ABIRATERONE: 34,511 Adverse Event Reports & Safety Profile

AKEEGA ® (niraparib and abiraterone acetate) tablets contain niraparib tosylate (as the monohydrate) and abiraterone acetate.

Niraparib

Niraparib is a poly (ADP-ribose) polymerase (PARP) inhibitor. The chemical name for niraparib tosylate monohydrate is 2-{4-[(3S)-piperidin-3-yl]phenyl}- 2H -indazole 7-carboxamide 4-methylbenzenesulfonate hydrate (1:1:1). The molecular formula is C 26 H 30 N 4 O 5 S and it has a molecular weight of 510.61 g/mol. The molecular structure is shown below: Niraparib tosylate monohydrate is a white to off-white, non-hygroscopic crystalline solid. Niraparib tosylate monohydrate is highly soluble in aqueous media over the pH range 1.2 to 6.8 (1.65–1.77 mg/mL determined at 37 ± 1°C).

Chemical Structure Abiraterone Acetate

Abiraterone acetate is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Its molecular formula is C 26 H 33 N O 2 and it has a molecular weight of 391.55 g/mol. Abiraterone acetate is designated chemically as (3β)-17-(3-pyridinyl) androsta-5,16-dien-3-yl acetate and its structure is: Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19. AKEEGA tablets are supplied as 50 mg/500 mg niraparib/abiraterone acetate and 100 mg/500 mg niraparib/abiraterone acetate film-coated tablets for oral administration. Each AKEEGA tablet (50 mg/500 mg) contains 50 mg of niraparib (equivalent to 76.9 mg niraparib tosylate) and 500 mg of abiraterone acetate. Each AKEEGA tablet (100 mg/500 mg) contains 100 mg of niraparib (equivalent to 153.7 mg niraparib tosylate) and 500 mg of abiraterone acetate. AKEEGA tablet core contains the following inactive ingredients: colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, sodium lauryl sulfate.

The

50 mg/500 mg tablets are finished with film-coating comprising the following inactive ingredients: iron oxide black, iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide.

The

100 mg/500 mg tablets are finished with film-coating comprising the following inactive ingredients: iron oxide red, iron oxide yellow, sodium lauryl sulphate, glycerol monocaprylocaprate, polyvinyl alcohol, talc, and titanium dioxide.

Chemical

Structure

AND USAGE AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA2 -mutated ( BRCA2 m) metastatic castration-sensitive prostate cancer (mCSPC). AKEEGA with prednisone is indicated for the treatment of adult patients with deleterious or suspected deleterious BRCA -mutated ( BRCA m) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved test for AKEEGA [see Dosage and Administration (2.1) ] . AKEEGA is a combination of niraparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, and abiraterone acetate, a CYP17 inhibitor indicated with prednisone for the treatment of adult patients with: deleterious or suspected deleterious BRCA2 -mutated ( BRCA2 m) metastatic castration-sensitive prostate cancer (mCSPC). deleterious or suspected deleterious BRCA -mutated ( BRCA m) metastatic castration-resistant prostate cancer (mCRPC). Select patients for therapy based on an FDA-approved test for AKEEGA. ( 1 , 2.1 )

AND ADMINISTRATION BRCA2 m mCSPC: The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 5 mg prednisone daily until disease progression or unacceptable toxicity. ( 2.2 ) BRCA m mCRPC : The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone daily until disease progression or unacceptable toxicity. ( 2.2 ) Patients receiving AKEEGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.2 ) Take AKEEGA on an empty stomach at least one hour before or two hours after food. ( 2.2 ) For adverse reactions, consider interruption of treatment, dose reduction, or dose discontinuation. ( 2.3 )

2.1 Patient Selection Select patients for the treatment of mCSPC with AKEEGA based on the presence of a BRCA2 gene alteration <span class="opacity-50 text-xs">[see Clinical Studies (14.1) ]</span> . Select patients for the treatment of mCRPC with AKEEGA based on the presence of a BRCA gene alteration <span class="opacity-50 text-xs">[see Clinical Studies (14.2) ]</span> . Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosage BRCA2- mutated ( BRCA2 m)

Metastatic

Castration-Sensitive Prostate Cancer (mCSPC) The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 5 mg prednisone once daily until disease progression or unacceptable toxicity. BRCA -mutated ( BRCA m)

Metastatic

Castration-Resistant Prostate Cancer (mCRPC) The recommended dosage of AKEEGA is 200 mg niraparib/1,000 mg abiraterone acetate orally once daily in combination with 10 mg prednisone once daily until disease progression or unacceptable toxicity. Patients receiving AKEEGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Take AKEEGA on an empty stomach at least one hour before or two hours after food. Swallow tablets whole with water. Do not break, crush, or chew tablets. If a patient misses a dose, instruct patients to take the dose as soon as possible on the same day and resume their next dose at the normal schedule the following day.

