Abiraterone Acetate

Pronunciation

Class: Antineoplastic Agents
Chemical Name: (3β)-17-(3-Pyridinyl)-16-dien-3-ol-androsta-5 acetate(ester)
Molecular Formula: C26H33NO2
CAS Number: 154229-18-2
Brands: Zytiga

Introduction

Antineoplastic agent; inhibitor of 17α-hydroxylase/C17,20-lyase (CYP17).1 5 6 10 13

Uses for Abiraterone Acetate

Prostate Cancer

In combination with prednisone for the treatment of metastatic castration-resistant prostate cancer previously treated with docetaxel-containing therapy.1 4 18

Slideshow: Flashback: FDA Drug Approvals 2013

Abiraterone Acetate Dosage and Administration

General

  • Increasing the corticosteroid dosage before, during, and after stressful situations may be indicated to prevent adrenocortical insufficiency.1 (See Adrenocortical Insufficiency under Cautions.)

  • Women who are or may be pregnant should not handle abiraterone acetate tablets without protection (e.g., gloves).1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Administration

Oral Administration

Administer orally once daily on an empty stomach; consume no food for at least 2 hours before or 1 hour after a dose.1 18 (See Effect of Food on Abiraterone Absorption under Cautions.)

Administer tablets whole with water.1

Dosage

Available as abiraterone acetate; dosage expressed in terms of the salt.1

Adults

Prostate Cancer
Oral

1 g once daily in combination with prednisone 5 mg orally twice daily.1 4

Continue therapy for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1 3

Dosage Modification for Toxicity
Hepatic Toxicity

For ALT and/or AST elevations >5 times ULN or total bilirubin elevations >3 times ULN, interrupt dosing until liver function test results return to baseline or until ALT and AST return to ≤2.5 times ULN and total bilirubin returns to ≤1.5 times ULN, and then resume at a reduced dosage of 750 mg once daily.1

If hepatic toxicity recurs on dosage of 750 mg daily, interrupt dosing until liver function test results return to baseline or until ALT and AST return to ≤2.5 times ULN and total bilirubin returns to ≤1.5 times ULN, and then resume at a reduced dosage of 500 mg once daily.1

If hepatic toxicity recurs on dosage of 500 mg daily, discontinue abiraterone.1

In patients reinitiating therapy, measure serum transaminases and bilirubin at least every 2 weeks for 3 months and then monthly thereafter.1 (See Hepatic Toxicity under Cautions.)

Safety of reinitiating abiraterone in patients who exhibited ALT or AST elevations ≥20 times ULN and/or bilirubin elevations ≥10 times ULN is unknown.1

Special Populations

Hepatic Impairment

Mild preexisting hepatic impairment (Child-Pugh class A): No dosage adjustment required.1

Moderate preexisting hepatic impairment (Child-Pugh class B): 250 mg once daily.1 Monitor serum transaminases and bilirubin at baseline, every week for the first month of therapy, every 2 weeks during the second and third months, and then monthly thereafter.1 If elevations in ALT and/or AST to >5 times ULN or in total bilirubin to >3 times ULN occur, permanently discontinue abiraterone.1 (See Pharmacokinetics and also see Hepatic Toxicity under Cautions.)

Severe preexisting hepatic impairment (Child-Pugh class C): Use not recommended.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required.1

Geriatric Patients

No dosage adjustment required.1

Cautions for Abiraterone Acetate

Contraindications

  • Women who are or may become pregnant.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Contraindicated in women who are or may become pregnant.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1

Women who are or may be pregnant should not handle abiraterone acetate tablets without protection (e.g., gloves).1

Not known whether abiraterone or its metabolites distribute into semen.1 During and for 1 week following discontinuance of abiraterone therapy, men receiving the drug should use a condom during sexual encounters with pregnant women and should use a condom in conjunction with another effective contraceptive method during sexual encounters with women of childbearing potential.1

Excessive Mineralocorticoid Activity

Mineralocorticoid excess occurs secondary to CYP17 blockade by abiraterone; commonly manifested as hypertension, hypokalemia, and fluid retention.1 9 10 12 14 Concomitant glucocorticoid administration may reduce severity and incidence of these adverse effects.1 5 7 8 9 10 12 14

