Abiraterone – Drug information

Abiraterone: Drug information
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(For additional information see “Abiraterone: Patient drug information”)

Brand Names: U.S. Zytiga™
Brand Names: Canada Zytiga™
Pharmacologic Category Antiandrogen
Dosing: Adult Prostate cancer, metastatic, castration-resistant: Oral: 1000 mg once daily (in combination with prednisone 5 mg twice daily)
Dosing: Geriatric Refer to adult dosing.
Dosing: Renal Impairment No adjustment required.
Dosing: Hepatic Impairment
Hepatic impairment prior to treatment initiation:

Mild (Child-Pugh class A): No adjustment required

Moderate (Child-Pugh class B): 250 mg once daily (Note: Canadian labeling does not recommend use). Permanently discontinue treatment if ALT and/or AST >5 times the upper limit of normal (ULN) or total bilirubin >3 times ULN.

Severe (Child-Pugh class C): Avoid use

Hepatotoxicity during treatment:

U.S. labeling:

ALT and/or AST >5 times ULN or total bilirubin >3 times ULN: Withhold treatment until liver function tests return to baseline or ALT and AST ≤2.5 times ULN and total bilirubin ≤1.5 times ULN, then reinitiate at 750 mg once daily.

Recurrent hepatotoxicity on 750 mg/day: Withhold treatment until liver function tests return to baseline or ALT and AST ≤2.5 times ULN and total bilirubin ≤1.5 times ULN, then reinitiate at 500 mg once daily.

Recurrent hepatotoxicity on 500 mg/day: Discontinue treatment

Canadian labeling:

ALT and/or AST >5 times ULN or total bilirubin >3 times ULN:

Withhold treatment until liver function tests return to baseline, then reinitiate at 500 mg once daily

Recurrent hepatotoxicity on 500 mg/day: Discontinue treatment

ALT >20 times ULN (any time during treatment): Discontinue permanently.

Dosing: Adjustment for Toxicity Hepatotoxicity: Refer to Dosing: Hepatic Impairment.
Dosage Forms: U.S. Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:

Zytiga™: 250 mg

Generic Equivalent Available: U.S. No
Administration Administer orally on an empty stomach, at least 1 hour before and 2 hours after food. Swallow tablets whole with water.
Use Treatment of metastatic, castration-resistant prostate cancer (in combination with prednisone) in patients previously treated with docetaxel
Adverse Reactions Significant Note: Adverse reactions reported for use in combination with prednisone.
>10%:

Cardiovascular: Edema (27%)

Endocrine & metabolic: Triglycerides increased (63%), hypokalemia (28%; grades 3/4: 5%), hypophosphatemia (24%; grades 3/4: 7%), hot flush (19%)

Gastrointestinal: Diarrhea (18%)

Genitourinary: Urinary tract infection (12%)

Hepatic: AST increased (31%; grades 3/4: 2%), ALT increased (11%; grades 3/4: 1%)

Neuromuscular & skeletal: Joint swelling/discomfort (30%), muscle discomfort (26%)

Respiratory: Cough (11%)

1% to 10%:

Cardiovascular: Hypertension (9%; grades 3/4: 1%), arrhythmia (7%), chest pain/discomfort (4%), heart failure (2%)

Gastrointestinal: Dyspepsia (6%)

Genitourinary: Polyuria (7%), nocturia (6%)

Hepatic: Bilirubin increased (7%; grades 3/4: <1%)

Respiratory: Upper respiratory infection (5%)

<1% (Limited to important or life-threatening): Adrenal insufficiency

Contraindications Use in women who are or may become pregnant
Canadian labeling: Additional contraindication (not in U.S. labeling): Hypersensitivity to abiraterone acetate or any component of the formulation or container

Warnings/Precautions
Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal.

Concerns related to adverse effects:

• Adrenocortical insufficiency: Concurrent infection, stress, or interruption of daily corticosteroids is associated with reports of adrenocortical insufficiency. Monitor closely for signs and symptoms of adrenocorticoid insufficiency, which could be masked by adverse events associated with mineralocorticoid excess. Diagnostic testing for insufficiency may be clinically indicated. Increased corticosteroid doses may be required before, during, and after stress.

