NUBEQA vs. 0.2% receiving placebo. Seizure occurred 261 and 456 days after initiation of NUBEQA. In ARASENS, seizure occurred in 0.6% of patients receiving NUBEQA with docetaxel, including one Grade 3 event, vs. 0.2% receiving placebo with docetaxel. Seizure occurred 38 to 340 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.
Embryo-Fetal Toxicity – Safety and efficacy of NUBEQA have not been established in females. NUBEQA can cause fetal harm and loss of pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment with NUBEQA and for 1 week after the last dose.
Adverse Reactions
In ARAMIS, serious adverse reactions occurred in 25% of patients receiving NUBEQA vs. 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 vs. 3.2% of patients receiving placebo. Fatal adverse reactions in 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%). The most common adverse reactions (>2% with a ≥2% increase over placebo), including laboratory test abnormalities, were increased AST, decreased neutrophil count, fatigue, increased bilirubin, pain in extremity, and rash. Clinically relevant adverse reactions occurring in ≥2% of patients treated with NUBEQA included ischemic heart disease and heart failure.
In ARASENS, serious adverse reactions occurred in 45% of patients receiving NUBEQA with docetaxel vs. 42% of patients receiving placebo with docetaxel. Serious adverse reactions in ≥2% of patients who received NUBEQA with docetaxel included febrile neutropenia (6%), decreased neutrophil count (2.8%), musculoskeletal pain (2.6%), and pneumonia (2.6%). Fatal adverse reactions occurred in 4% of patients receiving NUBEQA with docetaxel vs. 4% of patients receiving placebo with docetaxel. Fatal adverse reactions in patients who received NUBEQA included COVID-19/COVID-19 pneumonia (0.8%), myocardial infarction (0.3%), and sudden death (0.3%). The most common adverse reactions (≥10% with a ≥2% increase over placebo with docetaxel) were constipation, rash, decreased appetite, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (≥30%) were anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST, increased ALT, and hypocalcemia. Clinically relevant adverse reactions in <10% of patients who received NUBEQA with docetaxel included fractures, ischemic heart disease, seizures, and drug-induced liver injury.
Drug Interactions
Effect of Other Drugs on NUBEQA – Combined P-gp and strong or moderate CYP3A4 inducers decrease NUBEQA exposure, which may decrease NUBEQA activity. Avoid concomitant use.
Combined P-gp and strong CYP3A4 inhibitors increase NUBEQA exposure, which may increase the risk of NUBEQA adverse reactions. Monitor more frequently and modify NUBEQA dose as needed.
Effects of NUBEQA on Other Drugs – NUBEQA inhibits breast cancer resistance protein (BCRP) transporter. Concomitant use increases exposure (AUC) and maximal concentration of BCRP substrates, which may increase the risk of BCRP substrate-related toxicities. Avoid concomitant use where possible. If used together, monitor more frequently for adverse reactions, and consider dose reduction of the BCRP substrate.
NUBEQA inhibits OATP1B1 and OATP1B3 transporters. Concomitant use may increase plasma concentrations of OATP1B1 or OATP1B3 substrates. Monitor more frequently for adverse reactions and consider dose reduction of these substrates.
Review the Prescribing Information of drugs that are BCRP, OATP1B1, and OATP1B3 substrates when used concomitantly with NUBEQA.
Please see the full Prescribing Information.
You are encouraged to report side effects or quality complaints of products to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.
References: 1. NUBEQA (darolutamide) [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; October 2023. 2. University of Washington Pharmacy Services. Anticoagulation Services. Rivaroxaban Drug Interaction Potential. Accessed August 13, 2024. https://sites.uw.edu/anticoag/drugs/rivaroxaban/#Drug_Interactions. 3. FDA.gov. Center for Drug Evaluation and Research. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. U.S. Food and Drug Administration. Accessed August 13, 2024. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers. 4. Lexi-Comp. Modafinil (Lexi-Drugs) - UpToDate Lexidrug. Accessed August 13, 2024. https://online.lexi.com. 5. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158(3):693-705. 6. Deng F, Tuomi S-K, Neuvonen M, et al. Comparative hepatic and intestinal efflux transport of statins. Drug Metab Dispos. 2021;49(9):750-759. 7. Xu D, Li F, Zhang M, et al. Decreased exposure of simvastatin and simvastatin acid in a rat model of type 2 diabetes. Acta Pharmacol Sin. 2014;35(9):1215-1225. 8. Data on file. Bayer HealthCare Pharmaceuticals, Inc.; Whippany, NJ. 9. NUBEQA (darolutamide) [summary of product characteristics]. Leverkusen, Germany: Bayer AG; October 2024. 10. Shore N, Zurth C, Fricke R, et al. Evaluation of clinically relevant drug-drug interactions and population pharmacokinetics of darolutamide in patients with nonmetastatic castration-resistant prostate cancer: results of pre-specified and post hoc analyses of the phase III ARAMIS trial. Target Oncol. 2019;14(5):527-539. 11. Jantoven (warfarin) [prescribing information]. Maple Grove, MN: Upsher-Smith Laboratories, LLC; 2017. 12. Lexi-Comp. Interactions - UpToDate Lexidrug. Accessed August 15, 2024. https://online.lexi-com.proxy.libraries.rutgers.edu/lco/action/interact. 13. Eliquis (apixaban) [prescribing information]. Princeton; NJ: Bristol-Myers Squibb Company. New York, NY: Pfizer Inc; September 2021. 14. Xarelto (rivaroxaban) [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. Leverkusen, Germany: Bayer HealthCare AG; February 2023. 15. Savaysa (edoxaban) [prescribing information]. Basking Ridge, NJ: Daiichi Sankyo, Inc.; October 2023. 16. Argatroban [prescribing information]. Lake Forest, IL: Hospira Inc.; September 2019. 17. Pradaxa (dabigatran etexilate) [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; November 2023. 18. Fragmin (dalteparin sodium) [prescribing information]. New York, New York: Pfizer Labs; October 2024. 19. Lovenox (enoxaparin sodium) [prescribing information]. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; April 2022. 20. Arixtra (fondaparinux sodium injection) [prescribing information]. Morgantown, WV: Mylan Institutional LLC; August 2020. 21. Heparin sodium injection [prescribing information]. Eatontown, NJ: Hikma Pharmaceuticals USA Inc.; April 2024.
