Xbira

Abiraterone Instructions

Common name: Abiraterone

Trade name: Abiraterone

All names : Abiraterone, Zyco, Abiraterone, Zytiga

Indications:

Used in combination with prednisone, it is suitable for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received previous docetaxel-containing chemotherapy.

Usage and dosage:

Recommended dosage

The recommended dosage of this product is 1000 mg (4x250 mg tablets) orally once a day, combined with 5 mg of prednisone orally twice a day. This product must be taken on an empty stomach. Taking it with food will increase the systemic exposure of this product. Do not eat for at least 2 hours before taking this product and for at least 1 hour after taking this product (see Pharmacokinetics). This product should be swallowed whole with water. Do not crush or chew.

Adverse Reactions

The most common adverse reactions (≥ 5%) of abiraterone are joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flashes, diarrhea, urinary tract infection, cough, hypertension, cardiac arrhythmia, urinary frequency, nocturia, indigestion, and upper respiratory tract infection.

Contraindications:

Abiraterone may cause fetal harm when administered to pregnant women. ZYTIGA is contraindicated in women who are pregnant or may become pregnant. If the drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be counseled about the potential hazard to the fetus.

Precautions:

Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess

Use ZYTIGA with caution in patients with a history of cardiovascular disease. Hypertension, hypokalemia, and fluid retention due to increased mineralocorticoid levels may occur as a result of ZYTIGA's inhibition of CYP17 [see Adverse Reactions and Clinical Pharmacology]. Coadministration of corticosteroids inhibits adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. It must be used with caution when the patient is being treated for a medical condition that may be compromised by increased blood pressure, hypokalemia, or fluid retention, such as in patients with heart failure, recent myocardial infarction, or ventricular arrhythmias. The safety of ZYTIGA has not been established in patients with left ventricular ejection fraction <50% or NYHA class III or IV heart failure because 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.

Adrenocortical Insufficiency

Adrenocortical insufficiency has been reported in patients receiving ZYTIGA in combination with prednisone in clinical trials, after discontinuation of daily steroids and/or with current infection or stress. Use caution and monitor for signs and symptoms of adrenocortical insufficiency, especially if the patient is withdrawn from prednisone, has a prednisone dose reduction, or experiences unusual stress. Adverse effects associated with mineralocorticoid overdose seen in patients treated with ZYTIGA may mask symptoms and signs of adrenocortical insufficiency. If clinically indicated, perform appropriate testing to confirm the diagnosis of adrenocortical insufficiency. Increased corticosteroid dosage may be indicated before, during, and after stressful situations [see Warnings and Precautions].

Hepatotoxicity

Significant increases in hepatic enzymes have occurred leading to discontinuation of the drug or dose adjustment [see Adverse Reactions]. Before initiating treatment with ZYTIGA, measure serum aminotransferase (ALT and AST) and bilirubin levels every 2 weeks for the first three 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 before initiating treatment weekly for the first month, every 2 weeks for 2 months after treatment, and monthly thereafter. If clinical symptoms and signs suggest the occurrence of hepatotoxicity, measure serum total bilirubin promptly. Elevations in AST, ALT, or bilirubin from baseline in patients should prompt more frequent monitoring of AST, and ALT. If at any time AST or ALT rises more than five times the ULN, or bilirubin is rises more than three times the ULN, interrupt ZYTIGA treatment and monitor liver function closely.

Re-treatment with ZYTIGA at a reduced dose level may only be possible after liver function tests have returned to the patient's baseline or until AST and ALT are less than or equal to 2.5 × ULN and total bilirubin is less than or equal to 1.5 × ULN [see Dosage and Administration].

The safety of ZYTIGA re-treatment 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 at least 2 hours before taking a dose of ZYTIGA and at least 1 hour after taking a dose of ZYTIGA. When a single dose of abiraterone acetate is given with a meal, the abiraterone Cmax and AUC0-∞ (exposure) are increased up to 17- and 10-fold, respectively, when compared to the fasting state. The safety of these increased exposures when abiraterone acetate is administered multiple times with food has not been evaluated [see Dosage and Administration and Clinical Pharmacology].

Pregnant and lactating women:

Pregnancy

ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used in humans, or if a patient becomes pregnant while taking this drug, the patient should be counseled of the potential harm to the fetus and the potential risk of pregnancy loss. It is recommended that women of childbearing age should avoid becoming pregnant during treatment with ZYTIGA.

Breastfeeding mothers

ZYTIGA is not suitable for 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, decisions should be made to either discontinue breastfeeding, or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

Abiraterone is not suitable for children.

Geriatric Use

Of the total number of patients in a Phase 3 ZYTIGA trial, 71% of patients were 65 years and older and 28% were 75 and older. No overall differences in safety and efficacy were observed between these older patients and younger patients.