2.3 Dosage Modification for Adverse Reactions The recommended dosage modifications for AKEEGA are provided in Table 1. Treatment with AKEEGA should not be reinitiated until the toxicity has resolved to Grade 1 or baseline. If the toxicity is attributed to one component of AKEEGA, the other component of AKEEGA may be continued as a single agent at the current dose until the adverse reaction resolves and AKEEGA can be resumed (see Table 1 ).

Table

1: Dosage Modifications for Adverse Reactions Adverse Reaction Severity Dosage Modification Myelosuppression [see Warnings and Precautions (5.2) ] Hemoglobin <8 g/dL Withhold AKEEGA and monitor blood counts weekly. When hemoglobin returns to ≥9 g/dL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated. Permanently discontinue AKEEGA if hemoglobin has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg/1,000 mg once daily. If myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) is confirmed, discontinue AKEEGA [see Warnings and Precautions (5.1)]. Platelet count <100,000/mcL First occurrence: Withhold AKEEGA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL. Resume AKEEGA at same or the reduced dose of 100 mg/1,000 mg once daily. If platelet count is <75,000/mcL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Second occurrence: Withhold AKEEGA for a maximum of 28 days and monitor blood counts weekly until platelet counts return to ≥100,000/mcL. Resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Permanently discontinue AKEEGA if the platelet count has not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg/1,000 mg once daily. Neutrophil <1,000/mcL Withhold AKEEGA and monitor blood counts weekly. When neutrophil counts return to ≥1,500/mcL, resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily and monitor blood counts weekly for 28 days and as clinically indicated. Permanently discontinue AKEEGA if neutrophils have not returned to acceptable levels within 28 days of the dose interruption period or if the patient has already undergone dose reduction to 100 mg/1,000 mg once daily. Hematologic adverse reaction requiring transfusion Consider platelet transfusion for patients with platelet count ≤10,000/mcL. If there are other risk factors such as coadministration of anticoagulation or antiplatelet drugs, consider interrupting these drugs and/or transfusion at a higher platelet count. Resume at the reduced dose of AKEEGA 100 mg/1,000 mg once daily. Hepatotoxicity [see Warnings and Precautions (5.4) ] ALT and/or AST greater than 5 × ULN or total bilirubin greater than 3 × ULN Withhold AKEEGA and closely monitor liver function. Permanently discontinue AKEEGA if: ALT or AST ≥ 20 times the ULN – OR– ALT > 3 × ULN and total bilirubin > 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation -OR- Hepatotoxicity recurs at the reduced dose 100 mg/500 mg. When AST and ALT resolves to less ≤ 2.5 × ULN and total bilirubin ≤ 1.5 × ULN, AKEEGA may be resumed at the reduced dose of 100 mg/500 mg once daily. When resumed, monitor serum transaminases every two weeks for three months, monthly thereafter, and as clinically indicated. Other non-hematological adverse reactions that persist despite medical management [see Warnings and Precautions (5) and Adverse Reactions (6.1) ]

Grade

3 or 4 Discontinue AKEEGA in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions [see Warnings and Precautions (5.3)]. Withhold AKEEGA until resolution of adverse reaction or for a maximum of 28 days. If resolves in 28 days or less, AKEEGA may be resumed at the reduced dose. Permanently discontinue AKEEGA if adverse reaction(s) has not resolved after 28 days or Grade 3 or 4 adverse reaction reoccurs after dose reduction.

