DOSING & MONITORING
ZYTIGA® Dosing & Monitoring
HOW TO TAKE ZYTIGA® (abiraterone acetate)
- Must be taken on an empty stomach, either 1 hour before or 2 hours after a meal
- Tablets should be swallowed whole with water
- Tablets should not be crushed or chewed
- Patients should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy
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, 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 When To Modify Dose.
THE ROLE OF PREDNISONE
Co-administration of Prednisone Supresses Adrenocorticotropic Hormone (ACTH) Drive, Reducing the Incidence and Severity of Mineralocorticoid-Related Adverse Reactions1
Adrenocortical Insufficiency - AI was reported in patients receiving ZYTIGA® in combination with prednisone, after an interruption of daily steroids and/or with concurrent infection or stress. Monitor patients for symptoms and signs of AI if prednisone is stopped or withdrawn, if prednisone dose is reduced, or if the patient experiences unusual stress.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.
|Hypertension, hypokalemia, and fluid retention||Baseline and at least once a month|
|Liver function tests (ALT, AST, bilirubin)||Baseline and every 2 weeks for the first 3 months of treatment and monthly thereafter†|
- Control hypertension and correct hypokalemia before starting and during treatment with ZYTIGA®
- 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®.
- Monitor patients 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 >3X ULN and total bilirubin >2X in the absence of biliary obstruction 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
- 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.
- For more information on Dose Modification Guidelines in Hepatic Impairment and Hepatotoxicity and information on Dose Modification Guidelines for Strong CYP3A4 Inducers, see When To Modify Dose
WHEN TO MODIFY DOSE
|No/Mild Hepatic Impairment||
Impairment (Child-Pugh Class
B) Prior to treatment
Impairment (Child Pugh
Class C) Prior to treatment
No dosage adjustment is
Reduce ZYTIGA® dose to
250mg orally QD
|Do not use ZYTIGA® in patients with severe hepatic impairment (Child-Pugh Class C)|
OD = once daily; BID= twice daily.
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®.
Permanently discontinue ZYTIGA® (abiraterone acetate) for patients who develop a concurrent elevation of ALT greater than3X 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 during treatment with ZYTIGA®: ALT (alanine aminotransferase) and/or AST (aspartate aminotransferase) >5X ULN (upper limit ofnormal) 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
- 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
For patients taking CYP2D6 and CYP2C8 substrates
- Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (eg., thioridazine)
- If alternative treatments cannot be used, consider a dose reduction of the concomitant CYP2D6 substrate drug
- Patients should be monitored closely for signs of toxicity related to a CYP2C8 substrates with a narrow therapeutic index if used concomitantly with ZYTIGA®