These Highlights Do Not Include All The Information Needed To Use Erleada Safely And Effectively. See Full Prescribing Information For Erleada.

Disperse Tablet(s) in Water and Administer with Orange Juice, Applesauce, or Additional Water

For patients who cannot swallow tablets whole, the recommended dose of ERLEADA tablet(s) can be dispersed in non-carbonated water and then administered with either orange juice, applesauce, or additional water as follows:

• Place the entire prescribed dose of ERLEADA tablet(s) in a cup. Do not crush or split the tablet(s).
• For one 240 mg tablet:Add about 2 teaspoons (10 mL) of non-carbonated water to make sure that the tablet is completely immersed in water.
  
  For 60 mg tablets (prescribed dose of 240 mg, 180 mg, or 120 mg):Add about 4 teaspoons (20 mL) of non-carbonated water to make sure that the tablets are completely immersed in water.
• Wait 2 minutes until the tablet(s) are broken up and spread out, then stir the mixture.
• Add 2 tablespoons (30 mL) of either orange juice, applesauce, or additional water and stir the mixture.
• Swallow the mixture immediately.
• Rinse the cup with enough water to make sure the whole dose is taken and drink it immediately.

Do not store ERLEADA that is mixed with non-carbonated water, orange juice, or applesauce for later use.

Storage and Handling

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature].

Store in original package to protect from light and moisture. Do not discard desiccant.

Falls occurred in patients receiving ERLEADA with increased frequency in the elderly [see Use in Specific Populations (8.5)] . Evaluate patients for fall risk.

In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA compared to 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure.

Seizure occurred in patients receiving ERLEADA. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

In two randomized studies (SPARTAN and TITAN), five patients (0.4%) treated with ERLEADA and one patient treated with placebo (0.1%) experienced a seizure. Seizure occurred from 159 to 650 days after initiation of ERLEADA. Patients with a history of seizure, predisposing factors for seizure, or receiving drugs known to decrease the seizure threshold or to induce seizure were excluded. There is no clinical experience in re-administering ERLEADA to patients who experienced a seizure.

There is no known specific antidote for apalutamide overdose. In the event of an overdose, stop ERLEADA, undertake general supportive measures until clinical toxicity has been diminished or resolved.

Fractures occurred in patients receiving ERLEADA. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

In a randomized study (SPARTAN) of patients with non-metastatic castration-resistant prostate cancer, fractures occurred in 12% of patients treated with ERLEADA and in 7% of patients treated with placebo. Grade 3–4 fractures occurred in 2.7% of patients treated with ERLEADA and in 0.8% of patients treated with placebo. The median time to onset of fracture was 314 days (range: 20 to 953 days) for patients treated with ERLEADA. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the SPARTAN study.

In a randomized study (TITAN) of patients with metastatic castration-sensitive prostate cancer, fractures occurred in 9% of patients treated with ERLEADA and in 6% of patients treated with placebo. Grade 3–4 fractures were similar in both arms at 1.5%. The median time to onset of fracture was 56 days (range: 2 to 111 days) for patients treated with ERLEADA. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the TITAN study.

Apalutamide, the active ingredient of ERLEADA, is an androgen receptor inhibitor. Each ERLEADA tablet contains either 60 mg or 240 mg of apalutamide. The chemical name is (4-[7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide). Apalutamide is a white to slightly yellow powder. Apalutamide is practically insoluble in aqueous media over a wide range of pH values.

The molecular weight is 477.44 and molecular formula is C ₂₁H ₁₅F ₄N ₅O ₂S. The structural formula is:

ERLEADA ^®(apalutamide) tablets are available in 240 mg tablets and 60 mg tablets with the following inactive ingredients:

• 240 mg film-coated tablets: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose-acetate succinate, silicified microcrystalline cellulose, and magnesium stearate. The coating contains glyceryl monocaprylocaprate, iron oxide black, polyvinyl alcohol, talc, titanium dioxide, and vinyl alcohol grafted copolymer.
• 60 mg film-coated tablets: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose-acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose. The coating contains iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Safety and effectiveness of ERLEADA in pediatric patients have not been established.

