Dosing &
Monitoring

How to Take ZYTIGA®(abiraterone acetate)

ZYTIGA® 1,000 mg

(four 250 mg tablets) administered orally once daily

+ 

PREDNISONE 5 mg

administered orally twice daily

4-250mg 2-500mg FCT

URO duo

Without Food

Without food
No food should be eaten for at least 2 hours before taking ZYTIGA® and for 1 hour after. 

With Water

Swallow whole with water 
Tablets should be swallowed whole with water. Do not crush or chew tablets.

With Prednisone

With prednisone
The recommended dose of prednisone is 5 mg orally twice daily.

Patients receiving gonadotropin-releasing hormone agonists should maintain this treatment during the course of treatment with ZYTIGA® + prednisone.

Drug Interactions—Based on in vitro data, ZYTIGA® 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 ZYTIGA® treatment. If a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency only during the co-administration period [see Dosage and Administration (2.3)]. In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.

ZYTIGA® is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. Avoid co-administration with CYP2D6 substrates with a narrow therapeutic index. If alternative treatments cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate drug. In a CYP2C8 drug interaction trial in healthy subjects, the AUC of pioglitazone, a CYP2C8 substrate, was increased by 46% when administered with a single dose of ZYTIGA®. Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with ZYTIGA®.

For more information on Dose Modification Guidelines in Hepatic Impairment and Hepatotoxicity and information on Dose Modification Guidelines, see the dose modifications.

 

The Role of Prednisone

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.

View Established Safety Profile

​View Prednisone Coadministration Brochure​

Monitoring Considerations

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®

monitoring table


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.

 

 

When to Modify Dose

Dosing Modifications

hepatic table

For patients with moderate hepatic impairment (Child-Pugh Class B)* monitor serum transaminases (ALT [alanine aminotransferase] and AST [aspartate aminotransferase]) and bilirubin levels:

  • Prior to the start of treatment
  • For the first month of treatment, monitor every week
  • For the following 2 months of treatment, monitor every 2 weeks
  • Monthly thereafter

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

  • Patient develops hepatotoxicity: ALT (alanine aminotransferase) and/or AST (aspartate aminotransferase)
    >5X ULN (upper limit of normal) or total bilirubin >3X ULN
    • Withhold ZYTIGA® treatment and monitor LFTs*
    • Patient's LFTs return to baseline levels or patient's AST and ALT ≤2.5X ULN and total bilirubin ≤1.5X ULN
      — Resume ZYTIGA® at 750 mg once daily
    • Monitor AST, ALT, and bilirubin at a minimum of every 2 weeks for 3 months and monthly thereafter

Recurrence of hepatotoxicity (at 750 mg dose)

  • If hepatotoxicity recurs at 750 mg once daily:
    • Withhold ZYTIGA® treatment and monitor LFTs*
    • When patient's LFTs return to baseline levels or patient's AST and ALT ≤2.5X ULN and total bilirubin ≤1.5X ULN
      —    Resume ZYTIGA® at 500 mg once daily

* LFT: Liver Function Test

Recurrence of hepatotoxicity (at 500 mg dose)

  • If hepatotoxicity recurs at 500 mg once daily:
            —    Discontinue treatment with ZYTIGA®

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

  • Avoid concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during ZYTIGA® treatment
  • Although there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers, because of the potential for an interaction, if a strong CYP3A4 inducer must be co-administered, increase the ZYTIGA® dosing frequency to twice a day only during the co-administration period (eg, from 1,000 mg once daily to 1,000 mg twice a day)
  • Reduce the dose back to previous dose and frequency if the concomitant strong CYP3A4 inducer is discontinued

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.