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Zytiga (Abiraterone) 250 Mg 120 Tablets

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

2.2 Dose Modification Guidelines in Hepatic Impairment and Hepatotoxicity

2.3 Dose Modification Guidelines for Strong CYP3A4 Inducers

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

4.1 Pregnancy

5 WARNINGS AND PRECAUTIONS

5.1 Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess

5.2 Adrenocortical Insufficiency

5.3 Hepatotoxicity

5.4 Increased ZYTIGA Exposures with Food

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Post Marketing Experience

7 DRUG INTERACTIONS

7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes

7.2 Effects of Abiraterone on Drug Metabolizing Enzymes

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Hepatic Impairment

8.7 Patients with Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

12.6 QT Prolongation

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

ZYTIGA is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dose of ZYTIGA is 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken [seeClinical Pharmacology (12.3)]. The tablets should be swallowed whole with water. Do not crush or chew tablets.

2.2 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 ZYTIGA to 250 mg once daily. A once daily dose of 250 mg in patients with moderate hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 1,000 mg once daily. However, there are no clinical data at the dose of 250 mg once daily in patients with moderate hepatic impairment and caution is advised. 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 ZYTIGA and do not re-treat patients with ZYTIGA [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Hepatotoxicity

For patients who develop hepatotoxicity during treatment with ZYTIGA (ALT and/or AST greater than 5X ULN or total bilirubin greater than 3X ULN), interrupt treatment with ZYTIGA [seeWarnings 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 ZYTIGA. The safety of ZYTIGA 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.

2.3 Dose Modification Guidelines for Strong CYP3A4 Inducers

Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during ZYTIGA treatment. Although there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers, because of the potential for an interaction, if a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA 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

ZYTIGA (abiraterone acetate) 250 mg tablets are white to off-white, oval-shaped tablets debossed with AA250 on one side.

4 CONTRAINDICATIONS

4.1 Pregnancy

ZYTIGA can cause fetal harm when administered to a pregnant woman. ZYTIGA is not indicated for use in women. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss [see Use in Specific Populations (8.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess

ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with ZYTIGA. [see Adverse Reactions (6)].

Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use ZYTIGA with caution in patients with a history of cardiovascular disease. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14)]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA.

5.2 Adrenocortical Insufficiency

Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking ZYTIGA and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor 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 ZYTIGA. 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 the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received ZYTIGA, 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 liver enzyme increases occurred in 1% of patients taking ZYTIGA. No deaths clearly related to ZYTIGA were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA 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 ZYTIGA treatment and closely monitor liver function.

Re-treatment with ZYTIGA 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 (2.2)].

The safety of ZYTIGA 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.

5.4 Increased ZYTIGA Exposures with Food

ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0–∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3)].

6 ADVERSE REACTIONS

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

  • Hypertension, Hypokalemia, and Fluid Retention 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 ZYTIGA Exposures with Food [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 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 ZYTIGA was administered 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 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 ≥2.5 XULN 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 ZYTIGA 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 ZYTIGA was 8 months.

Table 1: Adverse Reactions due to ZYTIGA in Study 1

 

ZYTIGA with Prednisone 
(N=791)

Placebo with Prednisone 
(N=394)

System/Organ Class
  Adverse reaction

All Grades* 
%

Grade 3–4
%

All Grades
%

Grade 3–4
%

*Adverse events graded according to CTCAE version 3.0

†Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

‡Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness

§Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema

¶Includes all fractures with the exception of pathological fracture

#Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia

ÞIncludes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

ßIncludes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased

Musculoskeletal and connective tissue disorders

       

  Joint swelling/discomfort†

29.5

4.2

23.4

4.1

  Muscle discomfort‡

26.2

3.0

23.1

2.3

General disorders

       

  Edema§

26.7

1.9

18.3

0.8

Vascular disorders

       

