FDA Approves Yonsa

Sun Pharmaceutical Industries Ltd. and includes its subsidiaries and/or associate companies) and Churchill Pharmaceuticals, LLC. (Churchill) today announced that one of Sun Pharma’s wholly owned subsidiary companies has received approval from the U.S. Food and Drug Administration (FDA) for Yonsa (abiraterone acetate), a novel formulation in combination with methylprednisolone, for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

"We are pleased to add Yonsa to our growing oncology portfolio and continue to deliver on Sun Pharma’s commitment for enhanced patient access to innovative cancer therapies," said Abhay Gandhi, CEO - North America, Sun Pharma.

Yonsa in combination with methylprednisolone was filed as a New Drug Application (NDA) under the 505(b)(2) regulatory pathway and will be promoted as a branded product in the U.S.

About Yonsa (abiraterone acetate) tablets

Yonsa is a CYP17 inhibitor which uses proprietary SoluMatrix Fine Particle Technology™ to create a micronized (smaller particle size) formulation of abiraterone acetate tablets - for the treatment of metastatic castration-resistant prostate cancer, in combination with methylprednisolone. The active ingredient is converted in vivo to abiraterone, an androgen biosynthesis inhibitor that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). The CYP17 enzyme is expressed in testicular, adrenal and prostatic tumor tissues and is required for androgen biosynthesis.

INDICATION

Yonsa (abiraterone acetate) in combination with methylprednisolone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Important Administration Instructions

To avoid substitution errors and overdose, be aware that Yonsa 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.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

Yonsa can cause fetal harm and potential loss of pregnancy.

WARNINGS AND PRECAUTIONS

Hypertension, Hypokalemia, and Fluid Retention Due to Mineralocorticoid Excess: Yonsa may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with Yonsa.

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 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) was not established because these patients were excluded from these randomized clinical trials.

Adrenocortical Insufficiency (AI): AI was reported in patients receiving abiraterone acetate in combination with corticosteroid, following an interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of AI, particularly if patients are withdrawn from corticosteroids, have corticosteroid dose reductions, or experience unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with Yonsa. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.

Hepatotoxicity: In postmarketing experience, there have been abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths. 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.

Permanently discontinue treatment with abiraterone acetate 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.

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.

ADVERSE REACTIONS

The most common adverse reactions (≥10%) are fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

The most common laboratory abnormalities (>20%) are anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.

DRUG INTERACTIONS

Based on in vitro data, Yonsa is a substrate of CYP3A4. In a drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during Yonsa treatment. If a strong CYP3A4 inducer must be co-administered, increase the Yonsa dosing frequency only during the co-administration period.

Abiraterone is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8.

Avoid coadministration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug.

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 an abiraterone acetate single dose equivalent to Yonsa 500 mg. 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.

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