ABIRATERONE ACETATE (Page 2 of 7)

5.4 Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride

Abiraterone acetate plus prednisone/prednisolone is not recommended for use in combination with radium 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 (28.6% vs 11.4%) and deaths (38.5% vs 35.5%) 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/prednisolone.

5.5 Embryo-Fetal Toxicity

The safety and efficacy of abiraterone acetate have not been established in females. Based on animal reproductive studies and mechanism of action, abiraterone acetate can cause fetal harm and loss of pregnancy when administered to a pregnant female. 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 with abiraterone acetate and for 3 weeks after the last dose of abiraterone acetate [see Use in Specific Populations (8.1, 8.3)] . Abiraterone acetate should not be handled by females who are or may become pregnant [see How Supplied/Storage and Handling (16)] .

5.6 Hypoglycemia

Severe hypoglycemia has been reported when abiraterone acetate was administered to patients with pre-existing diabetes receiving medications containing thiazolidinediones (including pioglitazone) or repaglinide [see Drug Interactions (7.2)] . Monitor blood glucose in patients with diabetes during and after discontinuation of treatment with abiraterone acetate. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.

6 ADVERSE REACTIONS

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

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 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

System/Organ Class

Adverse reaction

Abiraterone Acetate with Prednisone (N=791)

Placebo with Prednisone (N=394)

All Grades 1

Grade 3 to 4

All Grades

Grade 3 to 4

%

%

%

%

Musculoskeletal and connective tissue disorders

Joint swelling/discomfort 2

30

4.2

23

4.1

Muscle discomfort 3

26

3.0

23

2.3

General disorders

Edema 4

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 5

5.9

1.4

2.3

0

Cardiac disorders

Arrhythmia 6

7.2

1.1

4.6

1.0

Chest 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

Laboratory Abnormality

Abiraterone Acetate with Prednisone (N=791)

Placebo with Prednisone (N=394)

All Grades (%)

Grade 3 to 4 (%)

All Grades (%)

Grade 3 to 4 (%)

Hypertriglyceridemia

63

0.4

53

0

High AST

31

2.1

36

1.5

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 1,088 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

System/Organ Class

Adverse reaction

Abiraterone Acetate with Prednisone (N=542)

Placebo with Prednisone (N=540)

All Grades 1

Grade 3 to 4

All Grades

Grade 3 to 4

%

%

%

%

General disorders

Fatigue

39

2.2

34

1.7

Edema 2

25

0.4

21

1.1

Pyrexia

8.7

0.6

5.9

0.2

Musculoskeletal and connective tissue disorders

Joint swelling/discomfort 3

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

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

Laboratory Abnormality

Abiraterone Acetate with Prednisone (N=542)

Placebo with Prednisone (N=540)

Grade 1 to 4

Grade 3 to 4

Grade 1 to 4

Grade 3 to 4

%

%

%

%

Hematology

Lymphopenia

38

8.7

32

7.4

Chemistry

Hyperglycemia 1

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

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.

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