Enzalutamide (Monograph)

Brand name: Xtandi
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Aug 10, 2024. Written by ASHP.

Introduction

Antineoplastic agent; a nonsteroidal antiandrogen.

Uses for Enzalutamide

Prostate Cancer

Treatment of castration-resistant prostate cancer.

Treatment of metastatic castration-sensitive prostate cancer.

Treatment of non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis.

Enzalutamide Dosage and Administration

General

Pretreatment Screening

Assess for fall and fracture risk.

Patient Monitoring

In patients at risk for fracture, monitor and manage fracture risk.
Monitor for signs and symptoms of ischemic heart disease.

Other General Considerations

Patients with castration-resistant prostate cancer or metastatic castration-sensitive prostate cancer: Use concurrently with a gonadotropin-releasing hormone (GnRH) analog unless patient has undergone bilateral orchiectomy.
Patients with non-metastatic castration-sensitive prostate cancer with high-risk biochemical recurrence: May receive enzalutamide with or without GnRH analog.

Administration

Oral Administration

Administer orally once daily without regard to meals.

Commercially available as capsule and tablet formulations; these formulations are equivalent on a mg-per-mg basis.

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

Swallow tablets whole: do not cut, crush, or chew tablets.

Dosage

Adults

Prostate Cancer

Oral

160 mg once daily.

Continue until disease progression or unacceptable toxicity occurred.

For non-metastatic castration-sensitive prostate cancer, treatment can be suspended if prostate specific antigen (PSA) is undetectable (<0.2 ng/mL) after 36 weeks of therapy. Treatment can be reinitiated when PSA has increased to ≥2 ng/mL for those who have undergone radical prostatectomy or ≥5 ng/mL for patients with primary radiation therapy.

Dosage Modifications

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; therapy may then be resumed at the same or reduced dosage. If dosage reduction is necessary, reduce dosage to 120 or 80 mg daily.

Concomitant Use with Strong CYP2C8 Inhibitors

Oral

Avoid concomitant use with strong CYP2C8 inhibitors. If use cannot be avoided, reduce enzalutamide dosage to 80 mg once daily. Upon discontinuation of the strong CYP2C8 inhibitor, increase enzalutamide dosage to the dosage used prior to initiation of the strong CYP2C8 inhibitor.

Concomitant Use with Strong CYP3A4 Inducers

Oral

Avoid concomitant use with strong CYP3A4 inducers. If use cannot be avoided, increase enzalutamide dosage from 160 mg to 240 mg once daily. Upon discontinuation of the strong CYP3A4 inducers, decrease enzalutamide dosage to the dosage used prior to initiation of the strong CYP3A4 inducer.

Special Populations

Hepatic Impairment

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

Renal Impairment

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

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

Geriatric Patients

No specific dosage recommendations; greater sensitivity of some older individuals cannot be ruled out.

Cautions for Enzalutamide

Contraindications

None.

Warnings/Precautions

Seizures

Seizures reported; resolved following enzalutamide discontinuance. Onset occurred 13–2250 days following initiation of the drug.

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). Seizures may recur following resumption of therapy.

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

Permanently discontinue enzalutamide if seizure occurs.

Posterior Reversible Encephalopathy Syndrome

Posterior reversible encephalopathy syndrome (PRES) reported. PRES is a neurologic disorder that may manifest with seizure, headache, lethargy, confusion, blindness, or other visual and neurologic disturbances; hypertension also may be present. Brain imaging, preferably MRI, necessary to confirm the diagnosis.

Discontinue enzalutamide if PRES occurs.

Hypersensitivity Reactions

Hypersensitivity reactions, including angioedema, reported.

Permanently discontinue enzalutamide if serious hypersensitivity reactions occur.

Cardiovascular Effects

Ischemic heart disease, sometimes fatal, and hypertension reported.

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

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

Falls and Fractures

Falls and fractures reported. Median time to occurrence of fracture was 420 days (range: 1–2348 days). Use of bone-targeting agents for bone loss prevention in the setting of osteoporosis was not permitted in clinical studies.

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

Embryo-fetal Toxicity

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

Not known whether enzalutamide distributes into semen. During enzalutamide therapy and for 3 months following the last dose, males receiving the drug should use a condom during sexual encounters with pregnant females and should use an effective contraceptive method during sexual encounters with females of reproductive potential.

Specific Populations

Pregnancy

May cause fetal harm and potential loss of pregnancy.