Of the 1327 patients who received ERLEADA in clinical studies, 19% of patients were less than 65 years, 41% of patients were 65 years to 74 years, and 40% were 75 years and over.

No overall differences in effectiveness were observed between older and younger patients.

Of patients treated with ERLEADA (n=1073), Grade 3–4 adverse reactions occurred in 39% of patients younger than 65 years, 41% of patients 65–74 years, and 49% of patients 75 years or older. Falls in patients receiving ERLEADA with androgen deprivation therapy was elevated in the elderly, occurring in 8% of patients younger than 65 years, 10% of patients 65–74 years, and 19% of patients 75 years or older.

The efficacy and safety of ERLEADA was established in two randomized placebo-controlled clinical trials.

None. ( 4)

The following are discussed in more detail in other sections of the labeling:

• Cerebrovascular and Ischemic Cardiovascular Events [see Warnings and Precautions (5.1)] .
• Fractures [see Warnings and Precautions (5.2)] .
• Falls [see Warnings and Precautions (5.3)] .
• Seizure [see Warnings and Precautions (5.4)] .
• Severe Cutaneous Adverse Reactions (SCARs) [see Warnings and Precautions (5.5)] .
• Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] .

Concomitant use with medications that are sensitive substrates of CYP3A4, CYP2C19, CYP2C9, UGT, P-gp, BCRP, or OATP1B1 may result in loss of activity of these medications. ( 7.2)

Apalutamide 240 mg daily in addition to ADT in patients with mCSPC (TITAN) reduced PSA to undetectable levels (<0.2 ng/mL) in 68% of patients compared to 32% of patients taking ADT alone.

Apalutamide 240 mg daily in addition to ADT in patients with nmCRPC (SPARTAN) reduced PSA to undetectable levels (<0.2 ng/mL) in 38% of patients compared to no patients (0%) taking ADT alone.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of apalutamide have not been fully characterized.

Apalutamide pharmacokinetic parameters are presented as the mean [standard deviation (SD)] unless otherwise specified. Apalutamide C _maxand area under the concentration curve (AUC) increased proportionally following repeated once-daily dosing of 30 to 480 mg (0.125 to 2 times the recommended dosage). Following administration of the recommended dosage, apalutamide steady-state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold. Apalutamide C _maxwas 6.0 mcg/mL (1.7) and AUC was 100 mcg∙h/mL (32) at steady-state. Daily fluctuations in apalutamide plasma concentrations were low, with mean peak-to-trough ratio of 1.63. An increase in apparent clearance (CL/F) was observed with repeat dosing, likely due to induction of apalutamide's own metabolism. The auto-induction effect likely reached its maximum at the recommended dosage because exposure of apalutamide across the dose range of 30 to 480 mg is dose-proportional.

The major active metabolite N-desmethyl apalutamide C _maxwas 5.9 mcg/mL (1.0) and AUC was 124 mcg∙h/mL (23) at steady-state after the recommended dosage. N-desmethyl apalutamide was characterized by a flat concentration-time profile at steady-state with a mean peak-to-trough ratio of 1.27. Mean AUC metabolite/parent drug ratio for N-desmethyl apalutamide following repeat-dose administration was 1.3. Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributed to the clinical activity of apalutamide.

The recommended dose of ERLEADA is 240 mg administered orally once daily. This could be administered as one 240 mg tablet or four 60 mg tablets. Swallow the tablet(s) whole. Do not crush or split tablet(s). ERLEADA can be taken with or without food.

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

ERLEADA is indicated for the treatment of patients with

• Metastatic castration-sensitive prostate cancer (mCSPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

If Grade 3 or greater adverse reactions, or other intolerable adverse reactions occur, withhold ERLEADA. Consider permanent discontinuation of ERLEADA for Grade 3 or 4 cerebrovascular and ischemic cardiovascular events [see Warnings and Precautions (5.1)] . Permanently discontinue ERLEADA for severe ILD/pneumonitis or if no other potential causes of ILD/pneumonitis are identified, or confirmed SCARs, or for other Grade 4 skin reactions [see Warnings and Precautions (5.5, 5.6)and Adverse Reactions (6.1)] . For other adverse reactions, when symptoms improve to less than or equal to Grade 1 or original grade, resume ERLEADA at the same dose or a reduced dose (180 mg or 120 mg), if warranted.

