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Enzalutamide

Medically reviewed by Drugs.com. Last updated on Aug 12, 2020.

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; carboxylesterase 1 metabolizes N-desmethyl enzalutamide and enzalutamide to the inactive carboxylic acid metabolite.

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: Treatment of castration-resistant prostate cancer; treatment of metastatic castration-sensitive prostate cancer.

Contraindications

There are no contraindications listed in the manufacturer's US labeling.

Canadian labeling: Hypersensitivity to enzalutamide or any component of the formulation; women who are or may become pregnant or are lactating

Dosing: Adult

Note: Patients receiving enzalutamide should also receive a gonadotropin-releasing hormone analog concurrently (or have had a bilateral orchiectomy).

Prostate cancer, castration-resistant: Oral: 160 mg once daily until disease progression or unacceptable toxicity (Beer 2014; Hussain 2018; Scher 2012; Shore 2016).

Prostate cancer, metastatic, castration-sensitive: Oral: 160 mg once daily until disease progression or unacceptable toxicity (Armstrong 2019).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

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.

Hypersensitivity reaction, serious: Permanently discontinue treatment.

Ischemic heart disease, grade 3 or 4: Discontinue treatment.

Posterior reversible encephalopathy syndrome: Discontinue treatment.

Seizures: Permanently discontinue treatment.

Administration

Oral: Administer at the same time each day, either with or without food. Swallow capsules whole; do not chew, dissolve, or open the capsules.

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

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

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. Consider therapy modification

Acalabrutinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Acalabrutinib. Management: Avoid co-administration of strong CYP3A inducers in patients taking acalabrutinib. If strong CYP3A inducers cannot be avoided, increase the dose of acalabrutinib to 200 mg twice daily. Consider therapy modification

Alfentanil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Alfentanil. Management: If concomitant use of alfentanil and strong CYP3A4 inducers is necessary, consider dosage increase of alfentanil until stable drug effects are achieved. Monitor patients for signs of opioid withdrawal. Consider therapy modification

Alpelisib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Alpelisib. 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. Management: Avoid concurrent use of apixaban with strong CYP3A4 inducers whenever possible. Use of a strong CYP3A4 inducer with apixaban should be strictly avoided in any patient who is using an agent (either the CYP3A4 inducer or a third drug) that induces P-gp. Consider therapy modification

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 (Strong) may decrease the serum concentration of ARIPiprazole. Management: For indications other than major depressive disorder: double the oral aripiprazole dose over 1 to 2 weeks and closely monitor. Avoid use of strong 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 higher 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

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

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

Avatrombopag: Enzalutamide may decrease the serum concentration of Avatrombopag. Management: For chronic immune thrombocytopenia, increase initial avatrombopag dose to 40 mg daily. No dosage adjustment needed for patients with chronic liver disease-associated thrombocytopenia using altrombopag prior to a procedure. Consider therapy modification

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

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

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

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

Bictegravir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Bictegravir. Management: Rifampin is specifically contraindicated, and the use of carbamazepine, phenytoin, or phenobarbital is not recommended when alternatives are acceptable Monitor therapy

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

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

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

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. Decrease brexpiprazole to original dose over 1 to 2 weeks if the strong CYP3A4 inducer is discontinued. Consider therapy modification

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

Brivaracetam: CYP2C19 Inducers (Moderate) may decrease the serum concentration of Brivaracetam. Monitor therapy

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

BusPIRone: CYP3A4 Inducers (Strong) may decrease the serum concentration of BusPIRone. Management: Consider alternatives to this combination. If coadministration of these agents is deemed necessary, monitor patients for reduced buspirone effects and increase buspirone doses as needed. Consider therapy modification

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

Cabozantinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Cabozantinib. Management: Avoid use of strong CYP3A4 inducers with cabozantinib if possible. If combined, increase cabozantinib capsules (Cometriq) by 40 mg from previous dose, max 180 mg daily. Increase cabozantinib tablets (Cabometyx) by 20 mg from previous dose, max 80 mg daily 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

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

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

Carisoprodol: CYP2C19 Inducers (Moderate) may increase serum concentrations of the active metabolite(s) of Carisoprodol. CYP2C19 Inducers (Moderate) may decrease the serum concentration of Carisoprodol. Monitor therapy

Celecoxib: CYP2C9 Inducers (Moderate) may decrease the serum concentration of Celecoxib. Monitor therapy

