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
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
OralIf 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
OralCertain 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 (Clcr 30–89 mL/minute): No initial dosage adjustment required.
Severe renal impairment (Clcr <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 (Clcr 30–89 mL/minute) did not substantially affect clearance of enzalutamide.
Not evaluated systematically in patients with severe renal impairment (Clcr <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
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) |
Potent 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 (Clcr 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.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules, liquid-filled |
40 mg |
Xtandi |
Astellas |
Tablets, film-coated |
40 mg |
Xtandi |
Astellas |
|
80 mg |
Xtandi |
Astellas |
AHFS DI Essentials™. © Copyright 2023, Selected Revisions May 13, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
Reload page with references included
Frequently asked questions
- Does it lower prostate-specific antigen (PSA)?
- Is this a chemotherapy drug and how does it work?
- What is it used for?
- Erleada vs. Xtandi: What's the difference?
More about enzalutamide
- Check interactions
- Compare alternatives
- Reviews (21)
- Side effects
- Dosage information
- During pregnancy
- Drug class: antiandrogens
- En español