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Enzalutamide

Pronunciation

(en za LOO ta mide)

Index Terms

  • MDV3100

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Xtandi: 40 mg

Brand Names: U.S.

  • Xtandi

Pharmacologic Category

  • Antineoplastic Agent, Antiandrogen

Pharmacology

Enzalutamide is a pure androgen receptor signaling inhibitor; unlike other antiandrogen therapies, it has no known agonistic properties. It inhibits androgen receptor nuclear translocation, DNA binding, and coactivator mobilization, leading to cellular apoptosis and decreased prostate tumor volume.

Absorption

Rapid

Distribution

110 L

Metabolism

Primarily hepatic via CYP2C8 (responsible for formation of active metabolite N-desmethyl enzalutamide) and CYP3A4

Excretion

Urine (71%); feces (14%); primarily as inactive metabolite

Time to Peak

1 hour (range: 0.5 to 3 hours)

Half-Life Elimination

Parent drug: 5.8 days (range: 2.8 to 10.2 days); N-desmethyl enzalutamide: 7.8 to 8.6 days

Protein Binding

Parent drug: 97% to 98% to primarily albumin; active metabolite: 95% to plasma proteins

Use: Labeled Indications

Prostate cancer, metastatic: Treatment of metastatic, castration-resistant prostate cancer

Contraindications

Pregnancy

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to enzalutamide or any component of the formulation; women who are lactating

Dosing: Adult

Prostate cancer, metastatic, castration-resistant: Oral: 160 mg once daily

Dosage adjustment for concomitant strong CYP2C8 inhibitors: Avoid concomitant use if possible. If coadministration is necessary, reduce enzalutamide dose to 80 mg once daily. If the strong CYP2C8 inhibitor is discontinued, adjust the enzalutamide dose back up to the dose used prior to the initiation of the strong CYP2C8 inhibitor.

Dosage adjustment for concomitant strong CYP3A4 inducers: Avoid concomitant use if possible. If coadministration is necessary, increase the enzalutamide dose to 240 mg once daily. If the strong CYP3A4 inducer is discontinued, adjust the enzalutamide dose back to the dose used prior to the initiation of the strong CYP3A4 inducer.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Preexisting mild-to-moderate impairment (CrCl 30 to 89 mL/minute): No initial dosage adjustment necessary.

Preexisting severe impairment (CrCl <30 mL/minute), including end-stage renal disease: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

Preexisting mild, moderate, or severe impairment (Child-Pugh class A, B, or C): No dosage adjustment necessary.

Dosing: Adjustment for Toxicity

If ≥grade 3 toxicity or intolerable side effects occur, withhold treatment for 1 week or until symptom(s) improve to ≤grade 2, then resume at same dose, or reduce dose to 120 mg or 80 mg once daily, if necessary.

Seizures: Permanently discontinue treatment.

Administration

May be administered with or without food; take at the same time each day. Swallow capsules whole; do not chew, dissolve, or open the capsules. Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2016 [group 1]). NIOSH recommends single-gloving for administration of intact capsules (NIOSH 2016).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from moisture; keep bottle tightly closed.

Drug Interactions

Abiraterone Acetate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Abiraterone Acetate. Management: Avoid whenever possible. If such a combination cannot be avoided, increase abiraterone acetate dosing frequency from once daily to twice daily during concomitant use. Avoid combination

Alfentanil: Enzalutamide may decrease the serum concentration of Alfentanil. Avoid combination

Antihepaciviral Combination Products: CYP3A4 Inducers (Strong) may decrease the serum concentration of Antihepaciviral Combination Products. Avoid combination

Apixaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apixaban. Avoid combination

Apremilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Apremilast. Avoid combination

Aprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Patients taking the 441 mg dose of aripiprazole lauroxil increase their dose to 662 mg if used with a strong CYP3A4 inducer for more than 14 days. No dose adjustment is necessary for patients using the 662 mg or 882 mg doses of aripiprazole lauroxil. Consider therapy modification

