Abiraterone

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# Overview
Abiraterone is an antiandrogen that is FDA approved for the treatment of metastatic castration-resistant prostate cancer.   Common adverse reactions include fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Dosing Information
- The recommended dose of Abiraterone is 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. Abiraterone must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. The tablets should be swallowed whole with water. Do not crush or chew tablets.
- Hepatic Impairment
- In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of Abiraterone to 250 mg once daily. A once daily dose of 250 mg in patients with moderate hepatic impairment is predicted to result in an area under the concentration curve (AUC) similar to the AUC seen in patients with normal hepatic function receiving 1,000 mg once daily. However, there are no clinical data at the dose of 250 mg once daily in patients with moderate hepatic impairment and caution is advised. In patients with moderate hepatic impairment monitor 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. If elevations in ALT and/or AST greater than 5X upper limit of normal (ULN) or total bilirubin greater than 3X ULN occur in patients with baseline moderate hepatic impairment, discontinue Abiraterone and do not re-treat patients with Abiraterone.
- Do not use Abiraterone in patients with baseline severe hepatic impairment (Child-Pugh Class C).
- Hepatotoxicity
- For patients who develop hepatotoxicity during treatment with Abiraterone (ALT and/or AST greater than 5X ULN or bilirubin-total bilirubin greater than 3X ULN), interrupt treatment with Abiraterone. Treatment may be restarted at a reduced dose of 750 mg once daily following 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. For patients who resume treatment, monitor serum transaminases and bilirubin at a minimum of every two weeks for three months and monthly thereafter.
- If hepatotoxicity recurs at the dose of 750 mg once daily, re-treatment may be restarted at a reduced dose of 500 mg once daily following 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.
- If hepatotoxicity recurs at the reduced dose of 500 mg once daily, discontinue treatment with Abiraterone. The safety of Abiraterone 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.
- Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during Abiraterone treatment. Although there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers, because of the potential for an interaction, if a strong CYP3A4 inducer must be co-administered, increase the Abiraterone dosing frequency to twice a day only during the co-administration period (e.g., from 1,000 mg once daily to 1,000 mg twice a day). Reduce the dose back to the previous dose and frequency, if the concomitant strong CYP3A4 inducer is discontinued.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Abiraterone in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Abiraterone in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Abiraterone in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Abiraterone in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Abiraterone in pediatric patients.

# Contraindications
- Pregnancy
- Abiraterone can cause fetal harm when administered to a pregnant woman. Abiraterone is not indicated for use in women. Abiraterone is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss.

# Warnings

### Precautions
- Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess
- Abiraterone may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition. In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated with Abiraterone.
- Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. Use Abiraterone with caution in patients with a history of cardiovascular disease. The safety of Abiraterone in patients with left ventricular ejection fraction <50% or New York Heart Association (NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in Study 2) was not established because these patients were excluded from these randomized clinical trials. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with Abiraterone.
- Adrenocortical Insufficiency
- Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking Abiraterone and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving Abiraterone in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with Abiraterone. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations.
- Hepatotoxicity
- In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 4% of patients who received Abiraterone, typically during the first 3 months after starting treatment. Patients whose baseline ALT or AST were elevated were more likely to experience liver test elevation than those beginning with normal values. Treatment discontinuation due to cardiovascular disease increases occurred in 1% of patients taking Abiraterone. No deaths clearly related to Abiraterone were reported due to hepatotoxicity events.
- Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with Abiraterone, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced Abiraterone 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 Abiraterone treatment and closely monitor liver function.
- Re-treatment with Abiraterone 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 Abiraterone 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.
- Increased Abiraterone Exposures with Food
- Abiraterone must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. Abiraterone Cmax and AUC0 (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed.

