阿比特龙ZYTIGA (Abiraterone)

【Function and indications】
Abiraterone ZYTIGA combined with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

【Zytiga models and specifications】
Tablets: oval tablets with AA250 debossed on one side.

【Usage and Dosage】
Recommended dose

Recommended dose: ZYTIGA is 1,000 mg orally administered once daily in combination with prednisone 5 mg orally administered twice daily. ZYTIGA must be taken on an empty stomach. Food should not be consumed at least 2 hours before and at least 1 hour after taking ZYTIGA [see Clinical Pharmacology]. The tablet should be swallowed whole with water.

Hepatic impairment dose adjustment guidance

Reduced recommended dose in patients with baseline moderate hepatic impairment (Child-Pugh class B): ZYTIGA is reduced to 250 mg once daily. A dose of 250 mg once daily is expected to result in an area under the curve (AUC) in patients with moderate hepatic impairment similar to the AUC seen with normal hepatic function receiving 1,000 mg once daily. However, there are no clinical data and caution is advised at a dose of 250 mg once daily in patients with moderate hepatic impairment. Monitor ALT, AST, and bilirubin prior to initiating treatment, weekly for the first month, every 2 weeks after two months of treatment, and monthly thereafter in patients with moderate hepatic impairment. If elevations of ALT and/or AST greater than 5 × upper limit of normal (ULN) or total bilirubin greater than 3 × ULN occur in patients with baseline severe hepatic impairment, discontinue ZYTIGA and do not retreat the patient with ZYTIGA [see Use in Specific Populations and Clinical Pharmacology]. Avoid ZYTIGA in patients with baseline severe hepatic impairment (Child-Pugh Class C) as ZYTIGA has not been studied in this population, and dose adjustments are not possible to predict.

Hepatotoxicity

For patients who develop hepatotoxicity (ALT and/or AST greater than 5 × ULN or total bilirubin greater than 3 × ULN) during treatment with ZYTIGA, interrupt ZYTIGA treatment [see WARNINGS AND PRECAUTIONS]. Restart treatment at a reduced dose of 750 mg once daily after liver function tests return to the patient’s baseline or to AST and ALT less than or equal to 2.5 × ULN and total bilirubin less than or equal to 1.5 × ULN. For patients resuming treatment, monitor serum transaminases and bilirubin at least every 2 weeks for three months and monthly thereafter.

If hepatotoxicity recurs at a dose of 750 mg once daily, restart-treatment at a reduced dose of 500 mg once daily after liver function tests return to the patient’s baseline or to AST and ALT less than or equal to 2.5 × ULN and total bilirubin less than or equal to 1.5 × ULN.

If hepatotoxicity recurs at the lower dose of 500 mg once daily. Discontinue treatment with ZYTIGA. The safety of retreatment with ZYTIGA in patients who develop AST or ALT greater than or equal to 20 × ULN and/or bilirubin greater than or equal to 10 × ULN is unknown.

【Clinical Studies】
The active ingredient in ZYTIGA is abiraterone acetate, 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 chemically designated 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 C26H33NO2 and molecular weight is 391.55. Abiraterone acetate is a lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is extremely insoluble in water. The pKa of aromatic nitrogen is 5.19.

The inactive ingredients in the tablets are lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, polyvinylpyridone, sodium lauryl sulfate, magnesium stearate, and colloidal silicon dioxide.

[Precautions]
History of cardiovascular disease

Hypertension, hypokalemia, and fluid retention due to excessive mineralocorticoids

Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention due to increased mineralocorticoid levels as a result of its inhibition of CYP17 [see ADVERSE REACTIONS AND CLINICAL PHARMACOLOGY]. Co-administration of corticosteroids suppresses the adrenocorticotropic hormone (ACTH) drive, resulting in a decrease in the incidence and severity of these adverse reactions. Caution must be used when treating patients whose medical conditions may be compromised by increased blood pressure, hypokalemia, or fluid retention, such as patients with heart failure, recent myocardial infarction, or ventricular arrhythmias. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA class III or IV heart failure has not been established as these patients were excluded from randomized clinical trials. Monitor patients for hypertension, hypokalemia, and fluid retention at least monthly. Control hypertension and correct hypokalemia before and during treatment with ZYTIGA.