Artemether: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Artemether. Specifically, dihydroartemisinin concentrations may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Artemether. Avoid combination

Asunaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Asunaprevir. Avoid combination

Axitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Axitinib. Avoid combination

Bedaquiline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bedaquiline. Avoid combination

Benperidol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Benperidol. Monitor therapy

Boceprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Boceprevir. Avoid combination

Bortezomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bortezomib. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be decreased. Monitor therapy

Brexpiprazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with a strong CYP3A4 inducer, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Consider therapy modification

Cabozantinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification

Calcifediol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Calcifediol. Monitor therapy

Cannabidiol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabidiol. Monitor therapy

Cannabis: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be decreased. Monitor therapy

Cariprazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cariprazine. Avoid combination

Ceritinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ceritinib. Avoid combination

Choline C 11: Antiandrogens may diminish the therapeutic effect of Choline C 11. Monitor therapy

Clarithromycin: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Clarithromycin. Clarithromycin may increase the serum concentration of CYP3A4 Inducers (Strong). CYP3A4 Inducers (Strong) may decrease the serum concentration of Clarithromycin. Management: Consider alternative antimicrobial therapy for patients receiving a CYP3A inducer. Drugs that enhance the metabolism of clarithromycin into 14-hydroxyclarithromycin may alter the clinical activity of clarithromycin and may impair clarithromycin efficacy. Consider therapy modification

Clindamycin (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Clindamycin (Systemic). Refer to the specific clindamycin (systemic) - rifampin drug interaction monograph for information concerning that combination. Monitor therapy

CloZAPine: CYP3A4 Inducers (Strong) may decrease the serum concentration of CloZAPine. Avoid combination

Cobimetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cobimetinib. Avoid combination

Corticosteroids (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Corticosteroids (Systemic). Exceptions: Hydrocortisone (Systemic); PrednisoLONE (Systemic); PredniSONE. Monitor therapy

Crizotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Crizotinib. Avoid combination

CycloSPORINE (Systemic): Enzalutamide may decrease the serum concentration of CycloSPORINE (Systemic). Avoid combination

CYP2C19 Substrates: Enzalutamide may decrease the serum concentration of CYP2C19 Substrates. Conversely, concentrations of active metabolites may be increased for those drugs activated by CYP2C19. Management: Concurrent use of enzalutamide with CYP2C19 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C19 substrate should be performed with caution and close monitoring. Consider therapy modification

CYP2C8 Inducers (Strong): May decrease the serum concentration of Enzalutamide. Avoid combination

CYP2C8 Inhibitors (Moderate): May decrease the metabolism of CYP2C8 Substrates. Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Enzalutamide. Management: Avoid concurrent use of strong CYP2C8 inhibitors and enzalutamide if possible. If the combination must be used, reduce enzalutamide to 80 mg once daily. Avoid combination

CYP2C9 Substrates: Enzalutamide may decrease the serum concentration of CYP2C9 Substrates. Management: Concurrent use of enzalutamide with CYP2C9 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP2C9 substrate should be performed with caution and close monitoring. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Enzalutamide. Management: Consider using an alternative agent that has no or minimal CYP3A4 induction potential when possible. If this combination cannot be avoided, increase the dose of enzalutamide from 160 mg daily to 240 mg daily. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Enzalutamide. Monitor therapy

CYP3A4 Substrates: Enzalutamide may decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Dabrafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dabrafenib. Avoid combination

Daclatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Daclatasvir. Avoid combination

Dasabuvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasabuvir. Avoid combination

Dasatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dasatinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing dasatinib dose and monitor clinical response and toxicity closely. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May increase the serum concentration of CYP2C8 Substrates. Monitor therapy

Delamanid: CYP3A4 Inducers (Strong) may decrease the serum concentration of Delamanid. Avoid combination

Dexamethasone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Dexamethasone (Systemic). Management: Consider dexamethasone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Consider therapy modification

Dienogest: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dienogest. Management: Avoid use of dienogest for contraception when using medications that induce CYP3A4 and for at least 28 days after discontinuation of a CYP3A4 inducer. An alternative form of contraception should be used during this time. Avoid combination

