androgen receptor inhibitors
Management of metastatic castration-resistant prostate cancer.
- 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.
Decreased growth and spread of prostate cancer.
Absorption: Well absorbed following oral administration.
Protein Binding: Enzalutamide–97–98%; N-desmethylenzalutamide–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)
- 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 (may ↑ risk 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
CV: peripheral edema, hypertension
GU: hematuria, urinary frequency
Derm: hot flush, dry skin, pruritus
MS: arthralgia, musculoskeletal pain, muscular stiffness, muscular weakness
Neuro: hypoesthesia, paresthesia
* CAPITALS indicate life-threatening.
Underline indicate most frequent.
- Strong CYP2C8 inhibitors, including gemfibrozil, may ↑ levels and risk of toxicity; avoid concurrent use (if concurrent administration necessary, ↓ enzalutamide dose).
- Strong CYP3A4 inducers, including carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, and rifapentine may ↓ levels and response; avoid concurrent use (if concurrent administration necessary, ↑ enzalutamide dose).
- May ↓ levels of CYP3A4, CYP2C9, and CYP2C19 substrates that have narrow therapeutic indexes including cyclosporine, fentanyl, phenytoin, sirolimus, tacrolimus, and warfarin; avoid concurrent use.
- Drugs that ↓ seizure threshold may ↑ risk of seizures.
St. John's wort may ↓ levels and response; avoid concurrent use (if concurrent administration necessary, ↑ enzalutamide dose)
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.
Capsules: 40 mg
- Monitor for seizures. Implement seizure precautions. If a seizure occurs during therapy, permanently discontinue enzalutamide therapy.
- Monitor for signs and symptoms of PRES (seizure, headache, lethargy, confusion, blindness, other visual and neurological disturbances, hypertension) during therapy. Diagnosis is made with MRI. Discontinue enzalutamide in patients who develop PRES.
Lab Test Considerations:
May cause hematuria.
- Activity intolerance
- PO Administer 4 capsules once daily without regard to food. Swallow capsules whole; do not open, dissolve, or chew.
- If ≥Grade 3 toxicity or intolerable side effects occur, withhold dose for 1 wk or until symptoms improve to <Grade 2, then resume at same or reduced dose (120 mg or 80 mg).
- Instruct patient to take enzalutamide as directed at the same time each day. Take missed doses as soon as remembered within the same day. If a whole day is missed, omit dose and take next day's scheduled dose; do not double doses. Advise patient not to interrupt, modify dose, or stop taking enzalutamide without consulting health care professional. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
- May cause seizures, dizziness, mental impairment, paresthesia, hypoesthesia, falls, and hallucinations. Caution patient to avoid driving and other activities requiring alertness until response to medication is known. Notify health care professional immediately if loss of consciousness, seizure, or signs and symptoms of PRES occur.
- Inform patient of common side effects associated with enzalutamide: asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper and lower respiratory infection, muscular weakness, dizziness, insomnia, spinal cord compression, cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Notify health care professional if falls or problems thinking clearly, or if side effects are bothersome.
- Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other Rx, OTC, or herbal products.
- Rep: Caution patients that enzalutamide is teratogenic. Advise patient to avoid pregnancy and breast feeding during and for 3 mo following completion of therapy. Male patients should use a condom if having sex with a pregnant woman, and a condom and another effective method of birth control should be used if having sex with a woman of reproductive potential.
Decreased growth and spread of prostate cancer.
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