17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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

Dosage and Administration

• Inform patients receiving concomitant gonadotropin-releasing hormone (GnRH) analog therapy that they need to maintain this treatment during the course of treatment with ERLEADA.
• Instruct patients to take their dose at the same time each day (once daily). ERLEADA can be taken with or without food. Each tablet should be swallowed whole. Do not crush or split tablets [see Dosage and Administration (2.1)].
• Instruct patients who cannot swallow tablets whole to follow the instructions for the prescribed strength of ERLEADA tablets for alternate methods of administration [see Dosage and Administration (2.3)].
• Instruct patients on administration of the ERLEADA 240 mg tablet through a feeding tube [see Dosage and Administration (2.3)].
• Inform patients that in the event of a missed daily dose of ERLEADA, they should take their normal dose as soon as possible on the same day with a return to the normal schedule on the following day. The patient should not take extra tablets to make up the missed dose [see Dosage and Administration (2.1)].

Newly added subsection:

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)].

Additions and revisions underlined:

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)].

Additions and revisions underlined:

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

Newly added information:

Severe Cutaneous Adverse Reactions (SCARs)

• Inform patients that ERLEADA has been associated with SCARs (including SJS/TEN and DRESS), which can be life-threatening or fatal. Advise patients to stop taking ERLEADA and contact their healthcare provider or seek medical attention right away if they experience signs or symptoms of SCARs [see Warnings and Precautions (5.5)].

Newly added information:

• Severe skin reactions. Treatment with ERLEADA may cause severe skin reactions that can be life-threatening or may lead to death. Stop taking ERLEADA and get medical help right away if you develop any of these signs or symptoms of a severe skin reaction:

  • severe rash or rash that continues to get worse

  • blisters or sores in the mouth, throat, nose, eyes, or genital area

  • fever or flu-like symptoms                                                  

  • swollen lymph nodes                                                    

  • blistering or peeling of the skin

. . .

Your healthcare provider may reduce your dose, temporarily stop, or permanently stop treatment with ERLEADA if you have certain side effects.

. . .

• The ERLEADA bottle comes with a child-resistant closure.

5.1 Cerebrovascular and Ischemic Cardiovascular Events

(Additions and/or revisions are underlined)

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.

5.2 Fractures

(Additions and/or revisions are underlined)

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%...

6.1 Clinical Trial Experience

(Additions and/or revisions are underlined)

Metastatic Castration-sensitive Prostate Cancer (mCSPC)

TITAN, a randomized (1:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had mCSPC…

Ten patients (1.9%) who were treated with ERLEADA died from adverse reactions. The reasons for death were ischemic cardiovascular events (n=3), acute kidney injury (n=2), cardio-respiratory arrest (n=1), sudden cardiac death (n=1), respiratory failure (n=1), cerebrovascular accident (n=1), and large intestinal ulcer perforation (n=1). ERLEADA was discontinued due to adverse reactions in 8% of patients, most commonly from rash (2.3%)…

Table 1 shows adverse reactions occurring in greater than or equal to 10% on the ERLEADA arm in TITAN that occurred with a greater than or equal to 2% absolute increase in frequency compared to placebo…

Additional adverse reactions of interest occurring in 2%, but less than 10% of patients treated with ERLEADA included diarrhea (9% versus 6% on placebo), muscle spasm (3.1% versus 1.9% on placebo), dysgeusia (3.2% versus 0.6% on placebo), and hypothyroidism (3.6% versus 0.6% on placebo).

Non-metastatic Castration-resistant Prostate Cancer (nmCRPC)

Twenty-four patients (3%) who were treated with ERLEADA died from adverse reactions. The reasons for death with greater than or equal to 2 patients included infection (n=7), myocardial infarction (n=3), cerebrovascular event (n=2), and unknown reason (n=3). ERLEADA was discontinued due to adverse reactions in 11% of patients, most commonly from rash (3.2%). Adverse reactions leading to dose interruption or reduction of ERLEADA occurred in 33% of patients; the most common (>1%) were rash, diarrhea, fatigue, nausea, vomiting, hypertension, and hematuria. Serious adverse reactions occurred in 25% of ERLEADA-treated patients and 23% in patients receiving placebo. The most frequent serious adverse reactions (>2%) were fracture (3.4%) in the ERLEADA arm and urinary retention (3.8%) in the placebo arm.

