Abiraterone

Abiraterone acetate tablets are indicated in combination with prednisone for the treatment of patients with Metastatic castration-resistant prostate cancer (CRPC) Abiraterone acetate tablets are a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Metastatic castration-resistant prostate cancer: Abiraterone acetate tablets 1,000 mg orally once daily with prednisone 5 mg orally twice daily. Patients receiving abiraterone acetate tablets should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Abiraterone acetate tablets must be taken on an empty stomach with water at least 1 hour before or 2 hours after a meal. Do not crush or chew tablets. Dose Modification: For patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the abiraterone acetate tablets starting dose to 250 mg once daily. For patients who develop hepatotoxicity during treatment, hold abiraterone acetate tablets until recovery. Retreatment may be initiated at a reduced dose. Abiraterone acetate tablets should be discontinued if patients develop severe hepatotoxicity.

2.1Recommended Dose for

metastatic CRPC The recommended dose of abiraterone acetate tablets are 1,000 mg (four 250 mg tablets) orally once daily with prednisone 5 mg orally twice daily.

2.3Important Administration Instructions Patients

receiving abiraterone acetate tablets should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. Abiraterone acetate tablets must be taken on an empty stomach, either one hour before or two hours after a meal . The tablets should be swallowed whole with water. Do not crush or chew tablets.

2.4Dose Modification Guidelines in Hepatic Impairment

and Hepatotoxicity Hepatic Impairment In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of abiraterone acetate tablets to 250 mg once daily. In patients with moderate hepatic impairment monitor ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. If elevations in ALT and/or AST greater than 5X upper limit of normal (ULN) or total bilirubin greater than 3X ULN occur in patients with baseline moderate hepatic impairment, discontinue abiraterone acetate tablets and do not re-treat patients with abiraterone acetate tablets . Do not use abiraterone acetate tablets in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Hepatotoxicity For patients who develop hepatotoxicity during treatment with abiraterone acetate tablets (ALT and/or AST greater than 5X ULN or total bilirubin greater than 3X ULN), interrupt treatment with abiraterone acetate tablets . Treatment may be restarted at a reduced dose of 750 mg once daily following return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. For patients who resume treatment, monitor serum transaminases and bilirubin at a minimum of every two weeks for three months and monthly thereafter. If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be restarted at a reduced dose of 500 mg once daily following return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN. If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment with abiraterone acetate tablets. Permanently discontinue abiraterone acetate tablets for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation .

2.5Dose Modification Guidelines for Strong CYP3A4

Inducers Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during abiraterone acetate tablets treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate tablets dosing frequency to twice a day only during the co-administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). Reduce the dose back to the previous dose and frequency, if the concomitant strong CYP3A4 inducer is discontinued .

Mineralocorticoid excess: Closely monitor patients with cardiovascular disease. Control hypertension and correct hypokalemia before treatment. Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly. Adrenocortical insufficiency: Monitor for symptoms and signs of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations. Hepatotoxicity: Can be severe and fatal. Monitor liver function and modify, interrupt, or discontinue abiraterone acetate dosing as recommended.

5.1Hypertension, Hypokalemia and Fluid Retention Due

to Mineralocorticoid Excess Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition . Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with abiraterone acetate. In the combined data from 4 placebo-controlled trials using prednisone 5 mg twice daily in combination with 1,000 mg abiraterone acetate daily, grades 3 to 4 hypokalemia were detected in 4% of patients on the abiraterone acetate arm and 2% of patients on the placebo arm.

Grades 3 to 4 hypertension were observed in 2% of patients each arm and grades 3 to 4 fluid retention in 1% of patients each arm. 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. The safety of abiraterone acetate in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in COU-AA-301) or NYHA Class II to IV heart failure (in COU-AA-302) has not been established because these patients were excluded from these randomized clinical trials .

5.2Adrenocortical Insufficiency Adrenal

insufficiency occurred in 0.3% of 2,230 patients taking abiraterone acetate and in 0.1% of 1,763 patients taking placebo in the combined data of randomized, placebo-controlled clinical studies. Adrenocortical insufficiency was reported in patients receiving abiraterone acetate 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 dosage of corticosteroids may be indicated before, during and after stressful situations .