Lactation

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

Females and Males of Reproductive Potential

Males with female partners of reproductive potential should use effective contraception during therapy and for 3 months after last dose of the drug. Males should also use a condom during sexual intercourse with pregnant females.

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

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

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

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).

Renal Impairment

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

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

Common Adverse Effects

Most common adverse effects (≥10% of patients and ≥2% higher than placebo): Musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, hypertension, hemorrhage, fall, fracture, headache.

Drug Interactions

Metabolized by CYP2C8 and CYP3A4; formation of major active metabolite (N-desmethylenzalutamide) is mediated by CYP2C8.

Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19 in vivo. Induces CYP2B6 in vitro. Does not induce CYP1A2 at clinically relevant concentrations.

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.

In vitro, N-desmethylenzalutamide is not a substrate of CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, or 3A4/5.

Neither enzalutamide nor its 2 major metabolites are substrates of P-glycoprotein (P-gp) in vitro; enzalutamide and N-desmethylenzalutamide inhibit P-gp.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP2C8 inhibitors: Possible increased AUC of major active forms of enzalutamide (parent drug plus N-desmethyl metabolite). Avoid concomitant use if possible. If concomitant use cannot be avoided, reduce enzalutamide dosage to 80 mg once daily. If concomitant use of the strong CYP2C8 inhibitor is discontinued, return enzalutamide dosage to the dosage used prior to initiation of the strong CYP2C8 inhibitor.

Strong CYP3A4 inhibitors: Possible increased AUC of major active forms of enzalutamide (parent drug plus N-desmethyl metabolite). Initial dosage adjustment not necessary.

Strong CYP3A4 inducers: Possible decreased AUC of major active forms of enzalutamide (parent drug plus N-desmethyl metabolite). Avoid concomitant use, if possible. If concomitant use cannot be avoided, increase enzalutamide dosage from 160 mg to 240 mg once daily. If concomitant use of the strong CYP3A4 inducer is discontinued, return enzalutamide dosage to the dosage used prior to initiation of the strong CYP3A4 inducer.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A4, 2C9, or 2C19: Possible decreased plasma concentrations of the substrate drug. Avoid concomitant use of enzalutamide and CYP3A4, 2C9, or 2C19 substrates with narrow therapeutic indices.

CYP2C8 substrates: No substantial change in plasma concentrations of a probe substrate for CYP2C8. Dosage adjustment not necessary.

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

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

Protein-bound Drugs

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

Specific Drugs

Drug	Interaction	Comments
Anticonvulsants (carbamazepine, phenobarbital)	Possible decreased plasma concentrations of enzalutamide	Avoid concomitant use, if possible; if concomitant use cannot be avoided, increase enzalutamide dosage from 160 mg to 240 mg once daily If anticonvulsant is discontinued, resume enzalutamide at dosage used prior to initiation of the anticonvulsant
Anticonvulsants (phenytoin)	Possible decreased plasma concentrations of enzalutamide and/or phenytoin	Avoid concomitant use
Antimycobacterials (rifabutin, rifampin, rifapentine)	Strong CYP3A4 inducers: Possible decreased plasma concentrations of enzalutamide Rifampin decreased AUC of major active forms of enzalutamide (parent drug plus N-desmethyl metabolite) by 37%; peak plasma concentrations not affected	Avoid concomitant use, if possible; if concomitant use cannot be avoided, increase enzalutamide dosage from 160 mg to 240 mg once daily If antimycobacterial is discontinued, resume enzalutamide at dosage used prior to initiation of the antimycobacterial
Caffeine	No substantial change in AUC of caffeine	No dosage adjustment required
Clopidogrel	Possible decreased concentrations of clopidogrel	Avoid concomitant use
Dextromethorphan	No substantial change in AUC of dextromethorphan	No dosage adjustment required
Ergot derivatives (e.g., dihydroergotamine, ergotamine)	Possible decreased concentrations of the ergot derivative	Avoid concomitant use
Gemfibrozil	Increased AUC of major active forms of enzalutamide (parent drug plus N-desmethyl metabolite)	Avoid concomitant use; if concomitant use cannot be avoided, reduce enzalutamide dosage to 80 mg once daily If gemfibrozil is discontinued, resume enzalutamide at dosage used prior to initiation of gemfibrozil
Immunosuppressive agents (cyclosporine, sirolimus, tacrolimus)	Possible decreased concentrations of the immunosuppressive agent	Avoid concomitant use
Itraconazole	Increased AUC of major active forms of enzalutamide (parent drug plus N-desmethyl metabolite)	No initial dosage adjustment required
Midazolam	Decreased AUC and peak plasma concentration of midazolam
NSAIAs	In vitro data suggest displacement of enzalutamide and/or NSAIAs from plasma proteins unlikely
Omeprazole	Decreased AUC and peak plasma concentration of omeprazole
Opiate agonists (alfentanil, fentanyl)	Possible decreased concentrations of the opiate agonist	Avoid concomitant use
Pimozide	Possible decreased concentrations of pimozide	Avoid concomitant use
Pioglitazone	No substantial change in AUC or peak plasma concentration of pioglitazone	No dosage adjustment required
Quinidine	Possible decreased concentrations of quinidine	Avoid concomitant use
Salicylates	In vitro data suggest displacement of enzalutamide and/or salicylates from plasma proteins unlikely
St. John's wort (Hypericum perforatum)	Possible decreased plasma concentrations of enzalutamide	Avoid concomitant use
Warfarin	Decreased AUC of S-warfarin	Avoid concomitant use If concomitant use cannot be avoided, additional INR monitoring recommended