Pregnancy Abiraterone acetate can cause fetal harm and potential loss of pregnancy [see Use in Specific Populations (8.1) ]. Pregnancy. (4, 8.1)

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

• Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions due to Mineralocorticoid Excess [see Warnings and Precautions (5.1) ] .
• Adrenocortical Insufficiency [see Warnings and Precautions (5.2) ] .
• Hepatotoxicity [see Warnings and Precautions (5.3) ] .
• Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride [see Warnings and Precautions (5.4) ] . The most common adverse reactions (≥ 10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache. ( 6.1 ) The most common laboratory abnormalities (> 20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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 clinical practice. Two randomized placebo-controlled, multicenter clinical trials (COU-AA-301 and COU-AA¬302) enrolled patients who had metastatic CRPC in which abiraterone acetate tablets were administered orally at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to patients on the control arm. A third randomized placebo-controlled, multicenter clinical trial (LATITUDE) enrolled patients who had metastatic high-risk CSPC in which abiraterone acetate tablets were administered at a dose of 1,000 mg daily in combination with prednisone 5 mg once daily. Placebos were administered to patients in the control arm. Additionally, two other randomized, placebo-controlled trials were conducted in patients with metastatic CRPC. The safety data pooled from 2230 patients in the 5 randomized controlled trials constitute the basis for the data presented in the Warnings and Precautions, Grade 1-4 adverse reactions, and Grade 1-4 laboratory abnormalities. In all trials, a gonadotropin-releasing hormone (GnRH) analog or prior orchiectomy was required in both arms. In the pooled data, median treatment duration was 11 months (0.1, 43) for abiraterone acetate tablets-treated patients and 7.2 months (0.1, 43) for placebo-treated patients. The most common adverse reactions (≥ 10%) that occurred more commonly (&gt; 2%) in the abiraterone acetate tablets arm were fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache. The most common laboratory abnormalities (&gt; 20%) that occurred more commonly (≥ 2%) in the abiraterone acetate tablets arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia.

Grades

3-4 adverse events were reported for 53% of patients in the abiraterone acetate tablets arm and 46% of patients in the placebo arm. Treatment discontinuation was reported in 14% of patients in the abiraterone acetate tablets arm and 13% of patients in the placebo arm. The common adverse events (≥ 1%) resulting in discontinuation of abiraterone acetate tablets and prednisone were hepatotoxicity and cardiac disorders. Deaths associated with treatment-emergent adverse events were reported for 7.5% of patients in the abiraterone acetate tablets arm and 6.6% of patients in the placebo arm. Of the patients in the abiraterone acetate tablets arm, the most common cause of death was disease progression (3.3%). Other reported causes of death in ≥ 5 patients included pneumonia, cardio-respiratory arrest, death (no additional information), and general physical health deterioration. COU-AA-301 Metastatic CRPC Following Chemotherapy COU-AA-301 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥ 2.5 x ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT > 5 x ULN.

Table

1 shows adverse reactions on the abiraterone acetate tablets arm in COU-AA-301 that occurred with a ≥ 2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with abiraterone acetate tablets with prednisone was 8 months.

Table

1: Adverse Reactions due to Abiraterone Acetate Tablets in COU-AA-301 System/Organ Class Abiraterone Acetate Tablets with Prednisone (N = 791) Placebo with Prednisone (N = 394)

All Grades

Adverse events graded according to CTCAE version 3.0.

Grade

3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. 30 4.2 23

4.1 Muscle discomfort Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness. 26 3.0 23

2.3 General disorders Edema Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema. 27 1.9 18

0.8 Vascular disorders Hot flush 19 0.3 17

0.3 Hypertension 8.5 1.3 6.9

0.3 Gastrointestinal disorders Diarrhea 18 0.6 14

1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 12 2.1 7.1

0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 11 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1

0.3 Nocturia 6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures Includes all fractures with the exception of pathological fracture. 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia. 7.2 1.1 4.6

1.0 Chest pain or chest discomfort Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the abiraterone acetate tablets arm (1.3% vs. 1.1% respectively). 3.8 0.5 2.8 0 Cardiac failure Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased. 2.3 1.9 1.0

0.3 Table 2 shows laboratory abnormalities of interest from COU-AA-301.

Table

2: Laboratory Abnormalities of Interest in COU-AA-301 Abiraterone Acetate Tablets with Prednisone (N = 791) Placebo with Prednisone (N = 394)

Laboratory Abnormality All

Grades (%)

Grade

3-4 (%)

All

Grades (%)

Grade

3-4 (%)

Hypertriglyceridemia

63 0.4 53 0 High AST 31 2.1 36

1.5 Hypokalemia 28 5.3 20

1.0 Hypophosphatemia 24 7.2 16

5.8 High ALT 11 1.4 10

0.8 High Total Bilirubin 6.6 0.1 4.6 0 COU-AA-302 Metastatic CRPC Prior to Chemotherapy COU-AA-302 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5 x ULN and patients were excluded if they had liver metastases.

