Zytiga
(abiraterone acetate)Dosage & Administration
Metastatic castration-resistant prostate cancer:
Metastatic castration-sensitive prostate cancer:
Patients receiving ZYTIGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ZYTIGA tablets must be taken as a single dose once daily on an empty stomach. Do not eat food 2 hours before and 1 hour after taking ZYTIGA. The tablets must be swallowed whole with water. Do not crush or chew tablets. ( 2.3)
Dose Modification:
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Zytiga Prescribing Information
ZYTIGA is indicated in combination with prednisone for the treatment of patients with
- Metastatic castration-resistant prostate cancer (CRPC)
- Metastatic high-risk castration-sensitive prostate cancer (CSPC)
Recommended Dose for Metastatic CRPC
The recommended dose of ZYTIGA is 1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily with prednisone 5 mg orally twice daily.
Recommended Dose for Metastatic High-risk CSPC
The recommended dose of ZYTIGA is 1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily with prednisone 5 mg administered orally once daily.
Important Administration Instructions
Patients receiving ZYTIGA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.
ZYTIGA tablets must be taken as a single dose once daily on an empty stomach. Do not eat food 2 hours before and 1 hour after taking ZYTIGA. The tablets must be swallowed whole with water. Do not crush or chew tablets.
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. 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 5 × upper limit of normal (ULN) or total bilirubin greater than 3 × 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 5 × ULN or total bilirubin greater than 3 × ULN), interrupt treatment with ZYTIGA [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 ZYTIGA.
Permanently discontinue ZYTIGA for patients who develop a concurrent elevation of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Warnings and Precautions (5.3)] .
Dose Modification Guidelines for Strong CYP3A4 Inducers
Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during ZYTIGA treatment.
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)] .
Tablets (500 mg): purple, oval-shaped, film-coated tablets debossed with "AA" one side and "500" on the other side.
Tablets (250 mg): white to off-white, oval-shaped tablets debossed with "AA250" on one side.
Pregnancy
Risk Summary
The safety and efficacy of ZYTIGA have not been established in females. Based on findings from animal studies and the mechanism of action, ZYTIGA can cause fetal harm and potential loss of pregnancy.
There are no human data on the use of ZYTIGA 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.
Lactation
Risk Summary
The safety and efficacy of ZYTIGA have not been established in females. There is no information available on the presence of abiraterone in human milk, or on the effects on the breastfed child or milk production.
Females and Males of Reproductive Potential
Contraception
Males
Based on findings in animal reproduction studies and its mechanism of action, advise males with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the final dose of ZYTIGA [see Use in Specific Populations (8.1)] .
Infertility
Based on animal studies, ZYTIGA may impair reproductive function and fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)].
Pediatric Use
Safety and effectiveness of ZYTIGA in pediatric patients have not been established.
Geriatric Use
Of the total number of patients receiving ZYTIGA in randomized clinical trials, 70% of patients were 65 years and over and 27% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Patients with Hepatic Impairment
The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.
In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (N=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7-fold and the fraction of free drug increased 2-fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function.
No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not use ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5 × ULN or total bilirubin >3 × ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.4)and Clinical Pharmacology (12.3)] .
For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].
Patients with Renal Impairment
No dosage adjustment is necessary for patients with renal impairment [see Clinical Pharmacology (12.3)] .
None.
Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions 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)] . Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA.
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 3–4 hypokalemia were detected in 4% of patients on the ZYTIGA arm and 2% of patients on the placebo arm. Grades 3–4 hypertension were observed in 2% of patients each arm and grades 3–4 fluid retention in 1% of patients each arm.
In LATITUDE (a randomized placebo-controlled, multicenter clinical trial), which used prednisone 5 mg daily in combination with 1,000 mg abiraterone acetate daily, grades 3–4 hypokalemia were detected in 10% of patients on the ZYTIGA arm and 1% of patients on the placebo arm, grades 3–4 hypertension were observed in 20% of patients on the ZYTIGA arm and 10% of patients on the placebo arm. Grades 3–4 fluid retention occurred in 1% of patients each arm [see Adverse Reactions (6)] .
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. In postmarketing experience, QT prolongation and Torsades de Pointes have been observed in patients who develop hypokalemia while taking ZYTIGA.
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 COU-AA-301) or NYHA Class II to IV heart failure (in COU-AA-302 and LATITUDE) has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies (14)] .
Adrenocortical Insufficiency
Adrenal insufficiency occurred in 0.3% of 2230 patients taking ZYTIGA and in 0.1% of 1763 patients taking placebo in the combined data of the 5 randomized, placebo-controlled clinical studies. Adrenocortical insufficiency was reported in patients receiving ZYTIGA 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 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)].
Hepatotoxicity
In postmarketing experience, there have been ZYTIGA-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions (6.2)] .
In the combined data of 5 randomized clinical trials, grade 3–4 ALT or AST increases (at least 5 × ULN) were reported in 6% of 2230 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 ALT and AST increases or abnormal hepatic function occurred in 1.1% of 2230 patients taking ZYTIGA. In these clinical trials, 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 2.5 × ULN and total bilirubin less than or equal to 1.5 × ULN [see Dosage and Administration (2.4)] .
Permanently discontinue ZYTIGA for patients who develop a concurrent elevation of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Dosage and Administration (2.4)] .
The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20 × ULN and/or bilirubin greater than or equal to 10 × ULN is unknown.
Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride
ZYTIGA plus prednisone/prednisolone 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 ZYTIGA plus prednisone/prednisolone and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study (ERA-223 trial) 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 ZYTIGA plus prednisone/prednisolone in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with ZYTIGA plus prednisone/prednisolone.
Embryo-Fetal Toxicity
The safety and efficacy of ZYTIGA have not been established in females. Based on animal reproductive studies and mechanism of action, ZYTIGA 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 ZYTIGA and for 3 weeks after the last dose of ZYTIGA [see Use in Specific Populations (8.1, 8.3)] . ZYTIGA should not be handled by females who are or may become pregnant [see How Supplied/Storage and Handling (16)].
Hypoglycemia
Severe hypoglycemia has been reported when ZYTIGA 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 ZYTIGA. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.