Version May 2024
Note: Patients receiving darolutamide should also receive a gonadotropin-releasing hormone analog concurrently (or have had bilateral orchiectomy). Assess for cardiovascular risk factors (diabetes, dyslipidemia, hypertension) and optimize management of these conditions.
Prostate cancer, metastatic, hormone sensitive: Oral: 600 mg twice daily (in combination with docetaxel); continue until disease progression or unacceptable toxicity (Ref). Administer the first 6 cycles of docetaxel within 6 weeks after initiating darolutamide.
Prostate cancer, nonmetastatic, castration resistant: Oral: 600 mg twice daily; continue until disease progression or unacceptable toxicity (Ref).
Missed dose: If a dose is missed, administer as soon as possible prior to the next scheduled dose; do not take 2 doses at the same time to make up for a missed dose.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
eGFR 30 to 89 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 15 to 29 mL/minute/1.73 m2 (not receiving hemodialysis): Reduce the dose to 300 mg twice daily.
End-stage renal disease (eGFR <15 mL/minute/1.73 m2): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate impairment (Child-Pugh class B): Reduce the dose to 300 mg twice daily.
Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Grade 3 or higher toxicity (or intolerable adverse reaction): Withhold darolutamide or reduce dose to 300 mg twice daily until symptoms improve; may then resume therapy at 600 mg twice daily when the adverse reaction returns to baseline. Dose reduction <300 mg twice daily is not recommended.
Grade 3 or 4 ischemic heart disease: Discontinue darolutamide.
Seizure: Consider discontinuing darolutamide in patients who develop a seizure during treatment.
Metastatic hormone-sensitive prostate cancer: If docetaxel is delayed, interrupted, or discontinued, darolutamide may be continued.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adults.
>10%:
Hematologic & oncologic: Decreased neutrophils (20%; grades 3/4: 4%)
Hepatic: Increased serum aspartate aminotransferase (23%), increased serum bilirubin (16%)
Nervous system: Asthenia (≤16%), fatigue (≤16%)
1% to 10%:
Cardiovascular: Heart failure (2%), ischemic heart disease (4%)
Dermatologic: Skin rash (4%)
Neuromuscular & skeletal: Limb pain (6%)
Frequency not defined:
Cardiovascular: Hypertension
Gastrointestinal: Diarrhea, nausea
Genitourinary: Hematuria, urinary retention
Respiratory: Pneumonia
There are no contraindications listed in the manufacturer's US labeling.
Canadian labeling: Hypersensitivity to darolutamide or any component of the formulation.
Concerns related to adverse effects:
• Cardiotoxicity: Ischemic heart disease has occurred with darolutamide, including grades 3 and 4 events; some cases were fatal. Optimize management of cardiovascular risk factors (diabetes, dyslipidemia, hypertension). Androgen-deprivation therapy may increase the risk for cardiovascular disease (Levine 2010).
• Seizure: Seizure has occurred in patients receiving darolutamide, including a report of a grade 3 event. It is not known if antiseizure medications will prevent darolutamide-related seizures. Advise patients of the risk of seizures during darolutamide treatment and of the risk of engaging in activities where sudden loss of consciousness could cause serious harm to themselves or others.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Nubeqa: 300 mg
No
Tablets (Nubeqa Oral)
300 mg (per each): $135.74
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Nubeqa: 300 mg
Darolutamide is available through specialty pharmacy network. Refer to https://www.nubeqahcp.com/sites/g/files/kmftyc1081/files/2019-07/Nubeqa_SpecialtyPharmacyNetwork_0.pdf for more information.
Oral: Administer with food. Swallow tablets whole.
This medication is not on the NIOSH (2016) list; however, it may meet the criteria for a hazardous drug. Darolutamide may cause reproductive toxicity and has a structural/toxicity profile similar to existing hazardous agents.
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020). Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Prostate cancer, metastatic, hormone-sensitive: Treatment of metastatic hormone-sensitive prostate cancer (in combination with docetaxel) in adults.
Prostate cancer, nonmetastatic, castration-resistant: Treatment of nonmetastatic castration-resistant prostate cancer in adults.