  Hot flush

19.0

0.3

16.8

0.3

  Hypertension

8.5

1.3

6.9

0.3

Gastrointestinal disorders

       

  Diarrhea

17.6

0.6

13.5

1.3

  Dyspepsia

6.1

0

3.3

0

Infections and infestations

       

  Urinary tract infection

11.5

2.1

7.1

0.5

  Upper respiratory tract infection

5.4

0

2.5

0

Respiratory, thoracic and mediastinal disorders

       

  Cough

10.6

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¶

5.9

1.4

2.3

0

Cardiac disorders

       

  Arrhythmia#

7.2

1.1

4.6

1.0

  Chest pain or chest discomfortÞ

3.8

0.5

2.8

0

  Cardiac failureß

2.3

1.9

1.0

0.3

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 ZYTIGA arm.

Table 2: Laboratory Abnormalities of Interest in Study 1

 

Abiraterone (N=791)

Placebo (N=394)

Laboratory Abnormality

All Grades (%)

Grade 3–4 (%)

All Grades (%)

Grade 3–4 (%)

Hypertriglyceridemia

62.5

0.4

53.0

0

High AST

30.6

2.1

36.3

1.5

Hypokalemia

28.3

5.3

19.8

1.0

Hypophosphatemia

23.8

7.2

15.7

5.8

High ALT

11.1

1.4

10.4

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 ZYTIGA arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with ZYTIGA was 13.8 months.

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

 

ZYTIGA with Prednisone (N=542)

Placebo with Prednisone (N=540)

System/Organ Class
  Adverse reaction

All Grades* 
%

Grade 3–4
%

All Grades
%

Grade 3–4
%

*Adverse events graded according to CTCAE version 3.0

†Includes terms Edema peripheral, Pitting edema, and Generalized edema

‡Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness

General disorders

       

  Fatigue

39.1

2.2

34.3

1.7

  Edema†

25.1

0.4

20.7

1.1

  Pyrexia

8.7

0.6

5.9

0.2

Musculoskeletal and connective tissue disorders

       

  Joint swelling/discomfort‡

30.3

2.0

25.2

2.0

  Groin pain

6.6

0.4

4.1

0.7

Gastrointestinal disorders

       

  Constipation

23.1

0.4

19.1

0.6

  Diarrhea

21.6

0.9

17.8

0.9

  Dyspepsia

11.1

0.0

5.0

0.2

Vascular disorders

       

  Hot flush

22.3

0.2

18.1

0.0

  Hypertension

21.6

3.9

13.1

3.0

Respiratory, thoracic and mediastinal disorders

       

  Cough

17.3

0.0

13.5

0.2

  Dyspnea

11.8

2.4

9.6

0.9

Psychiatric disorders

       

  Insomnia

13.5

0.2

11.3

0.0

Injury, poisoning and procedural complications

       

  Contusion

13.3

0.0

9.1

0.0

  Falls

5.9

0.0

3.3

0.0

Infections and infestations

       

  Upper respiratory tract infection

12.7

0.0

8.0

0.0

  Nasopharyngitis

10.7

0.0

8.1

0.0

Renal and urinary disorders

       

  Hematuria

10.3

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 (>5%) in the ZYTIGA arm compared to placebo in Study 2. Grade 3–4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the ZYTIGA arm.

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

 

Abiraterone (N=542)

Placebo (N=540)

Laboratory Abnormality

Grade 1–4 
%

Grade 3–4 
%

Grade 1–4 
%

Grade 3–4 
%

*Based on non-fasting blood draws

Hematology

       

  Lymphopenia

38.2

8.7

31.7

7.4

Chemistry

       

  Hyperglycemia*

56.6

6.5

50.9<

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Zytiga (Abiraterone) 250 Mg 120 Tablets

  • Manufacturer: Johnson&Johnson
  • Generic Name: Abiraterone
  • Availability: In Stock
  • $3,750.00

Tags: Zytiga, Abiraterone