Table

3 shows adverse reactions on the abiraterone acetate tablets arm in COU-AA-302 that occurred in ≥ 5% of patients with a ≥ 2% absolute increase in frequency compared to placebo. The median duration of treatment with abiraterone acetate tablets with prednisone was 13.8 months.

Table

3: Adverse Reactions in ≥ 5% of Patients on the Abiraterone Acetate Tablets Arm in COU-AA-302 System/Organ Class Abiraterone Acetate Tablets with Prednisone (N = 542) Placebo with Prednisone (N = 540)

All Grades

Adverse events graded according to CTCAE version 3.0.

Grade

3-4 All Grades Grade 3-4 Adverse reaction % % % % General disorders Fatigue 39 2.2 34

1.7 Edema Includes terms Edema peripheral, Pitting edema, and Generalized edema. 25 0.4 21

1.1 Pyrexia 8.7 0.6 5.9

0.2 Musculoskeletal and connective tissue disorders Joint swelling/discomfort Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. 30 2.0 25

2.0 Groin pain 6.6 0.4 4.1

0.7 Gastrointestinal disorders Constipation 23 0.4 19

0.6 Diarrhea 22 0.9 18

0.9 Dyspepsia 11 0.0 5.0

0.2 Vascular disorders Hot flush 22 0.2 18

0.0 Hypertension 22 3.9 13

3.0 Respiratory, thoracic and mediastinal disorders Cough 17 0.0 14

0.2 Dyspnea 12 2.4 9.6

0.9 Psychiatric disorders Insomnia 14 0.2 11

0.0 Injury, poisoning and procedural complications Contusion 13 0.0 9.1

0.0 Falls 5.9 0.0 3.3

0.0 Infections and infestations Upper respiratory tract infection 13 0.0 8.0

0.0 Nasopharyngitis 11 0.0 8.1

0.0 Renal and urinary disorders Hematuria 10 1.3 5.6

0.6 Skin and subcutaneous tissue disorders Rash 8.1 0.0 3.7

0.0 Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (&gt; 5%) in the abiraterone acetate tablets arm compared to placebo in COU-AA-302.

Table

4: Laboratory Abnormalities in > 15% of Patients in the Abiraterone Acetate Tablets Arm of COU-AA-302 Abiraterone Acetate Tablets with Prednisone (N = 542) Placebo with Prednisone (N = 540)

Laboratory Abnormality Grade

1-4 % Grade 3-4 % Grade 1-4 % Grade 3-4 % Hematology Lymphopenia 38 8.7 32

7.4 Chemistry Hyperglycemia Based on non-fasting blood draws 57 6.5 51

5.2 High ALT 42 6.1 29

0.7 High AST 37 3.1 29

1.1 Hypernatremia 33 0.4 25

0.2 Hypokalemia 17 2.8 10

1.7 LATITUDE Patients with Metastatic High-Risk CSPC LATITUDE enrolled 1199 patients with newly-diagnosed metastatic, high-risk CSPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5 x ULN or if they had liver metastases. All the patients received GnRH analogs or had prior bilateral orchiectomy during the trial. The median duration of treatment with abiraterone acetate tablets and prednisone was 24 months.

Table

5 shows adverse reactions on the abiraterone acetate tablets arm that occurred in ≥ 5% of patients with a ≥ 2% absolute increase in frequency compared to those on the placebos arm.

Table

5: Adverse Reactions in ≥ 5% of Patients on the Abiraterone Acetate Tablets Arm in LATITUDE All patients were receiving an GnRH agonist or had undergone orchiectomy.