Darolutamide may be confused with abiraterone, apalutamide, bicalutamide, dutasteride, enzalutamide, flutamide, nilutamide
Substrate of CYP3A4 (minor), P-glycoprotein/ABCB1 (minor), UGT1A1, UGT1A9; Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits BCRP/ABCG2, OATP1B1/1B3 (SLCO1B1/1B3); Induces CYP3A4 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Risk D: Consider therapy modification
Asunaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir. Risk X: Avoid combination
Atogepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Atogepant. Management: For episodic migraine, the recommended atogepant dose is 10 mg or 30 mg once daily if given with OATP1B1/1B3 inhibitors. For chronic migraine, the recommended atogepant dose is 30 mg once daily with OATP1B1/1B3 inhibitors. Risk D: Consider therapy modification
Atogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Atogepant. Management: For treatment of episodic migraine, the recommended dose of atogepant is 30 mg once daily or 60 mg once daily when combined with CYP3A4 inducers. When used for treatment of chronic migraine, use of atogepant with CYP3A4 inducers should be avoided. Risk D: Consider therapy modification
BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors): Darolutamide may increase the serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Berotralstat: BCRP/ABCG2 Inhibitors may increase the serum concentration of Berotralstat. Management: Decrease the berotralstat dose to 110 mg daily when combined with BCRP inhibitors. Risk D: Consider therapy modification
Brincidofovir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Brincidofovir. Management: Consider alternatives to OATP1B/1B3 inhibitors in patients treated with brincidofovir. If coadministration is required, administer OATP1B1/1B3 inhibitors at least 3 hours after brincidofovir and increase monitoring for brincidofovir adverse reactions. Risk D: Consider therapy modification
Choline C 11: Antiandrogens may diminish the therapeutic effect of Choline C 11. Risk C: Monitor therapy
Cladribine: BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. Risk D: Consider therapy modification
CloZAPine: CYP3A4 Inducers (Weak) may decrease the serum concentration of CloZAPine. Risk C: Monitor therapy
Elagolix: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix. Risk X: Avoid combination
Elagolix, Estradiol, and Norethindrone: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix, Estradiol, and Norethindrone. Specifically, concentrations of elagolix may be increased. Risk X: Avoid combination
Elbasvir and Grazoprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elbasvir and Grazoprevir. Risk X: Avoid combination
Eluxadoline: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with OATP1B1/1B3 inhibitors and monitor patients for increased eluxadoline effects/toxicities. Risk D: Consider therapy modification
Flotufolastat F18: Antiandrogens may diminish the diagnostic effect of Flotufolastat F18. Management: Therapies targeting the androgen pathway may result in changes in the uptake of flotufolastat F18 in prostate cancer. The impact of these therapies on the performance of flotufolastat F18 is unknown; consider use of alternative agents. Risk D: Consider therapy modification
Gallium Ga 68 PSMA-11: Antiandrogens may diminish the therapeutic effect of Gallium Ga 68 PSMA-11. Management: Therapies targeting the androgen pathway may result in changes in the uptake of gallium Ga 68 PSMA-11 (gozetotide) in prostate cancer. The impact on the performance of gallium Ga 68 PSMA-11 (gozetotide) is unknown; consider use of alternative agents. Risk D: Consider therapy modification
Hormonal Contraceptives: CYP3A4 Inducers (Weak) may decrease the serum concentration of Hormonal Contraceptives. Management: Advise patients to use an alternative method of contraception or a back-up method during coadministration, and to continue back-up contraception for 28 days after discontinuing a weak CYP3A4 inducer to ensure contraceptive reliability. Risk D: Consider therapy modification
Indium 111 Capromab Pendetide: Antiandrogens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
Inducers of CYP3A4 (Moderate) and P-glycoprotein: May decrease the serum concentration of Darolutamide. Risk X: Avoid combination
Inducers of CYP3A4 (Strong) and P-glycoprotein: May decrease the serum concentration of Darolutamide. Risk X: Avoid combination
Inhibitors of CYP3A4 (Strong) and P-glycoprotein: May increase the serum concentration of Darolutamide. Risk C: Monitor therapy
Mitapivat: May decrease the serum concentration of UGT1A1 Substrates. Risk C: Monitor therapy
Momelotinib: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Momelotinib. Risk C: Monitor therapy
NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Risk C: Monitor therapy
OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors): Darolutamide may increase the serum concentration of OATP1B1/1B3 (SLCO1B1/1B3) Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Risk X: Avoid combination
