Xtandi

Warnings and Precautions ( 5.8 ) 12/2025

1 INDICATIONS AND USAGE XTANDI ® is indicated for the treatment of patients 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) XTANDI is an androgen receptor inhibitor indicated for the treatment of patients with: • castration-resistant prostate cancer. ( 1 ) • metastatic castration-sensitive prostate cancer. ( 1 ) • non‐metastatic castration‐sensitive prostate cancer with biochemical recurrence at high risk for metastasis. ( 1 )

2 DOSAGE AND ADMINISTRATION • Take XTANDI 160 mg administered orally once daily with or without food. ( 2.1 ) • Advise patients to take each capsule or tablet whole with a sufficient amount of water to ensure that all medication is successfully swallowed. ( 2.1 , 5.7 ) • Patients receiving XTANDI for castration-resistant prostate cancer, or metastatic castration-sensitive prostate cancer should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.1 ) • Patients with non-metastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis may be treated with or without a GnRH analog. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of XTANDI is 160 mg administered orally once daily with or without food [see Clinical Pharmacology ( 12.3 )] until disease progression or unacceptable toxicity. Advise patients to take each capsule or tablet whole with a sufficient amount of water to ensure that all medication is successfully swallowed. Do NOT chew, dissolve, or open the capsules. Do NOT cut, crush, or chew the tablets. Patients with CRPC or mCSPC receiving XTANDI should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Patients with nmCSPC with high-risk BCR may be treated with XTANDI with or without a GnRH analog. For patients who receive XTANDI with or without a GnRH analog, treatment can be suspended if PSA is undetectable (< 0.2 ng/mL) after 36 weeks of therapy. Reinitiate treatment when PSA has increased to ≥ 2.0 ng/mL for patients who had prior radical prostatectomy or ≥ 5.0 ng/mL for patients who had prior primary radiation therapy [see Clinical Studies ( 14 )] . 2.2 Dosage Modifications for Adverse Reactions If a patient experiences a ≥ Grade 3 or an intolerable adverse reaction, withhold XTANDI for one week or until symptoms improve to ≤ Grade 2, then resume at the same or a reduced dose (120 mg or 80 mg) if warranted [see Warnings and Precautions ( 5.1 , 5.2 )] . 2.3 Dosage Modifications for Drug Interactions Strong CYP2C8 Inhibitors Avoid the coadministration of strong CYP2C8 inhibitors. If the coadministration of a strong CYP2C8 inhibitor cannot be avoided, reduce the XTANDI dosage to 80 mg once daily. If the coadministration of the strong inhibitor is discontinued, increase the XTANDI dosage to the dosage used prior to initiation of the strong CYP2C8 inhibitor [see Clinical Pharmacology ( 12.3 )]. Strong CYP3A4 Inducers Avoid the coadministration of strong CYP3A4 inducers. If the coadministration of a strong CYP3A4 inducer cannot be avoided, increase the XTANDI dosage from 160 mg to 240 mg orally once daily. If the coadministration of the strong CYP3A4 inducer is discontinued, decrease the XTANDI dosage to the dosage used prior to initiation of the strong CYP3A4 inducer [see Clinical Pharmacology ( 12.3 )].