# Adverse Reactions

## Clinical Trials 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 clinical practice.
- Two randomized placebo-controlled, multicenter clinical trials enrolled patients who had metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy. In both Study 1 and Study 2 Abiraterone was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arms. Placebo plus prednisone 5 mg twice daily was given to control patients.
- The most common adverse drug reactions (10%) reported in the two randomized clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were fatigue, joint swelling or discomfort, edema, hot flush, diarrhea, vomiting, cough, hypertension, dyspnea, urinary tract infection and contusion.
- The most common laboratory abnormalities (>20%) reported in the two randomized clinical trials that occurred more commonly (2%) in the abiraterone acetate arm were anemia, elevated alkaline phosphatase, hypertriglyceridemia, lymphopenia, hypercholesterolemia, hyperglycemia, elevated AST, hypophosphatemia, elevated ALT and hypokalemia.
- Study 1: Metastatic CRPC Following Chemotherapy
- Study 1 enrolled 1195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT 2.5 XULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5X ULN.
- Table 1 shows adverse reactions on the Abiraterone arm in Study 1 that occurred with a 2% absolute increase in frequency compared to placebo or were events of special interest. The median duration of treatment with Abiraterone was 8 months.
- Table 2 shows laboratory abnormalities of interest from Study 1. Grade 34 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the Abiraterone arm.
- Study 2: Metastatic CRPC Prior to Chemotherapy
- Study 2 enrolled 1088 patients with metastatic CRPC who had not received prior cytotoxic chemotherapy. Patients were ineligible if AST and/or ALT 2.5X ULN and patients were excluded if they had liver metastases.
- Table 3 shows adverse reactions on the Abiraterone arm in Study 2 that occurred with a 2% absolute increase in frequency compared to placebo. The median duration of treatment with Abiraterone was 13.8 months.
- Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the Abiraterone arm compared to placebo in Study 2. Grade 34 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the Abiraterone arm.
- Cardiovascular Adverse Reactions:
- In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with Abiraterone compared to patients on the placebo arm (2.1% versus 0.7%). Grade 34 cardiac failure occurred in 1.6% of patients taking Abiraterone and led to 5 treatment discontinuations and 2 deaths. Grade 34 cardiac failure occurred in 0.2% of patients taking placebo. There were no treatment discontinuations and one death due to cardiac failure in the placebo group.
- In Study 1 and 2, the majority of arrhythmias were grade 1 or 2. There was one death associated with arrhythmia and one patient with sudden death in the Abiraterone arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the Abiraterone arms and 3 (0.3%) deaths in the placebo arms. Myocardial ischemia or myocardial infarction led to death in 3 patients in the placebo arms and 2 deaths in the Abiraterone arms.

## Postmarketing Experience
- The following additional adverse reactions have been identified during post approval use of Abiraterone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Respiratory, Thoracic and Mediastinal Disorders: non-infectious pneumonitis.

# Drug Interactions
- Drugs that Inhibit or Induce CYP3A4 Enzymes
- Based on in vitro data, Abiraterone is a substrate of CYP3A4.
- In a dedicated drug interaction trial, co-administration of rifampin, a strong CYP3A4 inducer, decreased exposure of abiraterone by 55%. Avoid concomitant strong CYP3A4 inducers during Abiraterone treatment. If a strong CYP3A4 inducer must be co-administered, increase the Abiraterone dosing frequency.
- In a dedicated drug interaction trial, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.
- Effects of Abiraterone on Drug Metabolizing Enzymes
- Abiraterone is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug.
- In vitro, Abiraterone inhibits CYP2C8. There are no clinical data on the use of Abiraterone with drugs that are substrates of CYP2C8. However, patients should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used concomitantly with abiraterone acetate.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category X
- Abiraterone can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. While there are no adequate and well-controlled studies with Abiraterone in pregnant women and Abiraterone is not indicated for use in women, it is important to know that maternal use of a CYP17 inhibitor could affect development of the fetus. Abiraterone acetate caused developmental toxicity in pregnant rats at exposures that were lower than in patients receiving the recommended dose. Abiraterone is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus and the potential risk for pregnancy loss. Advise females of reproductive potential to avoid becoming pregnant during treatment with Abiraterone.
- In an embryo-fetal developmental toxicity study in rats, abiraterone acetate caused developmental toxicity when administered at oral doses of 10, 30 or 100 mg/kg/day throughout the period of organogenesis (gestational days 617). Findings included embryo-fetal lethality (increased post implantation loss and resorptions and decreased number of live fetuses), fetal developmental delay (skeletal effects) and urogenital effects (bilateral ureter dilation) at doses 10 mg/kg/day, decreased fetal ano-genital distance at 30 mg/kg/day, and decreased fetal body weight at 100 mg/kg/day. Doses 10 mg/kg/day caused maternal toxicity. The doses tested in rats resulted in systemic exposures (AUC) approximately 0.03, 0.1 and 0.3 times, respectively, the AUC in patients.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Abiraterone in women who are pregnant.

