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Enzalutamide

Class: Antineoplastic Agents
- Antiandrogens
Chemical Name: 4-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxo-1-imidazolidinyl]-2-fluoro-N-methyl-benzamide
Molecular Formula: C21H16F4N4O2S
CAS Number: 915087-33-1
Brands: Xtandi

Medically reviewed by Drugs.com. Last updated on Sep 16, 2019.

Introduction

Antineoplastic agent; a nonsteroidal antiandrogen.1 2 3 4 8

Uses for Enzalutamide

Prostate Cancer

Treatment of castration-resistant prostate cancer.1 2 5 14 16 17 18

Enzalutamide Dosage and Administration

General

  • Use concurrently with a gonadotropin-releasing hormone (GnRH) analog unless patient has undergone bilateral orchiectomy.1

Restricted Distribution

  • Obtain enzalutamide only through designated specialty pharmacies.22

  • Contact manufacturer at 855-898-2634 or consult the Xtandi website ([Web]) for specific ordering and availability information.22

Administration

Oral Administration

Administer orally once daily without regard to meals.1

Swallow capsules whole; do not chew, dissolve, or open capsules.1

Dosage

Certain CYP-mediated interactions may affect dosage and administration.1 (See Interactions.)

Adults

Prostate Cancer
Oral

160 mg once daily.1

In clinical trials, treatment could be continued until disease progression or unacceptable toxicity occurred.1 2 16 17 18

Dosage Modification for Toxicity
Oral

If an intolerable adverse effect or grade 3 or greater toxicity occurs, interrupt therapy for 1 week or until symptoms improve to grade 2 or less; then may resume therapy with or without dosage reduction.1 If dosage reduction is necessary, reduce dosage to 120 or 80 mg daily.1

Special Populations

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C): No initial dosage adjustment required.1

Renal Impairment

Mild to moderate renal impairment (Clcr 30–89 mL/minute): No initial dosage adjustment required.1

Severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease: Not evaluated systematically.1

Geriatric Patients

No special dosage recommendations; most clinical trial participants were geriatric.1

Cautions for Enzalutamide

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including angioedema, reported.1

Permanently discontinue enzalutamide if serious hypersensitivity reactions occur.1

Seizures

Seizures reported;1 2 resolved following enzalutamide discontinuance.1 Onset occurred 13–604 days following initiation of the drug.1

Patients with predisposing factors for seizures generally excluded from clinical trials; however, seizures reported in a trial designed to assess risk in patients with predisposing factors for seizures (i.e., concomitant use of drugs that lower seizure threshold; history of cerebrovascular accident, TIA, head trauma, seizure, cerebral arteriovenous malformation, or CNS infection; Alzheimer's disease; meningioma; prostate cancer with leptomeningeal involvement; unexplained loss of consciousness within past 12 months; presence of space-occupying brain lesion).1 Seizures may recur following resumption of therapy.1

Not known whether anticonvulsants will prevent seizures in enzalutamide-treated patients.1

Permanently discontinue enzalutamide if seizure occurs.1

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) reported.1 RPLS is a neurologic disorder that may manifest with seizure, headache, lethargy, confusion, blindness, or other visual and neurologic disturbances; hypertension also may be present.1 Brain imaging, preferably magnetic resonance imaging (MRI), necessary to confirm the diagnosis.1

Discontinue enzalutamide if RPLS occurs.1

Cardiovascular Effects

Ischemic heart disease, sometimes fatal, and hypertension reported.1

Monitor for signs or symptoms of ischemic heart disease and optimize management of preexisting cardiovascular risk factors (e.g., hypertension, diabetes mellitus, dyslipidemia).1

Discontinue enzalutamide in patients who develop grade 3 or 4 ischemic heart disease.1

Falls and Fractures

Falls and fractures reported.1 Median time to occurrence of fracture was 337 days (range: 2–996 days).1 Use of bone-targeting agents for bone loss prevention in the setting of osteoporosis was not permitted in clinical studies.1

Evaluate patients for fracture and fall risk.1 Monitor patients at risk for fractures and manage according to established treatment guidelines; consider therapy with bone-targeting agents.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity, embryotoxicity, and fetotoxicity demonstrated in animals.1 Safety and efficacy not established in females.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Women who are or may become pregnant should not handle enzalutamide capsules.1

Not known whether enzalutamide distributes into semen.15 During enzalutamide therapy and for 3 months following the last dose, men receiving the drug should use a condom during sexual encounters with pregnant women and should use a condom in conjunction with another effective contraceptive method during sexual encounters with women of childbearing potential.1

Impairment of Fertility

Results of animal studies suggest that enzalutamide may impair male fertility.1

Specific Populations

Pregnancy

May cause fetal harm and potential loss of pregnancy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Women who are or may become pregnant should not handle enzalutamide capsules.1

