Nubeqa

Drug overview for NUBEQA (darolutamide):

Generic name: darolutamide (DAR-oh-LOO-ta-mide)
Drug class: Antiandrogen
Therapeutic class: Antineoplastics

Darolutamide, a nonsteroidal antiandrogen, is an antineoplastic agent.

No enhanced Uses information available for this drug.

DRUG IMAGES

NUBEQA 300 MG TABLET

The following indications for NUBEQA (darolutamide) have been approved by the FDA:

Indications:
Metastatic castration-sensitive prostate cancer
Non-metastatic castration-resistant prostate cancer

Professional Synonyms:
Metastatic hormone sensitive prostate cancer
Non-metastatic hormone refractory prostate cancer

Dosing information for NUBEQA
DRUG LABEL	DOSING TYPE	DOSING INSTRUCTIONS
NUBEQA 300 MG TABLET	Maintenance	Adults take 2 tablets (600 mg) by oral route 2 times per day

The following drug interaction information is available for NUBEQA (darolutamide):

Contraindicated
Severe
Moderate

There are 1 contraindications. These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.

Drug Interaction	Drug Names
Rosuvastatin (Greater Than 5 mg)/Darolutamide SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Darolutamide inhibits BCRP, which may result in increased absorption of rosuvastatin.(1,2) CLINICAL EFFECTS: Administration of darolutamide with rosuvastatin may result in elevated levels of rosuvastatin, which could result in rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of darolutamide recommends avoiding concomitant use of BCRP substrates, like rosuvastatin, whenever possible.(1) The manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 5 mg daily when used concurrently with darolutamide.(2) If these drugs are used concurrently, patients should be monitored more closely for rosuvastatin toxicity. DISCUSSION: Concurrent administration of darolutamide 600 mg twice daily for 5 days with single-dose rosuvastatin 5 mg increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(1,2)	CRESTOR, EZALLOR SPRINKLE, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET

Drug Interaction

Drug Names

Rosuvastatin (Greater Than 5 mg)/Darolutamide

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Darolutamide inhibits BCRP, which may result in increased absorption of rosuvastatin.(1,2)

CLINICAL EFFECTS: Administration of darolutamide with rosuvastatin may result in elevated levels of rosuvastatin, which could result in rhabdomyolysis.(1,2)

PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy.

PATIENT MANAGEMENT: The US manufacturer of darolutamide recommends avoiding concomitant use of BCRP substrates, like rosuvastatin, whenever possible.(1) The manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 5 mg daily when used concurrently with darolutamide.(2) If these drugs are used concurrently, patients should be monitored more closely for rosuvastatin toxicity.

DISCUSSION: Concurrent administration of darolutamide 600 mg twice daily for 5 days with single-dose rosuvastatin 5 mg increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(1,2)

CRESTOR, EZALLOR SPRINKLE, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET

There are 14 severe interactions. These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.