Patients with Hepatic Impairment

No dose adjustment is required in patients with mild hepatic impairment at baseline. In patients with baseline moderate hepatic impairment (Child-Pugh Category B), reduce the recommended dose of ZYTIGA to 250 mg once daily. Discontinue ZYTIGA therapy if an increase in ALT or AST >5 × ULN or total bilirubin >3 × ULN occurs in patients with baseline moderate hepatic impairment [see Dosage and Administration and Clinical Pharmacology].

The safety of ZYTIGA has not been studied in patients with severe hepatic impairment at baseline. These patients should not receive ZYTIGA.

For patients who develop hepatotoxicity during treatment, treatment is interrupted and dose adjustments may be necessary [see Dosage and Administration, Warnings and Precautions, and Clinical Pharmacology].

Patients with renal impairment

In a dedicated renal impairment trial, mean PK parameters following a single oral 1,000 mg dose of ZYTIGA were comparable between healthy subjects with normal renal function (N=8) and subjects with end-stage renal disease (ESRD) undergoing hemodialysis (N=8). No dosage adjustment is required in patients with renal impairment [see Dosage and Administration and Clinical Pharmacology].

Overdose

In the event of overdose, discontinue ZYTIGA and institute general supportive measures, including monitoring for cardiac arrhythmias and heart failure and evaluation of liver function.

Pharmacological toxicity

Pharmacological effects

Abiraterone acetate is converted into abiraterone in the body. Abiraterone is an androgen biosynthesis inhibitor that can inhibit 17α-hydroxylase/C17,20-lyase (CYP17), which is expressed in testis, adrenal gland and prostate tumor tissues and is required for androgen biosynthesis.

CYP17 catalyzes two consecutive reactions:

The conversion of pregnenolone and progesterone into their respective 17α-hydroxy derivatives is catalyzed by 17α-hydroxylase;

The subsequent formation of dehydroepiandrosterone and androstenedione, respectively, is catalyzed by C17 and 20 lyases. Dehydroepiandrosterone and androstenedione are both androgens and precursors to testosterone. Abiraterone printing also results in increased adrenal mineralocorticoid production.

Androgen-sensitive prostate cancer may respond to androgen-lowering therapy. Androgen-depriving therapies such as gonadotropin-releasing hormone (GnRH) agonists or orchiectomy reduce androgen production in the testicles but do not affect androgen production in the adrenal glands or tumors.

In a placebo-controlled phase III clinical trial, abiraterone acetate caused a decrease in serum testosterone and other androgen levels in patients. During clinical use, there is no need to monitor the effect of this product on serum testosterone levels.

Serum prostate-specific antigen (PSA) levels may vary, but their correlation with clinical benefit in individual patients has not been proven.

Toxicological studies

Repeated dose toxicity:

In repeated dose toxicity studies in rats at 13 and 26 weeks and in monkeys at 13 and 39 weeks, abiraterone acetate caused a decrease in circulating testosterone levels at approximately half the human clinical exposure (AUC). Accordingly, decreased organ weight and some toxicity were observed in the male and female reproductive systems, adrenal glands, liver, pituitary gland (in rats only), and male mammary glands. Changes in reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate. A dose-dependent increase in the incidence of cataracts in rats was observed after 26 weeks of administration at doses of ≥50 mg/kg/day (approximate human AUC). In a 39-week study in monkeys, no cataracts were observed at higher doses (>2 times the human AUC). All other toxicities caused by abiraterone acetate were reversed or partially recovered after a 4-week recovery period.

Genotoxicity:

Abiraterone acetate and abiraterone Ames tests, human lymphocyte cytogenetic tests and rat micronucleus tests were all negative.

Reproductive toxicity:

According to animal test results, abiraterone acetate may damage human reproductive function and fertility. In repeated-dose toxicity studies in male rats (13 and 26 weeks) and monkeys (39 weeks), reproductive system atrophy, azoospermia/penospermia, and proliferative changes were seen at doses of ≥ 50 mg/kg/day (rats) and ≥ 250 mg/kg/day (monkeys). The effects are consistent with the anti-androgenic pharmacological activity of abiraterone. These effects were observed in rats and monkeys at AUCs close to and approximately 0.6 times the clinical exposure in humans, respectively.

Carcinogenicity:

A two-year carcinogenicity test in rats after oral administration showed that: male rats were given abiraterone acetate at 5, 15 and 50 mg/kg/day, and female rats at 15, 50 and 150 mg/kg/day. Each dose could induce testicular Leydig cell adenoma and Leydig cell carcinoma, which is believed to be related to the pharmacological activity of abiraterone. Abiraterone acetate was not shown to be carcinogenic in female mice at 0.8 times the human exposure. No carcinogenicity was seen in a 6-month carcinogenicity study in Tg.rasH2 transgenic mice.

Action Category

Abiraterone is an inhibitor of the hepatic drug metabolizing enzyme CYP2D6. Because of the narrow therapeutic index, avoid coadministration of abiraterone with CYP2D6 substrates. If alternative treatment cannot be used, exercise caution and consider reducing the dose of concurrently administered CYP2D6 substrates.

