Dosing and uses of Xtandi (enzalutamide)
Adult dosage forms and strengths
capsule
- 40mg
Prostate Cancer
Androgen receptor inhibitor indicated for the treatment of metastatic castration-resistant prostate cancer in patients who have not received chemotherapy and those who have previously received docetaxeL
160 mg PO qDay
Dosage modifications
≥Grade 3 toxicity or an intolerable side effect: Withhold dose for 1 week or until symptoms improve to ≤Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg), if warranted
Concomitant strong CYP2C8 inhibitors
- Avoided if possible
- If must be coadministered with a strong CYP2C8 inhibitor, reduce enzalutamide dose to 80 mg qDay
- If coadministration of the strong inhibitor is discontinued, re-establish enzalutamide to the dose used prior to initiation of the strong CYP2C8 inhibitor
Pediatric dosage forms and strengths
Not indicated in this population
Xtandi (enzalutamide) adverse (side) effects
>10%
Asthenic conditions (50.6%)
Back pain (26.4%)
Diarrhea (21.8%)
Arthralgia (20.5%)
Hot flush (20.3%)
Neutropenia, all grades (15%)
Musculoskeletal pain (15%)
Peripheral edema (15.4%)
Headache (12.1%)
URI (10.9%)
1-10%
Muscular weakness (9.8%)
Dizziness (9.5%)
Insomnia (8.8%)
Pneumonia/bronchitis (8.5%)
Spinal cord compression (7.4%)
Hematuria (6.9%)
Paresthesia (6.6%)
Anxiety (6.5%)
Hypertension (6.4%)
Pollakiuria (4.8%)
Fall (4.6%)
Mental impairment (4.3%)
Hypoesthesia (4%)
Nonpathologic fracture (4%)
Pruritus (3.8%)
Dry skin (3.5%)
Epistaxis (3.3%)
Hallucinations (1.6%)
Neutropenia, grades III/IV (1%)
<1%
Seizures (0.9%)
Warnings
Contraindications
Pregnancy; not indicated for use in women; can cause fetal harm and potential loss of pregnancy
Cautions
Because of risk of seizure associated with enzalutamide use, 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
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
Posterior reversible encephalopathy syndrome (PRES) reported with use; discontinue therapy in patients who develop PREs
Pregnancy and lactation
Pregnacy
Contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy
Not indicated for use in females
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.
Pharmacology of Xtandi (enzalutamide)
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 (active metabolite)
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)
Administration
Oral Administration
May administer with or without food
Swallow capsule whole; do not chew, dissolve, or open the capsules