### Labor and Delivery
There is no FDA guidance on use of Abiraterone during labor and delivery.

### Nursing Mothers
- Abiraterone is not indicated for use in women. It is not known if 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 Abiraterone, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

### Pediatric Use
There is no FDA guidance on the use of Abiraterone with respect to pediatric patients.

### Geriatic Use
- Of the total number of patients receiving Abiraterone in phase 3 trials, 73% of patients were 65 years and over and 30% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

### Gender
There is no FDA guidance on the use of Abiraterone with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Abiraterone with respect to specific racial populations.

### Renal Impairment
- In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of Abiraterone. No dosage adjustment is necessary for patients with renal impairment.

### 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 hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of Abiraterone 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.
- In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7 fold and the fraction of free drug increased 2 fold in subjects with severe baseline hepatic impairment 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 Abiraterone to 250 mg once daily. Do not use Abiraterone in patients with baseline severe hepatic impairment (Child-Pugh Class C). If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue Abiraterone treatment.
- For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Abiraterone in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Abiraterone in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Oral

### Monitoring
- Monitor blood pressure, serum potassium and symptoms of fluid retention at least monthly.
- Monitor for symptoms and signs of adrenocortical insufficiency.

# IV Compatibility
There is limited information regarding IV Compatibility of Abiraterone in the drug label.

# Overdosage

## Acute Overdose

### Signs and Symptoms
- Human experience of overdose with Abiraterone is limited.

### Management
- There is no specific antidote. In the event of an overdose, stop Abiraterone, undertake general supportive measures, including monitoring for pparrhythmias]] and cardiac failure and assess liver function.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Abiraterone in the drug label.

# Pharmacology

## Mechanism of Action
- Abiraterone acetate (Abiraterone) is converted in vivo to abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 -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 17-hydroxy derivatives by 17-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.
- Abiraterone 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 Abiraterone 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.

## Structure
- Abiraterone acetate, the active ingredient of Abiraterone is the acetyl ester of abiraterone. Abiraterone is an inhibitor of CYP17 (17-hydroxylase/C17,20-lyase). Each Abiraterone tablet contains 250 mg of abiraterone acetate. Abiraterone acetate is designated chemically as (3)-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 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 colloidal silicon dioxide, croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl sulfate.

## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Abiraterone in the drug label.