5.3Hepatotoxicity In

postmarketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths . In the combined data of randomized clinical trials, grade 3 to 4 ALT or AST increases (at least 5X ULN) were reported in 6% of 2,230 patients who received abiraterone acetate, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to ALT and AST increases or abnormal hepatic function occurred in 1.1% of 2,230 patients taking abiraterone acetate.

In these clinical trials, no deaths clearly related to abiraterone acetate were reported due to hepatotoxicity events. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with abiraterone acetate, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced abiraterone acetate dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two 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’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt abiraterone acetate treatment and closely monitor liver function.

Re-treatment with abiraterone acetate at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN . Permanently discontinue abiraterone acetate for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation . The safety of abiraterone acetate re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Pregnancy Abiraterone acetate can cause fetal harm and potential loss of pregnancy . Pregnancy. (4, 8.1)

8.1Pregnancy Risk Summary Based on

findings from animal studies and the mechanism of action, abiraterone acetate is contraindicated for use in pregnant women because the drug can cause fetal harm and potential loss of pregnancy. Abiraterone acetate is not indicated for use in females. There are no human data on the use of abiraterone acetate in pregnant women.

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 . Data Animal Data In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 6 to 17). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased fetal ano-genital distance at ≥30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses ≥10 mg/kg/day caused maternal toxicity.

The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.

8.3Females and Males of Reproductive Potential Contraception

Males Based on findings in animal reproduction studies and its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of abiraterone acetate . Infertility Based on animal studies, abiraterone acetate may impair reproductive function and fertility in males of reproductive potential .

The following are discussed in more detail in other sections of the labeling: Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess . Adrenocortical Insufficiency . Hepatotoxicity . The most common adverse reactions (≥10%) are fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache. The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia. To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 was 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.

Another randomized placebo-controlled, multicenter clinical trial enrolled patients who had another indication in which abiraterone acetate was administered in combination with prednisone. 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 2,230 patients in randomized controlled trials constitute the basis for the data presented in the Warnings and Precautions, Grade 1 to 4 adverse reactions, and Grade 1 to 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-treated patients and 7.2 months (0.1, 43) for placebo-treated patients. The most common adverse reactions (≥10%) that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, arthralgia, hypertension, nausea, edema, hypokalemia, hot flush, diarrhea, vomiting, upper respiratory infection, cough, and headache.

The most common laboratory abnormalities (>20%) that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, and hypokalemia. Grades 3 to 4 adverse events were reported for 53% of patients in the abiraterone acetate arm and 46% of patients in the placebo arm. Treatment discontinuation was reported in 14% of patients in the abiraterone acetate arm and 13% of patients in the placebo arm.

The common adverse events (≥1%) resulting in discontinuation of abiraterone acetate 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 arm and 6.6% of patients in the placebo arm. Of the patients in the abiraterone acetate 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 ≥2.5X ULN in the absence of liver metastases.

Patients with liver metastases were excluded if AST and/or ALT >5X ULN. Table 1 shows adverse reactions on the abiraterone acetate 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 with prednisone was 8 months. Table 1: Adverse Reactions due to abiraterone acetate in COU-AA-301 Abiraterone Acetate with Prednisone (N=791) Placebo with Prednisone (N=394) System/Organ Class All Grades 1 Grade 3 to 4 All Grades Grade 3 to 4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders Joint swelling/discomfort 2 30 4.2 23

4.1Muscle

discomfort 3 26 3.0 23

2.3General

disorders Edema 4 27 1.9 18

0.8Vascular

disorders Hot flush 19 0.3 17

0.3Hypertension

8.5 1.3 6.9

0.3Gastrointestinal

disorders Diarrhea 18 0.6 14

1.3Dyspepsia

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

0.5Upper

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

0.3Nocturia

6.2 0 4.1 0 Injury, poisoning and procedural complications Fractures 5 5.9 1.4 2.3 0 Cardiac disorders Arrhythmia 6 7.2 1.1 4.6

1.0Chest

pain or chest discomfort 7 3.8 0.5 2.8 0 Cardiac failure 8 2.3 1.9 1.0 0.3 1 Adverse events graded according to CTCAE version 3.0. 2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. 3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness. 4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema. 5 Includes all fractures with the exception of pathological fracture. 6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia. 7 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 arm (1.3% vs. 1.1% respectively). 8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased. Table 2 shows laboratory abnormalities of interest from COU-AA-301.

