YONSA (Page 2 of 7)

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

YONSA plus methylprednisolone 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 a corticosteroid and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study 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 a corticosteroid in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus a corticosteroid.

5.5 Embryo-Fetal Toxicity

The safety and efficacy of YONSA have not been established in females. Based on animal reproductive studies and mechanism of action, YONSA 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 YONSA and for 3 weeks after the last dose of YONSA [see Use in Specific Populations ( 8.1, 8.3) ]. YONSA 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 YONSA. 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:

  • 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)].

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 (Study 1 and Study 2) enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 abiraterone acetate was administered at a dose equivalent to 500 mg of YONSA daily in combination with a different corticosteroid twice daily in the active treatment arms. Placebo plus corticosteroid was given to control patients.

The most common adverse drug reactions (>10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (≥2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

Study 1: Metastatic CRPC Following Chemotherapy

Study 1 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 Study 1 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 a corticosteroid was 8 months.


Table 1: Adverse Reactions due to Abiraterone Acetate in Study 1

Abiraterone Acetate with Corticosteroid(N=791) Placebo with Corticosteroid (N=394)

System Organ Class

Adverse Reaction

All Grades1

%

Grade 3-4

%

All Grades

%

Grade 3-4

%

Musculoskeletal and connective tissue disorders

Joint swelling/ discomfort2

30

4.2

23

4.1

Muscle discomfort3

26

3.0

23

2.3

General Disorders

Edema4

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

Fractures5

5.9

1.4

2.3

0

Cardiac disorders

Arrhythmia6

7.2

1.1

4.6

1.0

Chest pain or chest discomfort7

3.8

0.5

2.8

0

Cardiac failure8

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 Study 1. Grade 3-4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the abiraterone acetate with a corticosteroid arm.


Table 2: Laboratory Abnormalities of Interest in Study 1

Abiraterone Acetate with Corticosteroid(N=791) Placebo with Corticosteroid(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

Study 2: Metastatic CRPC Prior to Chemotherapy

Study 2 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 Study 2 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 a corticosteroid was 13.8 months.


Table 3: Adverse Reactions in ≥5% of Patients on the Abiraterone Acetate Arm in Study 2

Abiraterone Acetate with Corticosteroid(N=542) Placebo with Corticosteroid(N=540)

System Organ Class

Adverse Reaction

All Grades1

%

Grade 3-4

%

All Grades

%

Grade 3-4

%

General Disorders

Fatigue

39

2.2

34

1.7

Edema2

25

0.4

21

1.1

Pyrexia

8.7

0.6

5.9

0.2

Musculoskeletal and connective tissue disorders

Joint swelling/ discomfort3

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 Study 2.


Table 4: Laboratory Abnormalities in > 15% of Patients in the Abiraterone Acetate Arm of Study 2

Abiraterone Acetate with Corticosteroid(N=542) Placebo with Corticosteroid(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

Hyperglycemia1

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 for studies 1 and 2, cardiac failure occurred more commonly in patients treated with abiraterone acetate compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking abiraterone acetate and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.

In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the abiraterone acetate arms and no deaths in the placebo arms. There were 7 (0.5 %) deaths due to cardiorespiratory arrest in the abiraterone acetate arms and 3 (0.3 %) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the abiraterone acetate arms.

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