Yonsa

Recommended Dosage

The recommended dose of YONSA is 500 mg (four 125 mg tablets) administered orally once daily in combination with methylprednisolone 4 mg administered orally twice daily.

Important Administration Instructions

To avoid medication errors and overdose, be aware that YONSA (abiraterone acetate) tablets may have different dosing and food effects than other abiraterone acetate products. Patients receiving YONSA should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy.

YONSA tablets must be taken as a single dose once daily with or without food [see Clinical Pharmacology ( 12.3)].  The tablets should 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 YONSA to 125 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 YONSA and do not re-treat patients with abiraterone acetate [see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)].

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

Hepatotoxicity

For patients who develop hepatotoxicity during treatment with YONSA (ALT and/or AST greater than 5X ULN or total bilirubin greater than 3X ULN), interrupt treatment with YONSA [see Warnings and Precautions ( 5.3)].  Treatment may be restarted at a reduced dose of 375 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 375 mg once daily, re-treatment may be restarted at a reduced dose of 250 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 250 mg once daily, discontinue treatment with YONSA. 

Permanently discontinue YONSA 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)].

Dose Modification Guidelines for Strong CYP3A4 Inducers

Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during YONSA treatment.

If a strong CYP3A4 inducer must be co-administered, increase the YONSA dosing frequency to twice a day only during the co-administration period (e.g., from 500 mg once daily to 500 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)].

Pregnancy

Risk Summary

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

There are no human data on the use of YONSA in pregnant women.  In animal reproduction studies, oral administration of abiraterone acetate to pregnant rats during organogenesis, caused adverse developmental effects at maternal exposures of 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 YONSA have not been established in females.  There is no information available on the presence of abiraterone acetate 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 male patients with female partners of reproductive potential to use effective contraception during treatment and for 3 weeks after the last dose of YONSA [see Use in Specific Populations ( 8.1)]. 

Infertility

Based on animal studies, abiraterone acetate may impair reproductive function and fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1)].

Pediatric Use

Safety and effectiveness of abiraterone acetate in pediatric patients have not been established.

Geriatric Use

Of the total number of patients receiving abiraterone acetate in the two randomized trials, 73% of patients were 65 years and over and 30% 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.

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 dose equivalent to 500 mg of YONSA 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 modification is recommended for patients with baseline mild hepatic impairment (Child-Pugh Class A).  In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of YONSA to 125 mg once daily.  Do not use YONSA in patients with baseline severe hepatic impairment (Child-Pugh Class C).  If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue abiraterone acetate treatment [see Dosage and Administration ( 2.3) 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 ( 2.3), Warnings and Precautions ( 5.3), and Clinical Pharmacology ( 12.3)].

Renal Impairment

No dosage modification is recommended for patients with renal impairment [see Clinical Pharmacology ( 12.3)].

Hypokalemia, Fluid Retention, and Cardiovascular Adverse Reactions due to Mineralocorticoid Excess  

YONSA 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 YONSA.

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 abiraterone acetate [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 abiraterone acetate.

The safety of YONSA 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)  has not been established because these patients were excluded from these randomized clinical trials [see Clinical Studies ( 14)].

Adrenocortical Insufficiency

Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking abiraterone acetate and in 0.2% of patients taking placebo.  Adrenocortical insufficiency was reported in patients receiving abiraterone acetate in combination with a corticosteroid, 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 corticosteroids, have corticosteroid 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 YONSA.  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 abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions ( 6.2)].

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 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 occurred in 1% of 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 YONSA, every two weeks for the first three months of treatment and monthly thereafter.  In patients with baseline moderate hepatic impairment receiving a reduced YONSA dose of 125 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 YONSA treatment and closely monitor liver function.

Re-treatment with YONSA 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 ( 2.3)].

Permanently discontinue treatment with YONSA 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 ( 2.3)].

The safety of YONSA 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.

Increased Fractures and Mortality in Combination with Radium Ra 223 Dichloride

YONSA plus methylprednisolone 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 abiraterone acetate plus a corticosteroid and radium Ra 223 dichloride was assessed in a randomized, placebo-controlled multicenter study 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 abiraterone acetate plus a corticosteroid in combination with radium Ra 223 dichloride compared to patients who received placebo in combination with abiraterone acetate plus a corticosteroid. 

Embryo-Fetal Toxicity

The safety and efficacy of YONSA have not been established in females. Based on animal reproductive studies and mechanism of action, YONSA 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 YONSA and for 3 weeks after the last dose of YONSA [see Use in Specific Populations ( 8.1, 8.3)]. YONSA 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 abiraterone acetate 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 YONSA. Assess if antidiabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.