## Pharmacokinetics
- Following administration of abiraterone acetate, the pharmacokinetics of abiraterone and abiraterone acetate have been studied in healthy subjects and in patients with metastatic castration-resistant prostate cancer (CRPC). In vivo, abiraterone acetate is converted to abiraterone. In clinical studies, abiraterone acetate plasma concentrations were below detectable levels (99% of the analyzed samples.
- Absorption
- Following oral administration of abiraterone acetate to patients with metastatic CRPC, the median time to reach maximum plasma abiraterone concentrations is 2 hours. Abiraterone accumulation is observed at steady-state, with a 2-fold higher exposure (steady-state AUC) compared to a single 1,000 mg dose of abiraterone acetate.
- At the dose of 1,000 mg daily in patients with metastatic CRPC, steady-state values (mean  SD) of Cmax were 226  178 ng/mL and of AUC were 993  639 ng.hr/mL. No major deviation from dose proportionality was observed in the dose range of 250 mg to 1,000 mg. However, the exposure was not significantly increased when the dose was doubled from 1,000 to 2,000 mg (8% increase in the mean AUC).
- 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 the content and composition of meals, taking Abiraterone with meals has the potential to result in increased and highly variable exposures. Therefore, no food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. The tablets should be swallowed whole with water.
- Distribution and Protein Binding
- Abiraterone is highly bound (>99%) to the human plasma proteins, albumin and alpha-1 acid glycoprotein. The apparent steady-state volume of distribution (mean  SD) is 19,669  13,358 L. In vitro studies show that at clinically relevant concentrations, abiraterone acetate and abiraterone are not substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp. No studies have been conducted with other transporter proteins.
- Metabolism
- Following oral administration of 14C-abiraterone acetate as capsules, abiraterone acetate is hydrolyzed to abiraterone (active metabolite). The conversion is likely through esterase activity (the esterases have not been identified) and is not CYP mediated. The two main circulating metabolites of abiraterone in human plasma are abiraterone sulphate (inactive) and N-oxide abiraterone sulphate (inactive), which account for about 43% of exposure each. CYP3A4 and SULT2A1 are the enzymes involved in the formation of N-oxide abiraterone sulphate and SULT2A1 is involved in the formation of abiraterone sulphate.
- Excretion
- In patients with metastatic CRPC, the mean terminal half-life of abiraterone in plasma (mean  SD) is 12  5 hours. Following oral administration of 14C-abiraterone acetate, approximately 88% of the radioactive dose is recovered in feces and approximately 5% in urine. The major compounds present in feces are unchanged abiraterone acetate and abiraterone (approximately 55% and 22% of the administered dose, respectively).
- Patients with Hepatic Impairment
- The pharmacokinetics of abiraterone was 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. Systemic exposure to abiraterone after a single oral 1,000 mg dose given 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 is prolonged to approximately 18 hours in subjects with mild hepatic impairment and to approximately 19 hours in subjects with moderate hepatic impairment.
- In another trial, the pharmacokinetics of abiraterone were examined in subjects with baseline severe (n=8) hepatic impairment (Child-Pugh Class C) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone increased by approximately 7 fold in subjects with severe baseline hepatic impairment compared to subjects with normal hepatic function. In addition, the mean protein binding was found to be lower in the severe hepatic impairment group compared to the normal hepatic function group, which resulted in a two-fold increase in the fraction of free drug in patients with severe hepatic impairment.
- Patients with Renal Impairment
- The pharmacokinetics of abiraterone were examined in patients with end-stage renal disease (ESRD) on a stable hemodialysis schedule (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 Abiraterone dose was given under fasting conditions 1 hour after dialysis, and samples for pharmacokinetic analysis were collected up to 96 hours post dose. Systemic exposure to abiraterone after a single oral 1,000 mg dose did not increase in subjects with end-stage renal disease on dialysis, compared to subjects with normal renal function.
- Drug Interactions
- In vitro studies with human hepatic microsomes showed that abiraterone is a strong inhibitor of CYP1A2, CYP2D6 and CYP2C8 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) were increased 2.8- and 2.9-fold, respectively when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily (plus prednisone 5 mg twice daily). The AUC for dextrorphan, the active metabolite of dextromethorphan, increased approximately 1.3 fold.
- In a clinical study to determine the effects 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. In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer (rifampin, 600 mg daily for 6 days) followed by a single dose of abiraterone acetate 1,000 mg, the mean plasma AUC of abiraterone was decreased by 55%.
- In a separate clinical pharmacokinetic interaction study of healthy subjects, co-administration of ketoconazole, a strong inhibitor of CYP3A4, had no clinically meaningful effect on the pharmacokinetics of abiraterone.
- QT Prolongation
- In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received Abiraterone orally at a dose of 1,000 mg once daily at least 1 hour before or 2 hours after a meal in combination with prednisone 5 mg orally twice daily. Assessments up to Cycle 2 Day 2 showed no large changes in the QTc interval (i.e., >20 ms) from baseline. However, small increases in the QTc interval (i.e., <10 ms) due to abiraterone acetate cannot be excluded due to study design limitations

