enzalutamide

Enzalutamide is an anticancer (antineoplastic) medication used in the treatment of prostate cancer in adult males. Prostate is a walnut-sized gland located below the bladder that produces seminal fluid in men which nourishes and transports sperm, the male reproductive cell. Prostate also plays a role in the metabolism of male sex hormones (androgens) such as testosterone, and blocks urine flow during ejaculation. Prostate cancer is the second most diagnosed solid cancer in adult males and the second leading cause of male cancer deaths.

The prostate needs androgens to function normally, but androgens also fuel the growth of prostate cancer cells. Enzalutamide is an androgen receptor (AR) inhibitor that binds to protein molecules (ARs) on the prostate gland which are activated by androgens, and prevent the interaction between ARs and androgens. By blocking the AR signaling pathway, enzalutamide inhibits the proliferation of cancerous prostate cells and induces programmed death (apoptosis) of the cancer cells.

Enzalutamide is FDA-approved for the treatment of adult males with:

• Castration-resistant prostate cancer (CRPC)
• Metastatic castration-sensitive prostate cancer (mCSPC)
• Non-metastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR)

• Seizures have been reported in patients treated with enzalutamide.
  • The risk of seizure is higher in patients with predisposing factors such as:
    • Past history of seizure
    • History of traumatic head or brain injury
    • History of cerebrovascular accident or transient ischemic attack
    • History of arteriovenous malformation
    • Alzheimer’s disease
    • Meningioma, a tumor that develops in the membranes of brain or spine
    • Cancer metastasis to the cerebrospinal fluid (leptomeningeal disease)
    • Unexplained loss of consciousness in the previous 12 months
    • Presence of space-occupying lesion of the brain
    • History of brain infection
    • Concurrent use of other medications that lower seizure threshold
  • Advise patients at risk for seizure to avoid engaging in hazardous activities during treatment with enzalutamide.
  • It is not known if anti-epileptic medications can prevent seizures with enzalutamide.
  • If the patient develops seizure during treatment, permanently discontinue enzalutamide.
• In some patients, enzalutamide treatment has been associated with posterior reversible encephalopathy syndrome (PRES), a neurological disorder. Evaluate patients who develop neurological symptoms, and discontinue enzalutamide if PRES is confirmed with brain imaging, preferably magnetic resonance imaging (MRI).
• Enzalutamide can cause hypersensitivity reactions including edema of the face, tongue, lip, and/or throat.
  • Advise patients to report hypersensitivity reactions and seek medical care immediately.
  • Interrupt enzalutamide treatment and treat hypersensitivity reactions appropriately.
  • In the event of severe reactions, discontinue enzalutamide permanently.
• Enzalutamide can impair blood flow to the heart and cause ischemic heart disease that may be fatal.
  • Monitor patients for signs and symptoms of ischemic heart disease.
  • Optimize management of cardiovascular risk factors such as diabetes, unhealthy blood fat levels (dyslipidemia) and high blood pressure (hypertension).
  • Discontinue enzalutamide in patients who develop Grade 3-4 ischemic heart disease.
• Falls and fractures not associated with seizures or loss of consciousness occurred in patients treated with enzalutamide. Evaluate patients for risk of fall and fracture, and monitor and manage those at risk, including use of bone-targeted agents.
• Enzalutamide is not intended for use in women and may cause fetal harm and loss of pregnancy if a pregnant woman is exposed to the drug. Women who are pregnant or may get pregnant should avoid handling enzalutamide. Men with women partners of pregnancy potential should use effective contraception for the recommended period during and after completion of treatment.

Common side effects of enzalutamide include:

• Fatigue
• Weakness
• Decrease in hemoglobin level
• Decrease in count of neutrophil immune cells
• Decrease in white blood cell count
• High blood glucose level (hyperglycemia)
• Electrolyte disturbances including:
  • High magnesium levels in blood (hypermagnesemia)
  • Low blood sodium (hyponatremia)
  • Low phosphate levels (hypophosphatemia)
  • High calcium in blood (hypercalcemia)
• Back pain
• Joint pain (arthralgia)
• Musculoskeletal pain
• Muscular weakness
• Musculoskeletal stiffness
• Joint degeneration (osteoarthritis)
• Fall
• Non-pathologic fractures
• Hot flush
• High blood pressure (hypertension)
• Swelling from fluid collection in extremities (peripheral edema)
• Constipation
• Diarrhea
• Nausea
• Decreased appetite
• Weight loss
• Upper respiratory tract infection
• Lower respiratory tract and lung infection
• Shortness of breath (dyspnea)
• Impaired blood flow to heart (ischemic heart disease)
• Fainting (syncope)
• Hemorrhage
• Headache
• Dizziness
• Taste disorder (dysgeusia)
• Spinal cord compression and cauda equina syndrome
• Abnormal skin sensations (paresthesia)
• Reduced skin sensation (hypoesthesia)
• Restless legs syndrome
• Insomnia
• Anxiety
• Memory impairment
• Memory loss (amnesia)
• Cognitive disorder
• Disturbance in attention
• Blood in urine (hematuria)
• Frequent daytime urination (pollakiuria)
• Itching (pruritus)
• Dry skin
• Nasal bleeding (epistaxis)
• Abnormal breast tissue growth (gynecomastia)
• Breast tenderness