Diethylstilbestrol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Diethylstilbestrol. Monitor therapy

Dihydroergotamine: Enzalutamide may decrease the serum concentration of Dihydroergotamine. Avoid combination

Doxercalciferol: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Doxercalciferol. Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inducers (Strong) may decrease the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inducers in patients treated with doxorubicin. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronabinol. Monitor therapy

Dronedarone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dronedarone. Avoid combination

Eliglustat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eliglustat. Avoid combination

Ergotamine: Enzalutamide may decrease the serum concentration of Ergotamine. Avoid combination

Erlotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erlotinib. Management: Avoid combination if possible. If combination must be used, increase erlotinib dose by 50 mg increments every 2 weeks as tolerated, to a maximum of 450 mg/day. Consider therapy modification

Estriol (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): CYP3A4 Inducers (Strong) may decrease the serum concentration of Estriol (Topical). Monitor therapy

Etoposide: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide. If these combinations cannot be avoided, monitor patients closely for diminished etoposide response. Consider therapy modification

Etoposide Phosphate: CYP3A4 Inducers (Strong) may decrease the serum concentration of Etoposide Phosphate. Management: When possible, seek alternatives to strong CYP3A4-inducing medications in patients receiving etoposide phosphate. If these combinations cannot be avoided, monitor patients closely for diminished etoposide phosphate response. Consider therapy modification

Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers, but if strong CYP3A4 inducers cannot be avoided, consider gradually (in 5 mg increments) increasing the everolimus dose from 10 mg/day to 20 mg/day (adult doses). Avoid combination

Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Exemestane U.S. product labeling recommends using an increased dose (50 mg/day) in patients receiving concurrent strong CYP3A4 inducers. The Canadian product labeling does not recommend a dose adjustment with concurrent use of strong CYP3A4 inducers. Consider therapy modification

FentaNYL: Enzalutamide may decrease the serum concentration of FentaNYL. Avoid combination

Flibanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Flibanserin. Avoid combination

Fosphenytoin-Phenytoin: Enzalutamide may decrease the serum concentration of Fosphenytoin-Phenytoin. Avoid combination

Gefitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Gefitinib. Management: In the absence of severe adverse reactions, increase gefitinib dose to 500 mg daily in patients receiving strong CYP3A4 inducers; resume 250 mg dose 7 days after discontinuation of the strong inducer. Carefully monitor clinical response. Consider therapy modification

Grazoprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inducers (Strong) may decrease the serum concentration of GuanFACINE. Management: Increase the guanfacine dose by up to double when initiating concomitant therapy with strong CYP3A4 inducers. Increase guanfacine dose gradually over 1-2 weeks if strong CYP3A4 inducer therapy is just beginning. Consider therapy modification

Hydrocortisone (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Hydrocortisone (Systemic). Monitor therapy

Ibrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ibrutinib. Avoid combination

Idelalisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Idelalisib. Avoid combination

Ifosfamide: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Ifosfamide. CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Imatinib. Management: Avoid concurrent use of imatinib with strong CYP3A4 inducers when possible. If such a combination must be used, increase imatinib dose by at least 50% and monitor the patient's clinical response closely. Consider therapy modification

Indium 111 Capromab Pendetide: Antiandrogens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination

Irinotecan Products: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be reduced. CYP3A4 Inducers (Strong) may decrease the serum concentration of Irinotecan Products. Avoid combination

Isavuconazonium Sulfate: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inducers (Strong) may decrease isavuconazole serum concentrations. Avoid combination

Itraconazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Itraconazole. Avoid combination

Ivabradine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivacaftor. Avoid combination

Ixabepilone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixabepilone. Management: Avoid this combination whenever possible. If this combination must be used, a gradual increase in ixabepilone dose from 40 mg/m2 to 60 mg/m2 (given as a 4-hour infusion), as tolerated, should be considered. Consider therapy modification

Ixazomib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ixazomib. Avoid combination

Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If therapy overlap cannot be avoided, consider titrating lapatinib gradually from 1,250 mg/day up to 4,500 mg/day (HER2 positive metastatic breast cancer) or 1,500 mg/day up to 5,500 mg/day (hormone receptor/HER2 positive breast cancer) as tolerated. Avoid combination

Linagliptin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Linagliptin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification

Lumefantrine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumefantrine. Avoid combination

Lurasidone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lurasidone. Avoid combination

Macitentan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Macitentan. Avoid combination

Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with CrCl less than 30 mL/min. Consider therapy modification

MethylPREDNISolone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy. Consider therapy modification

MiFEPRIStone: CYP3A4 Inducers (Strong) may decrease the serum concentration of MiFEPRIStone. Avoid combination

Mirodenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Mirodenafil. Management: Consider avoiding the concomitant use of mirodenafil and strong CYP3A4 inducers. If combined, monitor for decreased mirodenafil effects. Mirodenafil dose increases may be required to achieve desired effects. Consider therapy modification

Naloxegol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Naloxegol. Avoid combination

Netupitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Netupitant. Avoid combination

NIFEdipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NIFEdipine. Avoid combination

Nilotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nilotinib. Avoid combination

NiMODipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of NiMODipine. Avoid combination

Nisoldipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Olaparib. Avoid combination

Osimertinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osimertinib. Consider therapy modification

Palbociclib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Palbociclib. Avoid combination

Panobinostat: CYP3A4 Inducers (Strong) may decrease the serum concentration of Panobinostat. Avoid combination

PAZOPanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PAZOPanib. Avoid combination

Perampanel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Perampanel. Management: Avoid use of perampanel with strong CYP3A inducers other than enzyme-inducing antiepileptic drugs (EIAEDs). Increase perampanel starting dose to 4 mg/day when used with EIAEDs such as phenytoin, carbamazepine, or oxcarbazepine. Avoid combination

Pimavanserin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pimavanserin. Monitor therapy

Pimozide: Enzalutamide may decrease the serum concentration of Pimozide. Avoid combination

PONATinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of PONATinib. Avoid combination

Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Management: Avoid concomitant use of praziquantel with strong CYP3A4 inducers. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. Avoid combination

PrednisoLONE (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of PrednisoLONE (Systemic). Monitor therapy

PredniSONE: CYP3A4 Inducers (Strong) may decrease the serum concentration of PredniSONE. Monitor therapy

Propafenone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Propafenone. Monitor therapy

QUEtiapine: CYP3A4 Inducers (Strong) may decrease the serum concentration of QUEtiapine. Management: Quetiapine dose increases to as much as 5 times the regular dose may be required to maintain therapeutic benefit. Reduce the quetiapine dose back to the previous/regular dose within 7-14 days of discontinuing the inducer. Consider therapy modification

QuiNIDine: Enzalutamide may decrease the serum concentration of QuiNIDine. Avoid combination

Ramelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ramelteon. Monitor therapy

Ranolazine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ranolazine. Avoid combination

Reboxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Reboxetine. Monitor therapy

Regorafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Regorafenib. Avoid combination

Rivaroxaban: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rivaroxaban. Avoid combination

Roflumilast: CYP3A4 Inducers (Strong) may decrease the serum concentration of Roflumilast. Management: Roflumilast U.S. prescribing information recommends against combining strong CYP3A4 inducers with roflumilast. The Canadian product monograph makes no such recommendation but notes that such agents may reduce roflumilast therapeutic effects. Avoid combination

Rolapitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Rolapitant. Management: Avoid rolapitant use in patients requiring chronic administration of strong CYP3A4 inducers. Monitor for reduced rolapitant response and the need for alternative or additional antiemetic therapy even with shorter-term use of such inducers. Consider therapy modification

RomiDEPsin: CYP3A4 Inducers (Strong) may decrease the serum concentration of RomiDEPsin. Avoid combination

SAXagliptin: CYP3A4 Inducers may decrease the serum concentration of SAXagliptin. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Simeprevir. Avoid combination