Apalutamide is an Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of apalutamide in an in vitrotranscriptional reporter assay. Apalutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer.

The safety and efficacy of ERLEADA have not been established in females. Based on findings from animals and its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy when administered to a pregnant female. In an animal reproduction study, oral administration of apalutamide to pregnant rats during and after organogenesis resulted in fetal abnormalities and embryo-fetal lethality at maternal exposures ≥ 2 times the human clinical exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA [see Use in Specific Populations (8.1, 8.3)and Clinical Pharmacology (12.1)] .

• Cerebrovascular and ischemic cardiovascular events occurred in patients receiving ERLEADA. Monitor for signs and symptoms of cerebrovascular disorders and ischemic heart disease. Optimize management of cardiovascular risk factors. ( 5.1).
• Fractures occurred in patients receiving ERLEADA. Evaluate patients for fracture risk and treat patients with bone-targeted agents according to established guidelines. ( 5.2)
• Falls occurred in patients receiving ERLEADA with increased incidence in the elderly. Evaluate patients for fall risk. ( 5.3)
• Seizure occurred in 0.4% of patients receiving ERLEADA. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. ( 5.4)
• Severe Cutaneous Adverse Reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), occurred in patients treated with ERLEADA. Interrupt ERLEADA if signs or symptoms of SCARs develop. Permanently discontinue if SCARs are confirmed. ( 5.5)
• Interstitial Lung Disease (ILD)/pneumonitis occurred in patients treated with ERLEADA. Withhold ERLEADA for suspected ILD/pneumonitis. Permanently discontinue ERLEADA in patients with severe ILD/pneumonitis or if no other potential causes of ILD/pneumonitis are identified. ( 2.2, 5.6)
• Embryo-Fetal Toxicity: ERLEADA can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception. ( 5.7, 8.1, 8.3)

ERLEADA 240 mg administered orally once daily. Swallow tablets whole. ERLEADA can be taken with or without food. ( 2.1, 2.3)

Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.1)

Tablets:

• 240 mg: bluish grey to grey, oval, film-coated and debossed with "E240" on one side.
• 60 mg: slightly yellowish to greyish green, oblong, film-coated and debossed with "AR 60" on one side.

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 most common adverse reactions (≥ 10%) that occurred more frequently in the ERLEADA-treated patients (≥ 2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.

The following additional adverse reactions have been identified during post-approval use of ERLEADA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders:interstitial lung disease/pneumonitis [see Warnings and Precautions (5.6)]

Skin and Subcutaneous Tissue Disorders:Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS).

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

ERLEADA ^®(apalutamide) tablets are available in the strengths and packages listed below:

• ERLEADA ^®240 mg Tablets
  
  Film coated, bluish grey to grey, oval-shaped tablets debossed with "E240" on one side.
  
  NDC Number 59676‐604‐30 - 30 tablets available in bottles with a silica gel desiccant and has a child-resistant closure

• ERLEADA ^®60 mg Tablets
  
  Film coated, slightly yellowish to greyish green, oblong-shaped tablets debossed with "AR 60" on one side.
  
  NDC Number 59676‐600‐12 - 120 tablets available in bottles with a silica gel desiccant and has a child-resistant closure

Fatal and life-threatening cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), occurred in patients receiving ERLEADA [see Adverse Reactions (6.2)] .

Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).

If a SCAR is suspected, interrupt ERLEADA until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other grade 4 skin reactions, permanently discontinue ERLEADA [see Dosage and Administration (2.2)and Adverse Reactions (6.1)] .

Fatal and life-threatening interstitial lung disease (ILD) or pneumonitis can occur in patients treated with ERLEADA.

Post-marketing cases of ILD/pneumonitis, including fatal cases, occurred in patients treated with ERLEADA. Across clinical trials (TITAN and SPARTAN, n=1327), 0.8% of patients treated with ERLEADA experienced ILD/pneumonitis, including 0.2% who experienced Grade 3 events [see Adverse Reactions (6.1, 6.2)].

