Enzalutamide (Monograph)

Brand name: Xtandi
Drug 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

Medically reviewed by Drugs.com on May 13, 2022. 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.

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

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

Administration

Oral Administration

Administer orally once daily without regard to meals.

Commercially available in 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.

In clinical trials, treatment could be continued until disease progression or unacceptable toxicity occurred.

Dosage Modification

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 Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Oral

Certain CYP-mediated interactions may affect dosage and administration.

Special Populations

Hepatic Impairment

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

Renal Impairment

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

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

Geriatric Patients

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

Cautions for Enzalutamide

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity reactions, including angioedema, reported.

Permanently discontinue enzalutamide if serious hypersensitivity reactions occur.

Seizures

Seizures reported; resolved following enzalutamide discontinuance. Onset occurred 13–1776 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.

Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) reported. 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. Brain imaging, preferably magnetic resonance imaging (MRI), necessary to confirm the diagnosis.

Discontinue enzalutamide if RPLS occurs.

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 336 days (range: 2–1914 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.

Fetal/Neonatal Morbidity and Mortality

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 a condom in conjunction with another effective contraceptive method during sexual encounters with females of reproductive potential.

Impairment of Fertility

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

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.

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

Adverse effects reported in ≥10% of patients and at an incidence that is ≥2% higher than that reported with placebo: Asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, hypertension. Laboratory abnormalities reported in ≥5% of patients and at an incidence that is >2% higher than that reported with placebo: Leukopenia, neutropenia, hyperglycemia, hypermagnesemia, hyponatremia, hypercalcemia.

Adverse effects reported in ≥10% of patients and at an incidence that is ≥ 2% higher than that reported with bicalutamide: Asthenia/fatigue, musculoskeletal pain, hot flush, hypertension, diarrhea, upper respiratory tract infection, decreased weight.

Interactions for Enzalutamide

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

Enzalutamide is a potent 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

Potent 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 potent CYP2C8 inhibitor is discontinued, return enzalutamide dosage to the dosage used prior to initiation of the potent CYP2C8 inhibitor.

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

Potent 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 potent CYP3A4 inducer is discontinued, return enzalutamide dosage to the dosage used prior to initiation of the potent CYP3A4 inducer.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP 3A4, 2C9, or 2C19: Possible decreased plasma concentrations of the substrate drug. Avoid concomitant use of enzalutamide and CYP 3A4, 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

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

• Importance of taking enzalutamide as directed and at the same time each day. 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.

• Importance of swallowing enzalutamide capsules whole; do not chew, dissolve, or open the capsules. Importance of swallowing enzalutamide tablets whole; do not cut, crush, or chew the tablets.

• For patients currently receiving GnRH agonist therapy, importance of continuing this therapy during enzalutamide therapy.

• Risk of seizures. Importance of avoiding activities where sudden loss of consciousness could cause serious harm to self or others. Importance of informing clinician immediately if loss of consciousness or seizure occurs.

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

• Risk of ischemic heart disease. 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. Importance of informing clinician if such adverse effects occur.

• Risk of hypertension.

• Risk of impairment of male fertility.

• Risk of fetal harm. 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.

• 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.

• Importance of informing patients of other important precautionary information. (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. Contact manufacturer for specific ordering and availability information.

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