Abiraterone Acetate: Package Insert and Label Information

ABIRATERONE ACETATE- abiraterone acetate tablet
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1 INDICATIONS AND USAGE

Abiraterone acetate tablets are indicated in combination with prednisone for the treatment of patients with

  • Metastatic castration-resistant prostate cancer (CRPC)

2 DOSAGE AND ADMINISTRATION

2.1 Recommended 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.

2.3 Important 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 [see Clinical Pharmacology (12.3)]. The tablets should be swallowed whole with water. Do not crush or chew tablets.

2.4 Dose 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 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

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 [see Warnings and Precautions (5.3)]. 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 [see Warnings and Precautions (5.3)].

2.5 Dose 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 [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS AND STRENGTHS

Abiraterone acetate tablets, USP 250 mg are white to off-white, oval-shaped, uncoated tablets debossed with “AN65” on one side and plain on the other side.

4 CONTRAINDICATIONS

Pregnancy

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

5 WARNINGS AND PRECAUTIONS

5.1 Hypertension, 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 [see Clinical Pharmacology (12.1)]. 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 [see Clinical Studies (14)].

5.2 Adrenocortical 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 [see Warnings and Precautions (5.1)].

5.3 Hepatotoxicity

In postmarketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions (6.2)].

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 [see Dosage and Administration (2.4)].

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 [see Dosage and Administration (2.4)].

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.

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

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

4.1

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

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

1.5

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 ≥2.5X 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

1.7

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

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

7.4

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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