Less common side effects of enzalutamide include:

• Vomiting
• Hypersensitivity reactions including:
  • Facial edema
  • Tongue edema
  • Lip edema
  • Throat (pharyngeal) edema
• Posterior reversible encephalopathy syndrome (PRES), a neurological disorder
• Rash
• Severe skin reactions including:
  • Stevens-Johnson syndrome (SJS)
  • Erythema multiforme
  • Toxic epidermal necrolysis (TEN)
  • Drug reaction with eosinophilia and systemic symptoms (DRESS)
  • Acute generalized exanthematous pustulosis (AGEP)

Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:

• Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
• Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
• Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
• Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.

This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.

Capsule

• 40 mg

Tablet

• 40 mg
• 80 mg

Adult:

Prostate Cancer

Indications

• Castration-resistant prostate cancer (CRPC)
• Metastatic castration-sensitive prostate cancer (mCSPC)
• Non-metastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR)

Dosage

• 160 mg orally once daily
• CRPC or mCSPC: Patients should also receive a gonadotropic-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy
• nmCSPC with high-risk BCR
  • May be treated with enzalutamide with or without a GnRH analog
  • Treatment can be suspended if PSA is undetectable (below 0.2 ng/mL) after 36 weeks of therapy
  • Reinitiate treatment when PSA increases to 2 ng/mL or above for patients who had prior radical prostatectomy or 5 ng/mL or above for patients who had prior primary radiation therapy

Dosage Modifications

Dosage modifications based on drug-related toxicities

• Grade 3 or higher toxicity or an intolerable side effect: Withhold for 1 week or until symptoms improve to Grade 2 or lower, then resume at same or reduced dose (e.g., 120 mg or 80 mg), if necessary

Concomitant strong CYP2C8 inhibitors

• Avoid use
• If coadministration unavoidable, reduce enzalutamide dose to 80 mg once daily
• If strong inhibitor discontinued, return enzalutamide to dose before initiating the strong CYP2C8 inhibitor

Concomitant strong CYP3A4 inducers

• Avoid use
• If coadministration unavoidable, increase enzalutamide dose from 160 mg to 240 mg once daily
• If strong inducer discontinued, return enzalutamide to dose before initiating the strong CYP3A4 inducer

Renal impairment

• Mild-to-moderate (creatinine clearance [CrCl] 30-89 mL/minute): No dosage adjustment necessary
• Severe (CrCl below 30 mL/minute) and end-stage renal disease: Not assessed

Hepatic impairment

• Mild-to-severe (Child Pugh A to C): No dosage adjustment necessary

Dosing Considerations

• Patients receiving enzalutamide should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy

Pediatric:

• Safety and efficacy not established

Overdose

Enzalutamide overdose can increase the risk for seizures. Overdose should be treated with discontinuation of enzalutamide and general supportive care.

Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.

• Enzalutamide has severe interactions with at least 27 different drugs.
• Enzalutamide has serious interactions with at least 238 different drugs.
• Enzalutamide has moderate interactions with at least 114 different drugs.
• Minor interactions of enzalutamide include:
  • acetazolamide
  • anastrozole
  • cyclophosphamide
  • larotrectinib

The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.

It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.

• Enzalutamide is not intended for use in women.
• Based on its mechanism of action and animal reproductive studies, enzalutamide can cause fetal harm.
• Pregnant women and women who may become pregnant should not handle enzalutamide.
• Men with women partners of pregnancy potential must use effective contraception during treatment and for 3 months following the final dose of enzalutamide.
• Animal studies show enzalutamide may impair male fertility.
• It is not known if enzalutamide is present in breastmilk or its effects on milk production or the breastfed infant. Animal studies showed enzalutamide and its metabolites are excreted in rat milk.

• Take enzalutamide exactly as instructed by your physician.
• Enzalutamide may increase the risk of seizures if you have pre-disposing risk factors for developing seizures.
  • If you experience seizure or loss of consciousness, inform your physician immediately.
  • Avoid driving and engaging in other such activities where seizure or sudden loss of consciousness can cause serious harm to yourself and/or others around you.
• Report to your physician if you experience:
  • Hypersensitivity reactions such as swelling of lip, tongue, face or throat
  • Heart-related symptoms
  • Neurological symptoms such as seizure, headache, reduced alertness, confusion, reduced eyesight or blurred vision
  • Dizziness, vertigo, falls or fractures
  • Increase in blood pressure
• Store enzalutamide safely out of reach of children.
• In case of overdose, seek medical help or contact Poison Control.