Abiraterone Acetate

ABIRATERONE ACETATE — abiraterone acetate tablet
Rising Pharmaceuticals, Inc.

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 is 1,000 mg (four 250 mg tablets) orally once daily in combination with prednisone 5 mg administered 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 5× ULN or total bilirubin greater than 3× 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 2.5× ULN and total bilirubin less than or equal to 1.5× 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 2.5× ULN and total bilirubin less than or equal to 1.5× 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 tablets are white to off-white, oval-shaped tablets debossed with “NA250″ 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 1000 mg abiraterone acetate daily, grades 3-4 hypokalemia were detected in 4% of patients on the abiraterone acetate arm and 2% of patients on the placebo arm. Grades 3-4 hypertension were observed in 2% patients each arm and grades 3-4 fluid retention in 1% of patients 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 occured in 0.3% of 2230 patients taking abiraterone acetate and in 0.1% of 1763 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 3-4 ALT or AST increases (at least 5X ULN) were reported in 6% of 2230 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 2230 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 3X ULN and total bilirubin greater than 2X 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.

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