Monitor at least monthly for hypertension, hypokalemia, and fluid retention.1 Control BP and correct hypokalemia before and during treatment.1

Use with caution in patients with a history of cardiovascular disease or underlying medical condition that might be compromised by increased BP, hypokalemia, or fluid retention (e.g., heart failure, recent MI, ventricular arrhythmia).1

Safety not established in patients with left ventricular ejection fraction <50% or NYHA class III or IV heart failure.1

Adrenocortical Insufficiency

Adrenocortical insufficiency reported following interruption of daily corticosteroid regimen and/or during periods of infection or stress.1

Use with caution and monitor for manifestations of adrenocortical insufficiency, especially following prednisone dosage reduction or discontinuance or when patient is subjected to unusual stress.1 Consider possible need for increased corticosteroid dosage before, during, and after stressful situations.1

Symptoms of mineralocorticoid excess may mask manifestations of adrenocortical insufficiency; perform appropriate tests to confirm diagnosis of adrenocortical insufficiency if clinically indicated.1

Hepatic Toxicity

ALT or AST elevations of >5 times ULN reported in 2.3% of patients, generally during the initial 3 months of therapy.1

Elevations in liver function test results reported more frequently in patients with preexisting ALT or AST elevations than in patients with normal baseline values.1

Monitor serum transaminase and bilirubin concentrations at baseline, every 2 weeks for the first 3 months of therapy, and then monthly thereafter.1 In patients with moderate preexisting hepatic impairment, monitor serum transaminase and bilirubin concentrations at baseline, every week for the first month of therapy, every 2 weeks during the second and third months, and then monthly thereafter.1 (See Dosage Modification for Toxicity under Dosage and Administration.)

More frequent monitoring is indicated if transaminase or bilirubin concentrations rise above pretreatment levels.1 Evaluate liver function tests promptly if manifestations suggestive of hepatotoxicity develop.1

Effect of Food on Abiraterone Absorption

Systemic exposure and peak plasma concentration of abiraterone are increased up to tenfold and 17-fold, respectively, when administered with a meal instead of in fasted state.1 8 13 (See Food under Pharmacokinetics.)

Because of normal variations in content and composition of meals, administration with food is likely to result in highly variable exposure to the drug.1 Safety of administering multiple doses with food not established.1

Abiraterone acetate must be taken on an empty stomach; consume no food for at least 2 hours before or 1 hour after a dose.1

Specific Populations

Pregnancy

Category X.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether distributed into milk; discontinue nursing or drug.1

Pediatric Use

Not indicated in children; safety and efficacy not established.1

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults.1

Hepatic Impairment

Systemic exposure may be increased.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Dosage adjustment and careful monitoring of hepatic function required in patients with moderate hepatic impairment (Child-Pugh class B).1 (See Hepatic Impairment under Dosage and Administration.)

Not studied and not recommended in patients with severe hepatic impairment (Child-Pugh class C).1 Patients with active hepatitis or with baseline ALT and/or AST concentrations ≥2.5 times ULN in the absence of liver metastases or >5 times ULN in the presence of liver metastases were excluded from clinical trials.1 4

Common Adverse Effects

Joint swelling or discomfort,1 hypokalemia,1 4 edema,1 4 muscle discomfort,1 hot flush,1 diarrhea,1 4 urinary tract infection,1 4 cough,1 hypertension,1 4 arrhythmia,1 4 urinary frequency,1 nocturia,1 dyspepsia,1 upper respiratory tract infection,1 hypertriglyceridemia,1 hypophosphatemia,1 elevated transaminase and total bilirubin concentrations.1 4

Interactions for Abiraterone Acetate

Abiraterone is a potent inhibitor of CYP1A2 and CYP2D6, a moderate inhibitor of CYP isoenzymes 2C9, 2C19, and 3A4/5, and a substrate of CYP3A4 in vitro.1

Neither abiraterone acetate nor abiraterone is a substrate of P-glycoprotein (P-gp) in vitro at clinically relevant concentrations; abiraterone acetate inhibits P-gp.1

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Possible increased serum concentrations of abiraterone.1 18 Avoid concomitant use or use with caution.1 (See Specific Drugs and Foods under Interactions.)

Potent CYP3A4 inducers: Possible decreased serum concentrations of abiraterone.1 18 Avoid concomitant use or use with caution.1 (See Specific Drugs and Foods under Interactions.)

