eventually [30:<30 mL/minute) or end-stage renal disease. 1 Common Adverse Effects Asthenia/fatigue, 1 2 5 back pain, 1 diarrhea, 1 2 arthralgia, 1 hot flush, 1 2 peripheral edema, 1 musculoskeletal pain, 1 2 headache, 1 2 upper respiratory tract infection, 1 muscular weakness, 1 dizziness, 1 insomnia, 1 lower respiratory tract infection, 1 spinal cord compression and cauda equina syndrome, 1 hematuria, 1 paresthesia, 1 anxiety, 1 hypertension. 1 Interactions for Enzalutamide Metabolized by CYP2C8 and CYP3A4; formation of major active metabolite ( N -desmethylenzalutamide) is mediated by CYP2C8. 1 Enzalutamide is a potent inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19 in vivo. 1 Not expected to induce CYP1A2 at clinically relevant concentrations. 1 In vitro, enzalutamide and its 2 major metabolites (active N -desmethyl metabolite and inactive carboxylic acid metabolite) inhibit CYP isoenzymes 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5; enzalutamide causes time-dependent inhibition of CYP1A2 in vitro. 1 Neither enzalutamide nor its 2 major metabolites are substrates of P-glycoprotein (P-gp) in vitro; enzalutamide and N -desmethylenzalutamide inhibit P-gp. 1 Drugs Affecting Hepatic Microsomal Enzymes Potent CYP2C8 inhibitors: Possible increased AUC of major active forms of enzalutamide (parent drug plus N -desmethyl metabolite). 1 Avoid concomitant use if possible. 1 If concomitant use cannot be avoided, reduce enzalutamide dosage to 80 mg once daily. 1 If concomitant use of the potent CYP2C8 inhibitor is discontinued, return enzalutamide dosage to the dosage used prior to initiation of the potent CYP2C8 inhibitor. 1 Potent CYP3A4 inhibitors: Possible increased AUC of major active forms of enzalutamide (parent drug plus N -desmethyl metabolite). 1 Initial dosage adjustment not necessary. 1 Potent or moderate CYP2C8 inducers: In vivo effects of CYP2C8 inducers not established to date; possible alteration of enzalutamide AUC. 1 Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP2C8 induction potential. 1 Potent or moderate CYP3A4 inducers: In vivo effects of CYP3A4 inducers not established to date; possible decreased plasma concentrations of enzalutamide. 1 Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential. 1 Drugs Metabolized by Hepatic Microsomal Enzymes Substrates of CYP 3A4, 2C9, or 2C19: Possible decreased plasma concentrations of the substrate drug. 1 Avoid concomitant use of enzalutamide and CYP 3A4, 2C9, or 2C19 substrates with narrow therapeutic indices. 1 CYP2C8 substrates: No substantial change in plasma concentrations of a probe substrate for CYP2C8. 1 Dosage adjustment not necessary. 1 Specific Drugs Drug Interaction Comments Anticonvulsants (carbamazepine, phenobarbital, phenytoin) In vivo effects of CYP inducers not established to date; possible decreased plasma concentrations of enzalutamide 1 Possible decreased plasma concentrations of phenytoin 1 Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential 1 Avoid concomitant use of phenytoin 1 Antimycobacterials (rifabutin, rifampin, rifapentine) In vivo effects of CYP inducers not established to date; possible alterations in plasma concentrations of enzalutamide 1 Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP2C8 or CYP3A4 induction potential 1 Bosentan Possible decreased plasma concentrations of enzalutamide 1 Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential 1 Efavirenz Possible decreased plasma concentrations of enzalutamide 1 Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential 1 Ergot derivatives (e.g., dihydroergotamine, ergotamine) Possible decreased concentrations of the ergot derivative 1 Avoid concomitant use 1 Etravirine Possible decreased plasma concentrations of enzalutamide 1 Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential 1 Gemfibrozil Increased AUC of major active forms of enzalutamide (parent drug plus N -desmethyl metabolite) 1 Avoid concomitant use; if concomitant use cannot be avoided, reduce enzalutamide dosage to 80 mg once daily 1 Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus) Possible decreased