System/Organ

Class Adverse reaction Abiraterone Acetate Tablets with Prednisone (N = 597) Placebos (N = 602)

All Grades

Adverse events graded according to CTCAE version 4.0 % Grade 3-4 % All Grades % Grade 3-4 % Vascular disorders Hypertension 37 20 13 10 Hot flush 15 0.0 13

0.2 Metabolism and nutrition disorders Hypokalemia 20 10 3.7

1.3 Investigations Alanine aminotransferase increased Reported as an adverse event or reaction 16 5.5 13

1.3 Aspartate aminotransferase increased 15 4.4 11

1.5 Infections and infestations Urinary tract infection 7.0 1.0 3.7

0.8 Upper respiratory tract infection 6.7 0.2 4.7

0.2 Nervous system disorders Headache 7.5 0.3 5.0

0.2 Respiratory, Thoracic and Mediastinal Disorders Cough Including cough, productive cough, upper airway cough syndrome 6.5 0.0 3.2 0 Table 6 shows laboratory abnormalities that occurred in ≥ 15% of patients, and more frequently (&gt; 5%) in the abiraterone acetate tablets arm compared to placebos.

Table

6: Laboratory Abnormalities in > 15% of Patients in the Abiraterone Acetate Tablets Arm of LATITUDE Laboratory Abnormality Abiraterone Acetate Tablets with Prednisone (N = 597) Placebos (N= 602)

Grade

1-4 % Grade 3-4 % Grade 1-4 % Grade 3-4 % Hematology Lymphopenia 20 4.1 14

1.8 Chemistry Hypokalemia 30 9.6 6.7

1.3 Elevated ALT 46 6.4 45

1.3 Elevated total bilirubin 16 0.2 6.2

0.2 Cardiovascular Adverse Reactions In the combined data of 5 randomized, placebo-controlled clinical studies, cardiac failure occurred more commonly in patients on the abiraterone acetate tablets arm compared to patients on the placebo arm (2.6% versus 0.9%).

Grade

3-4 cardiac failure occurred in 1.3% of patients taking abiraterone acetate tablets and led to 5 treatment discontinuations and 4 deaths.

Grade

3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and two deaths due to cardiac failure in the placebo group. In the same combined data, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and three patients with sudden death in the abiraterone acetate tablets arms and five deaths in the placebo arms. There were 7 (0.3%) deaths due to cardiorespiratory arrest in the abiraterone acetate tablets arms and 2 (0.1%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 3 deaths in the abiraterone acetate tablets arms.

6.2 Postmarketing Experience The following additional adverse reactions have been identified during post approval use of abiraterone acetate tablets with prednisone. 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. Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis. Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

Hepatobiliary

Disorders: fulminant hepatitis, including acute hepatic failure and death.

Cardiac

Disorders: QT prolongation and Torsades de Pointes (observed in patients who developed hypokalemia or had underlying cardiovascular conditions).

Immune System

Disorders: Hypersensitivity: anaphylactic reactions (severe allergic reactions that include, but are not limited to difficulty swallowing or breathing, swollen face, lips, tongue or throat, or an itchy rash (urticaria)).

AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) : MDS/AML, including a case with fatal outcome, has been observed in patients treated with AKEEGA. Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed. ( 5.1 ) Myelosuppression: Test complete blood counts weekly for the first month, every two weeks for the next two months, monthly for the remainder of the first year, then every other month, and as clinically indicated. ( 2.3 , 5.2 ) Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions: Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention. Control hypertension and correct hypokalemia before and during treatment with AKEEGA. ( 5.3 ) Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue treatment as recommended. ( 2.3 , 5.4 ) Adrenocortical insufficiency : Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. ( 5.5 ) Hypoglycemia: Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide. Monitor blood glucose in patients with diabetes during and assess if antidiabetic agent dose modifications are required. ( 5.6 ) Increased fractures and mortality in combination with radium Ra 223 dichloride : Use of AKEEGA plus prednisone in combination with radium Ra 223 dichloride is not recommended. ( 5.7 )

Posterior Reversible Encephalopathy

Syndrome (PRES): PRES has been observed in patients treated with niraparib, a component of AKEEGA. Discontinue AKEEGA if PRES is confirmed. ( 5.8 ) Embryo-Fetal Toxicity: AKEEGA can cause fetal harm. Advise males with female partners of reproductive potential to use effective contraception. ( 5.9 , 8.1 , 8.3 )

5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia AKEEGA may cause myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). In the individual AMPLITUDE and MAGNITUDE studies, MDS or AML, including cases with fatal outcomes, were reported in 0.6% (2/347) and 0.5% (1/212) of patients treated with AKEEGA plus prednisone, respectively. All patients in other tumor types treated with niraparib, a component of AKEEGA, who developed secondary MDS/cancer-therapy-related AML had received previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy. For suspected MDS/AML or prolonged hematological toxicities, refer the patient to a hematologist for further evaluation. Discontinue AKEEGA if MDS/AML is confirmed.