Adrenal Insufficiency

Adrenal insufficiency has been reported in patients receiving ZYTIGA in combination with prednisone in clinical trials, after interruption of daily steroids and/or with current infection or stress. Use with caution and monitor for signs and symptoms of adrenal insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA may mask signs and symptoms of adrenal insufficiency. Confirm the diagnosis of adrenal insufficiency with appropriate testing as clinically indicated. Increased corticosteroid doses may be indicated before, during, and after stressful situations [see WARNINGS AND PRECAUTIONS].

Hepatotoxicity

Significant increases in liver enzymes leading to drug discontinuation or dose adjustment have occurred [see ADVERSE REACTIONS]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to initiating treatment with ZYTIGA, every 2 weeks for the first 3 months of treatment, and monthly thereafter. In patients with baseline severe hepatic impairment receiving a reduced dose of ZYTIGA 250 mg, measure ALT, AST, and bilirubin prior to initiating treatment, weekly for the first month, every 2 weeks for 2 months of treatment, and monthly thereafter. Promptly measure serum total bilirubin if clinical signs and symptoms suggest the development of hepatotoxicity. If AST, ALT, or bilirubin are elevated from a patient’s baseline, prompt more frequent monitoring of AST, and ALT. If AST or ALT rises above five times the ULN at any time, or bilirubin is elevated above three times the ULN, interrupt ZYTIGA treatment and monitor liver function closely.

Re-treatment with ZYTIGA at a reduced dose level is possible only after liver function tests return to the patient’s baseline or to AST and ALT less than or equal to 2.5 × ULN and total bilirubin less than or equal to 1.5 × ULN [see DOSAGE AND ADMINISTRATION].

The safety of re-treatment with ZYTIGA in patients who develop AST or ALT greater than or equal to 20 × ULN and/or bilirubin greater than or equal to 10 × ULN is unknown.

Food Effects

ZYTIGA must be taken on an empty stomach. Food should not be consumed for at least 2 hours before and at least 1 hour after taking a dose of ZYTIGA. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was given with a meal compared to the fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been evaluated [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

[Adverse Reactions and Contraindications]
The following are discussed in more detail in other sections of the labeling:

(1) Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions].

(2) Adrenal insufficiency [see Warnings and Precautions].

(3) Hepatotoxicity [see Warnings and Precautions].

(4) Food effects [see Warnings and Precautions].

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a placebo-controlled, multicenter Phase 3 clinical trial in patients with metastatic castration-resistant prostate cancer who were being treated with a gonadotropin-releasing hormone (GnRH) agonist or who had previous orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment group (N = 791). Control patients (N = 394) were given placebo plus prednisone 5 mg twice daily. The median duration of treatment with ZYTIGA was 8 months.

The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection.

The most common adverse drug reactions leading to drug discontinuation were aspartate transaminase increased, alanine transaminase increased, urosepsis, and heart failure (each <1% in patients taking ZYTIGA).

Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more frequently in patients treated with ZYTIGA than in those treated with placebo: hypokalemia 28% vs. 20%, hypertension 9% vs. 7%, and fluid retention (edema) 27% vs. 18%, respectively (see Table 1). In patients treated with ZYTIGA, Grade 3 to 4 hypokalemia occurred in 5% of patients and Grade 3 to 4 hypertension was reported in 1% of patients [see WARNINGS AND PRECAUTIONS].

Table 1 shows adverse reactions (mineralocorticoid overdose, cardiac adverse reactions, and hepatotoxicity) that occurred or had an absolute increase in frequency of ≥ 2% compared with placebo or events of special significance due to ZYTIGA.

Table 1

Cardiovascular adverse reactions

Table 1 shows cardiovascular adverse reactions in the Phase 3 trial. The majority of arrhythmias were Grade 1 or 2. The incidence of Grade 3-4 arrhythmias was similar in both groups. There was one death associated with an arrhythmia and one sudden death in the ZYTIGA group. There were no sudden deaths or arrhythmias in the placebo group. Cardiac ischemia or myocardial infarction resulted in death in two patients in the placebo group and one in the ZYTIGA group. There was one death due to heart failure in both groups.