concentrations of the immunosuppressive agent 1 Avoid concomitant use 1 Itraconazole Increased AUC of major active forms of enzalutamide (parent drug plus N -desmethyl metabolite) 1 No initial dosage adjustment required 1 Midazolam Decreased AUC and peak plasma concentration of midazolam 1 13 Modafinil Possible decreased plasma concentrations of enzalutamide 1 Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential 1 Nafcillin Possible decreased plasma concentrations of enzalutamide 1 Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential 1 Omeprazole Decreased AUC and peak plasma concentration of omeprazole 1 13 Opiate agonists (alfentanil, fentanyl) Possible decreased concentrations of the opiate agonist 1 Avoid concomitant use 1 Pimozide Possible decreased concentrations of pimozide 1 Avoid concomitant use 1 Pioglitazone No substantial change in AUC or peak plasma concentration of pioglitazone 1 No dosage adjustment required 1 Quinidine Possible decreased concentrations of quinidine 1 Avoid concomitant use 1 St. John's wort ( Hypericum perforatum ) Possible decreased plasma concentrations of enzalutamide 1 Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential 1 Warfarin Decreased AUC of S -warfarin 1 13 Avoid concomitant use 1 If concomitant use cannot be avoided, additional INR monitoring recommended 1 Enzalutamide Pharmacokinetics Absorption Bioavailability Following oral administration, peak plasma concentrations are attained in about 1 hour. 1 Food High-fat meal does not substantially affect bioavailability. 1 Special Populations Mild or moderate hepatic impairment (Child-Pugh class A or B) does not substantially alter AUC of major active forms of enzalutamide (parent drug plus N -desmethyl metabolite) following single dose. 1 Age and body weight do not substantially affect exposure to enzalutamide. 1 Distribution Extent Not known whether enzalutamide is distributed into human milk. 1 Plasma Protein Binding Enzalutamide: 97 98% (mainly albumin). 1 N -desmethylenzalutamide: 95%. 1 Elimination Metabolism Metabolized in the liver by CYP2C8 and CYP3A4. 1 Major metabolites are N -desmethylenzalutamide (active) and a carboxylic acid derivative (inactive); formation of N -desmethyl metabolite is mediated principally by CYP2C8. 1 Elimination Route Excreted in urine (71%) and feces (14%); only trace to minimal amounts of dose are recovered in urine and feces as unchanged drug and N -desmethyl metabolite. 1 Half-life Enzalutamide: 5.8 days. 1 N -desmethylenzalutamide: Approximately 7.8 8.6 days. 1 Special Populations Mild to moderate renal impairment (Cl cr 30 89 mL/minute) does not appear to substantially alter clearance of enzalutamide. 1 Stability Storage Oral Capsules 20 25 C (may be exposed to 15 30 C). 1 Actions Competitively inhibits androgen binding to androgen receptors. 1 6 Inhibition of the androgen receptor results in growth arrest or apoptosis through inhibition of nuclear translocation of the androgen receptor and androgen-dependent DNA binding. 4 6 7 9 Binding affinity of enzalutamide at the androgen receptor is 5 8 times greater than that of bicalutamide. 3 5 Main circulating metabolite, N -desmethylenzalutamide, has activity similar to that of enzalutamide in vitro. 1 Unlike conventional antiandrogens (e.g., bicalutamide, flutamide, nilutamide), enzalutamide appears to lack agonistic effects on the androgen receptor in cells that overexpress the androgen receptor, which may result in retained antagonism of the receptor. 2 3 5 8 Advice to Patients Importance of taking enzalutamide as directed and at the same time each day. 1 If a dose is missed, importance of administering the missed dose on the same day as soon as it is remembered; do not take 2 doses on the same day to make up for a missed dose. 1 Importance of swallowing enzalutamide capsules whole; do not chew, dissolve, or open the capsules. 1 For patients currently receiving gonadotropin-releasing hormone (GnRH) agonist therapy, importance of continuing this therapy during enzalutamide therapy. 1 Risk of seizures. 1 Importance of avoiding activities where sudden loss of consciousness could cause serious harm to self or others. 