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold ERLEADA if ILD/pneumonitis is suspected.

Permanently discontinue ERLEADA in patients with severe ILD/pneumonitis or if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.2)] .

NDC 59676-600-12

Erleada ^®

(apalutamide) tablets

60 mg

Each film-coated tablet

contains 60 mg of apalutamide.

This package is child-resistant.

Keep out of reach of children.

Rx only

120 film-coated

tablets

NDC 59676-604-30

Erleada ^®

(apalutamide) tablets

240 mg

Each film-coated tablet contains

240 mg of apalutamide.

This package is child-resistant.

Keep out of reach of children.

Rx only

30 film-coated tablets

Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA. Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA for Grade 3 and 4 events.

In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 3.7% of patients treated with ERLEADA and 2% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4.4% of patients treated with ERLEADA and 1.5% of patients treated with placebo. Across the SPARTAN and TITAN studies, 4 patients (0.3%) treated with ERLEADA, and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event.

In the SPARTAN study, cerebrovascular events occurred in 2.5% of patients treated with ERLEADA and 1% of patients treated with placebo [see Adverse Reactions (6.1)] . In the TITAN study, cerebrovascular events occurred in 1.9% of patients treated with ERLEADA and 2.1% of patients treated with placebo. Across the SPARTAN and TITAN studies, 3 patients (0.2%) treated with ERLEADA, and 2 patients (0.2%) treated with placebo died from a cerebrovascular event.

Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within six months of randomization were excluded from the SPARTAN and TITAN studies.

In a 2-year carcinogenicity study in male rats, apalutamide was administered by oral gavage at doses of 5, 15 and 50 mg/kg/day. Apalutamide increased the incidence of Leydig interstitial cell adenoma in the testes at doses ≥ 5 mg/kg/day (0.2 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of apalutamide. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Oral administration of apalutamide to male rasH2 transgenic mice for 6 months did not result in increased incidence of neoplasms at doses up to 30 mg/kg/day.

Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitrochromosome aberration assay or the in vivorat bone marrow micronucleus assay or the in vivorat Comet assay.

In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate gland and seminal vesicles, aspermia/hypospermia, tubular degeneration and/or hyperplasia or hypertrophy of the interstitial cells in the reproductive system were observed at ≥ 25 mg/kg/day in rats (1.4 times the human exposure based on AUC) and ≥ 2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC).

In a fertility study in male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day (0.8 times the human exposure based on AUC). A reduced number of live fetuses due to increased pre- and/or post-implantation loss was observed following 4 weeks of 150 mg/kg/day administration (5.7 times the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration.

Disperse Tablet(s) in Water and Administer with Orange Juice, Applesauce, or Additional Water

For patients who cannot swallow tablets whole, the recommended dose of ERLEADA tablet(s) can be dispersed in non-carbonated water and then administered with either orange juice, applesauce, or additional water as follows:

• Place the entire prescribed dose of ERLEADA tablet(s) in a cup. Do not crush or split the tablet(s).
• For one 240 mg tablet:Add about 2 teaspoons (10 mL) of non-carbonated water to make sure that the tablet is completely immersed in water.
  
  For 60 mg tablets (prescribed dose of 240 mg, 180 mg, or 120 mg):Add about 4 teaspoons (20 mL) of non-carbonated water to make sure that the tablets are completely immersed in water.
• Wait 2 minutes until the tablet(s) are broken up and spread out, then stir the mixture.
• Add 2 tablespoons (30 mL) of either orange juice, applesauce, or additional water and stir the mixture.
• Swallow the mixture immediately.
• Rinse the cup with enough water to make sure the whole dose is taken and drink it immediately.

Do not store ERLEADA that is mixed with non-carbonated water, orange juice, or applesauce for later use.

Storage and Handling

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted to 15 °C to 30 °C (59 °F to 86 °F) [see USP Controlled Room Temperature].

Store in original package to protect from light and moisture. Do not discard desiccant.

Falls occurred in patients receiving ERLEADA with increased frequency in the elderly [see Use in Specific Populations (8.5)] . Evaluate patients for fall risk.