Drug Interaction	Drug Names
Pazopanib/Selected Inhibitors of P-gp or BCRP SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption of pazopanib.(1) CLINICAL EFFECTS: The concurrent administration of pazopanib with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of pazopanib and signs of toxicity.(1) PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The US manufacturer of pazopanib states concurrent use of P-gp inhibitors or BCRP inhibitors should be avoided.(1) Monitor patients for increased side effects from pazopanib. If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Pazopanib is a substrate of P-gp and BCRP. Inhibitors of these transporters are expected to increase pazopanib levels.(1) BCRP inhibitors linked to this monograph include: asciminib, belumosudil, clopidogrel, cyclosporine, darolutamide, eltrombopag, gefitinib, grazoprevir, lazertinib, leflunomide, momelotinib, oteseconazole, rolapitant, roxadustat, tafamidis, teriflunomide, and vadadustat.(1,3-5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daridorexant, diltiazem, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, isavuconazonium, ivacaftor, ledipasvir, neratinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, tezacaftor, ticagrelor, valbenazine, verapamil, vimseltinib, and voclosporin.(3,4)	PAZOPANIB HCL, VOTRIENT
Cladribine/Selected Inhibitors of BCRP SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inhibitors of BCRP may increase the absorption of cladribine.(1-2) CLINICAL EFFECTS: The concurrent administration of cladribine with an inhibitor of BCRP may result in elevated levels of cladribine and signs of toxicity.(1-2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of cladribine states concurrent use of BCRP inhibitors should be avoided during the 4- to 5-day cladribine treatment.(1-2) Selection of an alternative concurrent medication with no or minimal transporter inhibiting proprieties should be considered. If this is not possible, dose reduction to the minimum mandatory dose of the BCRP inhibitor, separation in timing of administration, and careful patient monitoring is recommended.(1-2) Monitor for signs of hematologic toxicity. Lymphocyte counts should be monitored. DISCUSSION: Cladribine is a substrate of BCRP. Inhibitors of this transporter are expected to increase cladribine levels.(1-2) BCRP inhibitors linked to this monograph include: capmatinib, clopidogrel, cobicistat, curcumin, danicopan, darolutamide, eltrombopag, elvitegravir, grazoprevir, lazertinib, oteseconazole, pacritinib, ritonavir, roxadustat, tafamidis, ticagrelor, turmeric, and vadadustat.(1-4)	CLADRIBINE, MAVENCLAD
Darolutamide/P-gp and Strong CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Apalutamide, carbamazepine, enzalutamide, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort may induce the metabolism of darolutamide by both P-gp and CYP3A4. CLINICAL EFFECTS: Concurrent or recent use of apalutamide, carbamazepine, enzalutamide, fosphenytoin, phenytoin, rifampin, rifapentine, or St. John's wort may result in decreased levels and effectiveness of darolutamide. PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: If possible, avoid the concurrent use of agents that are combined P-gp and strong CYP3A4 inducers, such as apalutamide, carbamazepine, enzalutamide, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort, in patients receiving darolutamide. DISCUSSION: Concurrent rifampin (combined P-gp and strong CYP3A4 inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of darolutamide by 72% and 52%, respectively.(1)	CARBAMAZEPINE, CARBAMAZEPINE ER, CARBATROL, CEREBYX, DILANTIN, DILANTIN-125, EPITOL, EQUETRO, ERLEADA, FOSPHENYTOIN SODIUM, PHENYTEK, PHENYTOIN, PHENYTOIN SODIUM, PHENYTOIN SODIUM EXTENDED, PRIFTIN, RIFADIN, RIFAMPIN, TEGRETOL, TEGRETOL XR, XTANDI
Darolutamide/P-gp and Moderate CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Agents that are combined P-gp and moderate CYP3A4 inducers may induce the metabolism of darolutamide by both pathways.(1) CLINICAL EFFECTS: Concurrent or recent use of inducers of both P-gp and CYP3A4 may result in decreased levels and effectiveness of darolutamide.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: If possible, avoid the concurrent use of agents that are combined P-gp and moderate CYP3A4 inducers in patients receiving darolutamide.(1) DISCUSSION: Concurrent rifampin (combined P-gp and strong CYP3A4 inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of darolutamide by 72% and 52%, respectively. Combined P-gp and moderate CYP3A4 inducers are expected to decrease the AUC by 36-58%.(1) Agents that are combined P-gp and moderate CYP3A4 inducers linked to this monograph include: efavirenz, lorlatinib and rifabutin.(2)	EFAVIRENZ, EFAVIRENZ-EMTRIC-TENOFOV DISOP, EFAVIRENZ-LAMIVU-TENOFOV DISOP, LORBRENA, RIFABUTIN, SYMFI, SYMFI LO, TALICIA