Hepatotoxicity

Drug-related hepatotoxicity with elevations in ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, 2.3% of patients receiving ZYTIGA reported elevations in liver function tests (increases in ALT or AST > 5 × ULN), typically during the first 3 months after initiation of treatment. In the Phase 3 trials, patients with elevated baseline ALT or AST were more likely to experience liver function tests above the patient’s starting normal values. Withhold or discontinue ZYTIGA when ALT or AST elevations > 5 × ULN, or bilirubin elevations > 3 × ULN, are observed. Significant increases in liver function tests occurred in both cases [see Warnings and Precautions (5.2)]. These two patients, who had normal baseline liver function, experienced ALT or AST elevations of 15 to 40 × ULN and bilirubin elevations of 2 to 6 × ULN. When ZYTIGA was discontinued, liver function tests normalized in both patients and one patient retreated with ZYTIGA without recurrence of the elevations.

In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5 × ULN in the absence of liver metastases, and patients with ALT and/or AST > 5 × ULN in the presence of liver metastases. Liver function test abnormalities in patients participating in clinical trials were managed by interruption of treatment, dose modification and/or discontinuation [see Dosage and Administration and Warnings and Precautions]. Patients with ALT or AST elevations > 20 × ULN were discontinued from treatment.

Other Adverse Reactions

Adrenal insufficiency occurred in 2 patients (< 1%) in the Phase 3 clinical trial with abiraterone.

Laboratory Abnormalities

Laboratory abnormalities were reported as significant.

[Use in Pregnancy]

Pregnancy

Pregnancy Category X [see Contraindications].

ZYTIGA is contraindicated in women who are pregnant or who may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be advised of the potential hazard to the fetus and the potential risk of pregnancy loss. Women of childbearing potential should avoid becoming pregnant during treatment with ZYTIGA.

Nursing Mothers

ZYTIGA is not for use in women. It is not known whether 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 discontinue nursing or to discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: ZYTIGA is not for use in children.

Drug Interactions:

Abiraterone acetate (ZYTIGA) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor that inhibits 17 alpha-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in testicular, adrenal, and prostate tumor tissues and is required for androgen biosynthesis.

CYP17 catalyzes two sequential reactions: 1) conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives via 17α-hydroxylase activity and 2) subsequent formation of dehydroepiandrosterone (DHEA) and androstenedione via C17,20 lyase activity, respectively. DHEA and androstenedione are androgens and are precursors of testosterone. Inhibition of CYP17 by abiraterone may also result in increased mineralocorticoid production by the adrenal glands (see WARNINGS AND PRECAUTIONS).

Androgen-sensitive prostate cancer responds to treatment with reduced androgen levels. Androgen deprivation therapy, such as treatment with gonadotropin-releasing hormone agonists [GnRH agonists] or orchiectomy, reduces androgen production in the testes but does not affect adrenal or intratumoral androgen production.

ZYTIGA reduced serum testosterone and other androgens in patients in placebo-controlled Phase 3 clinical trials. Monitoring of the effect of ZYTIGA on serum testosterone levels is not required.

Changes in serum prostate-specific antigen (PSA) levels may be observed but have not been shown to be associated with clinical benefit in individual patients.

Pharmacokinetics

The pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects and in patients with metastatic castration-resistant prostate cancer (CRPC) following administration of abiraterone acetate. In vivo, abiraterone acetate is converted to abiraterone. In clinical studies, >99% of the samples analyzed were

Abiraterone acetate plasma concentrations in the product were below detectable levels (< 0.2 ng/mL).

Absorption

After oral administration of abiraterone acetate to patients with metastatic CRPC, the median time to reach maximum plasma abiraterone concentration was 2 hours. Abiraterone accumulation was observed at steady state, with exposure (steady-state AUC) 2-fold higher compared to a single 1,000 mg dose of abiraterone acetate.

In patients with metastatic CRPC at a dose of 1,000 mg daily, Cmax steady-state values ​​(mean ± SD) were 226 ± 178 ng/mL and AUC was 1173 ± 690 ng .hr/mL. No major deviations from dose proportionality were observed over the dose range of 250 mg to 1,000 mg.