## Nonclinical Toxicology
- A two-year carcinogenicity study was conducted in rats at oral abiraterone acetate doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone acetate increased the combined incidence of interstitial cell adenomas and carcinomas in the testes at all dose levels tested. This finding is considered to be related to the pharmacological activity of abiraterone. Rats are regarded as more sensitive than humans to developing interstitial cell tumors in the testes. Abiraterone acetate was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure based on AUC. Abiraterone acetate was not carcinogenic in a 6-month study in the transgenic (Tg.rasH2) mouse.
- Abiraterone acetate and abiraterone did not induce mutations in the microbial mutagenesis (Ames) assay and was not clastogenic in both the in vitro cytogenetic assay using primary human lymphocytes and in the in vivo rat micronucleus assay.
- Abiraterone has the potential to impair reproductive function and fertility in humans based on findings in animals. In repeat-dose toxicity studies in male 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 at systemic exposures similar to humans and in monkeys at exposures approximately 0.6 times the AUC in humans.
- In fertility studies in rats, reduced organ weights of the reproductive system, sperm counts, sperm motility, altered sperm morphology and decreased fertility were observed in males dosed for 4 weeks at 30 mg/kg/day. Mating of untreated females with males that received 30 mg/kg/day abiraterone acetate resulted in a reduced number of corpora lutea, implantations and live embryos and an increased incidence of pre-implantation loss. Effects on male rats were reversible after 16 weeks from the last abiraterone acetate administration. Female rats dosed for 2 weeks until day 7 of pregnancy at 30 mg/kg/day had an increased incidence of irregular or extended estrous cycles and pre-implantation loss (300 mg/kg/day). There were no differences in mating, fertility, and litter parameters in female rats that received abiraterone acetate. Effects on female rats were reversible after 4 weeks from the last abiraterone acetate administration. The dose of 30 mg/kg/day in rats is approximately 0.3 times the recommended dose of 1,000 mg/day based on body surface area.
- In 13- and 26-week studies in rats and 13- and 39-week studies in monkeys, a reduction in circulating testosterone levels occurred with abiraterone acetate at approximately one half the human clinical exposure based on AUC. As a result, decreases in organ weights and toxicities were observed in the male and female reproductive system, adrenal glands, liver, pituitary (rats only), and male mammary glands. The changes in the reproductive organs are consistent with the antiandrogenic pharmacological activity of abiraterone acetate. A dose-dependent increase in cataracts was observed in rats at 26 weeks starting at 50 mg/kg/day (similar to the human clinical exposure based on AUC). In the 39-week monkey study, no cataracts were observed at higher doses (2 times greater than the clinical exposure based on AUC). All other toxicities associated with abiraterone acetate reversed or were partially resolved after a 4-week recovery period.