Pharmacokinetics

The pharmacokinetics of abiraterone and abiraterone acetate following administration of abiraterone acetate have been studied in healthy subjects and patients with metastatic castration-resistant prostate cancer (CRPC). In the body, abiraterone acetate is converted to abiraterone. In clinical studies, abiraterone acetate plasma concentrations were below detectable levels (< 0.2 ng/mL) in >99% of samples analyzed.

Absorption

After oral administration of abiraterone acetate to patients with metastatic CRPC, the median time to reach the highest plasma abiraterone concentration is 2 hours. Accumulation of abiraterone acetate 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, the Cmax steady-state value (mean ± SD) was 226 ± 178 ng/mL and the AUC was 1173 ± 690 ng .hr/mL. No important deviations from dose proportionality were observed in the dose range 250 mg to 1,000 mg.

Systemic exposure of abiraterone acetate 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 normal variation in meal content and composition, taking 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 dosing ZYTIGA and for at least 1 hour after dosing ZYTIGA. Swallow the tablets whole 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 steady-state volume of distribution (mean ± SD) was 19,669 ± 13,358 L. In vitro studies have shown that at clinically relevant concentrations, abiraterone acetate and abiraterone acetate are not substrates of P-glycoprotein (P-gp) and abiraterone acetate is an inhibitor of P-gp. Studies have not been performed with other transport proteins.

Metabolism

After oral administration of 14C-abiraterone acetate capsules, abiraterone acetate is hydrolyzed to abiraterone (active metabolite). Conversion may be mediated by esterase activity (esterase has not yet been identified) rather than CYP. The two major circulating metabolites of abiraterone in human plasma are abiraterone sulfate (inactive) and abiraterone oxynitroxide sulfate (inactive), each accounting for approximately 43% of exposure. CYP3A4 and SULT2A1 are enzymes involved in the formation of nitroxide abiraterone 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. After oral administration of 14C-abiraterone acetate, approximately 88% of the radioactivity dose is recovered in feces and approximately 5% in urine. The main compounds present in the feces were unchanged abiraterone acetate and abiraterone acetate (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 categories 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 on an empty stomach 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 extended 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 Category 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 trial ESRD cohort, a single 1,000 mg dose of ZYTIGA was administered under fasting conditions 1 hour after dialysis, and samples were collected up to 96 hours postdose for pharmacokinetic analyses. A single oral 1,000 mg dose did not increase systemic exposure to abiraterone in subjects with end-stage renal disease on dialysis compared with subjects with normal renal function [see Use in Specific Populations].

Drug Interactions

In vitro studies using human liver microsomes have shown 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 study, the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan 30 mg daily was administered with abiraterone acetate 1,000 mg (plus prednisone 5 mg twice daily). The AUC of dextrorphan, the active metabolite of dextromethorphan, increased nearly 1.3-fold [see Drug Interactions].

In a clinical study determining 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 to theophylline was observed.

Abiraterone is a substrate of CYP3A4 in vitro. The effects of strong CYP3A4 inhibitors or inducers on abiraterone pharmacokinetics 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-arm 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. Assessment through Day 2 of Cycle 2 showed no large change in QTc interval from baseline (i.e., >20 ms). However, small increases in QTc interval (i.e., <10 ms) cannot be excluded due to abiraterone acetate due to study design limitations.

Mechanism of action:

Abiraterone (ZYTIGA) is an androgen biosynthesis inhibitor that inhibits 17 α-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. Pregnenolone and progesterone are converted into their 17α-hydroxy derivatives through 17α-hydroxylase activity.

2. Through C17, 20 lyase activity, dehydroepiandrosterone (DHEA) and androstenedione are subsequently formed respectively. DHEA and androstenedione are androgens and precursors to testosterone.

Inhibition of CYP17 may also lead to increased adrenal mineralocorticoid production (see Warnings and Precautions).

Androgen-sensitive prostate cancer responds to androgen-lowering treatments. ZYTIGA may reduce serum testosterone and other androgen levels.

Approval and Use

In April 2011, the FDA approved Johnson & Johnson’s abiraterone in combination with prednisone for mCRPC patients who had previously received docetaxel chemotherapy;

In July 2011, abiraterone was approved in Canada for the treatment of patients with metastatic advanced prostate cancer who had previously received paclitaxel;

In September 2011, abiraterone was launched in the UK for the initial use of paclitaxel. mCRPC patients treated with paclitaxel chemotherapy;

In October 2011, Johnson & Johnson launched abiraterone in Germany, Portugal, and Denmark, and in Norway in November,

In April 2012, it was approved in Switzerland;

In December 2012, abiraterone was again approved in the United States for the treatment of mCRPC patients who received chemotherapy for the first time after failure of androgen therapy;

In January 2013, the European Union approved this indication;

In May 2013, Canada approved it for use in combination with prednisone to treat patients with mCRPC who have failed mild to moderate androgen therapy;

In September 2014, abiraterone was launched in Japan for the treatment of prostate cancer;

In April 2015, China approved it for the treatment of mCRPC.

Storage:

Disposal and storage at 20℃ to 25℃; going out is allowed at 15℃ to 30℃.