1 Risk of dizziness, mental impairment, paresthesia, hypoesthesia, and falls. 1 Risk of fetal harm. 1 Necessity of advising men receiving the drug to use a condom during sexual encounters with pregnant women and to use a condom in conjunction with another effective contraceptive method during sexual encounters with women of childbearing potential; these contraceptive measures are required during therapy and for 3 months after drug discontinuance. 1 Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., drugs that lower seizure threshold) and OTC drugs and herbal supplements, as well as any concomitant illnesses or conditions that might predispose to seizures. 1 Importance of informing patients of other important precautionary information. 1 (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. Enzalutamide Routes Dosage Forms Strengths Brand Names Manufacturer Oral Capsules, liquid-filled 40 mg Xtandi Astellas AHFS DI Essentials. Copyright 2017, Selected Revisions September 17, 2013. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. References 1. Astellas Pharma US, Inc. Xtandi (enzalutamide) capsules prescribing information. Northbrook, IL; 2012 Nov. 2. Scher HI, Fizazi K, Saad F et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med . 2012; 367:1187-97. [PubMed 22894553] 3. Golshayan AR, Antonarakis ES. Enzalutamide: an evidence-based review of its use in the treatment of prostate cancer. Core Evid . 2013; 8:27-35. [PubMed 23589709] 4. Sternberg CN. Novel hormonal therapy for castration-resistant prostate cancer. Ann Oncol . 2012; 23 Suppl 10:x259-63. [PubMed 22987973] 5. Scher HI, Beer TM, Higano CS et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet . 2010; 375:1437-46. [PubMed 20398925] 6. Vogelzang NJ. Enzalutamide--a major advance in the treatment of metastatic prostate cancer. N Engl J Med . 2012; 367:1256-7. [PubMed 23013078] 7. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203415Orig1s000: Summary review. From FDA website. 8. Tran C, Ouk S, Clegg NJ et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science . 2009; 324:787-90. [PubMed 19359544] 9. Abdulla A, Kapoor A. Emerging novel therapies in the treatment of castrate-resistant prostate cancer. Can Urol Assoc J . 2011; 5:120-33. [PubMed 21470540] 10. Small EJ, Halabi S, Dawson NA et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol . 2004; 22:1025-33. [PubMed 15020604] 11. Taplin ME, Bubley GJ, Shuster TD et al. Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer. N Engl J Med . 1995; 332:1393-8. [PubMed 7723794] 12. Nieh PT. Withdrawal phenomenon with the antiandrogen casodex. J Urol . 1995; 153:1070-2; discussion 1072-3. [PubMed 7531785] 13. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203415Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. 14. Cookson MS, Roth BJ, Dahm P et al. Castration-Resistant Prostate Cancer: AUA Guideline. J Urol . 2013; :. 15. Astellas Pharma Europe. Xtandi (enzalutamide) capsules. Annex I: Summary of product characteristics. Leiden, Netherlands. (undated) Next Interactions Print this page Add to My Med List More about enzalutamide Side Effects During Pregnancy Dosage Information Drug Interactions Support Group En Español 4 Reviews Add your own review/rating Drug class: antiandrogens Consumer resources Enzalutamide Enzalutamide (Advanced Reading) Professional resources Enzalutamide (Wolters Kluwer) Other brands: Xtandi Related treatment guides Prostate Cancer> ]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Rx Availability Prescription only X Pregnancy Category Not for use in pregnancy N/A CSA Schedule Not a controlled drug Approval History Drug history at FDA Drug Class Antiandrogens Hormones / antineoplastics Related Drugs Prostate Cancer estradiol , Premarin , Estrace , bicalutamide , Casodex , Eligard , Xtandi , Zytiga , leuprolide , Taxotere , Lupron Depot , conjugated estrogens , docetaxel , Firmagon , Trelstar , Zoladex , abiraterone , degarelix , Menest , flutamide , flax , Delestrogen , Xofigo , More... 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