Additional clinically significant adverse reactions occurring in 2% or more of patients treated with ERLEADA included hypothyroidism (8% versus 2% on placebo), pruritus (6% versus 1.5% on placebo), and heart failure (2.2% versus 1% on placebo).

Hypothyroidism

In the combined data of two randomized, placebo-controlled clinical studies, SPARTAN and TITAN, hypothyroidism was reported for 8% of patients treated with ERLEADA and 1.5% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months. Elevated TSH occurred in 25% of patients treated with ERLEADA and 7% of patients treated with placebo. The median onset was at the first scheduled assessment. There were no Grade 3 or 4 adverse reactions. Thyroid replacement therapy was initiated in 4.9% of patients treated with ERLEADA…

(Additions and/or revisions underlined)

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 greater than or equal to 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)].

(Additions and/or revisions underlined)

Risk Summary

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 [see Clinical Pharmacology (12.1)]. There are no available data on ERLEADA use in pregnant women to inform a drug-associated risk. 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 greater than or equal to 2 times the human clinical exposure (AUC) at the recommended dose (see Data).

Data

Animal Data

In a pilot embryo-fetal developmental toxicity study in rats, apalutamide caused developmental toxicity when administered at oral doses of 25, 50 or 100 mg/kg/day throughout and after the period of organogenesis (gestational days 6-20). Findings included embryo-fetal lethality (resorptions) at doses greater than or equal to 50 mg/kg/day, decreased fetal anogenital distance, misshapen pituitary gland, and skeletal variations (unossified phalanges, supernumerary short thoracolumbar rib(s), and small, incomplete ossification, and/or misshapen hyoid bone) at greater than or equal to 25 mg/kg/day. A dose of 100 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 2, 4 and 6 times, respectively, the AUC in patients.

Additions and/or revisions underlined:

5.1 Cerebrovascular and Ischemic Cardiovascular Events

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 …

… In the SPARTAN study, cerebrovascular events occurred in 4.7% of patients treated with ERLEADA and 0.8% of patients treated with placebo [see Clinical Trials Experience (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.

Additions and/or revisions underlined:

• Cerebrovascular and Ischemic Cardiovascular Events [see Warnings and Precautions (5.1)].

6.1 Clinical Trials Experience

Non-metastatic Castration-resistant Prostate Cancer (nmCRPC)

Additions and/or revisions underlined:

SPARTAN, a randomized (2:1), double-blind, placebo-controlled, multi-center clinical study, enrolled patients who had nmCRPC. In this study, patients received either ERLEADA at a dose of 240 mg daily or a placebo. All patients in the SPARTAN study received a concomitant gonadotropin-releasing hormone (GnRH) analog or had a bilateral orchiectomy. The median duration of exposure was 33 months (range: 0.1 to 75 months) in patients who received ERLEADA and 11 months (range: 0.1 to 37 months) in patients who received placebo.

Twenty-four patients (3%) who were treated with ERLEADA died from adverse reactions. The reasons for death with greater than or equal to 2 patients included infection (n=7), myocardial infarction (n=3), cerebrovascular event (n=2), and unknown reason (n=3). ERLEADA was discontinued due to …

Hypothyroidism

In the combined data of two randomized, placebo-controlled clinical studies, SPARTAN and TITAN, hypothyroidism was reported for 8% of patients treated with ERLEADA and 2% of patients treated with placebo based on assessments of thyroid-stimulating hormone (TSH) every 4 months.

Additions and/or revisions underlined:

What are the possible side effects of ERLEADA?

ERLEADA may cause serious side effects including:

• Heart disease, stroke, or mini-stroke. Bleeding in the brain or blockage of the arteries in the heart or in part of the brain have happened in some people during treatment with ERLEADA and can lead to death. Your healthcare provider will monitor you for signs and symptoms of heart or brain problems during your treatment with ERLEADA.

