enzalutamide (en-za-loo-ta-mide) Xtandi

 Indications

Management of metastatic castration-resistant prostate

cancer.

Action

Acts as an androgen receptor inhibitor, preventing the

binding of androgen; also inhibits androgen nuclear

translocation and DNA interaction. Decreases proliferation

and induces cell death of prostate cancer cells.

Therapeutic Effects: Decreased growth and spread

of prostate cancer.

Pharmacokinetics

Absorption: Well absorbed following oral administration.

Distribution: Unknown.

Protein Binding: Enzalutamide—97–98%; Ndesmethylenzalutamide—

95%.

Metabolism and Excretion: Extensively metabolized

by the liver (CYP2C8 and CYP3A4 enzyme systems);

one metabolite (N-desmethylenzalutamide) has

antineoplastic activity. Metabolites are primarily renally

excreted, only minimal amounts as unchanged drug.

Half-life: Enzalutamide—5.8 days; N-desmethylenzalutamide—

7.8–8.6 days.

TIME/ACTION PROFILE (improved survival)

ROUTE ONSET PEAK DURATION

PO 3 mo unknown unknown

Contraindications/Precautions

Contraindicated in: OB: Rep: Pregnancy (may

cause fetal harm) or women of reproductive potential.

Use Cautiously in: History of seizures, underlying

brain pathology, cerebrovascular accident, transient ischemic

attack (within 12 mo), brain metastases or

brain arteriovenous malformation (mayqrisk of seizures);

Geri: May be more sensitive to drug effects;

Pedi: Safety and effectiveness not established.

Adverse Reactions/Side Effects

CNS: POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME

(PRES), SEIZURES, SPINAL CORD COMPRESSION/

CAUDA EQUINA SYNDROME, headache, weakness, anxiety,

dizziness, hallucinations, insomnia, mental impairment

disorders. EENT: epistaxis. CV: peripheral edema,

hypertension. GI: diarrhea. GU: hematuria, urinary

frequency. Derm: hot flush, dry skin, pruritus. MS:

arthralgia, musculoskeletal pain, muscular stiffness,

muscular weakness. Neuro: hypoesthesia, paresthesia.

Interactions

Drug-Drug: Strong CYP2C8 inhibitors, including

gemfibrozil, mayqlevels and risk of toxicity; avoid

concurrent use (if concurrent administration necessary,

penzalutamide dose). Strong CYP3A4 inducers,

including carbamazepine, phenobarbital,

phenytoin, rifabutin, rifampin, and rifapentine

mayplevels and response; avoid concurrent use (if

concurrent administration necessary,qenzalutamide

dose). Mayplevels of CYP3A4, CYP2C9, and

CYP2C19 substrates that have narrow therapeutic indexes

including cyclosporine, fentanyl, phenytoin,

sirolimus, tacrolimus, and warfarin; avoid concurrent

use. Drugs thatpseizure threshold mayqrisk

of seizures.

Drug-Natural Products: St. John’s wort mayp

levels and response; avoid concurrent use (if concurrent

administration necessary,qenzalutamide dose).

Route/Dosage

PO (Adults): 160 mg (four 40-mg capsules) once

daily; if Grade 3 toxicity or intolerable adverse reactions

occur, discontinue for 1 wk and resume at the

same or lower dose (80 or 120 mg). Concurrent use

of strong CYP2C8 inhibitors—80 mg once daily;

Concurrent use of strong CYP3A4 inducers—240

mg once daily.

Availability

Capsules: 40 mg.