# Clinical Studies
- The efficacy and safety of Abiraterone in patients with metastatic castration-resistant prostate cancer (CRPC) that has progressed on androgen deprivation therapy was demonstrated in two randomized, placebo-controlled, multicenter phase 3 clinical trials. Patients with prior ketoconazole treatment for prostate cancer and a history of adrenal gland or pituitary disorders were excluded from these trials.
- Study 1
- Patients with metastatic CRPC who had received prior docetaxel chemotherapy:
- A total of 1195 patients were randomized 2:1 to receive either Abiraterone 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.
- The following patient demographics and baseline disease characteristics were balanced between the treatment arms. The median age was 69 years (range 3995) 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 01 and 45% had a Brief Pain Inventory-Short Form 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 Abiraterone compared to patients in the placebo arm (Table 5 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 5).
- Study 2
- Patients with metastatic CRPC who had not received prior cytotoxic chemotherapy
- In Study 2, 1088 patients were randomized 1:1 to receive either Abiraterone at a dose of 1,000 mg once daily (N=546) or Placebo once daily (N=542). Both arms were given concomitant prednisone 5 mg twice daily. Patients continued treatment until radiographic or clinical (cytotoxic chemotherapy, radiation or surgical treatment for cancer, pain requiring chronic opioids, or ECOG performance status decline to 3 or more) disease progression, unacceptable toxicity or withdrawal. Patients with moderate or severe pain, opiate use for cancer pain, or visceral organ metastases were excluded.
- Patient demographics were balanced between the treatment arms. The median age was 70 years. The racial distribution of patients treated with Abiraterone was 95.4% Caucasian, 2.8% Black, 0.7% Asian and 1.1% Other. The ECOG performance status was 0 for 76% of patients, and 1 for 24% of patients. Co-primary efficacy endpoints were overall survival and radiographic progression-free survival (rPFS). Baseline pain assessment was 01 (asymptomatic) in 66% of patients and 23 (mildly symptomatic) in 26% of patients as defined by the Brief Pain Inventory-Short Form (worst pain over the last 24 hours).
- Radiographic progression-free survival was assessed with the use of sequential imaging studies and was defined by bone scan identification of 2 or more new bone lesions with confirmation (Prostate Cancer Working Group 2 criteria) and/or modified Response Evaluation Criteria In Solid Tumors (RECIST) criteria for progression of soft tissue lesions. Analysis of rPFS utilized centrally-reviewed radiographic assessment of progression.
- At the protocol pre-specified third interim analysis for overall survival, 37% (200 of 546) of patients treated with Abiraterone, compared with 43% (234 of 542) of patients treated with placebo, had died. Overall survival was longer for Abiraterone than placebo with a hazard ratio of 0.792 (95% CI: 0.655  0.956). The p-value was 0.0151 which did not meet the pre-specified value for statistical significance (Table 6 and Figure 2).
- At the pre-specified rPFS analysis, 150 (28%) patients treated with Abiraterone and 251 (46%) patients treated with placebo had radiographic progression. A significant difference in rPFS between treatment groups was observed (Table 7 and Figure 3).
- The primary efficacy analyses are supported by the following prospectively defined endpoints. The median time to initiation of cytotoxic chemotherapy was 25.2 months for patients receiving Abiraterone and 16.8 months for patients receiving placebo (HR=0.580; 95% CI: , p<0.0001).
- The median time to opiate use for prostate cancer pain was not reached for patients receiving Abiraterone and was 23.7 months for patients receiving placebo (HR=0.686; 95% CI: , p=0.0001). The time to opiate use result was supported by a delay in patient reported pain progression favoring the Abiraterone arm.

# How Supplied
- Abiraterone (abiraterone acetate) 250 mg tablets are white to off-white, oval tablets debossed with AA250 on one side. Abiraterone 250 mg tablets are available in high-density polyethylene bottles of 120 tablets.
- NDC Number 57894-150-12
- Storage and Handling
- Store at 20C to 25C (68F to 77F); excursions permitted in the range from 15C to 30C (59F to 86F).
- Based on its mechanism of action, Abiraterone may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle Abiraterone without protection, e.g., gloves.

## Storage
There is limited information regarding Abiraterone Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Patients should be informed that Abiraterone and prednisone are used together and that they should not interrupt or stop either of these medications without consulting their physician.
- Patients receiving GnRH agonists should be informed that they need to maintain this treatment during the course of treatment with Abiraterone and prednisone.
- Patients should be informed that Abiraterone must not be taken with food and that no food should be consumed for at least two hours before the dose of Abiraterone is taken and for at least one hour after the dose of Abiraterone is taken. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking Abiraterone with food causes increased exposure and this may result in adverse reactions.
- Patients should be informed that Abiraterone is taken once daily and prednisone is taken twice daily according to their physician's instructions.
- Patients should be informed that in the event of a missed daily dose of Abiraterone or prednisone, they should take their normal dose the following day. If more than one daily dose is skipped, patients should be told to inform their physician.
- Patients should be apprised of the common side effects associated with Abiraterone, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION.
- Patients should be advised that their liver function will be monitored using blood tests.
- Patients should be informed that Abiraterone may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle Abiraterone without protection, e.g., gloves. Patients should also be informed that it is not known whether abiraterone or its metabolites are present in semen and they should use a condom if having sex with a pregnant woman. The patient should use a condom and another effective method of birth control if he is having sex with a woman of child-bearing potential. These measures are required during and for one week after treatment with Abiraterone.

# Precautions with Alcohol
- Alcohol-Abiraterone interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- ZYTIGA

# Look-Alike Drug Names
There is limited information regarding Abiraterone Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price