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

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

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. Management: Avoid use with strong CYP3A4 inducers when possible. If combined, monitor patients closely and consider clozapine dose increases. Clozapine dose reduction and further monitoring may be required when strong CYP3A4 inducers are discontinued. Consider therapy modification

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

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

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

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

CycloSPORINE (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of CycloSPORINE (Systemic). Management: Monitor closely for reduced cyclosporine concentrations when combined with strong CYP3A4 inducers. Cyclosporine dose increases will likely be required to maintain adequate serum concentrations. Consider therapy modification

CYP2C8 Inhibitors (Moderate): May increase the serum concentration of Enzalutamide. 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. Once the inhibitor is discontinued, return enzalutamide to the dose used prior to inhibitor initiation Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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. Consider therapy modification

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

CYP3A4 Substrates (High risk with Inducers): Enzalutamide may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to concomitant therapy when possible. If concomitant therapy cannot be avoided, monitor for reduced clinical effects of the CYP3A4 substrate. Consider therapy modification

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 (High risk with Inducers). Monitor therapy

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

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 dexamethasone efficacy. Consider avoiding this combination when treating life threatening conditions (ie, multiple myeloma). Consider therapy modification

Diclofenac (Systemic): CYP2C9 Inducers (Moderate) may decrease the serum concentration of Diclofenac (Systemic). Monitor therapy

Dienogest: CYP3A4 Inducers (Strong) may decrease the serum concentration of Dienogest. 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

Doravirine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Doravirine. 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 whenever possible. Prescribing information for at least one doxorubicin product 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

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

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

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

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

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

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

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

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

Eravacycline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Eravacycline. Management: Increase the eravacycline dose to 1.5 mg/kg every 12 hours when combined with strong CYP3A4 inducers. Consider therapy modification

Erdafitinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Erdafitinib. 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 combined, monitor patients closely for diminished etoposide response and need for etoposide dose increases. 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

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

Everolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Everolimus. Management: Avoid concurrent use of strong CYP3A4 inducers if possible. If coadministration cannot be avoided, monitor for decreased everolimus serum concentrations and effects, and adjust everolimus dose as needed. Consider therapy modification

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

Exemestane: CYP3A4 Inducers (Strong) may decrease the serum concentration of Exemestane. Management: Increase the exemestane dose to 50 mg/day in patients receiving concurrent strong CYP3A4 inducers. Monitor patients closely for evidence of toxicity or inadequate clinical response. Consider therapy modification

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

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

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

Fluvastatin: CYP2C9 Inducers (Moderate) may decrease the serum concentration of Fluvastatin. Monitor therapy

Fosaprepitant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Fosaprepitant. Specifically, CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite aprepitant. Avoid combination

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

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

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

Fostemsavir: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Fostemsavir. 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

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

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

Glecaprevir and Pibrentasvir: CYP3A4 Inducers (Strong) may decrease the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

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 extended-release guanfacine dose by up to double when initiating guanfacine in patients taking CYP3A4 inducers or if initiating a CYP3A4 inducer in a patient already taking extended-release guanfacine. Monitor for reduced guanfacine efficacy. 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

Istradefylline: CYP3A4 Inducers (Strong) may decrease the serum concentration of Istradefylline. 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

Ivosidenib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Ivosidenib. 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

Ketoconazole (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Ketoconazole (Systemic). Management: The use of ketoconazole concurrently with or within 2 weeks of a strong CYP3A4 inducer is not recommended. If such a combination cannot be avoided, monitor patients closely for evidence of diminished clinical response to ketoconazole. Consider therapy modification

Lapatinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lapatinib. Management: If concomitant use cannot be avoided, titrate 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. Consider therapy modification

Larotrectinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inducers with larotrectinib. If this combination cannot be avoided, double the larotrectinib dose. Reduced to previous dose after stopping the inducer after a period of 3 to 5 times the inducer's half-life. Consider therapy modification

Lefamulin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin with strong CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification

Lefamulin (Intravenous): CYP3A4 Inducers (Strong) may decrease the serum concentration of Lefamulin (Intravenous). Management: Avoid concomitant use of lefamulin intravenous infusion with strong CYP3A4 inducers unless the benefits outweigh the risks. Consider therapy modification

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

Lesinurad: CYP2C9 Inducers (Moderate) may decrease the serum concentration of Lesinurad. Monitor therapy

Levonorgestrel (IUD): CYP3A4 Inducers (Strong) may diminish the therapeutic effect of Levonorgestrel (IUD). CYP3A4 Inducers (Strong) may decrease the serum concentration of Levonorgestrel (IUD). Monitor therapy