Systemic exposure of abiraterone is increased when abiraterone acetate is administered with food. Abiraterone Cmax and AUC0-∞ were approximately 7- and 5-fold higher, respectively, when abiraterone acetate was administered with a low-fat meal (7% fat, 300 calories) and approximately 17- and 10-fold higher, respectively, when abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal. Given the normal variation in meal content and composition, administration of ZYTIGA with a meal has the potential to result in increased and highly variable exposure. Therefore, food should not be consumed for at least 2 hours before and at least 1 hour after administration of ZYTIGA. Tablets should be swallowed intact with water [see DOSAGE AND ADMINISTRATION].

DISTRIBUTION AND PROTEIN BINDING

Abiraterone is highly bound (>99%) to human plasma proteins, albumin and alpha-1 acid glycoprotein. The apparent volume of distribution at steady state (mean ± SD) is 19,669 ± 13,358 L. In vitro studies have shown that abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp) at clinically relevant concentrations and that abiraterone acetate is an inhibitor of P-gp. Studies with other transporters have not been conducted.

Metabolism

After oral administration of 14C-abiraterone acetate in capsules, abiraterone acetate is hydrolyzed to abiraterone (active metabolite). The conversion is likely mediated by esterase activity (esterase not identified) rather than CYP. The two major circulating metabolites of abiraterone in human plasma are abiraterone sulfate (inactive) and abiraterone N-oxide sulfate (inactive), each accounting for approximately 43% of exposure. CYP3A4 and SULT2A1 are the enzymes involved in the formation of abiraterone N-oxide sulfate and SULT2A1 is involved in the formation of abiraterone sulfate.

Excretion

In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma (mean ± SD) was 12 ± 5 hours. Following oral administration of 14C-abiraterone acetate, approximately 88% of the radioactive dose was recovered in feces and approximately 5% in urine. The major compounds present in feces were unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).

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 function. Systemic exposure to abiraterone following a single oral 1,000 mg dose under fasting conditions increased approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively. The mean half-life of abiraterone was prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment. ZYTIGA has not been studied in patients with baseline severe hepatic impairment (Child-Pugh Class C) [see DOSAGE AND ADMINISTRATION and USE IN SPECIFIC POPULATIONS].

Patients with Renal Impairment

The pharmacokinetics of abiraterone were examined in patients with end-stage renal disease (ESRD) on a stable hemodialysis regimen (N=8) and in matched control subjects with normal renal function (N=8). In the ESRD cohort of the trial, a single 1,000 mg ZYTIGA dose was administered under fasting conditions 1 hour after dialysis, and samples were collected up to 96 hours post-dose for pharmacokinetic analysis. A single oral 1,000 mg dose did not increase systemic exposure of abiraterone in subjects with ESRD on dialysis compared to subjects with normal renal function [see USE IN SPECIFIC POPULATIONS].

Drug Interactions

In vitro studies using human liver microsomes showed that abiraterone is a strong inhibitor of CYP1A2 and CYP2D6 and a moderate inhibitor of CYP2C9, CYP2C19, and CYP3A4/5.

In an in vivo drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) increased 2.8- and 2.9-fold, respectively, when dextromethorphan 30 mg was given daily with abiraterone acetate 1,000 mg, (plus prednisone 5 mg twice daily). The AUC of dextromethorphan, the active metabolite of dextromethorphan, increased approximately 1.3-fold [see DRUG INTERACTIONS].

In a clinical study to determine the effect of abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily) on a single 100 mg dose of the CYP1A2 substrate theophylline, no increase in systemic exposure of theophylline was observed.

Abiraterone is a substrate of CYP3A4 in vitro. The effects of strong CYP3A4 inhibitors or inducers on the pharmacokinetics of abiraterone have not been evaluated in vivo. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution [see Drug Interactions].

QT prolongation

In a multicenter, open-label, single-group trial, 33 patients with metastatic CRPC received oral ZYTIGA at a dose of 1,000 mg once daily in combination with prednisone 5 mg orally twice daily at least 1 hour before or 2 hours after a meal. Evaluation up to Day 2 of Cycle 2 showed no significant change in QTc interval from baseline (i.e., >20 ms). However, due to study design limitations, a small increase in QTc interval (i.e., <10 ms) due to abiraterone acetate cannot be excluded.

[Storage] Store at room temperature.