5.2 Myelosuppression AKEEGA may cause myelosuppression (anemia, thrombocytopenia, or neutropenia). In AMPLITUDE, Grade 3–4 anemia, neutropenia, and thrombocytopenia were reported, respectively in 29%, 10%, and 4.9% of patients receiving AKEEGA. Overall, 25% of patients with anemia required a red blood cell transfusion, including 15% who required more than one transfusion. Discontinuation due to anemia occurred in 1.2% of patients. In MAGNITUDE Cohort 1, Grade 3–4 anemia, thrombocytopenia, and neutropenia were reported, respectively in 28%, 8%, and 7% of patients receiving AKEEGA. Overall, 27% of patients with anemia required a red blood cell transfusion, including 19.5% who required more than one transfusion. Discontinuation due to anemia occurred in 3% of patients. Monitor complete blood counts weekly during the first month of AKEEGA treatment, every two weeks for the next two months, monthly for the remainder of the first year and then every other month, and as clinically indicated. Do not start AKEEGA until patients have adequately recovered from hematologic toxicity caused by previous therapy. If hematologic toxicities do not resolve within 28 days following interruption, discontinue AKEEGA and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

5.3 Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions AKEEGA may cause hypokalemia and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.1) ]</span> . In post-marketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking abiraterone acetate, a component of AKEEGA. Hypertension and hypertensive crisis have also been reported in patients treated with niraparib, a component of AKEEGA. In AMPLITUDE, which used prednisone 5 mg daily in combination with AKEEGA, Grades 3–4 hypokalemia was detected in 9% of patients on the AKEEGA arm, and Grades 3–4 hypertension was observed in 30% of patients on the AKEEGA arm. In MAGNITUDE Cohort 1, which used prednisone 10 mg daily in combination with AKEEGA, Grade 3–4 hypokalemia was detected in 2.7% of patients on the AKEEGA arm and Grade 3–4 hypertension was observed in 14% of patients on the AKEEGA arm. Monitor patients for hypertension, hypokalemia, and fluid retention at least weekly for the first two months, then once a month. Closely monitor patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia, or fluid retention, such as those with heart failure, recent myocardial infarction, cardiovascular disease, or ventricular arrhythmia. Control hypertension and correct hypokalemia before and during treatment with AKEEGA. Discontinue AKEEGA in patients who develop hypertensive crisis or other severe cardiovascular adverse reactions. The safety of AKEEGA in patients with New York Heart Association (NYHA) Class II to IV heart failure has not been established because these patients were excluded from AMPLITUDE and MAGNITUDE.

5.4 Hepatotoxicity AKEEGA may cause hepatotoxicity. Hepatotoxicity in patients receiving abiraterone acetate, a component of AKEEGA, has been reported in clinical trials. In post-marketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure, and deaths. In AMPLITUDE, Grade 3–4 ALT or AST increases (at least 5 × ULN) were reported in 1.9% and 1.3% of patients, respectively. In MAGNITUDE Cohort 1, Grade 3–4 ALT or AST increases (at least 5 × ULN) were reported in 1.8% and 0.9% of patients, respectively. The safety of AKEEGA in patients with moderate or severe hepatic impairment has not been established as these patients were excluded from AMPLITUDE and MAGNITUDE. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with AKEEGA, every two weeks for the first three months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient&apos;s baseline should prompt more frequent monitoring and may require dosage modifications <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>. Permanently discontinue AKEEGA for patients who develop a concurrent elevation of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation, or in patients who develop ALT or AST ≥20 × ULN at any time after receiving AKEEGA.

5.5 Adrenocortical Insufficiency AKEEGA may cause adrenal insufficiency. Adrenocortical insufficiency has been reported in clinical trials in patients receiving abiraterone acetate, a component of AKEEGA, in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with abiraterone acetate. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased doses of corticosteroids may be indicated before, during, and after stressful situations.

