Manufacturer:
Astellas Pharma and Medivation

Pharmacological Class:
Androgen receptor inhibitor.

Active Ingredient(s):
Enzalutamide 40mg; caps.

Indication(s):
Treatment of metastatic castration-resistant prostate cancer in patients who have previously received docetaxel.

Pharmacology:

Enzalutamide is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. Enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA.

Clinical Trials:
The efficacy and safety of Xtandi in patients with metastatic castration-resistant prostate cancer who had received prior docetaxel-based therapy were assessed in a randomized, placebo-controlled, multicenter phase 3 clinical trial. The primary endpoint was overall survival. A total of 1199 patients were randomized 2:1 to receive either Xtandi 160mg once daily (N=800) or placebo orally once daily (N=399). All patients continued androgen deprivation therapy. Patients were allowed, but not required to continue or initiate glucocorticoids. Study treatment continued until disease progression (evidence of radiographic progression, a skeletal- related event, or clinical progression), initiation of new systemic antineoplastic treatment, unacceptable toxicity, or withdrawal. Patients with a history of seizure, taking medicines known to decrease the seizure threshold, or with other risk factors for seizure were not eligible.

The pre-specified interim analysis at the time of 520 events showed a statistically significant improvement in overall survival in patients on the Xtandi arm compared to patients on the placebo arm (number of deaths: 38.5% for Xtandi vs. 53.1% for placebo; median survival: 18.4 months for Xtandi vs. 13.6 months for placebo; P-value: <0.0001; HR: 0.63).

Legal Classification:
Rx

Adults:
Swallow whole. 160mg once daily. Dose modifications: ≥Grade 3 toxicity or intolerable side effect: withhold dosing for 1 week or until symptoms improve to ≤Grade 2, then resume at same or reduced dose, if warranted. Concomitant strong CYP2C8 inhibitors: avoid if possible. If co-administration necessary, reduce Xtandi dose to 80mg once daily; if inhibitor is discontinued, return Xtandi dose to dose used prior to initiation of inhibitor.

Children:
Not established.

Contraindication(s):
Pregnancy (Cat.X).

Warnings/Precautions:
Seizure risk. Severe renal or hepatic impairment. Nursing mothers.

Interaction(s):
Potentiated by strong CYP2C8 inhibitors (eg, gemfibrozil), CYP3A4 inhibitors (itraconazole). May be antagonized by CYP2C8 inducers (eg, rifampin), CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, bosentan, efavirenz, etravirine, modafinil, nafcillin, St. John’s Wort). Antagonizes midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Avoid concomitant drugs with narrow therapeutic indexes metabolized by CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), CYP2C19 (eg, S-mephenytoin); enzalutamide may decrease their exposure. Caution with concomitant drugs that may lower the seizure threshold. Monitor INR if concomitant warfarin cannot be avoided.

Adverse Reaction(s):
Asthenia/fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, hypertension, neutropenia; seizures.

How Supplied:
Caps—120

Last Updated:
9/24/2012

Publication details

 Contact address:

Xtandi (enzalutamide)
Company: Medivation, Inc.
Application No.: 203415
Approval Date: 8/31/2012

Persons with disabilities having problems accessing the PDF files below may call (301) 796-3634 for assistance.

• Approval Letter(s) (PDF)
• Summary Review (PDF)
• Officer/Employee List (PDF)
• Office Director Memo (PDF)
• Cross Discipline Team Leader Review (PDF)
• Printed Labeling (PDF)
• Medical Review(s) (PDF)
• Chemistry Review(s) (PDF)
• Pharmacology Review(s) (PDF)
• Statistical Review(s) (PDF)
• Microbiology Review(s) (PDF)
• Clinical Pharmacology Biopharmaceutics Review(s) (PDF)
• Risk Assessment and Risk Mitigation Review(s) (PDF)
• Proprietary Name Review(s) (PDF)
• Other Review(s) (PDF)
• Administrative Document(s) & Correspondence (PDF)

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