Selected BCRP Substrates/Darolutamide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Darolutamide inhibits BCRP, which may result in increased absorption of BCRP substrates.(1) CLINICAL EFFECTS: Administration of darolutamide with BCRP substrates may result in elevated levels of and toxicity from these agents.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer recommends avoiding concurrent use of darolutamide with BCRP substrates when possible. DISCUSSION: Concurrent administration of darolutamide with rosuvastatin increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(1) BCRP substrates linked to this monograph include: ciprofloxacin, diclofenac, glyburide, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, and topotecan.(1-3)	ARTHROTEC 50, ARTHROTEC 75, AZULFIDINE, CAMBIA, CAMPTOSAR, CIPRO, CIPROFLOXACIN, CIPROFLOXACIN HCL, CIPROFLOXACIN-D5W, DICLOFENAC, DICLOFENAC EPOLAMINE, DICLOFENAC POTASSIUM, DICLOFENAC SODIUM, DICLOFENAC SODIUM ER, DICLOFENAC SODIUM MICRONIZED, DICLOFENAC SODIUM-MISOPROSTOL, FLECTOR, GLEEVEC, GLYBURIDE, GLYBURIDE MICRONIZED, GLYBURIDE-METFORMIN HCL, HYCAMTIN, IMATINIB MESYLATE, IMKELDI, INFLAMMACIN, INFLATHERM(DICLOFENAC-MENTHOL), IRINOTECAN HCL, JYLAMVO, LAPATINIB, LICART, LOFENA, METHOTREXATE, METHOTREXATE SODIUM, MITOXANTRONE HCL, ONIVYDE, OTREXUP, RASUVO, SULFASALAZINE, SULFASALAZINE DR, TOPOTECAN HCL, TRESNI, TREXALL, TYKERB, XATMEP, ZIPSOR, ZORVOLEX
Lumateperone/CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lumateperone is a substrate of CYP3A4. Inducers of CYP3A4 may induce the metabolism of lumateperone.(1) CLINICAL EFFECTS: The concurrent administration of a CYP3A4 inducer may decrease the exposure to lumateperone.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of lumateperone states that concurrent use with CYP3A4 inducers should be avoided.(1) DISCUSSION: Coadministration of lumateperone with rifampin, a strong CYP3A4 inducer, resulted in a 98% reduction in area-under-curve (AUC) and a 90% reduction in concentration maximum (Cmax).(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(2,3) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, repotrectinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 include: amprenavir, armodafinil, bexarotene, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, garlic, genistein, gingko, ginseng, glycyrrhizin, nevirapine, omaveloxolone, oxcarbazepine, pioglitazone, quercetin, rufinamide, sotorasib, sulfinpyrazone, tecovirimat, terbinafine, ticlopidine, troglitazone, vemurafenib, and vinblastine.(2,3)	CAPLYTA
Selected CYP3A4 Substrates/Lonafarnib SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Lonafarnib is a strong inhibitor of CYP3A4 and may decrease the metabolism of drugs metabolized by the CYP3A4 enzyme. Lonafarnib is also an inhibitor of P-glycoprotein (P-gp) and may increase the absorption of sirolimus. CLINICAL EFFECTS: Concurrent use of lonafarnib may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway or P-gp.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of lonafarnib states that coadministration of CYP3A4 substrates should be avoided. If concomitant use is unavoidable, monitor for adverse effects and consider dose reduction of the CYP3A4 substrate according to its prescribing information.(1) The manufacturer of lonafarnib states that the dose of P-gp substrates may need to be reduced with coadministration with lonafarnib.(1) DISCUSSION: In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the area-under-the-curve (AUC) and maximum concentration (Cmax) of a single dose of midazolam (3 mg) by 639% and 180%, respectively.(1) In a study of healthy volunteers, lonafarnib (100 mg twice daily for 5 days) increased the AUC and Cmax of single-dose fexofenadine (180 mg) by 24% and 21%, respectively.(1) CYP3A4 substrates with a narrow therapeutic index linked to this monograph include: bromocriptine, cabergoline, cannabidiol-tetrahydrocannabinol, clonazepam, darolutamide, felodipine, mefloquine, nisoldipine, oliceridine, pomalidomide, regorafenib, sirolimus, and zanubrutinib.(1-3)	ZOKINVY
Sodium Iodide I 131/Myelosuppressives; Immunomodulators SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1) CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1) DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)	HICON, SODIUM IODIDE I-131
Atogepant/CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Strong, moderate, and weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1) CLINICAL EFFECTS: The concurrent use of strong, moderate, or weak CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant strong, moderate, or weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and avoid use of atogepant for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness. DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)	QULIPTA