5.6 Hypoglycemia AKEEGA may cause hypoglycemia in patients being treated with other medications for diabetes. Severe hypoglycemia has been reported when abiraterone acetate, a component of AKEEGA, was administered to patients receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span> . Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with AKEEGA. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

5.7 Increased Fractures and Mortality in Combination with Radium 223 Dichloride AKEEGA with prednisone is not recommended for use in combination with Ra-223 dichloride outside of clinical trials. The clinical efficacy and safety of concurrent initiation of abiraterone acetate plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) in 806 patients with asymptomatic or mildly symptomatic castration-resistant prostate cancer with bone metastases. The study was unblinded early based on an Independent Data Monitoring Committee recommendation. At the primary analysis, increased incidences of fractures (29% vs 11%) and deaths (39% vs 36%) have been observed in patients who received abiraterone acetate plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus prednisone. It is recommended that subsequent treatment with Ra-223 not be initiated for at least five days after the last administration of AKEEGA, in combination with prednisone.

5.8 Posterior Reversible Encephalopathy Syndrome AKEEGA may cause Posterior Reversible Encephalopathy Syndrome (PRES). PRES has been observed in patients treated with niraparib as a single agent at higher than the recommended dose of niraparib included in AKEEGA. Monitor all patients treated with AKEEGA for signs and symptoms of PRES. If PRES is suspected, promptly discontinue AKEEGA and administer appropriate treatment. The safety of reinitiating AKEEGA in patients previously experiencing PRES is not known.

5.9 Embryo-Fetal Toxicity The safety and efficacy of AKEEGA have not been established in females. Based on animal reproductive studies and mechanism of action, AKEEGA can cause fetal harm and loss of pregnancy when administered to a pregnant female <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.1) ]</span> . Niraparib has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1) ]</span> . In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis caused adverse developmental effects at maternal exposures approximately ≥ 0.03 times the human exposure (AUC) at the recommended dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the last dose of AKEEGA <span class="opacity-50 text-xs">[see Use in Specific Populations (8.1 , 8.3) ]</span> . Females who are or may become pregnant should handle AKEEGA with protection, e.g., gloves <span class="opacity-50 text-xs">[see How Supplied/Storage and Handling (16) ]</span>.

INTERACTIONS

• CYP3A4 Inducers: Avoid concomitant strong CYP3A4 inducers during abiraterone acetate tablets treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate tablets dosing frequency. ( 2.5 , 7.1 )
• CYP2D6 Substrates: Avoid co-administration of abiraterone acetate tablets with CYP2D6 substrates that have a narrow therapeutic index. If an alternative treatment cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate. ( 7.2 )

7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes Based on in vitro data, abiraterone acetate tablets are a substrate of CYP3A4. In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during abiraterone acetate tablets treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate tablets dosing frequency <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]</span> . In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> .

7.2 Effects of Abiraterone on Drug Metabolizing Enzymes Abiraterone acetate tablets are an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the C max and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone acetate tablets <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) and Warnings and Precautions (5.6) ]</span> .

Drug Interactions Studies Clinical Studies

Effect of Other Drugs on Abiraterone Acetate Tablets Strong CYP3A4 inducers: In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC ∞ of abiraterone was decreased by 55%. Strong CYP3A4 inhibitors: Co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone. Effect of Abiraterone Acetate Tablets on Other Drugs CYP2D6 substrates: The C max and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold. CYP1A2 substrates: When abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) was given with a single dose of 100 mg theophylline (CYP1A2 substrate), no increase in systemic exposure of theophylline was observed. CYP2C8 substrates: The AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given to healthy subjects with a single dose of 1,000 mg abiraterone acetate.

In Vitro Studies

Cytochrome P450 (CYP) Enzymes: Abiraterone is a substrate of CYP3A4 and has the potential to inhibit CYP1A2, CYP2D6, CYP2C8 and to a lesser extent CYP2C9, CYP2C19 and CYP3A4/5.

Transporter

Systems In vitro studies show that at clinically relevant concentrations, abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp. In vitro, abiraterone and its major metabolites were shown to inhibit the hepatic uptake transporter OATP1B1. There are no clinical data available to confirm transporter based interaction.