androgen receptor inhibitors
- Castration-resistant prostate cancer.
- Metastatic, castration-sensitive 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 via the CYP2C8 and CYP3A4 isoenzymes; 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)
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);
- Rep: Men with female partners of reproductive potential;
- Pedi: Safety and effectiveness not established in children;
- Geri: Older adults may be more sensitive to drug effects.
Adverse Reactions/Side Effects
CV: ISCHEMIC HEART DISEASE, peripheral edema, hypertension
Derm: hot flush, dry skin, pruritus
GU: hematuria, urinary frequency
MS: arthralgia, musculoskeletal pain, fracture, muscular stiffness, muscular weakness
Neuro: hypoesthesia, paresthesia, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), SEIZURES, SPINAL CORD COMPRESSION/CAUDA EQUINA SYNDROME, headache, weakness, anxiety, dizziness, hallucinations, insomnia, mental impairment disorders
Misc: HYPERSENSITIVITY REACTIONS (INCLUDING ANGIOEDEMA), falls
* 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)
Patients taking enzalutamide should also receive gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.
PO (Adults): 160 mg once daily. Concurrent use of strong CYP2C8 inhibitors– 80 mg once daily; Concurrent use of strong CYP3A4 inducers– 240 mg once daily.
Availability (generic available)
Capsules: 40 mg
Film-coated tablets: 40 mg, 80 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.
- Monitor for signs and symptoms of hypersensitivity reactions (swelling of face, tongue, lips or throat; dyspnea). Discontinue enzalutamide if serious hypersensitivity reactions occur.
- Monitor for signs and symptoms of ischemic heart disease (chest pain, fainting, dyspnea). Permanently discontinue enzalutamide if Grade 3 or 4 ischemic heart disease symptoms occur.
- Assess risk of falls and fractures periodically during therapy. May consider bone-targeted agents.
Lab Test Considerations:
May cause hematuria.
Administer (two 80 mg tablets or four 40 mg tablets or four 40 capsules) once daily without regard to food. DNC: Swallow capsules whole; do not open, dissolve, or chew.
- If ≥Grade 3 toxicity or intolerable side effects occur, hold 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, chest pain, or signs and symptoms of PRES or hypersensitivity reactions 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, especially St. John's wort.
- Rep: May cause fetal harm and loss of pregnancy. Advise females of reproductive potential to use effective contraception and avoid breast feeding during and for 3 mo following completion of therapy. Instruct females of reproductive potential to avoid handling enzalutamide tablets. Advise males with female partners of reproductive potential to use a condom and effective contraception during and for 3 mo after last dose. May impair fertility in males.
Decreased growth and spread of prostate cancer.
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