Enzalutamide Pharmacokinetics

Absorption

Bioavailability

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

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

Following a single 160 mg dose of enzalutamide in healthy males, extent of absorption comparable between the tablet and capsule formulations; however, mean peak plasma concentration following administration of tablet formulation is 10–28% lower than that of capsules.

Steady-state peak plasma concentration and AUC of enzalutamide and N-desmethyl enzalutamide were comparable between tablet and capsule formulations.

Food

High-fat meal does not substantially affect bioavailability.

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.

Age, body weight, and race do not substantially affect exposure to enzalutamide.

Distribution

Extent

Not known whether enzalutamide is distributed into human milk.

Plasma Protein Binding

Enzalutamide: 97–98% (mainly albumin).

N-Desmethylenzalutamide: 95%.

Elimination

Metabolism

Metabolized in the liver by CYP2C8 and CYP3A4. Major metabolites are N-desmethylenzalutamide (active) and a carboxylic acid derivative (inactive); formation of N-desmethyl metabolite is mediated principally by CYP2C8.

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.

Half-life

Enzalutamide: 5.8 days.

N-desmethylenzalutamide: Approximately 7.8–8.6 days.

Special Populations

Mild to moderate renal impairment (Cl_cr 30–89 mL/minute) does not appear to substantially alter clearance of enzalutamide.

Stability

Storage

Oral

Capsules or Tablets

20–25°C (may be exposed to 15–30°C). Store in a dry place in a tightly closed container.

Actions

Competitively inhibits androgen binding to androgen receptors. 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.
Binding affinity of enzalutamide at the androgen receptor is 5–8 times greater than that of bicalutamide.
Main circulating metabolite, N-desmethylenzalutamide, has activity similar to that of enzalutamide in vitro.
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.

Advice to Patients

Advise patients to take enzalutamide as directed and at the same time each day. If a dose is missed, administer 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.
Advise patients to swallow enzalutamide capsules whole; do not chew, dissolve, or open the capsules. Advise patients to swallow enzalutamide tablets whole; do not cut, crush, or chew the tablets.
For patients currently receiving GnRH agonist therapy, stress importance of continuing this therapy during enzalutamide therapy.
Risk of seizures. Advise patients to avoid activities where sudden loss of consciousness could cause serious harm to self or others. Stress importance of informing clinician immediately if loss of consciousness or seizure occurs.
Risk of PRES. Stress importance of informing clinician immediately if rapidly worsening symptoms suggestive of PRES (e.g., seizure, headache, decreased alertness, confusion, visual disturbances) occur.
Risk of hypersensitivity reactions, including angioedema. Stress importance of seeking immediate medical care if signs or symptoms of hypersensitivity reactions (e.g., edema of the face, lip, tongue, or throat) occur.
Risk of ischemic heart disease. Stress importance of seeking immediate medical care if signs or symptoms of a cardiovascular event (e.g., angina, shortness of breath) occur.
Risk of dizziness, vertigo, falls, and fractures. Stress importance of informing clinician if such adverse effects occur.
Risk of fetal harm. Advise men receiving the drug to use a condom during sexual encounters with pregnant women and to use an effective contraceptive method during sexual encounters with women of childbearing potential; these contraceptive measures are required during enzalutamide therapy and for 3 months after last dose.
Advise patients to inform their 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.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

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 can only be obtained through specialty pharmacies. Contact manufacturer for specific ordering and availability information.