Lactation

Enzalutamide and/or its metabolites are distributed into milk in rats; not known whether distributed into human milk.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults;1 21 however, increased sensitivity cannot be ruled out.1

Hepatic Impairment

Mild, moderate, or severe hepatic impairment (Child-Pugh class A, B, or C) did not substantially affect AUC of major active forms of the drug (enzalutamide plus N-desmethylenzalutamide).1 19

Renal Impairment

Mild or moderate renal impairment (Clcr 30–89 mL/minute) did not substantially affect clearance of enzalutamide.1

Not evaluated systematically in patients with severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease.1

Common Adverse Effects

Asthenia/fatigue,1 2 5 17 18 20 decreased appetite,1 18 20 hot flush,1 2 17 18 20 arthralgia,1 20 dizziness/vertigo,1 18 hypertension,1 17 18 20 headache,1 2 20 decreased weight,1 17 20 musculoskeletal pain,1 diarrhea,1 upper respiratory tract infection,1 hyperglycemia,1 hypermagnesemia,1 hyponatremia,1 neutropenia.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 Induces CYP2B6 in vitro.1 Does not 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

In vitro, N-desmethylenzalutamide is not a substrate of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, or 3A4/5.1

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 CYP3A4 inducers: Possible decreased 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, increase enzalutamide dosage from 160 mg to 240 mg once daily.1 If concomitant use of the potent CYP3A4 inducer is discontinued, return enzalutamide dosage to the dosage used prior to initiation of the potent CYP3A4 inducer.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

CYP1A2 substrates: No substantial change in systemic exposure of a probe substrate for CYP1A2.1 Dosage adjustment not necessary.1

CYP2D6 substrates: No substantial change in systemic exposure of a probe substrate for CYP2D6.1 Dosage adjustment not necessary.1

Protein-bound Drugs

In vitro data suggest displacement between enzalutamide and other highly protein-bound drugs unlikely at clinically relevant concentrations.1

Specific Drugs

Drug

Interaction

Comments

Anticonvulsants (carbamazepine, phenobarbital)

Possible decreased plasma concentrations of enzalutamide1

Avoid concomitant use, if possible; if concomitant use cannot be avoided, increase enzalutamide dosage from 160 mg to 240 mg once daily1

If anticonvulsant is discontinued, resume enzalutamide at dosage used prior to initiation of the anticonvulsant1

Anticonvulsants (phenytoin)

Possible decreased plasma concentrations of enzalutamide and/or phenytoin1

Avoid concomitant use1

Antimycobacterials (rifabutin, rifampin, rifapentine)

Potent CYP3A4 inducers: Possible decreased plasma concentrations of enzalutamide1

Rifampin decreased AUC of major active forms of enzalutamide (parent drug plus N-desmethyl metabolite) by 37%; peak plasma concentrations not affected1

Avoid concomitant use, if possible; if concomitant use cannot be avoided, increase enzalutamide dosage from 160 mg to 240 mg once daily1

If antimycobacterial is discontinued, resume enzalutamide at dosage used prior to initiation of the antimycobacterial 1

Caffeine

No substantial change in AUC of caffeine1

No dosage adjustment required1

Clopidogrel

Possible decreased concentrations of clopidogrel1

Avoid concomitant use1

Dextromethorphan

No substantial change in AUC of dextromethorphan1

No dosage adjustment required1

Ergot derivatives (e.g., dihydroergotamine, ergotamine)

Possible decreased concentrations of the ergot derivative1

Avoid concomitant use1

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 daily1

If gemfibrozil is discontinued, resume enzalutamide at dosage used prior to initiation of gemfibrozil1

Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)

Possible decreased concentrations of the immunosuppressive agent1

Avoid concomitant use1

Itraconazole

Increased AUC of major active forms of enzalutamide (parent drug plus N-desmethyl metabolite)1

No initial dosage adjustment required1

Midazolam

Decreased AUC and peak plasma concentration of midazolam1 13

NSAIAs

In vitro data suggest displacement of enzalutamide and/or NSAIAs from plasma proteins unlikely1

Omeprazole

Decreased AUC and peak plasma concentration of omeprazole1 13

Opiate agonists (alfentanil, fentanyl)

Possible decreased concentrations of the opiate agonist1

Avoid concomitant use1

Pimozide

Possible decreased concentrations of pimozide1

Avoid concomitant use1

Pioglitazone

No substantial change in AUC or peak plasma concentration of pioglitazone1

No dosage adjustment required1

Quinidine

Possible decreased concentrations of quinidine1

Avoid concomitant use1

Salicylates

In vitro data suggest displacement of enzalutamide and/or salicylates from plasma proteins unlikely1

St. John's wort (Hypericum perforatum)

Possible decreased plasma concentrations of enzalutamide1

Avoid concomitant use1

Warfarin

Decreased AUC of S-warfarin1 13

Avoid concomitant use1

If concomitant use cannot be avoided, additional INR monitoring recommended1

Enzalutamide Pharmacokinetics

Absorption

Bioavailability

Following oral administration, peak plasma concentrations are attained in about 1 hour.1 19