In a randomized study (SPARTAN), falls occurred in 16% of patients treated with ERLEADA compared to 9% of patients treated with placebo. Falls were not associated with loss of consciousness or seizure.

Seizure occurred in patients receiving ERLEADA. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. It is unknown whether anti-epileptic medications will prevent seizures with ERLEADA. Advise patients of the risk of developing a seizure while receiving ERLEADA and of engaging in any activity where sudden loss of consciousness could cause harm to themselves or others.

In two randomized studies (SPARTAN and TITAN), five patients (0.4%) treated with ERLEADA and one patient treated with placebo (0.1%) experienced a seizure. Seizure occurred from 159 to 650 days after initiation of ERLEADA. Patients with a history of seizure, predisposing factors for seizure, or receiving drugs known to decrease the seizure threshold or to induce seizure were excluded. There is no clinical experience in re-administering ERLEADA to patients who experienced a seizure.

There is no known specific antidote for apalutamide overdose. In the event of an overdose, stop ERLEADA, undertake general supportive measures until clinical toxicity has been diminished or resolved.

Fractures occurred in patients receiving ERLEADA. Evaluate patients for fracture risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

In a randomized study (SPARTAN) of patients with non-metastatic castration-resistant prostate cancer, fractures occurred in 12% of patients treated with ERLEADA and in 7% of patients treated with placebo. Grade 3–4 fractures occurred in 2.7% of patients treated with ERLEADA and in 0.8% of patients treated with placebo. The median time to onset of fracture was 314 days (range: 20 to 953 days) for patients treated with ERLEADA. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the SPARTAN study.

In a randomized study (TITAN) of patients with metastatic castration-sensitive prostate cancer, fractures occurred in 9% of patients treated with ERLEADA and in 6% of patients treated with placebo. Grade 3–4 fractures were similar in both arms at 1.5%. The median time to onset of fracture was 56 days (range: 2 to 111 days) for patients treated with ERLEADA. Routine bone density assessment and treatment of osteoporosis with bone-targeted agents were not performed in the TITAN study.

Apalutamide, the active ingredient of ERLEADA, is an androgen receptor inhibitor. Each ERLEADA tablet contains either 60 mg or 240 mg of apalutamide. The chemical name is (4-[7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide). Apalutamide is a white to slightly yellow powder. Apalutamide is practically insoluble in aqueous media over a wide range of pH values.

The molecular weight is 477.44 and molecular formula is C ₂₁H ₁₅F ₄N ₅O ₂S. The structural formula is:

ERLEADA ^®(apalutamide) tablets are available in 240 mg tablets and 60 mg tablets with the following inactive ingredients:

• 240 mg film-coated tablets: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose-acetate succinate, silicified microcrystalline cellulose, and magnesium stearate. The coating contains glyceryl monocaprylocaprate, iron oxide black, polyvinyl alcohol, talc, titanium dioxide, and vinyl alcohol grafted copolymer.
• 60 mg film-coated tablets: colloidal anhydrous silica, croscarmellose sodium, hydroxypropyl methylcellulose-acetate succinate, magnesium stearate, microcrystalline cellulose, and silicified microcrystalline cellulose. The coating contains iron oxide black, iron oxide yellow, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.

Safety and effectiveness of ERLEADA in pediatric patients have not been established.

Of the 1327 patients who received ERLEADA in clinical studies, 19% of patients were less than 65 years, 41% of patients were 65 years to 74 years, and 40% were 75 years and over.

No overall differences in effectiveness were observed between older and younger patients.

Of patients treated with ERLEADA (n=1073), Grade 3–4 adverse reactions occurred in 39% of patients younger than 65 years, 41% of patients 65–74 years, and 49% of patients 75 years or older. Falls in patients receiving ERLEADA with androgen deprivation therapy was elevated in the elderly, occurring in 8% of patients younger than 65 years, 10% of patients 65–74 years, and 19% of patients 75 years or older.

The efficacy and safety of ERLEADA was established in two randomized placebo-controlled clinical trials.