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6: Possible increased serum concentrations of CYP2D6 substrate drug and possible toxicity.1 18 Avoid concomitant use of abiraterone and CYP2D6 substrates with a narrow therapeutic index.1 15 If concomitant use cannot be avoided, consider dosage reduction of the CYP2D6 substrate drug and use with caution.1 15 (See Specific Drugs and Foods under Interactions.)

Substrates of CYP1A2: Pharmacokinetic interaction not observed to date.1

Specific Drugs and Foods

Drug or Food

Interaction

Comments

Antifungals, azoles (e.g., itraconazole, ketoconazole, voriconazole)

Possible increased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Antimycobacterials, rifamycins (e.g., rifabutin, rifampin, rifapentine)

Possible decreased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Carbamazepine

Possible decreased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Dextromethorphan

Increased peak concentrations and AUC of dextromethorphan1 2

Grapefruit or grapefruit juice

Possible increased abiraterone concentrations1 17 18

Avoid concomitant use or use concomitantly with caution1 17

HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)

Possible increased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Macrolides (clarithromycin, telithromycin)

Possible increased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Nefazodone

Possible increased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Phenobarbital

Possible decreased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Phenytoin

Possible decreased abiraterone concentrations1 18

Avoid concomitant use or use concomitantly with caution1

Theophylline

No change in systemic exposure of single-dose theophylline1

Thioridazine

Possible increased thioridazine concentrations1 15 18

Avoid concomitant use; if concomitant use cannot be avoided, consider thioridazine dosage reduction and use with caution1 15

Abiraterone Acetate Pharmacokinetics

Absorption

Bioavailability

Abiraterone acetate is a prodrug that is converted in vivo to abiraterone; peak plasma abiraterone concentrations are attained about 2 hours after abiraterone acetate dose.1 5 13

Food

Food increases systemic exposure.1 8 13 Oral administration of a single 1-g dose of abiraterone acetate with a low-fat or high-fat meal increases abiraterone AUC by approximately fivefold or tenfold, respectively, and increases peak plasma concentrations by approximately sevenfold or 17-fold, respectively.1

Special Populations

In patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, AUC is increased 1.1- or 3.6-fold, respectively, compared with individuals with normal hepatic function.1

Distribution

Plasma Protein Binding

>99% (mainly albumin and α1-acid glycoprotein).1

Elimination

Metabolism

Abiraterone acetate is hydrolyzed to abiraterone (active metabolite), most likely by esterases in non-CYP-dependent pathways.1 Further metabolized to 2 inactive sulfate conjugates, abiraterone sulfate (formed by SULT2A1, a sulfotransferase that catalyzes sulfate conjugation of dehydroepiandrosterone [DHEA] and other steroids) and N-oxide abiraterone sulfate (formed by CYP3A4 and SULT2A1).1 19

Elimination Route

Excreted in feces (88%), mainly as abiraterone acetate (55%) and abiraterone (22%), and in urine (5%).1

Half-life

Approximately 12 hours.1

Special Populations

Mean half-life in patients with mild or moderate hepatic impairment is approximately 18 hours or 19 hours, respectively.1

In patients with end-stage renal disease requiring hemodialysis, pharmacokinetic parameters were similar to those in individuals with normal renal function.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Actions

  • Abiraterone acetate is a prodrug of abiraterone, a potent, selective, and irreversible inhibitor of 17α-hydroxylase/C17,20-lyase (CYP17), an enzyme expressed in adrenal glands, testes, and prostate tumor.1 5 6 10 12 13 CYP17 inhibition results in suppression of androgen production.10 12

  • 17α-Hydroxylase catalyzes conversion of pregnenolone and progesterone to their 17α-hydroxy derivatives; C17,20-lyase catalyzes conversion of these 17α-hydroxy derivatives to DHEA and androstenedione, respectively.1 6 10 12 DHEA and androstenedione are androgenic precursors of testosterone.1 6 10 12

  • Abiraterone is tenfold to 30-fold more potent than ketoconazole (a nonspecific CYP inhibitor and weak inhibitor of CYP17) in its inhibition of CYP17.5 9