Piflufolastat F18: Antiandrogens may diminish the diagnostic effect of Piflufolastat F18. Management: Therapies targeting the androgen pathway may result in changes in the uptake of piflufolastat F18 in prostate cancer. The impact of these therapies on the performance of piflufolastat F18 is unknown; consider use of alternative agents. Risk D: Consider therapy modification
Revefenacin: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin. Risk X: Avoid combination
Rosuvastatin: Darolutamide may increase the serum concentration of Rosuvastatin. Management: Limit the dose of rosuvastatin to 5 mg daily when combined with darolutamide. Monitor closely for increased rosuvastatin effects/toxicities (eg, myalgias, rhabdomyolysis) when these agents are combined. Risk D: Consider therapy modification
Selpercatinib: CYP3A4 Inducers (Weak) may decrease the serum concentration of Selpercatinib. Risk C: Monitor therapy
Sirolimus (Conventional): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Conventional). Risk C: Monitor therapy
Sirolimus (Protein Bound): CYP3A4 Inducers (Weak) may decrease the serum concentration of Sirolimus (Protein Bound). Risk C: Monitor therapy
Tacrolimus (Systemic): CYP3A4 Inducers (Weak) may decrease the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Risk C: Monitor therapy
Taurursodiol: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Taurursodiol. Risk X: Avoid combination
Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Ubrogepant: CYP3A4 Inducers (Weak) may decrease the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 100 mg and second dose (if needed) of 100 mg when used with a weak CYP3A4 inducer. Risk D: Consider therapy modification
Ubrogepant: BCRP/ABCG2 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a BCRP inhibitor. Risk D: Consider therapy modification
Voxilaprevir: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Voxilaprevir. Risk X: Avoid combination
Zavegepant: OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Zavegepant. Risk X: Avoid combination
Bioavailability of darolutamide was increased by 2- to 2.5-fold when administered with food; exposure was similarly increased for ketodarolutamide (active metabolite). Management: Administer with food.
Patients with partners who could become pregnant should use effective contraception during darolutamide treatment and for 1 week after the last darolutamide dose.
Based on the mechanism of action, darolutamide may cause fetal harm and pregnancy loss if utero exposure occurs.
It is not known if darolutamide is present in breast milk.
Monitor hepatic and renal function as clinically necessary. Assess for cardiovascular risk factors (diabetes, dyslipidemia, hypertension). Monitor for signs/symptoms of ischemic heart disease; monitor for seizure. Monitor adherence.
Cardiovascular monitoring for patients with prostate cancer: Comprehensive assessment prior to treatment including a history and physical examination, screening for cardiovascular disease risk factors such as hypertension, diabetes, dyslipidemia, obesity, and smoking; baseline and serial ECGs are recommended in patients at risk of QTc prolongation during androgen deprivation therapy (ADT); estimate 10-year cardiovascular disease risk in patients without cardiovascular disease at baseline; assess cardiovascular risk annually during ADT (ASCO [Armenian 2017]; ESC [Lyon 2022]).
Darolutamide is a competitive androgen receptor inhibitor. In addition to androgen binding inhibition, darolutamide also inhibits androgen receptor translocation and androgen receptor-mediated transcription. Ketodarolutamide (active metabolite) has similar in vitro activity to darolutamide. Androgen receptor inhibition results in decreased proliferation of prostate tumor cells and increased apoptosis, leading to a decrease in tumor volume.
Distribution: Vd: 119 L; darolutamide has low blood-brain barrier penetration (Fizazi 2019).
Protein binding: Darolutamide: 92%; ketodarolutamide (active metabolite): 99.8%; primarily to serum albumin.
Metabolism: Primarily metabolized by CYP3A4, as well as by UGT1A9 and UGT1A1; active metabolite is ketodarolutamide.
Bioavailability: ~30% (following a 300 mg darolutamide dose under fasted conditions).
Half-life elimination: ~20 hours (darolutamide and ketodarolutamide).
Time to peak: ~4 hours.
Excretion: Urine: 63.4% (~7% as unchanged drug); feces: 32.4% (~30% as unchanged drug); Clearance: 116 mL/minute.
Altered kidney function: Darolutamide exposure was increased by ~2.5-fold in noncancer subjects with severe renal impairment (eGFR 15 to 29 mL/minute/1.73 m2) not receiving dialysis as compared to healthy subjects.
Hepatic function impairment: Darolutamide exposure was increased by ~1.9-fold in noncancer subjects with moderate (Child-Pugh class B) hepatic impairment as compared to healthy subjects.
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