The Recommended Dose of ZYTIGA®
ZYTIGA® 1,000 mg
(four 250 mg tablets) administered orally once daily
PREDNISONE 5 mg
administered orally twice daily
Prednisone Reduces the Incidence and Severity of Mineralocorticoid-Related Adverse Reactions Associated With ZYTIGA®
The inhibition of the CYP17 enzyme complex due to ZYTIGA® treatment can result in increased mineralocorticoid production and may cause hypokalemia, hypertension, and fluid retention. Secretion of adrenocorticotropic hormone (ACTH) by the pituitary gland drives the production of mineralocorticoids, androgens, and glucocorticoids such as cortisol in the adrenal cortex.1 Secreted levels of ACTH increase in response to decreased levels of cortisol due to CYP17 complex inhibition.1,2
CORTISOL PRODUCTION IS DRIVEN BY ACTH
Adrenocortical Insufficiency (AI)—AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress. Symptoms and signs of AI may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA®. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during, and after stressful situations.
Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA®.
Schedule for Required Monitoring for Patients on ZYTIGA®
Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress.
Permanently discontinue ZYTIGA® 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.
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.
*Assess more frequently as required.
†Suggested schedule for patients with no or mild baseline hepatic impairment. For patients with baseline hepatic impairment or who develop hepatotoxicity during treatment, see When to Modify. Do not use ZYTIGA® in patients with baseline severe hepatic impairment (Child-Pugh Class C). Please see additional safety information below and full Prescribing Information for complete dosage and administration and warnings and precautions.
For patients with moderate hepatic impairment (Child-Pugh Class B)* monitor serum transaminases (ALT [alanine aminotransferase] and AST [aspartate aminotransferase]) and bilirubin levels:
If elevations in ALT and/or AST >5X ULN (upper limit of normal) or total bilirubin >3X ULN occur, discontinue ZYTIGA® and do not re-treat patients with ZYTIGA®.
*There are no clinical data for ZYTIGA® 250 mg once daily in patients with moderate hepatic impairment, and caution is advised
To determine the Child-Pugh classification of your patient, view the FDA guidelines.
Permanently discontinue ZYTIGA® (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.
First occurrence of hepatotoxicity
Recurrence of hepatotoxicity (at 750 mg dose)
* LFT: Liver Function Test
Recurrence of hepatotoxicity (at 500 mg dose)
The safety of ZYTIGA® re-treatment of patients who develop AST or ALT ≥20X ULN and/or bilirubin ≥10X ULN is unknown.
For patients taking strong CYP3A4 inducers
References: 1. Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am. 2001;30(1):101-119. 2. Attard G, Reid AHM, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008;26(28):4563-4571. 3. Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA. 1999;282(7):671-676. 4. Kraan GPB, Dullaart RPF, Pratt JJ, Wolthers BG, Drayer NM, De Bruin R. The daily cortisol production reinvestigated in healthy men. The serum and urinary cortisol production rates are not significantly different. J Clin Endocrinol Metab. 1998;83(4):1247-1252.