Ubrogepant/Darolutamide SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Ubrogepant is a CYP3A4 and BCRP substrate.(1) Darolutamide is a weak CYP3A4 inducer and BCRP inhibitor.(2) CLINICAL EFFECTS: Concurrent use of ubrogepant with darolutamide may lead to increased or decreased levels and effectiveness of ubrogepant.(1) The net effect of darolutamide on ubrogepant is unknown. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of ubrogepant does not have recommendations for concurrent use with agents that are both weak CYP3A4 inducers and BCRP inhibitors. Concurrent use should be avoided.(1) For concurrent use of ubrogepant with weak CYP3A4 inducers: The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the the dose of ubrogepant should be 100 mg.(1) For concurrent use of ubrogepant with BCRP inhibitors: The manufacturer of ubrogepant recommends a dosage adjustment of ubrogepant. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For concurrent use of darolutamide with BCRP substrates: The manufacturer of darolutamide states that concurrent use of BCRP substrates should be avoided. If concurrent use cannot be avoided, monitor for adverse events more frequently and consider dose reduction of the BCRP substrate.(2) DISCUSSION: Ubrogepant is a substrate of CYP3A4 and the BCRP transporter.(1) Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1)	UBRELVY
Zavegepant/OATP1B3 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Zavegepant is a substrate of the organic anion transporting polypeptide 1B3 (OATP1B3) transporter. Inhibitors of OATP1B3 may increase zavegepant exposure.(1) CLINICAL EFFECTS: Concurrent use of OATP1B3 inhibitors may result in increased levels of and toxicity from zavegepant.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent administration of zavegepant with OATP1B3 inhibitors should be avoided.(1) DISCUSSION: In a study, rifampin (an OATP1B3 and NTCP inhibitor) at steady state increased the area-under-curve (AUC) and maximum concentration (Cmax) of zavegepant by 2.3-fold and 2.2-fold. Since rifampin is also a CYP3A4 inducer and zavegepant is metabolized by CYP3A4, concurrent use of zavegepant with other OATP1B3 inhibitors that are not CYP3A4 inducers may have an even more significant effect on zavegepant exposure.(1) OATP1B3 inhibitors include asciminib, atazanavir, belumosudil, cobicistat, cyclosporine, darolutamide, enasidenib, encorafenib, fostemsavir, glecaprevir/pibrentasvir, leflunomide, letermovir, lopinavir/ritonavir, paritaprevir, resmetirom, rifampin, ritonavir, teriflunomide, velpatasvir, voclosporin, and voxilaprevir.(2-9)	ZAVZPRET
Erlotinib/CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of erlotinib.(1) CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of erlotinib.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of CYP3A4 inducers in patients receiving therapy with erlotinib. Consider the use of alternative agents with less enzyme induction potential.(1) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(1) DISCUSSION: Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(1) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(1) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(2) In a study, concurrent use of sorafenib (400 mg twice daily) and erlotinib (150 mg daily) decreased the concentration minimum (Cmin), concentration maximum (Cmax), and AUC of erlotinib.(3) In an animal study, concurrent use of dexamethasone and erlotinib decreased the AUC of erlotinib by 0.6-fold.(4) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo, ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6)	ERLOTINIB HCL, TARCEVA
Zuranolone/CYP3A4 Inducers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1) CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1) DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)	ZURZUVAE
Atorvastatin/Selected BCRP Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: BCRP inhibitors may result in increased absorption of atorvastatin.(1,2) CLINICAL EFFECTS: Administration of atorvastatin with BCRP inhibitors may result in elevated levels of atorvastatin, which could result in rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. PATIENT MANAGEMENT: Atorvastatin is a substrate of the efflux transporter BCRP.(1) The US manufacturer of darolutamide recommends avoiding concurrent use with BCRP substrates such as atorvastatin.(2) If concurrent therapy is deemed medically necessary, monitor patients for signs and symptoms of myopathy/rhabdomyolysis, including muscle pain/tenderness/weakness, fever, unusual tiredness, changes in the amount of urine, and/or discolored urine.(2) DISCUSSION: Concurrent administration of darolutamide with rosuvastatin increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(2) The study authors found that darolutamide has no effect on total or renal clearance of rosuvastatin and thus no likely effect on OATP or OAT3, which suggests the increase in rosuvastatin plasma concentrations is due to BCRP inhibition.(3) BCRP inhibitors linked to this monograph include: darolutamide.(4,5)	AMLODIPINE-ATORVASTATIN, ATORVALIQ, ATORVASTATIN CALCIUM, CADUET, LIPITOR