3 DOSAGE FORMS AND STRENGTHS XTANDI 40 mg capsules are white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ. XTANDI 40 mg tablets are yellow, round, film-coated and debossed with E 40. XTANDI 80 mg tablets are yellow, oval, film-coated and debossed with E 80. • Capsules: 40 mg ( 3 ) • Tablets: 40 mg, 80 mg ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Seizure [see Warnings and Precautions ( 5.1 )] • Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions ( 5.2 )] • Hypersensitivity [see Warnings and Precautions ( 5.3 )] • Ischemic Heart Disease [see Warnings and Precautions ( 5.4 )] • Falls and Fractures [see Warnings and Precautions ( 5.5 )] • Dysphagia or Choking [see Warnings and Precautions ( 5.7 )] The most common adverse reactions (≥ 10%) that occurred more frequently (≥ 2% over placebo) in the XTANDI-treated patients are musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Astellas Pharma US, Inc. at 1-800-727-7003 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data in WARNINGS and PRECAUTIONS reflect eight randomized, controlled trials [AFFIRM, PREVAIL, TERRAIN, PROSPER, ARCHES, EMBARK, Asian PREVAIL (NCT02294461), and STRIVE (NCT01664923)] that were pooled to conduct safety analyses in patients with CRPC (N = 3651), mCSPC (N = 754), or nmCSPC with high‐risk BCR (N = 707) treated with XTANDI. Patients received XTANDI 160 mg (N = 5112) or placebo orally once daily (N = 2829) or bicalutamide 50 mg orally once daily (N = 387). In these eight trials, the median duration of treatment was 22.1 months (range: 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies. Table 8. Laboratory Abnormalities XTANDI (N = 3526) Placebo (N = 2636) Grade 1-4 (%) Grade 3-4 (%) Grade 1-4 (%) Grade 3-4 (%) Hematology Hemoglobin decreased 50 1.8 47 1.5 Neutrophil count decreased 20 1 17 0.5 White blood cell decreased 18 0.5 11 0.2 Chemistry Hyperglycemia 86 3.7 78 4.3 Hypermagnesemia 17 0.1 14 0.3 Hyponatremia 14 1.6 9 1.4 Hypophosphatemia 10 1.4 7 0.8 Hypercalcemia 8 0.1 5 0.1 Hypertension In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14% of patients receiving XTANDI and 7% of patients receiving placebo. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of patients in each arm. 6.2 Post-Marketing Experience The following additional adverse reactions have been identified during post-approval use of XTANDI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: vomiting, dysphagia (including choking related to XTANDI product size) Immune System Disorders: hypersensitivity (edema of the face, tongue, lip, or pharynx) Neurological Disorders: posterior reversible encephalopathy syndrome (PRES), dysgeusia Skin and Subcutaneous Tissue Disorders: rash, severe cutaneous adverse reactions (including Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP))

7 DRUG INTERACTIONS • Strong CYP2C8 Inhibitors: Avoid strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI. ( 2.3 , 7.1 ) • Strong CYP3A4 Inducers: Avoid strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI. ( 2.3 , 7.1 ) • Avoid coadministration with certain CYP3A4, CYP2C9, or CYP2C19 substrates for which a minimal decrease in concentration may lead to therapeutic failure of the substrate. In cases where active metabolites are formed, there may be increased exposure to the active metabolites. ( 7.2 ) 7.1 Effect of Other Drugs on XTANDI Strong CYP2C8 Inhibitors The coadministration of XTANDI with gemfibrozil (a strong CYP2C8 inhibitor) increases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may increase the incidence and severity of adverse reactions of XTANDI. Avoid the coadministration of XTANDI with strong CYP2C8 inhibitors. If the coadministration of XTANDI with a strong CYP2C8 inhibitor cannot be avoided, reduce the dosage of XTANDI [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )]. Strong CYP3A4 Inducers The coadministration of XTANDI with rifampin (a strong CYP3A4 inducer and a moderate CYP2C8 inducer) decreases plasma concentrations of enzalutamide plus N-desmethyl enzalutamide, which may decrease the efficacy of XTANDI. Avoid the coadministration of XTANDI with strong CYP3A4 inducers. If the coadministration of XTANDI with a strong CYP3A4 inducer cannot be avoided, increase the dosage of XTANDI [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 )]. 7.2 Effect of XTANDI on Other Drugs Certain CYP3A4, CYP2C9, or CYP2C19 Substrates XTANDI is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. The coadministration of XTANDI decreases the concentrations of certain CYP3A4, CYP2C9, or CYP2C19 substrates [see Clinical Pharmacology ( 12.3 )] , which may reduce the efficacy of these substrates. Avoid the coadministration of XTANDI with certain CYP3A4, CYP2C9, or CYP2C19 substrates for which a minimal decrease in concentration may lead to therapeutic failure of the substrate. If the coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites. 7.3 Laboratory Test Interference XTANDI can interfere with certain digoxin immunoassays (e.g., Chemiluminescent Microparticle Immunoassays), resulting in falsely elevated digoxin plasma concentration results. Notify the laboratory conducting the digoxin plasma concentration assay to use an appropriate method in patients receiving XTANDI and digoxin [see Warnings and Precautions ( 5.8 )] .