• Hepatotoxicity: Significant increases in liver enzymes have been reported; may require dosage reduction or discontinuation. ALT, AST, and bilirubin should be monitored prior to treatment, every 2 weeks for 3 months and monthly thereafter; patients with hepatic impairment, elevations in liver function tests, or experiencing hepatotoxicity require more frequent monitoring (see dosage adjustment for hepatic impairment and monitoring parameters). Evaluate liver function promptly with signs or symptoms of hepatotoxicity, The safety of retreatment after significant elevations (ALT or AST >20 times the upper limit of normal [ULN] or total bilirubin >10 times ULN) has not been evaluated.

• Mineralocorticoid excess: Increased mineralocorticoids due to CYP17 inhibition may result in hypertension, hypokalemia, and fluid retention. Concomitant administration with corticosteroids reduces the incidence and severity of these adverse events.

Disease-related concerns:

• Cardiovascular disease: May cause hypertension, hypokalemia, and fluid retention. Use with caution in patients with cardiovascular disease, particularly with heart failure, recent MI, or ventricular arrhythmia. Patients with left ventricular ejection fraction (LVEF) <50% or NYHA class III or IV heart failure were excluded from clinical trials. Monitor at least monthly for hypertension, hypokalemia, and fluid.

• Hepatic impairment: Avoid use in patients with pre-existing severe hepatic impairment; dosage reduction is recommended in patients with baseline moderate impairment. Canadian labeling (not in U.S. labeling) also recommends avoiding use in patients with pre-existing moderate hepatic impairment.

Concurrent drug therapy issues:

• CYP-mediated interactions: Avoid (or use caution) with concomitant CYP3A4 strong inhibitors and inducers. Avoid concurrent administration with CYP2D6 substrates with a narrow therapeutic index (eg, thioridazine); if concurrent administration cannot be avoided, consider a dose reduction of the CYP2D6 substrate.

Other warnings/precautions:

• Food: Must be administered on an empty stomach (administer at least 1 hour before and 2 hours after any food).

Drug Interactions
(For additional information: Launch Lexi-Interact™ Drug Interactions Program )
Atomoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Atomoxetine. Management: Initiate atomoxetine at a reduced dose (adult doses — patients up to 70kg: 0.5mg/kg/day; patients 70kg or more: 40mg/day) in patients receiving a strong CYP2D6 inhibitor. Risk D: Consider therapy modification

Bendamustine: CYP1A2 Inhibitors (Strong) may increase the serum concentration of Bendamustine. Concentrations of the active metabolites of bendamustine may be decreased. Risk C: Monitor therapy

Budesonide (Systemic, Oral Inhalation): CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Budesonide (Systemic, Oral Inhalation). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor. This interaction is likely less severe with orally inhaled budesonide. Monitor patients closely for signs/symptoms of corticosteroid excess. Risk D: Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination

Codeine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Risk D: Consider therapy modification

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Risk D: Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Risk X: Avoid combination

CYP1A2 Substrates: Abiraterone Acetate may increase the serum concentration of CYP1A2 Substrates. Risk C: Monitor therapy

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Risk C: Monitor therapy

CYP2C9 Substrates (High risk): CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates (High risk). Risk C: Monitor therapy

CYP2D6 Substrates: Abiraterone Acetate may increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Risk D: Consider therapy modification

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. According to Canadian labeling, dabigatran dose for prevention of venous thromboembolism post hip or knee replacement should be reduced to 150 mg/day in patients receiving amiodarone, verapamil, or quinidine. Risk D: Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: A lower starting dose of eplerenone (25 mg once daily for adults) is recommended in patients with hypertension who are also taking drugs that are moderate inhibitors of CYP3A4. Risk D: Consider therapy modification

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Management: Everolimus dose reductions are required for patients being treated for subependymal giant cell astrocytoma or renal cell carcinoma. See prescribing information for specific dose adjustment and monitoring recommendations. Risk D: Consider therapy modification

FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Management: Monitor patients extra closely for several days following initiation of the combination, and fentanyl dosage reductions should be made as appropriate. Risk D: Consider therapy modification

Fesoterodine: CYP2D6 Inhibitors may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy

Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Risk D: Consider therapy modification

Herbs (CYP3A4 Inducers): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

Iloperidone: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP2D6 inhibitor. Risk D: Consider therapy modification

Lurasidone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Lurasidone. Risk D: Consider therapy modification

Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy

P-glycoprotein/ABCB1 Substrates: May increase the serum concentration of P-glycoprotein/ABCB1 Inhibitors. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy

Rivaroxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy

Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Risk C: Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Risk X: Avoid combination

Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease the metabolism of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the formation of highly potent active metabolites. Risk X: Avoid combination

Tetrabenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Tetrabenazine adult dose should be reduced by 50% when starting a strong CYP2D6 inhibitor. Maximum tetrabenazine adult dose is 50 mg/day when used with a strong CYP2D6 inhibitor. Risk D: Consider therapy modification

Thioridazine: CYP2D6 Inhibitors may decrease the metabolism of Thioridazine. Risk X: Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination

TraMADol: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of TraMADol. These CYP2D6 inhibitors may prevent the metabolic conversion of tramadol to its active metabolite that accounts for much of its opioid-like effects. Risk C: Monitor therapy

Vilazodone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Vilazodone. Risk C: Monitor therapy

Ethanol/Nutrition/Herb Interactions Food: Do not administer with food (will increase systemic exposure).
Pregnancy Risk Factor X (show table)
Pregnancy Implications Animal reproduction studies have not been conducted. Adverse effects were observed in the reproductive system of animals during toxicology and pharmacology studies. Abiraterone is not indicated for use in women and is specifically contraindicated in women who are or may become pregnant. It is not known if abiraterone is excreted in semen, therefore, men should use a condom and another method of birth control during treatment and for 1 week following therapy if having intercourse with a woman of reproductive age. Pregnant women should wear gloves if contact with tablets may occur.
Lactation Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations Not indicated for use in women
Dietary Considerations Must be taken on an empty stomach, at least 1 hour before and 2 hours after food.
Monitoring Parameters ALT, AST, and bilirubin prior to treatment, every 2 weeks for 3 months and monthly thereafter; if baseline moderate hepatic impairment (Child-Pugh class B), monitor ALT, AST, and bilirubin prior to treatment, weekly for the first month, every 2 weeks for 2 months then monthly thereafter. If hepatotoxicity develops during treatment (and only after therapy is interrupted and liver function tests have returned to safe levels), monitor ALT, AST, and bilirubin every 2 weeks for 3 months and monthly thereafter. Monitoring of testosterone levels is not necessary.
Monitor for signs and symptoms of adrenocorticoid insufficiency; monthly for hypertension, hypokalemia, and fluid retention.

Mechanism of Action Selectively and irreversibly inhibits CYP17 (17 alpha-hydroxylase/C17,20-lyase), an enzyme required for androgen biosynthesis which is expressed in testicular, adrenal, and prostatic tumor tissues. Inhibits the formation of the testosterone precursors dehydroepiandrosterone (DHEA) and androstenedione.
Pharmacodynamics/Kinetics
Distribution: Vdss: 19,669 ± 13,358 L

Protein binding: >99%; to albumin and alpha1-acid glycoprotein

Metabolism: Abiraterone acetate is hydrolyzed to the active metabolite abiraterone; further metabolized to inactive metabolites abiraterone sulphate and N-oxide abiraterone sulphate via CYP3A4 and SULT2A1

Bioavailability: Systemic exposure is increased by food

Half-life elimination: 12 ± 5 hours

Time to peak: 2 hours

Excretion: Feces (~88%); urine (~5%)

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REFERENCES
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(23):3742-8. [PubMed 19470933]
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(9):1496-501. [PubMed 20159814]
de Bono JS, Logothetis CJ, Fizazi K, et al, “Aberitarone Acetate (AA) Plus Low Dose Prednisone (P) Improves Overall Survival in Patients (PTS) With Metastatic Castration-Resistant Prostate Cancer (MCRPC) Who Have Progressed After Docetaxel-Based Chemotherapy (CHEMO): Results of COU-AA-301, a Randomized Double-Blind Placebo-Controlled Phase III Study,” Ann Oncol, 2010, 21(8s):LBA5 [abstract LBA5 from 2010 ESMO Annual Meeting].
de Bono JS, Logothetis CJ, Molina A, et al, “Abiraterone and Increased Survival in Metastatic Prostate Cancer,” New Engl J Med, 2011, 364(21):1995-2005.
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(9):1489-95. [PubMed 20159823]
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(9):1481-8. [PubMed 20159824]