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

Lorlatinib: CYP3A4 Inducers (Strong) may enhance the hepatotoxic effect of Lorlatinib. CYP3A4 Inducers (Strong) may decrease the serum concentration of Lorlatinib. Avoid combination

Lornoxicam: CYP2C9 Inducers (Moderate) may decrease the serum concentration of Lornoxicam. Monitor therapy

Lumacaftor and Ivacaftor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Lumacaftor and Ivacaftor. Specifically, the serum concentration of ivacaftor may be decreased. Avoid combination

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

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

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

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

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

Manidipine: CYP3A4 Inducers (Strong) may decrease the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inducers. If combined, monitor closely for decreased manidipine effects and loss of efficacy. Increased manidipine doses may be required. Consider therapy modification

Maraviroc: CYP3A4 Inducers (Strong) may decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600mg twice/day, but only in the absence of a concurrent strong CYP3A4 inhibitor. Not recommended for pediatric patients not also receiving a strong CYP3A4 inhibitor. Do not use in patients with CrCl less than 30 mL/min. Consider therapy modification

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

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

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

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

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

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

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

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

Neratinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Neratinib. 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

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

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

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

Omeprazole: CYP2C19 Inducers (Moderate) may decrease the serum concentration of Omeprazole. Monitor therapy

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

Osimertinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Osimertinib. Management: Avoid coadministration of osimertinib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase osimertinib to 160 mg daily. Reduce osimertinib to 80 mg daily 3 weeks after discontinuation of the strong CYP3A4 inducer. Consider therapy modification

Ospemifene: Enzalutamide may decrease the serum concentration of Ospemifene. Monitor therapy

OXcarbazepine: CYP3A4 Inducers (Strong) may decrease the serum concentration of OXcarbazepine. Specifically, the concentrations of the 10-monohydroxy active metabolite of oxcarbazepine may be decreased. Monitor therapy

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

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

Perampanel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Perampanel. Management: Increase the perampanel starting dose to 4 mg/day when perampanel is used concurrently with moderate and strong CYP3A4 inducers. Monitor response to perampanel, particularly with changes to CYP3A4 inducer therapy. Consider therapy modification

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

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

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

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

Pitolisant: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pitolisant. Management: If on a stable pitolisant dose of 8.9 mg or 17.8 mg/day and starting a strong CYP3A4 inducer, double the pitolisant dose over 7 days (ie, to either 17.8 mg/day or 35.6 mg/day, respectively). Reduce pitolisant dose by 50% when the inducer is discontinued. Consider therapy modification

Polatuzumab Vedotin: CYP3A4 Inducers (Strong) may decrease the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be decreased. Monitor therapy

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

Pralsetinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Pralsetinib. Management: Avoid concomitant use of pralsetinib with strong CYP3A4 inducers when possible. If combined, increase the starting dose of pralsetinib to double the current pralsetinib dosage starting on day 7 of coadministration. Consider therapy modification

Praziquantel: CYP3A4 Inducers (Strong) may decrease the serum concentration of Praziquantel. Management: Use of praziquantel with strong CYP3A4 inducers is contraindicated. 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

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

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: An increase in quetiapine dose (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

Radotinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of Radotinib. Management: Consider alternatives to this combination when possible as the risk of radotinib treatment failure may be increased. Consider therapy modification

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

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

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

Rifabutin: May decrease the serum concentration of Enzalutamide. Monitor therapy

Rifapentine: May decrease the serum concentration of Enzalutamide. Monitor therapy

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

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

RisperiDONE: CYP3A4 Inducers (Strong) may decrease the serum concentration of RisperiDONE. Management: Consider increasing the dose of oral risperidone (to no more than double the original dose) if a strong CYP3A4 inducer is initiated. For patients on IM risperidone, consider an increased IM dose or supplemental doses of oral risperidone. Consider therapy modification

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

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

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

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

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

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

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

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

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

Sirolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Sirolimus. Management: Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels. Consider therapy modification

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

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

Sulfonylureas: CYP2C9 Inducers (Moderate) may decrease the serum concentration of Sulfonylureas. Monitor therapy

SUNItinib: CYP3A4 Inducers (Strong) may decrease the serum concentration of SUNItinib. Management: Avoid when possible. If combined, increase sunitinib dose to a max of 87.5 mg daily when treating GIST or RCC. Increase sunitinib dose to a max of 62.5 mg daily when treating PNET. Monitor patients for both reduced efficacy and increased toxicities. Consider therapy modification