None. ( 4)

The following are discussed in more detail in other sections of the labeling:

• Cerebrovascular and Ischemic Cardiovascular Events [see Warnings and Precautions (5.1)] .
• Fractures [see Warnings and Precautions (5.2)] .
• Falls [see Warnings and Precautions (5.3)] .
• Seizure [see Warnings and Precautions (5.4)] .
• Severe Cutaneous Adverse Reactions (SCARs) [see Warnings and Precautions (5.5)] .
• Interstitial Lung Disease (ILD) [see Warnings and Precautions (5.6)] .

Concomitant use with medications that are sensitive substrates of CYP3A4, CYP2C19, CYP2C9, UGT, P-gp, BCRP, or OATP1B1 may result in loss of activity of these medications. ( 7.2)

Apalutamide 240 mg daily in addition to ADT in patients with mCSPC (TITAN) reduced PSA to undetectable levels (<0.2 ng/mL) in 68% of patients compared to 32% of patients taking ADT alone.

Apalutamide 240 mg daily in addition to ADT in patients with nmCRPC (SPARTAN) reduced PSA to undetectable levels (<0.2 ng/mL) in 38% of patients compared to no patients (0%) taking ADT alone.

The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of apalutamide have not been fully characterized.

Apalutamide pharmacokinetic parameters are presented as the mean [standard deviation (SD)] unless otherwise specified. Apalutamide C _maxand area under the concentration curve (AUC) increased proportionally following repeated once-daily dosing of 30 to 480 mg (0.125 to 2 times the recommended dosage). Following administration of the recommended dosage, apalutamide steady-state was achieved after 4 weeks and the mean accumulation ratio was approximately 5-fold. Apalutamide C _maxwas 6.0 mcg/mL (1.7) and AUC was 100 mcg∙h/mL (32) at steady-state. Daily fluctuations in apalutamide plasma concentrations were low, with mean peak-to-trough ratio of 1.63. An increase in apparent clearance (CL/F) was observed with repeat dosing, likely due to induction of apalutamide's own metabolism. The auto-induction effect likely reached its maximum at the recommended dosage because exposure of apalutamide across the dose range of 30 to 480 mg is dose-proportional.

The major active metabolite N-desmethyl apalutamide C _maxwas 5.9 mcg/mL (1.0) and AUC was 124 mcg∙h/mL (23) at steady-state after the recommended dosage. N-desmethyl apalutamide was characterized by a flat concentration-time profile at steady-state with a mean peak-to-trough ratio of 1.27. Mean AUC metabolite/parent drug ratio for N-desmethyl apalutamide following repeat-dose administration was 1.3. Based on systemic exposure, relative potency, and pharmacokinetic properties, N-desmethyl apalutamide likely contributed to the clinical activity of apalutamide.

The recommended dose of ERLEADA is 240 mg administered orally once daily. This could be administered as one 240 mg tablet or four 60 mg tablets. Swallow the tablet(s) whole. Do not crush or split tablet(s). ERLEADA can be taken with or without food.

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

ERLEADA is indicated for the treatment of patients with

• Metastatic castration-sensitive prostate cancer (mCSPC)
• Non-metastatic castration-resistant prostate cancer (nmCRPC)

If Grade 3 or greater adverse reactions, or other intolerable adverse reactions occur, withhold ERLEADA. Consider permanent discontinuation of ERLEADA for Grade 3 or 4 cerebrovascular and ischemic cardiovascular events [see Warnings and Precautions (5.1)] . Permanently discontinue ERLEADA for severe ILD/pneumonitis or if no other potential causes of ILD/pneumonitis are identified, or confirmed SCARs, or for other Grade 4 skin reactions [see Warnings and Precautions (5.5, 5.6)and Adverse Reactions (6.1)] . For other adverse reactions, when symptoms improve to less than or equal to Grade 1 or original grade, resume ERLEADA at the same dose or a reduced dose (180 mg or 120 mg), if warranted.

Apalutamide is an Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of AR, and exhibited one-third the activity of apalutamide in an in vitrotranscriptional reporter assay. Apalutamide administration caused decreased tumor cell proliferation and increased apoptosis leading to decreased tumor volume in mouse xenograft models of prostate cancer.

