Abiraterone Acetate: Package Insert and Label Information (Page 4 of 8)

LATITUDE

Patients with Metastatic High-Risk CSPC

LATITUDE enrolled 1199 patients with newly-diagnosed metastatic, high-risk CSPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT ≥ 2.5 x ULN or if they had liver metastases. All the patients received GnRH analogs or had prior bilateral orchiectomy during the trial. The median duration of treatment with abiraterone acetate tablets and prednisone was 24 months.

Table 5 shows adverse reactions on the abiraterone acetate tablets arm that occurred in ≥ 5% of patients with a ≥ 2% absolute increase in frequency compared to those on the placebos arm.

Table 5: Adverse Reactions in ≥ 5% of Patients on the Abiraterone Acetate Tablets Arm in LATITUDE *
*
All patients were receiving an GnRH agonist or had undergone orchiectomy.
Adverse events graded according to CTCAE version 4.0
Reported as an adverse event or reaction
§
Including cough, productive cough, upper airway cough syndrome

System/Organ Class

Adverse reaction

Abiraterone Acetate Tablets with Prednisone

(N = 597)

Placebos

(N = 602)

All Grades

%

Grade 3-4

%

All Grades

%

Grade 3-4

%

Vascular disorders

Hypertension

37

20

13

10

Hot flush

15

0.0

13

0.2

Metabolism and nutrition disorders

Hypokalemia

20

10

3.7

1.3

Investigations

Alanine aminotransferase increased

16

5.5

13

1.3

Aspartate aminotransferase increased

15

4.4

11

1.5

Infections and infestations

Urinary tract infection

7.0

1.0

3.7

0.8

Upper respiratory tract infection

6.7

0.2

4.7

0.2

Nervous system disorders

Headache

7.5

0.3

5.0

0.2

Respiratory, Thoracic and Mediastinal Disorders

Cough §

6.5

0.0

3.2

0

Table 6 shows laboratory abnormalities that occurred in ≥ 15% of patients, and more frequently (> 5%) in the abiraterone acetate tablets arm compared to placebos.

Table 6: Laboratory Abnormalities in > 15% of Patients in the Abiraterone Acetate Tablets Arm of LATITUDE

Laboratory Abnormality

Abiraterone Acetate Tablets with Prednisone

(N = 597)

Placebos

(N= 602)

Grade 1-4

%

Grade 3-4

%

Grade 1-4

%

Grade 3-4

%

Hematology

Lymphopenia

20

4.1

14

1.8

Chemistry

Hypokalemia

30

9.6

6.7

1.3

Elevated ALT

46

6.4

45

1.3

Elevated total bilirubin

16

0.2

6.2

0.2

Cardiovascular Adverse Reactions

In the combined data of 5 randomized, placebo-controlled clinical studies, cardiac failure occurred more commonly in patients on the abiraterone acetate tablets arm compared to patients on the placebo arm (2.6% versus 0.9%). Grade 3-4 cardiac failure occurred in 1.3% of patients taking abiraterone acetate tablets and led to 5 treatment discontinuations and 4 deaths. Grade 3-4 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 tablets arms and five deaths in the placebo arms. There were 7 (0.3%) deaths due to cardiorespiratory arrest in the abiraterone acetate tablets 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 tablets arms.

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of abiraterone acetate tablets 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.

Cardiac Disorders: QT prolongation and Torsades de Pointes (observed in patients who developed hypokalemia or had underlying cardiovascular conditions).

Immune System Disorders: Hypersensitivity: anaphylactic reactions (severe allergic reactions that include, but are not limited to difficulty swallowing or breathing, swollen face, lips, tongue or throat, or an itchy rash (urticaria)).

7 DRUG INTERACTIONS

7.1 Drugs that Inhibit or Induce CYP3A4 Enzymes

Based on in vitro data, abiraterone acetate tablets are a substrate of CYP3A4.

In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during abiraterone acetate tablets treatment. If a strong CYP3A4 inducer must be co-administered, increase the abiraterone acetate tablets dosing frequency [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone [see Clinical Pharmacology (12.3)].

7.2 Effects of Abiraterone on Drug Metabolizing Enzymes

Abiraterone acetate tablets are an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3)].

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with abiraterone acetate tablets [see Clinical Pharmacology (12.3) and Warnings and Precautions (5.6)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The safety and efficacy of abiraterone acetate tablets have not been established in females. Based on findings from animal studies and the mechanism of action, abiraterone acetate tablets can cause fetal harm and potential loss of pregnancy.

There are no human data on the use of abiraterone acetate tablets 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 (see Data).

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 6-17). 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.

8.2 Lactation

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