Steady-state concentrations achieved in 28 days; accumulation ratio approximately 8.3-fold.1 19

Food

High-fat meal does not substantially affect bioavailability.1 19

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, body weight, and race 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 19

Half-life

Enzalutamide: 5.8 days.1

N-Desmethylenzalutamide: Approximately 7.8–8.6 days.1

Special Populations

Mild to moderate renal impairment (Clcr 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 Importance of advising patients that women who are or may become pregnant should not handle enzalutamide capsules.1

  • For patients currently receiving 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 Importance of informing clinician immediately if loss of consciousness or seizure occurs.1

  • Risk of hypersensitivity reactions, including angioedema.1 Importance of seeking immediate medical care if signs or symptoms of hypersensitivity reactions (e.g., edema of the face, lip, tongue, or throat) occur.1

  • Risk of RPLS.1 Importance of informing clinician immediately if rapidly worsening symptoms suggestive of RPLS (e.g., seizure, headache, decreased alertness, confusion, visual disturbances) occur.1

  • Risk of ischemic heart disease.1 Importance of seeking immediate medical care if signs or symptoms of a cardiovascular event (e.g., angina, shortness of breath) occur.1

  • Risk of dizziness, vertigo, falls, and fractures.1 Importance of informing clinician if such adverse effects occur.1

  • Risk of hypertension.1

  • Risk of impairment of male fertility.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 last dose.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.

Distribution of enzalutamide is restricted.22 (See Restricted Distribution under Dosage and Administration.)

Enzalutamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

40 mg

Xtandi

Astellas

AHFS DI Essentials™. © Copyright 2020, Selected Revisions September 16, 2019. 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; 2018 Jul.

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. http://www.ncbi.nlm.nih.gov/pubmed/22894553?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/23589709?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3622394&blobtype=pdf

4. Sternberg CN. Novel hormonal therapy for castration-resistant prostate cancer. Ann Oncol. 2012; 23 Suppl 10:x259-63. http://www.ncbi.nlm.nih.gov/pubmed/22987973?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/20398925?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2948179&blobtype=pdf

6. Vogelzang NJ. Enzalutamide--a major advance in the treatment of metastatic prostate cancer. N Engl J Med. 2012; 367:1256-7. http://www.ncbi.nlm.nih.gov/pubmed/23013078?dopt=AbstractPlus

7. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203415Orig1s000: Summary review. From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203415Orig1s000SumR.pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/19359544?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2981508&blobtype=pdf

9. Abdulla A, Kapoor A. Emerging novel therapies in the treatment of castrate-resistant prostate cancer. Can Urol Assoc J. 2011; 5:120-33. http://www.ncbi.nlm.nih.gov/pubmed/21470540?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3104424&blobtype=pdf

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. http://www.ncbi.nlm.nih.gov/pubmed/15020604?dopt=AbstractPlus

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. http://www.ncbi.nlm.nih.gov/pubmed/7723794?dopt=AbstractPlus

12. Nieh PT. Withdrawal phenomenon with the antiandrogen casodex. J Urol. 1995; 153:1070-2; discussion 1072-3. http://www.ncbi.nlm.nih.gov/pubmed/7531785?dopt=AbstractPlus

13. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203415Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/203415Orig1s000ClinPharmR.pdf

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)

16. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014; 371:1755-6. http://www.ncbi.nlm.nih.gov/pubmed/25354111?dopt=AbstractPlus

17. Shore ND, Chowdhury S, Villers A et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016; 17:153-163. http://www.ncbi.nlm.nih.gov/pubmed/26774508?dopt=AbstractPlus

18. Hussain M, Fizazi K, Saad F et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. N Engl J Med. 2018; 378:2465-2474. http://www.ncbi.nlm.nih.gov/pubmed/29949494?dopt=AbstractPlus

19. Gibbons JA, Ouatas T, Krauwinkel W et al. Clinical Pharmacokinetic Studies of Enzalutamide. Clin Pharmacokinet. 2015; 54:1043-55. http://www.ncbi.nlm.nih.gov/pubmed/25917876?dopt=AbstractPlus

20. Beer TM, Armstrong AJ, Rathkopf D et al. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. 2017; 71:151-154. http://www.ncbi.nlm.nih.gov/pubmed/27477525?dopt=AbstractPlus

21. Graff JN, Baciarello G, Armstrong AJ et al. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL. Ann Oncol. 2016; 27:286-94. http://www.ncbi.nlm.nih.gov/pubmed/26578735?dopt=AbstractPlus

22. Astellas. Xtandi: How to get Xtandi. From Xtandi for US Health Care Professionals website. Accessed 2019 May 23. https://www.xtandi.com/starting-treatment

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