enzalutamide (Rx)

>10%

All grades

• Asthenic conditions (47-51%)
• Back pain (26-29%)
• Constipation (23%)
• Diarrhea (22%)
• Arthralgia (21%)
• Hot flush (18-20%)
• Decreased appetite (19%)
• Upper respiratory tract infection (16%)
• Peripheral edema (12-15%)
• Musculoskeletal pain (15%)
• Hypertension (6.4-14%)
• Falls (4.6-13%)
• Headache (11-12%)
• Decreased weight (12%)
• Dyspnea (11%)
• Dizziness (9.5-11%)

1-10% H3

All grades

• Muscular weakness (9.8%)
• Insomnia (8.2-8.8%)
• Hematuria (6.9-8.8%)
• Nonpathologic fractures (4-8.8%)
• Lower respiratory tract and lung infection (7.9-8.5%)
• Dysgeusia (7.6%)
• Spinal cord compression and cauda equina syndrome (7.4%)
• Anxiety (6.5%)
• Pollakiuria (4.8%)
• Pruritus (3.8%)
• Dry skin (3.5%)
• Epistaxis (3.3%)

Grade 3-4

• Asthenic conditions (3.4-9%)
• Hypertension (7.2%)
• Spinal cord compression and cauda equina syndrome (6.6%)
• Paresthesia (6.6%)
• Back pain (2.5-5.3%)
• Mental impairment disorders (4.3-5.7%)
• Hypoesthesia (4%)
• Gynecomastia (3.4%)
• Arthralgia (1.6-2.5%)
• Lower respiratory tract and lung infection (1.5-2.4%)
• Hypertension (2.1%)
• Restless leg syndrome (2.1%)
• Nonpathologic fractures (1.4-2.1%)
• Hematuria (1.3-1.8%)
• Falls (0.3-1.6%)
• Muscular weakness (1.5%)
• Musculoskeletal pain (1.3%)
• Diarrhea (0.3-1.1%)
• Peripheral edema (0.2-1%)

<1%

Grade 3-4

• Headache (0.2-0.9%)
• Decreased weight (0.8%)
• Constipation (0.7%)
• Dyspnea (0.6%)
• Dizziness (0.3-0.5%)
• Mental impairment disorders (0.3%)
• Hypoesthesia (0.3%)
• Anxiety (0.3%)
• Decreased appetite (0.3%)
• Epistaxis (0.1%)
• Hot flush (0.1%)
• Dysgeusia (0.1%)
• Restless leg syndrome (0.1%)
• Insomnia (0.1%)

Postmarketing Reports

Body as a whole: Hypersensitivity (edema of the face, tongue, lip, or pharynx)

Gastrointestinal disorders: Vomiting

Neurological disorders: Posterior reversible encephalopathy syndrome (PRES), seizures

Skin and subcutaneous tissue disorders: Rash, severe cutaneous adverse reactions (including Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP)

Ischemic heart disease

Contraindications

None

Cautions

Seizure occurred in patients receiving enzalutamide in randomized clinical trials; advise patients of risk of engaging in activities where sudden loss of consciousness could cause serious harm to themselves or others; permanently discontinue therapy in patients who develop seizure during treatment

Posterior reversible encephalopathy syndrome (PRES) reported with use; discontinue therapy in patients who develop PRES

Hypersensitivity reactions, including edema of the face, tongue, or lip have been observed; pharyngeal edema reported in postmarketing cases; advise patients who experience any symptoms of hypersensitivity to temporarily discontinue treatment and promptly seek medical care; permanently discontinue drug for serious hypersensitivity reactions

In clinical studies, ischemic heart disease occurred; monitor for signs and symptoms of ischemic heart disease; optimize management of cardiovascular risk factors (eg, hypertension, diabetes, or dyslipidemia); discontinue treatment for Grade 3-4 ischemic heart disease

Falls and fractures occurred; evaluate patients for fracture and fall risk; monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents; routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the studies

Safety and efficacy not established in females (see Pregnancy)

Drug interaction overview

• CYP2C8 substrate; avoid coadministration with strong CYP2C8 inhibitors (see Dosage Modifications)
• Enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer; shown to reduce the plasma exposure to midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate); caution if coadministered with narrow therapeutic index drugs that are substrates of the aforementioned CYP isoenzymes

Pregnancy

Safety and efficacy not established in females

Drug should not be handled by females who are or may become pregnant

Animal data

• Based on animal reproductive studies and mechanism of action, enzalutamide may cause fetal harm and loss of pregnancy
• There are no human data on use in pregnant females
• In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose

Contraception

• Based on findings in animal reproduction studies, advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the final dose

Infertility

• Based on animal studies, may impair fertility in males of reproductive potential

Lactation

Not indicated for use in females; unknown whether distributed in breast milk

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Androgen receptor inhibitor; competitively inhibits androgen binding to androgen receptors; also inhibits androgen receptor nuclear translocation and interaction with DNA resulting in decreased proliferation and induced cell death

Major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide

Absorption

Peak plasma time: 1 hr

Peak plasma concentration (steady-state): 16.6 mcg/mL (parent compound); 12.7 mcg/mL (N-desmethyl enzalutamide)

Steady-state achieved by Day 28

Distribution

Protein Bound: 97-98% (parent compound); 95% (active metabolite)

Vd: 110 L

Metabolism

Metabolized by liver by CYP2C8 and CYP3A4; CYP2C8 is primarily responsible for the formation of the active metabolite (N-desmethyl enzalutamide)

Metabolites: N-desmethyl enzalutamide (active); carboxylic acid metabolite (inactive)

Strong CYP3A4 inducer; CYP2C9 and CYP2C19 moderate inducer

Elimination

Excretion: 14% feces, 71% urine (as inactive metabolites)

Half-life (single 160-mg oral dose): 5.8 days (metastatic CRPC patients); 7.8-8.6 days (healthy adults)

Clearance: 0.56 L/hr

Oral Administration

May administer with or without food

Swallow capsules or tablets whole; do not chew, dissolve, or open capsules or crush tablets

Storage

Capsules or tablets

Store at 20-25ºC (68-77ºF) in a dry place and keep the container tightly closed; excursions permitted from 15-30ºC (59-86ºF)