Generic Name: Enzalutamide
Class: Antineoplastic Agents
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

Introduction

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

Uses for Xtandi

Prostate Cancer

Treatment of metastatic castration-resistant prostate cancer previously treated with docetaxel-containing therapy.1 2 5 14

Slideshow: Flashback: FDA Drug Approvals 2013

Xtandi Dosage and Administration

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 trial, treatment could be continued until disease progression or unacceptable toxicity occurred.1 2

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

Severe hepatic impairment (Child-Pugh class C): Not studied.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 Xtandi

Contraindications

  • Women who are or may become pregnant.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Contraindicated in women who are or may become pregnant.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Not known whether enzalutamide distributes into semen.1 15 During and for 3 months following discontinuance of enzalutamide therapy, 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

Seizure

Seizures reported;1 2 resolved following drug discontinuance.1 Safety of resuming therapy after resolution of a seizure not established.1

Safety not established in patients with predisposing factors for seizures (e.g., history of seizure, underlying brain injury with loss of consciousness, TIA within past 12 months, cerebrovascular accident, brain metastases, cerebral arteriovenous malformation, concomitant use of drugs that lower seizure threshold).1

Specific Populations

Pregnancy

Category X.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk; discontinue nursing or drug.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; however, increased sensitivity cannot be ruled out.1

Hepatic Impairment

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

Not studied in patients with severe hepatic impairment (Child-Pugh class C).1

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 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 Xtandi

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 enzalutamide1

Possible decreased plasma concentrations of phenytoin1

Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential1

Avoid concomitant use of phenytoin1

Antimycobacterials (rifabutin, rifampin, rifapentine)

In vivo effects of CYP inducers not established to date; possible alterations in plasma concentrations of enzalutamide1

Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP2C8 or CYP3A4 induction potential1

Bosentan

Possible decreased plasma concentrations of enzalutamide1

Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential1

Efavirenz

Possible decreased plasma concentrations of enzalutamide1

Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential1

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

Possible decreased concentrations of the ergot derivative1

Avoid concomitant use1

Etravirine

Possible decreased plasma concentrations of enzalutamide1

Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential1

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

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

Modafinil

Possible decreased plasma concentrations of enzalutamide1

Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential1

Nafcillin

Possible decreased plasma concentrations of enzalutamide1

Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential1

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

St. John's wort (Hypericum perforatum)

Possible decreased plasma concentrations of enzalutamide1

Avoid concomitant use, if possible, and select alternative agent with minimal or no CYP3A4 induction potential1

Warfarin

Decreased AUC of S-warfarin1 13

Avoid concomitant use1

If concomitant use cannot be avoided, additional INR monitoring recommended1

Xtandi 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 (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

  • 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.

Enzalutamide

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

40 mg

Xtandi

Astellas

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 17, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, 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. [IDIS 342239] [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)

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