Call your healthcare provider or get medical help right away if you get:

• chest pain or discomfort at rest or with activity

• shortness of breath

• numbness or weakness of the face, arm, or leg, especially on one side of the body

• trouble talking or understanding

• trouble seeing in one or both eyes

• dizziness, loss of balance or coordination, or trouble walking

Additions and/or revisions underlined:

Cerebrovascular and Ischemic Cardiovascular Events

• Inform patients that ERLEADA has been associated with cerebrovascular and ischemic cardiovascular events. Advise patients to seek immediate medical attention if any symptoms suggestive of a cardiovascular or a cerebrovascular event occur [see Warnings and Precautions (5.1)].

(Additions and/or revisions underlined)

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

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome/toxic epidermal necrolysis

(New subsection added)

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

(Additions underlined)

…

• Instruct patients who have difficulty swallowing tablets whole to mix the recommended dose of ERLEADA tablets with applesauce. Do not crush tablets [see Dosage and Administration (2.3)].

…

PATIENT INFORMATION

(Additions underlined)

…

How should I take ERLEADA?

…

• If you are unable to swallow ERLEADA tablets whole, you may:

• Place your dose of ERLEADA in a container that contains 4 ounces (120 mL) of applesauce and stir. Do not crush the tablets.

• Wait 15 minutes and stir the mixture.

(new subsection added)

Ischemic cardiovascular events, including events leading to death, occurred in patients receiving ERLEADA. Monitor for signs and symptoms of ischemic heart disease. 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 4% of patients treated with ERLEADA and 3% of patients treated with placebo. In a randomized study (TITAN) in patients with mCSPC, ischemic cardiovascular events occurred in 4% of patients treated with ERLEADA and 2% of patients treated with placebo. Across the SPARTAN and TITAN studies, 6 patients (0.5%) treated with ERLEADA and 2 patients (0.2%) treated with placebo died from an ischemic cardiovascular event. Patients with current evidence of unstable angina, myocardial infarction, or congestive heart failure within six months of randomization were excluded from the SPARTAN and TITAN studies.

(subsection revised, additions underlined)

…

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 3% of patients treated with ERLEADA and in 1% of patients treated with placebo.

…

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 2%. 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.

(new subsection created)

Falls occurred in patients receiving ERLEADA with increased frequency in the elderly. 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.

(subsection revised, additions and revisions underlined)

…

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.

(new subsection added)

The safety and efficacy of ERLEADA have not been established in females. Based on its mechanism of action, ERLEADA can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA.

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

• Ischemic Cardiovascular Events

…

(extensive additions, please refer to label)

(subsection revised, additions and revisions underlined)

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.

(additions underlined)

…

Ischemic Cardiovascular Events

• Inform patients that ERLEADA has been associated with ischemic cardiovascular events. Advise patients to seek immediate medical attention if any symptoms suggestive of a cardiovascular event occur.

…

Embryo-Fetal Toxicity

Inform patients that ERLEADA can be harmful to a developing fetus. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of ERLEADA. Advise male patients to use a condom if having sex with a pregnant woman.

…

(additions underlined)

ERLEADA is a prescription medicine used for the treatment of prostate cancer:

• that has spread to other parts of the body and still responds to a medical or surgical treatment that lowers testosterone, OR

• that has not spread to other parts of the body and no longer responds to a medical or surgical treatment that lowers testosterone.

   

  It is not known if ERLEADA is safe and effective in females.

  It is not known if ERLEADA is safe and effective in children.

   

  Before taking ERLEADA, tell your healthcare provider about all your medical conditions, including if you:

• have a history of heart disease

• have high blood pressure

• have diabetes

• have abnormal amounts of fat or cholesterol in your blood (dyslipidemia)

• have a history of seizures, brain injury, stroke, or brain tumors

• are pregnant or plan to become pregnant. ERLEADA can cause harm to your unborn baby and loss of pregnancy (miscarriage).

  ...

• are breastfeeding or plan to breastfeed. It is not known if ERLEADA passes into breast milk.

   

  …

  What are the possible side effects of ERLEADA?

  ERLEADA may cause serious side effects including:

• Heart Disease. Blockage of the arteries in the heart that can lead to death has happened in some people during treatment with ERLEADA. Your healthcare provider will monitor you for signs and symptoms of heart problems during your treatment with ERLEADA. Call your healthcare provider or go to the nearest emergency room right away if you get chest pain or discomfort at rest or with activity, or shortness of breath during your treatment with ERLEADA.

…