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The safety and efficacy of XTANDI have not been established in females. Based on animal reproductive studies and mechanism of action, XTANDI can cause fetal harm and loss of pregnancy. There are no human data on the use of XTANDI in pregnant females. In animal reproduction studies, oral administration of enzalutamide in pregnant mice during organogenesis caused adverse developmental effects at doses lower than the maximum recommended human dose (see Data). Data Animal Data In an embryo-fetal developmental toxicity study in mice, enzalutamide caused developmental toxicity when administered at oral doses of 10 or 30 mg/kg/day throughout the period of organogenesis (gestational days 6-15). Findings included embryo-fetal lethality (increased post-implantation loss and resorptions) and decreased anogenital distance at ≥ 10 mg/kg/day, and cleft palate and absent palatine bone at 30 mg/kg/day. Doses of 30 mg/kg/day caused maternal toxicity. The doses tested in mice (1, 10 and 30 mg/kg/day) resulted in systemic exposures (AUC) approximately 0.04, 0.4 and 1.1 times, respectively, the exposures in patients. Enzalutamide did not cause developmental toxicity in rabbits when administered throughout the period of organogenesis (gestational days 6-18) at dose levels up to 10 mg/kg/day (approximately 0.4 times the exposures in patients based on AUC). In a pharmacokinetic study in pregnant rats with a single oral 30 mg/kg enzalutamide administration on gestation day 14, enzalutamide and/or its metabolites were present in the fetus at a C max that was approximately 0.3 times the concentration found in maternal plasma and occurred 4 hours after administration. 8.2 Lactation Risk Summary The safety and efficacy of XTANDI have not been established in females. There is no information available on the presence of XTANDI in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Enzalutamide and/or its metabolites were present in milk of lactating rats (see Data) . Data Following a single oral administration in lactating rats on postnatal day 14, enzalutamide and/or its metabolites were present in milk at a C max that was 4 times higher than concentrations in the plasma and occurred 4 hours after administration. 8.3 Females and Males of Reproductive Potential Contraception Males 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 last dose of XTANDI [see Use in Specific Populations ( 8.1 )] . Infertility Males Based on animal studies, XTANDI may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1 )] . 8.4 Pediatric Use Safety and effectiveness of XTANDI in pediatric patients have not been established. 8.5 Geriatric Use Of 5112 patients who received XTANDI in eight randomized, controlled clinical trials, 78% were 65 and over, while 33% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. 8.6 Renal Impairment No dosage modification is recommended for patients with mild to moderate renal impairment (creatinine clearance [CLcr] ≥ 30 mL/min). XTANDI has not been studied in patients with severe renal impairment (CLcr < 30 mL/min) or end-stage renal disease [see Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment No dosage modification is recommended for patients with mild, moderate, or severe hepatic impairment [see Clinical Pharmacology ( 12.3 )].

12.1 Mechanism of Action 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 consequently, inhibits nuclear translocation of androgen receptors and their interaction with DNA. A major metabolite, N‐desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. Enzalutamide decreased proliferation and induced cell death of prostate cancer cells in vitro , and decreased tumor volume in a mouse prostate cancer xenograft model.

11 DESCRIPTION Enzalutamide is an androgen receptor inhibitor. The chemical name is 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro- N -methylbenzamide. The molecular weight is 464.44 and molecular formula is C 21 H 16 F 4 N 4 O 2 S. The structural formula is: Enzalutamide is a white crystalline non-hygroscopic solid. It is practically insoluble in water. XTANDI is available as liquid-filled soft gelatin capsules for oral administration. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides. The inactive ingredients are caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide. XTANDI is also available as film-coated tablets for oral administration. Each tablet contains 40 mg or 80 mg of enzalutamide. The inactive ingredients are hypromellose acetate succinate, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, and magnesium stearate. The tablet film-coat contains hypromellose, talc, polyethylene glycol, titanium dioxide, and ferric oxide. Structural formula of Enzalutamide

10 OVERDOSAGE In the event of an overdosage, stop treatment with XTANDI and initiate general supportive measures taking into consideration the half-life of 5.8 days. In a dose escalation study, no seizures were reported at < 240 mg daily, whereas 3 seizures were reported, 1 each at 360 mg, 480 mg, and 600 mg daily. Patients may be at increased risk of seizure following an overdosage.

16 HOW SUPPLIED/STORAGE AND HANDLING XTANDI (enzalutamide) 40 mg capsules are supplied as white to off-white oblong soft gelatin capsules imprinted in black ink with ENZ and are available in the following package size: • Bottles of 120 capsules with child resistant closures (NDC 0469-0125-99) XTANDI (enzalutamide) 40 mg tablets are supplied as yellow, round, film-coated tablets debossed with E 40, and are available in the following package size: • Bottles of 120 tablets with child resistant closures (NDC 0469-0625-99) XTANDI (enzalutamide) 80 mg tablets are supplied as yellow, oval, film-coated tablets debossed with E 80, and are available in the following package size: • Bottles of 60 tablets with child resistant closures (NDC 0469-0725-60) Store XTANDI capsules and tablets at 20°C to 25°C (68°F to 77°F) in a dry place and keep the container tightly closed. Excursions permitted from 15°C to 30°C (59°F to 86°F).