The safety and efficacy of ERLEADA have not been established in females. Based on findings from animals and its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy when administered to a pregnant female. In an animal reproduction study, oral administration of apalutamide to pregnant rats during and after organogenesis resulted in fetal abnormalities and embryo-fetal lethality at maternal exposures ≥ 2 times the human clinical exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA [see Use in Specific Populations (8.1, 8.3)and Clinical Pharmacology (12.1)] .

• Cerebrovascular and ischemic cardiovascular events occurred in patients receiving ERLEADA. Monitor for signs and symptoms of cerebrovascular disorders and ischemic heart disease. Optimize management of cardiovascular risk factors. ( 5.1).
• Fractures occurred in patients receiving ERLEADA. Evaluate patients for fracture risk and treat patients with bone-targeted agents according to established guidelines. ( 5.2)
• Falls occurred in patients receiving ERLEADA with increased incidence in the elderly. Evaluate patients for fall risk. ( 5.3)
• Seizure occurred in 0.4% of patients receiving ERLEADA. Permanently discontinue ERLEADA in patients who develop a seizure during treatment. ( 5.4)
• Severe Cutaneous Adverse Reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), occurred in patients treated with ERLEADA. Interrupt ERLEADA if signs or symptoms of SCARs develop. Permanently discontinue if SCARs are confirmed. ( 5.5)
• Interstitial Lung Disease (ILD)/pneumonitis occurred in patients treated with ERLEADA. Withhold ERLEADA for suspected ILD/pneumonitis. Permanently discontinue ERLEADA in patients with severe ILD/pneumonitis or if no other potential causes of ILD/pneumonitis are identified. ( 2.2, 5.6)
• Embryo-Fetal Toxicity: ERLEADA can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception. ( 5.7, 8.1, 8.3)

ERLEADA 240 mg administered orally once daily. Swallow tablets whole. ERLEADA can be taken with or without food. ( 2.1, 2.3)

Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.1)

Tablets:

• 240 mg: bluish grey to grey, oval, film-coated and debossed with "E240" on one side.
• 60 mg: slightly yellowish to greyish green, oblong, film-coated and debossed with "AR 60" on one side.

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 most common adverse reactions (≥ 10%) that occurred more frequently in the ERLEADA-treated patients (≥ 2% over placebo) from the randomized placebo-controlled clinical trials (TITAN and SPARTAN) were fatigue, arthralgia, rash, decreased appetite, fall, weight decreased, hypertension, hot flush, diarrhea, and fracture.

The following additional adverse reactions have been identified during post-approval use of ERLEADA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Respiratory, Thoracic and Mediastinal Disorders:interstitial lung disease/pneumonitis [see Warnings and Precautions (5.6)]

Skin and Subcutaneous Tissue Disorders:Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS).

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

ERLEADA ^®(apalutamide) tablets are available in the strengths and packages listed below:

• ERLEADA ^®240 mg Tablets
  
  Film coated, bluish grey to grey, oval-shaped tablets debossed with "E240" on one side.
  
  NDC Number 59676‐604‐30 - 30 tablets available in bottles with a silica gel desiccant and has a child-resistant closure

• ERLEADA ^®60 mg Tablets
  
  Film coated, slightly yellowish to greyish green, oblong-shaped tablets debossed with "AR 60" on one side.
  
  NDC Number 59676‐600‐12 - 120 tablets available in bottles with a silica gel desiccant and has a child-resistant closure

Fatal and life-threatening cases of severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), occurred in patients receiving ERLEADA [see Adverse Reactions (6.2)] .

Monitor patients for the development of SCARs. Advise patients of the signs and symptoms of SCARs (e.g., a prodrome of fever, flu-like symptoms, mucosal lesions, progressive skin rash, or lymphadenopathy).

If a SCAR is suspected, interrupt ERLEADA until the etiology of the reaction has been determined. Consultation with a dermatologist is recommended. If a SCAR is confirmed, or for other grade 4 skin reactions, permanently discontinue ERLEADA [see Dosage and Administration (2.2)and Adverse Reactions (6.1)] .