Tacrolimus (Systemic): CYP3A4 Inducers (Strong) may decrease the serum concentration of Tacrolimus (Systemic). Management: Monitor for decreased tacrolimus concentrations and effects when combined with strong CYP3A4 inducers. Tacrolimus dose increases will likely be needed during concomitant use. Consider therapy modification

Tadalafil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Tadalafil. Management: Erectile dysfunction or BPH: 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

Tamoxifen: CYP3A4 Inducers (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. CYP3A4 Inducers (Strong) may decrease the serum concentration of Tamoxifen. Management: Consider alternatives to concomitant use of strong CYP3A4 inducers and tamoxifen. If the combination cannot be avoided, monitor for reduced therapeutic effects of tamoxifen. Consider therapy modification

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

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

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

Temsirolimus: CYP3A4 Inducers (Strong) may decrease the serum concentration of Temsirolimus. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inducers. If coadministration is unavoidable, increase temsirolimus dose to 50 mg per week. Resume previous temsirolimus dose after discontinuation of the strong CYP3A4 inducer. Consider therapy modification

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

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

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

Thiotepa: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inducers (Strong) may decrease the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inducers. If concomitant use is unavoidable, monitor for adverse effects. Consider therapy modification

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 (High risk with Inducers). 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: Avoid concurrent use of strong CYP3A4 inducers with the Jynarque brand of tolvaptan. For patients receiving the Samsca brand of tolvaptan, monitor patient response to tolvaptan and adjust tolvaptan dose if required. Consider therapy modification

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

Torsemide: CYP2C9 Inducers (Moderate) may decrease the serum concentration of Torsemide. Monitor therapy

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

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

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

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

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

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

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

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

Vandetanib: CYP3A4 Inducers (Strong) may increase serum concentrations of the active metabolite(s) of 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. Management: Avoid coadministration of vemurafenib and strong CYP3A4 inducers if possible. If coadministration is unavoidable, increase the vemurafenib dose by 240 mg as tolerated. Resume prior vemurafenib dose 2 weeks after discontinuation of strong CYP3A4 inducer. Consider therapy modification

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

Verapamil: CYP3A4 Inducers (Strong) may decrease the serum concentration of Verapamil. Management: Consider alternatives to this combination. If combined, monitor for reduced verapamil efficacy. Verapamil dose increases may be necessary. Consider therapy modification

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 to 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

Vitamin K Antagonists (eg, warfarin): Enzalutamide may decrease the serum concentration of Vitamin K Antagonists. Management: Avoid concurrent use of vitamin K antagonists and enzalutamide when possible. If combined, monitor for reduced vitamin K antagonist effects (ie, decreased INR, thrombosis) and increase vitamin K antagonist doses as needed. Consider therapy modification

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

Voriconazole: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voriconazole. Management: Consider alternatives to this combination when possible. If combined, monitor for decreased voriconazole concentrations and effects. Consider therapy modification

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

Voxelotor: CYP3A4 Inducers (Strong) may decrease the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inducers. If concomitant use is unavoidable, increase the voxelotor dose to 2,500 mg once daily. Consider therapy modification

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

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 zaleplon is combined with a strong CYP3A4 inducer, monitor for decreased effectiveness of zaleplon. Consider therapy modification

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

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

Test Interactions

May interfere with various assays resulting in falsely-elevated digoxin levels or even therapeutic digoxin levels for patients not taking digoxin; use of an alternate method (eg, mass spectrometry) should be considered in these situations (Kalra 2020).

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

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

Central nervous system: Fatigue (≤51%), falling (5% to 13%), dizziness (10% to 12%), headache (9% to 12%)

Endocrine & metabolic: Hyperglycemia (83%), hot flash (13% to 27%), hypermagnesemia (16%), hyponatremia (13%), weight loss (6% to 12%)

Gastrointestinal: Constipation (9% to 23%), diarrhea (12% to 22%), decreased appetite (5% to 19%), nausea (11% to 14%)

Hematologic & oncologic: Decreased neutrophils (20%; grades 3/4: <1%), decreased white blood cell count (17%; grades 3/4: <1%)

Neuromuscular & skeletal: Asthenia (≤51%), back pain (19% to 29%), arthralgia (21%), musculoskeletal pain (6% to 16%)

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

1% to 10%:

Cardiovascular: Ischemic heart disease (3%)

