table 4: laboratory abnormalities in >15% of Patients in the ZYtiga arm of
abiraterone (n=542) Placebo (n=540)
Laboratory Abnormality Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4
Lymphopenia 38. 2 8. 7 31. 7 7. 4
Hyperglycemia1 56. 6 6. 5 50. 9 5. 2
HighALT 41. 9 6.1 29.1 0.7
HighAST 37. 3 3.1 28. 7 1.1
Hypernatremia 32. 8 0.4 25.0 0.2
Hypokalemia 17. 2 2. 8 10. 2 1.7
1Based on non-fasting blood draws
cardiovascular adverse reactions:
In the combined data for studies 1 and 2, cardiac failure occurred more commonly
in patients treated with ZYTIGA compared to patients on the placebo arm ( 2.1%
versus 0.7%). Grade 3-4 cardiac failure occurred in 1.6% of patients taking ZYTIGA
and led to 5 treatment discontinuations and 2 deaths. Grade 3-4 cardiac failure
occurred in 0.2% of patients taking placebo. There were no treatment
discontinuations and one death due to cardiac failure in the placebo group.
In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one
death associated with arrhythmia and one patient with sudden death in the
ZYTIGA arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due
to cardiorespiratory arrest in the ZYTIGA arms and 3 (0.3%) deaths in the placebo
arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in
the placebo arms and 2 deaths in the ZYTIGA arms.
6. 2 Post marketing experience
The following additional adverse reactions have been identified during post
approval use of ZYTIGA. Because these reactions are reported voluntarily from
a population of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.
Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.
7 drUg interactions
7.1 drugs that inhibit or induce c YP3a4 enzymes
Based on in vitro data, ZYTIGA is a substrate of CYP3A4.
In a dedicated 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 [see Dosage
and Administration ( 2. 3) and Clinical Pharmacology ( 12. 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 [see Clinical Pharmacology ( 12. 3)].
7. 2 effects of abiraterone on drug metabolizing enzymes
ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a
CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan
(CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when
dextromethorphan was given with abiraterone acetate 1,000 mg daily and
prednisone 5 mg twice daily. Avoid co-administration 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 [see Clinical
Pharmacology ( 12. 3)].
In vitro, ZYTIGA inhibits CYP2C8. There are no clinical data on the use of ZYTIGA
with drugs that are substrates of CYP2C8. However, patients should be monitored
closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly
with abiraterone acetate.
8 Use in sPecific PoPUlations
Pregnancy category X [see Contraindications ( 4.1)].
ZYTIGA can cause fetal harm when administered to a pregnant woman based on
its mechanism of action and findings in animals. While there are no adequate
and well-controlled studies with ZYTIGA in pregnant women and ZYTIGA is not
indicated for use in women, it is important to know that maternal use of a CYP17
inhibitor could affect development of the fetus. Abiraterone acetate caused
developmental toxicity in pregnant rats at exposures that were lower than in
patients receiving the recommended dose. ZYTIGA is contraindicated in women
who are or may become pregnant while receiving the drug. If this drug is used
during pregnancy, or if the patient becomes pregnant while taking this drug,
apprise the patient of the potential hazard to the fetus and the potential risk for
pregnancy loss. Advise females of reproductive potential to avoid becoming
pregnant during treatment with ZYTIGA.
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.
8. 3 nursing mothers
ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate
is excreted in human milk. Because many drugs are excreted in human milk, and
because of the potential for serious adverse reactions in nursing infants from
ZYTIGA, a decision should be made to either discontinue nursing, or discontinue
the drug taking into account the importance of the drug to the mother.
8. 4 Pediatric Use
Safety and effectiveness of ZYTIGA in pediatric patients have not been
8. 5 geriatric Use
Of the total number of patients receiving ZYTIGA in phase 3 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.
8. 6 Patients with 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 1,000 mg dose of
ZYTIGA 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 adjustment is necessary for patients with baseline mild hepatic
impairment. In patients with baseline moderate hepatic impairment (Child-Pugh
Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Do not
use ZYTIGA 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 ZYTIGA
treatment [see Dosage and Administration ( 2.1) 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. 2),
Warnings and Precautions ( 5. 3), and Clinical Pharmacology ( 12. 3)].
8. 7 Patients with renal impairment
In a dedicated renal impairment trial, the mean PK parameters were comparable
between healthy subjects with normal renal function (N= 8) and those with end
stage renal disease (ESRD) on hemodialysis (N= 8) after a single oral 1,000 mg dose
of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment
[see Dosage and Administration ( 2.1) and Clinical Pharmacology ( 12. 3)].
Human experience of overdose with ZYTIGA is limited.
There is no specific antidote. In the event of an overdose, stop ZYTIGA,
undertake general supportive measures, including monitoring for arrhythmias
and cardiac failure and assess liver function.
Abiraterone acetate, the active ingredient of ZYTIGA is the acetyl ester of
abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase).
Each ZYTIGA tablet contains 250 mg of abiraterone acetate. Abiraterone acetate
is designated chemically as (3β)-17-(3-pyridinyl) androsta- 5,16-dien-3-yl acetate
and its structure is:
ZYtiga® (abiraterone acetate) tablets ZYtiga® (abiraterone acetate) tablets