  • CYP17 inhibition can result in increased mineralocorticoid synthesis.3

Advice to Patients

  • Importance of taking prednisone as directed to minimize adverse effects of abiraterone.1 If a dose of abiraterone or prednisone is missed, take the next dose at the regularly scheduled time; importance of advising clinician if more than one daily dose of abiraterone is missed.1

  • For patients currently receiving gonadotropin-releasing hormone (GnRH) agonist therapy, importance of continuing this therapy during abiraterone therapy.1

  • Risk of increased abiraterone exposure and adverse effects if the drug is taken with food.1 Importance of swallowing abiraterone acetate tablets whole with water and consuming no food for at least 2 hours before or 1 hour after a dose.1

  • Risk of peripheral edema, hypokalemia, hypertension, and urinary tract infection.1

  • Risk of hepatotoxicity and importance of liver function test monitoring.1

  • Importance of advising patients that abiraterone may cause fetal harm and that it is not known whether the drug distributes into semen.1 Necessity of advising men to use a condom during sexual encounters with pregnant women and to use a condom in conjunction with another effective contraceptive method during sexual encounters with women of childbearing potential; these contraceptive measures are required during and for 1 week after discontinuance of abiraterone therapy.1 Importance of advising patients that women who are or may be pregnant should not handle abiraterone acetate tablets without protection (e.g., gloves).1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Abiraterone Acetate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

250 mg

Zytiga

Centocor Ortho Biotech

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Zytiga 250MG Tablets (JANSSEN BIOTECH): 30/$1,491.00 or 90/$4,458.15

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 4, 2012. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Centocor Ortho Biotech Inc. Zytiga (abiraterone acetate) tablets prescribing information. Horsham, PA; 2011 Apr.

2. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 202379orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

3. US Food and Drug Administration. Center for Drug Evaluation and Research: Application number 202379: Summary review for abiraterone. From FDA website.

4. de Bono JS, Logothetis CJ, Molina A et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011; 364:1995-2005. [PubMed 21612468]

5. Reid AH, Attard G, Danila DC et al. Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. J Clin Oncol. 2010; 28:1489-95. [PubMed 20159823]

6. Salem M, Garcia JA. Abiraterone acetate, a novel adrenal inhibitor in metastatic castration-resistant prostate cancer. Curr Oncol Rep. 2011; 13:92-6. [PubMed 21243537]

7. Attard G, Reid AH, A’Hern R et al. Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol. 2009; 27:3742-8. [PubMed 19470933]

8. Attard G, Reid AH, Yap TA et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol. 2008; 26:4563-71. [PubMed 18645193]

9. Attard G, Richards J, de Bono JS. New strategies in metastatic prostate cancer: targeting the androgen receptor signaling pathway. Clin Cancer Res. 2011; 17:1649-57. [PubMed 21372223]

10. Massard C, Fizazi K. Targeting continued androgen receptor signaling in prostate cancer. Clin Cancer Res. 2011; 17:3876-83. [PubMed 21680543]

11. Heinlein CA, Chang C. Androgen receptor in prostate cancer. Endocr Rev. 2004; 25:276-308. [PubMed 15082523]

12. Molina A, Belldegrun A. Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling. J Urol. 2011; 185:787-94. [PubMed 21239012]

13. Ryan CJ, Smith MR, Fong L et al. Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. J Clin Oncol. 2010; 28:1481-8. [PubMed 20159824]

14. Danila DC, Morris MJ, de Bono JS et al. Phase II multicenter study of abiraterone acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant prostate cancer. J Clin Oncol. 2010; 28:1496-501. [PubMed 20159814]

15. Janssen. Titusville, NJ: Personal communication.

16. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 202379orig1s000: Medical review(s). From FDA website.

17. Lilja JJ, Kivistö KT, Neuvonen PJ. Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 substrate simvastatin. Clin Pharmacol Ther. 2000; 68:384-90. [PubMed 11061578]

18. . Abiraterone acetate (Zytiga) for metastatic castration-resistant prostate cancer. Med Lett Drugs Ther. 2011; 53:63-4. [PubMed 21836546]

19. Thomae BA, Eckloff BW, Freimuth RR et al. Human sulfotransferase SULT2A1 pharmacogenetics: genotype-to-phenotype studies. Pharmacogenomics J. 2002; 2:48-56. [PubMed 11990382]

Hide
(web2)