Central nervous system: Myasthenia (10%), insomnia (8% to 9%), paresthesia (7%), cauda equina syndrome (≤7%), spinal cord compression (≤7%), anxiety (3% to 7%), altered mental status (4% to 6%), cognitive dysfunction (5%), hypoesthesia (4%), restless leg syndrome (2%)

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

Endocrine & metabolic: Hypercalcemia (7%), gynecomastia (3%)

Gastrointestinal: Dysgeusia (8%)

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

Neuromuscular & skeletal: Bone fracture (4% to 10%), muscle rigidity (3%)

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

<1%, postmarketing, and/or case reports: Angioedema, hypersensitivity reaction, reversible posterior leukoencephalopathy syndrome, seizure, skin rash, vomiting

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular effects: Ischemic heart disease (including grades 3 or 4 ischemic events) occurred more commonly in patients receiving enzalutamide (compared to placebo); some events were fatal. 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. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors (including hypertension, diabetes, and/or dyslipidemia). Discontinue enzalutamide for grade 3 or 4 ischemic heart disease.

• Fractures: Falls and fractures have occurred in patients receiving enzalutamide; in clinical trials, the incidence of falls and fractures was higher in patients who received enzalutamide (vs placebo); grades 3/4 fractures have occurred. The median time to fracture onset was ~11 months (range: 2 days to ~5 years). Routine assessment of bone density and osteoporosis treatment with bone-modifying agents were not performed in studies. Evaluate fall and fracture risk. Monitor and manage fracture risk according to established treatment guidelines; consider the use of bone-modifying agents.

• Hypersensitivity: Hypersensitivity reactions, including facial, tongue, or lip edema, have been observed with enzalutamide; pharyngeal edema has also been reported. If hypersensitivity symptoms occur, advise patients to temporarily discontinue enzalutamide and obtain prompt medical care. Permanently discontinue enzalutamide for serious hypersensitivity reactions.

• 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 MRI. Discontinue enzalutamide in patients who develop PRES.

• Seizures: Seizures were observed in enzalutamide clinical trials; patients with predisposing risk factors for seizures were generally excluded from these studies. The onset of seizure ranged from 13 days to ~60 months after enzalutamide treatment initiation. Enzalutamide was permanently discontinued in patients experiencing seizures; seizures resolved upon therapy cessation. In a study designed to assess seizure risk in patients with predisposing factors, 2.2% of patients who received enzalutamide experienced a seizure; after the first seizure resolved, a few of those patients experienced a second seizure with continued enzalutamide treatment. It is not known if antiepileptic medications can prevent enzalutamide-related seizures. Patients in the study had one or more predisposing factors, including the use of concomitant medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident/transient ischemic attack, and Alzheimer disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, prior seizure history, presence of a space occupying brain lesion, history of arteriovenous malformation, or history of brain infection; some patients had more than one risk factor. Advise patients of the risk of seizures during enzalutamide treatment and of the risk of engaging in activities where sudden loss of consciousness could cause serious harm to themselves or others. Discontinue enzalutamide permanently if seizures develop during treatment.

Dosage forms specific issues:

• Sorbitol: May contain sorbitol.

Monitoring Parameters

CBC with differential and liver function tests (baseline and periodic); additional INR monitoring (if on warfarin); blood pressure (baseline and periodic). Monitor for signs/symptoms of ischemic heart disease, posterior reversible encephalopathy syndrome, and seizure; evaluate fall and fracture risk. Monitor adherence.

Reproductive Considerations

Male patients with female partners of reproductive potential should use effective contraception during treatment and for 3 months after the last enzalutamide dose.

Pregnancy Considerations

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to enzalutamide may cause fetal harm and loss of pregnancy.

Patient Education

What is this drug used for?

• It is used to treat prostate cancer.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Loss of strength and energy

• Fatigue

• Back pain

• Lack of appetite

• Constipation

• Muscle pain

• Muscle weakness

• Joint pain

• Diarrhea

• Hot flashes

• Common cold symptoms

• Weight loss

• Change in taste

• Trouble sleeping

• Anxiety

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Severe headache

• Severe dizziness

• Passing out

• Vision changes

• Chest pain

• Shortness of breath

• Burning or numbness feeling

• Blood in the urine

• Seizures

• Swelling of arms or legs

• Bone pain

• Trouble with memory

• Trouble focusing

• Infection

• Signs of posterior reversible encephalopathy syndrome like confusion, not alert, vision changes, seizures, or severe headache.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.