Sirolimus: Enzalutamide may decrease the serum concentration of Sirolimus. Avoid combination

Sonidegib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sonidegib. Avoid combination

SORAfenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SORAfenib. Avoid combination

St John's Wort: May decrease the serum concentration of Enzalutamide. Avoid combination

SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, consider increasing sunitinib dose and monitor clinical response and toxicity closely. Consider therapy modification

Suvorexant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Suvorexant. Avoid combination

Tacrolimus (Systemic): Enzalutamide may decrease the serum concentration of Tacrolimus (Systemic). Avoid combination

Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction: monitor for decreased effectiveness - no standard dose adjustments recommended. Avoid use of tadalafil for pulmonary arterial hypertension in patients receiving a strong CYP3A4 inducer. Consider therapy modification

Tasimelteon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tasimelteon. Avoid combination

Telaprevir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Telaprevir. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tetrahydrocannabinol. Monitor therapy

TiaGABine: CYP3A4 Inducers (Strong) may decrease the serum concentration of TiaGABine. Management: Approximately 2-fold higher tiagabine doses and a more rapid dose titration will likely be required in patients concomitantly taking a strong CYP3A4 inducer. Consider therapy modification

Ticagrelor: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inducers (Strong) may decrease the serum concentration of Ticagrelor. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tofacitinib. Avoid combination

Tolvaptan: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tolvaptan. Management: If concurrent use is necessary, increased doses of tolvaptan (with close monitoring for toxicity and clinical response) may be needed. Avoid combination

Toremifene: CYP3A4 Inducers (Strong) may decrease the serum concentration of Toremifene. Avoid combination

Trabectedin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Trabectedin. Avoid combination

Tropisetron: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tropisetron. Monitor therapy

Udenafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Udenafil. Monitor therapy

Ulipristal: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ulipristal. Avoid combination

Vandetanib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vandetanib. Avoid combination

Velpatasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Velpatasvir. Avoid combination

Vemurafenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vemurafenib. Avoid combination

Venetoclax: CYP3A4 Inducers (Strong) may decrease the serum concentration of Venetoclax. Avoid combination

Vilazodone: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vilazodone. Management: Consider increasing vilazodone dose by as much as 2-fold (do not exceed 80 mg/day), based on response, in patients receiving strong CYP3A4 inducers for > 14 days. Reduce to the original vilazodone dose over 1-2 weeks after inducer discontinuation. Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inducers (Strong) may decrease the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vinflunine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vinflunine. Avoid combination

Vorapaxar: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vorapaxar. Avoid combination

Vortioxetine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Vortioxetine. Management: Consider increasing the vortioxetine dose to no more than 3 times the original dose when used with a strong drug metabolism inducer for more than 14 days. The vortioxetine dose should be returned to normal within 14 days of stopping the strong inducer. Consider therapy modification

Warfarin: Enzalutamide may decrease the serum concentration of Warfarin. More specifically, enzalutamide may decrease concentrations of the S-warfarin enantiomer. Management: Avoid concurrent use of warfarin and enzalutamide whenever possible. If the combination must be used, conduct additional INR monitoring as serum concentrations may be decreased. Consider therapy modification

Zaleplon: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zaleplon. Management: Consider the use of an alternative hypnotic that is not metabolized by CYP3A4 in patients receiving strong CYP3A4 inducers. If zalephon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Consider therapy modification

Zuclopenthixol: CYP3A4 Inducers (Strong) may decrease the serum concentration of Zuclopenthixol. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Peripheral edema (12% to 15%), hypertension (6% to 14%)

Central nervous system: Fatigue (≤51%), falling (5% to 13%), headache (11% to 12%), dizziness (10% to 11%)

Endocrine & metabolic: Hot flash (18% to 20%), weight loss (12%)

Gastrointestinal: Constipation (23%), diarrhea (17% to 22%), decreased appetite (19%)

Hematologic & oncologic: Neutropenia (15%; grades 3/4: 1%)