Fatal and life-threatening interstitial lung disease (ILD) or pneumonitis can occur in patients treated with ERLEADA.

Post-marketing cases of ILD/pneumonitis, including fatal cases, occurred in patients treated with ERLEADA. Across clinical trials (TITAN and SPARTAN, n=1327), 0.8% of patients treated with ERLEADA experienced ILD/pneumonitis, including 0.2% who experienced Grade 3 events [see Adverse Reactions (6.1, 6.2)].

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold ERLEADA if ILD/pneumonitis is suspected.

Permanently discontinue ERLEADA in patients with severe ILD/pneumonitis or if no other potential causes of ILD/pneumonitis are identified [see Dosage and Administration (2.2)] .

NDC 59676-600-12

Erleada ^®

(apalutamide) tablets

60 mg

Each film-coated tablet

contains 60 mg of apalutamide.

This package is child-resistant.

Keep out of reach of children.

Rx only

120 film-coated

tablets

NDC 59676-604-30

Erleada ^®

(apalutamide) tablets

240 mg

Each film-coated tablet contains

240 mg of apalutamide.

This package is child-resistant.

Keep out of reach of children.

Rx only

30 film-coated tablets

Cerebrovascular and ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA. Monitor for signs and symptoms of ischemic heart disease and cerebrovascular disorders. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Consider discontinuation of ERLEADA for Grade 3 and 4 events.

In a randomized study (SPARTAN) of patients with nmCRPC, ischemic cardiovascular events occurred in 3.7% of patients treated with ERLEADA and 2% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4.4% of patients treated with ERLEADA and 1.5% of patients treated with placebo. Across the SPARTAN and TITAN studies, 4 patients (0.3%) treated with ERLEADA, and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event.

In the SPARTAN study, cerebrovascular events occurred in 2.5% of patients treated with ERLEADA and 1% of patients treated with placebo [see Adverse Reactions (6.1)] . In the TITAN study, cerebrovascular events occurred in 1.9% of patients treated with ERLEADA and 2.1% of patients treated with placebo. Across the SPARTAN and TITAN studies, 3 patients (0.2%) treated with ERLEADA, and 2 patients (0.2%) treated with placebo died from a cerebrovascular event.

Patients with history of unstable angina, myocardial infarction, congestive heart failure, stroke, or transient ischemic attack within six months of randomization were excluded from the SPARTAN and TITAN studies.

In a 2-year carcinogenicity study in male rats, apalutamide was administered by oral gavage at doses of 5, 15 and 50 mg/kg/day. Apalutamide increased the incidence of Leydig interstitial cell adenoma in the testes at doses ≥ 5 mg/kg/day (0.2 times the human exposure based on AUC). The findings in the testes are considered to be related to the pharmacological activity of apalutamide. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Oral administration of apalutamide to male rasH2 transgenic mice for 6 months did not result in increased incidence of neoplasms at doses up to 30 mg/kg/day.

Apalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either in vitrochromosome aberration assay or the in vivorat bone marrow micronucleus assay or the in vivorat Comet assay.

In repeat-dose toxicity studies in male rats (up to 26 weeks) and dogs (up to 39 weeks), atrophy of the prostate gland and seminal vesicles, aspermia/hypospermia, tubular degeneration and/or hyperplasia or hypertrophy of the interstitial cells in the reproductive system were observed at ≥ 25 mg/kg/day in rats (1.4 times the human exposure based on AUC) and ≥ 2.5 mg/kg/day in dogs (0.9 times the human exposure based on AUC).

In a fertility study in male rats, a decrease in sperm concentration and motility, increased abnormal sperm morphology, lower copulation and fertility rates (upon pairing with untreated females) along with reduced weights of the secondary sex glands and epididymis were observed following 4 weeks of dosing at ≥ 25 mg/kg/day (0.8 times the human exposure based on AUC). A reduced number of live fetuses due to increased pre- and/or post-implantation loss was observed following 4 weeks of 150 mg/kg/day administration (5.7 times the human exposure based on AUC). Effects on male rats were reversible after 8 weeks from the last apalutamide administration.