Table 2: Laboratory Abnormalities of Interest in COU-AA-301 Abiraterone Acetate with Prednisone (N=791) Placebo with Prednisone (N=394) Laboratory Abnormality All Grades (%) Grade 3 to 4 (%) All Grades (%) Grade 3 to 4 (%) Hypertriglyceridemia 63 0.4 53 0 High AST 31 2.1 36

1.5Hypokalemia

28 5.3 20

1.0Hypophosphatemia

24 7.2 16

5.8High

ALT 11 1.4 10

0.8High 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 ≥2.5X ULN and patients were excluded if they had liver metastases. Table 3 shows adverse reactions on the abiraterone acetate 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 with prednisone was 13.8 months. Table 3: Adverse Reactions in ≥5% of Patients on the Abiraterone Acetate Arm in COU-AA-302 Abiraterone Acetate with Prednisone (N=542) Placebo with Prednisone (N=540) System/Organ Class All Grades 1 Grade 3 to 4 All Grades Grade 3 to 4 Adverse reaction % % % % General disorders Fatigue 39 2.2 34

1.7Edema

2 25 0.4 21

1.1Pyrexia

8.7 0.6 5.9

0.2Musculoskeletal and

connective tissue disorders Joint swelling/discomfort 3 30 2.0 25

2.0Groin

pain 6.6 0.4 4.1

0.7Gastrointestinal

disorders Constipation 23 0.4 19

0.6Diarrhea

22 0.9 18

0.9Dyspepsia

11 0.0 5.0

0.2Vascular

disorders Hot flush 22 0.2 18

0.0Hypertension

22 3.9 13

3.0Respiratory,

thoracic and mediastinal disorders Cough 17 0.0 14

0.2Dyspnea

12 2.4 9.6

0.9Psychiatric

disorders Insomnia 14 0.2 11

0.0Injury,

poisoning and procedural complications Contusion 13 0.0 9.1

0.0Falls

5.9 0.0 3.3

0.0Infections and

infestations Upper respiratory tract infection 13 0.0 8.0

0.0Nasopharyngitis

11 0.0 8.1

0.0Renal and

urinary disorders Hematuria 10 1.3 5.6

0.6Skin and

subcutaneous tissue disorders Rash 8.1 0.0 3.7 0.0 1 Adverse events graded according to CTCAE version 3.0. 2 Includes terms Edema peripheral, Pitting edema, and Generalized edema. 3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness. Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the abiraterone acetate arm compared to placebo in COU-AA-302. Table 4: Laboratory Abnormalities in >15% of Patients in the Abiraterone Acetate Arm of COU-AA-302 Abiraterone Acetate with Prednisone (N=542) Placebo with Prednisone (N=540) Laboratory Abnormality Grade 1 to 4 Grade 3 to 4 Grade 1 to 4 Grade 3 to 4 % % % % Hematology Lymphopenia 38 8.7 32

7.4Chemistry Hyperglycemia

1 57 6.5 51

5.2High

ALT 42 6.1 29

0.7High

AST 37 3.1 29

1.1Hypernatremia

33 0.4 25

0.2Hypokalemia

17 2.8 10 1.7 1 Based on non-fasting blood draws Cardiovascular Adverse Reactions In the combined data of randomized, placebo-controlled clinical studies, cardiac failure occurred more commonly in patients on the abiraterone acetate arm compared to patients on the placebo arm (2.6% versus 0.9%). Grade 3 to 4 cardiac failure occurred in 1.3% of patients taking abiraterone acetate and led to 5 treatment discontinuations and 4 deaths. Grade 3 to 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 arms and five deaths in the placebo arms.

There were 7 (0.3%) deaths due to cardiorespiratory arrest in the abiraterone acetate 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 arms.

6.2Postmarketing Experience The

following additional adverse reactions have been identified during post approval use of abiraterone acetate 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. To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.