There are 5 moderate interactions. The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.

Drug Interaction	Drug Names
Exemestane/Selected Moderate-Weak CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of exemestane.(1) CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels and effectiveness of exemestane.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The US manufacturer of exemestane recommends that patients receiving concurrent therapy with a strong CYP3A4 inducer receive 50 mg of exemestane daily after a meal.(1) It may be prudent to consider a dosage increase for patients receiving weaker CYP3A4 inducers. DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of exemestane (25 mg) by 54% and 41%, respectively.(1) Strong inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 80% or more and include: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(1-3) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)	AROMASIN, EXEMESTANE
Darolutamide/Dual P-gp and Strong CYP3A4 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Combined inhibitors of P-glycoprotein (P-gp) and CYP3A4 may increase the absorption and inhibit the metabolism of darolutamide.(1-3) CLINICAL EFFECTS: Concurrent use of an agent that is both an inhibitor of P-gp and a strong inhibitor of CYP3A4 may result in elevated levels of and clinical effects of darolutamide.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of darolutamide recommends increased monitoring if agents that are combined P-gp and strong CYP3A4 inhibitors are used in patients receiving darolutamide.(1) Darolutamide dosage may need to be adjusted. Monitor absolute neutrophil count (ANC). If patient experiences a greater than or equal to Grade 3 toxicity, dose may need to be withheld or reduced until symptoms improve.(1) DISCUSSION: Concurrent itraconazole increased the area-under-curve (AUC) and maximum concentration (Cmax) of darolutamide by 1.7-fold and 1.4-fold, respectively.(1) P-gp and strong CYP3A4 inhibitors linked to this monograph are: adagrasib, cobicistat, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lopinavir, mifepristone, nirmatrelvir/ritonavir, posaconazole, ritonavir, saquinavir, telaprevir, tucatinib and telithromycin.	EVOTAZ, GENVOYA, ITRACONAZOLE, ITRACONAZOLE MICRONIZED, KALETRA, KETOCONAZOLE, KORLYM, KRAZATI, LOPINAVIR-RITONAVIR, MIFEPREX, MIFEPRISTONE, NORVIR, NOXAFIL, PAXLOVID, POSACONAZOLE, PREZCOBIX, RECORLEV, RITONAVIR, SPORANOX, STRIBILD, SYMTUZA, TOLSURA, TUKYSA, TYBOST
Rosuvastatin (Less Than or Equal To 5 mg)/Darolutamide SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Darolutamide inhibits BCRP, which may result in increased absorption of rosuvastatin.(1,2) CLINICAL EFFECTS: Administration of darolutamide with rosuvastatin may result in elevated levels of rosuvastatin, which could result in rhabdomyolysis.(1,2) PREDISPOSING FACTORS: The risk for myopathy or rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of myopathy or rhabdomyolysis. Patients with a SLCO1B1 polymorphism that leads to decreased function of the hepatic uptake transporter OATP1B1 may have increased statin concentrations and be predisposed to myopathy or rhabdomyolysis. Patients on rosuvastatin with ABCG2 polymorphisms leading to decreased or poor BCRP transporter function may have increased rosuvastatin concentrations and risk of myopathy. PATIENT MANAGEMENT: The US manufacturer of darolutamide recommends avoiding concomitant use of BCRP substrates, like rosuvastatin, whenever possible.(1) The manufacturer of rosuvastatin states that the dose of rosuvastatin should not exceed 5 mg daily when used concurrently with darolutamide.(2) If these drugs are used concurrently, patients should be monitored more closely for rosuvastatin toxicity. DISCUSSION: Concurrent administration of darolutamide 600 mg twice daily for 5 days with single-dose rosuvastatin 5 mg increased the mean area-under-the-curve (AUC) and maximum concentration (Cmax) of rosuvastatin approximately 5-fold.(1,2)	CRESTOR, EZALLOR SPRINKLE, ROSUVASTATIN CALCIUM, ROSUVASTATIN-EZETIMIBE, ROSZET
Tacrolimus/Moderate and Weak CYP3A4 Inducers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may accelerate the metabolism of tacrolimus.(1) CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of tacrolimus.(1) PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: The manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and adjusting tacrolimus dose if needed. Monitor clinical response closely.(1) DISCUSSION: A 13-year-old cystic fibrosis patient with a history of liver transplant on stable doses of tacrolimus underwent 2 separate courses of nafcillin therapy (a moderate CYP3A4 inducer). During the 1st course of nafcillin, his tacrolimus levels started to fall 3 days after starting nafcillin, became undetectable at day 8, and recovered to therapeutic levels without a change in tacrolimus dose 5 days after discontinuation of nafcillin. During the 2nd course of nafcillin, tacrolimus level became undetectable 4 days after starting nafcillin and recovered 3 days after stopping nafcillin.(2) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, repotrectinib, telotristat, and tovorafenib.(3,4) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, nevirapine, oritavancin, omaveloxolone, oxcarbazepine, pioglitazone, relugolix, rufinamide, sulfinpyrazone, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vinblastine, and zanubrutinib.(3,4)	ASTAGRAF XL, ENVARSUS XR, PROGRAF, TACROLIMUS, TACROLIMUS XL
Momelotinib/OATP1B1-3 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: OATP1B1 and 1B3 inhibitors may decrease the hepatic uptake of momelotinib.(1) CLINICAL EFFECTS: Concurrent use of OATP1B1 and 1B3 inhibitors may result in elevated levels of and side effects from momelotinib, including myelosuppression and hepatotoxicity.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of momelotinib with OATP1B1 and 1B3 inhibitors should be approached with caution. Monitor patients closely for adverse reactions and consider dose modifications per momelotinib prescribing recommendations.(1) DISCUSSION: Concurrent administration of a single dose rifampin, an OATP1B1/1B3 inhibitor, increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of momelotinib by 40% and 57%, respectively. The M21 metabolite Cmax increased 6% and AUC increased 12%.(1) OATP1B1 inhibitors include asciminib, atazanavir, belumosudil, boceprevir, cobicistat, cyclosporine, darolutamide, darunavir, eltrombopag, enasidenib, encorafenib, erythromycin, fostemsavir, gemfibrozil, glecaprevir-pibrentasvir, ledipasvir, letermovir, lopinavir, nirmatrelvir, paritaprevir, resmetirom, rifampin, roxadustat, saquinavir, simeprevir, telaprevir, tipranavir, vadadustat, velpatasvir, and voclosporin.(1,2)	OJJAARA

