Zytiga Information
Zytiga (Estrogens, conjugated) Indications And Usage
Zytiga (Estrogens, conjugated) in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.
Zytiga (Estrogens, conjugated) Dosage Forms And Strengths
Zytiga (Estrogens, conjugated) (abiraterone acetate) 250 mg tablets are white to off-white, oval-shaped tablets debossed with AA250 on one side.
Zytiga (Estrogens, conjugated) Warnings And Precautions
Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred . Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with Zytiga (Estrogens, conjugated) , every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced Zytiga (Estrogens, conjugated) dose of 250 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 Zytiga (Estrogens, conjugated) treatment and closely monitor liver function.
Re-treatment with Zytiga (Estrogens, conjugated) 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
The safety of Zytiga (Estrogens, conjugated) 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.
Zytiga (Estrogens, conjugated) Adverse Reactions
The following are discussed in more detail in other sections of the labeling:
Zytiga (Estrogens, conjugated) Use In Specific Populations
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 (Estrogens, conjugated) 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.
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 (Estrogens, conjugated) to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue Zytiga (Estrogens, conjugated) treatment .
The safety of Zytiga (Estrogens, conjugated) in patients with baseline severe hepatic impairment has not been studied. These patients should not receive Zytiga (Estrogens, conjugated) .
For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required
Zytiga (Estrogens, conjugated) Overdosage
There have been no reports of overdose of Zytiga (Estrogens, conjugated) during clinical studies.
There is no specific antidote. In the event of an overdose, stop Zytiga (Estrogens, conjugated) , undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.
Zytiga (Estrogens, conjugated) Description
Abiraterone acetate, the active ingredient of Zytiga (Estrogens, conjugated) is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). Each Zytiga (Estrogens, conjugated) 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:
Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its molecular formula is CHNO and it has a molecular weight of 391.55. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is practically insoluble in water. The pKa of the aromatic nitrogen is 5.19.
Inactive ingredients in the tablets are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, and colloidal silicon dioxide.
Zytiga (Estrogens, conjugated) Clinical Pharmacology
Abiraterone acetate (Zytiga (Estrogens, conjugated) ) is converted to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.
CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase activity. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production by the adrenals .
Androgen sensitive prostatic carcinoma responds to treatment that decreases androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or orchiectomy, decrease androgen production in the testes but do not affect androgen production by the adrenals or in the tumor.
Zytiga (Estrogens, conjugated) decreased serum testosterone and other androgens in patients in the placebo-controlled phase 3 clinical trial. It is not necessary to monitor the effect of Zytiga (Estrogens, conjugated) on serum testosterone levels.
Changes in serum prostate specific antigen (PSA) levels may be observed but have not been shown to correlate with clinical benefit in individual patients.
Zytiga (Estrogens, conjugated) Nonclinical Toxicology
Long-term animal studies have not been conducted to evaluate the carcinogenic potential of abiraterone acetate.
Abiraterone acetate and abiraterone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the cytogenetic assay using primary human lymphocytes and in the rat micronucleus assay.
Developmental or reproductive toxicology studies were not conducted with abiraterone acetate. In studies in rats (13- and 26-weeks) and monkeys (39-weeks), atrophy, aspermia/hypospermia, and hyperplasia in the reproductive system were observed at ≥50 mg/kg/day in rats and ≥250 mg/kg/day in monkeys and were consistent with the antiandrogenic pharmacological activity of abiraterone . These effects were observed in rats and monkeys at approximately 1.14 and 0.6 the human clinical exposure based on AUC, respectively.
Zytiga (Estrogens, conjugated) Clinical Studies
The efficacy and safety of Zytiga (Estrogens, conjugated) in patients with metastatic castration-resistant prostate cancer (CRPC) who had received prior chemotherapy containing docetaxel were assessed in a randomized, placebo-controlled, multicenter phase 3 clinical trial. A total of 1195 patients were randomized 2:1 to receive either Zytiga (Estrogens, conjugated) orally at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice daily (N=797) or placebo once daily plus prednisone 5 mg orally twice daily (N=398). Patients randomized to either arm were to continue treatment until disease progression (defined as a 25% increase in PSA over the patient's baseline/nadir together with protocol-defined radiographic progression and symptomatic or clinical progression), initiation of new treatment, unacceptable toxicity or withdrawal. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from this trial.
The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 39–95) and the racial distribution was 93.3% Caucasian, 3.6% Black, 1.7% Asian, and 1.6% Other. Eighty-nine percent of patients enrolled had an ECOG performance status score of 0–1 and 45% had a Brief Pain Inventory score of ≥ 4 (patient's reported worst pain over the previous 24 hours). Ninety percent of patients had metastases in bone and 30% had visceral involvement. Seventy percent of patients had radiographic evidence of disease progression and 30% had PSA-only progression. Seventy percent of patients had previously received one cytotoxic chemotherapy regimen and 30% received two regimens.
The protocol pre-specified interim analysis was conducted after 552 deaths and showed a statistically significant improvement in overall survival in patients treated with Zytiga (Estrogens, conjugated) compared to patients in the placebo arm (Table 3 and Figure 1). An updated survival analysis was conducted when 775 deaths (97% of the planned number of deaths for final analysis) were observed. Results from this analysis were consistent with those from the interim analysis (Table 3).
AA= Zytiga (Estrogens, conjugated)
Zytiga (Estrogens, conjugated) How Supplied/storage And Handling
Zytiga (Estrogens, conjugated) (abiraterone acetate) 250 mg tablets are white to off-white, oval tablets debossed with AA250 on one side. Zytiga (Estrogens, conjugated) 250 mg tablets are available in high-density polyethylene bottles of 120 tablets.
NDC Number 57894-150-12
Zytiga (Estrogens, conjugated) Patient Counseling Information
See FDA-approved patient labeling ()
Zytiga (Estrogens, conjugated)
Zytiga (Estrogens, conjugated)
Zytiga (Estrogens, conjugated)