Neuromuscular & skeletal: Weakness (≤51%), back pain (26% to 29%), arthralgia (21%), musculoskeletal pain (15%)

Respiratory: Upper respiratory tract infection (11% to 16%), dyspnea (11%)

1% to 10%:

Central nervous system: Myasthenia (10%), insomnia (8% to 9%), anxiety (7%), paresthesia (7%), cauda equina syndrome (≤7%), spinal cord compression (≤7%), altered mental status (4% to 6%), hypoesthesia (4%), hallucination (2%), restless leg syndrome (2%)

Dermatologic: Pruritus (4%), xeroderma (4%)

Endocrine & metabolic: Gynecomastia (3%)

Gastrointestinal: Dysgeusia (8%)

Genitourinary: Hematuria (7% to 9%), pollakiuria (5%)

Hematologic & oncologic: Thrombocytopenia (6%)

Hepatic: Increased serum bilirubin (3%)

Infection: Infection (≤6%; including sepsis)

Neuromuscular & skeletal: Bone fracture (4% to 9%), stiffness (3%)

Respiratory: Lower respiratory tract infection (8% to 9%), epistaxis (3%)

<1% (Limited to important or life-threatening): Reversible posterior leukoencephalopathy syndrome, seizure

Warnings/Precautions

Concerns related to adverse effects:

• Posterior reversible encephalopathy syndrome: Posterior reversible encephalopathy syndrome (PRES) has been reported in patients receiving enzalutamide. PRES is a neurological disorder which may present with rapidly evolving symptoms (headache, seizure, lethargy, confusion, blindness, and other visual/neurologic disturbances) with or without associated hypertension. PRES diagnosis may be confirmed with magnetic resonance imagining (MRI). Discontinue enzalutamide in patients who develop PRES.

• Seizures: Seizures were observed in clinical trials (onset: ~1 to 20 months after treatment initiation). Therapy was permanently discontinued and patients were not rechallenged; seizures resolved upon therapy cessation. Patients with predisposing factors for seizure were excluded from the trials; factors include seizure history, underlying brain injury with loss of consciousness, transient ischemic attack within the past 12 months, cerebral vascular accident, brain metastases, brain arteriovenous malformation, or (in one study) the use of concomitant medications which may lower the seizure threshold. Enzalutamide should be used with caution in patients with a history of seizure disorders or other predisposing factors. Discontinue permanently if seizures develop during treatment.

• Spermatogenesis: May cause hypospermatogenesis; may impair male fertility.

Disease-related concerns:

• Cardiovascular disease: Androgen-deprivation therapy may increase the risk for cardiovascular disease (Levine, 2010). An increase in systolic and diastolic blood pressures has been observed (Scher, 2012); may worsen preexisting hypertension.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage forms specific issues:

• Sorbitol: May contain sorbitol.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2016 [group 1]).

Monitoring Parameters

Monitor for signs/symptoms of seizure, loss of consciousness, dizziness, and hallucinations; CBC with differential and liver function tests (baseline and periodic); additional INR monitoring (if on warfarin); blood pressure (baseline and periodic), signs/symptoms of posterior reversible encephalopathy syndrome

Pregnancy Considerations

Enzalutamide is contraindicated in pregnant women and is not indicated for use in women. Adverse effects were observed in animal reproduction studies. Enzalutamide is an androgen receptor inhibitor; based on the mechanism of action, fetal harm and potential loss of pregnancy would be expected. Male patients with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last enzalutamide dose and should use a condom if having intercourse with a pregnant woman.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience dizziness, loss of strength and energy, back pain, lack of appetite, constipation, muscle pain, muscle weakness, joint pain, diarrhea, hot flashes, headache, weight loss, change in taste, insomnia, anxiety, rhinitis, rhinorrhea, cough, or sneezing. Have patient report immediately to prescriber shortness of breath, burning or numbness feeling, hematuria, seizures, swelling of arms or legs, bone pain, chills, pharyngitis, memory impairment, or signs of posterior reversible encephalopathy syndrome (confusion, not alert, vision changes, seizures, or severe headache) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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