The following contraindication information is available for NUBEQA (darolutamide):

Overview
Contraindicated
Severe
Moderate

Drug contraindication overview.

*None.

There are 0 contraindications.

There are 7 severe contraindications. Adequate patient monitoring is recommended for safer drug use.

Severe List
Child-pugh class B hepatic impairment
Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
Coronary artery disease
Disease of liver
Lower seizure threshold
Pregnancy
Seizure disorder

There are 2 moderate contraindications. Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.

Moderate List
Hyperlipidemia
Hypertension

The following adverse reaction information is available for NUBEQA (darolutamide):

Overview
Severe
Less Severe

Adverse reaction overview.

Adverse effects reported in >=2% of patients receiving darolutamide in the principal efficacystudyof patients with nmCRPCinclude fatigue, pain in extremity, and rash. Laboratory test abnormalities reported in >=2% of patients receiving darolutamide in the study include increased AST, decreased neutrophil count, and increased bilirubin. Adverse effects reported in >=10% of patients receiving darolutamide in the principal efficacy study of patients with mHSPC includeconstipation, decreased appetite, rash, hemorrhage, increased weight, and hypertension. The most common laboratory test abnormalities (>=30%) in this groupinclude anemia, hyperglycemia, decreased lymphocyte count, decreased neutrophil count, increased AST and ALT, and hypocalcemia.

There are 7 severe adverse reactions.

More Frequent	Less Frequent
Neutropenic disorder	Hematuria Myocardial ischemia Pneumonia

Rare/Very Rare
Heart failure Hypertension Seizure disorder

There are 7 less severe adverse reactions.

More Frequent	Less Frequent
Fatigue Hyperbilirubinemia Increased aspartate transaminase Pain Pain in extremities Skin rash	Urinary retention

Rare/Very Rare
None.

The following precautions are available for NUBEQA (darolutamide):

Pediatric
Pregnant
Lactation
Geriatric

Safety and efficacy of darolutamide have not been established in pediatric patients.

Contraindicated

None

Severe Precaution

None

Management or Monitoring Precaution

None

Based on its mechanism of action, darolutamide can cause fetal harm and potential loss of pregnancy if administered to pregnant women.

It is not known whether darolutamide or its metabolites are distributed into milk. The effects of darolutamide on nursing infants or on milk production also are not known.

The manufacturer makes no special dosage recommendations for geriatric patients; most patients (88%) in the principal efficacy study were 65 years of age or older. In the principal efficacy study evaluating darolutamide in men with nmCRPC, 88% of patients were 65 years of age or older, and 49% were 75 years of age or older. In the principal efficacy study evaluating darolutamide in men with mHSPC, 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 geriatric patients and younger adults in both studies.

Metastatic castration-sensitive prostate cancer
C61	Malignant neoplasm of prostate
Z19.1	Hormone sensitive malignancy status
Non-metastatic castration-resistant prostate cancer
C61	Malignant neoplasm of prostate