Abiraterone

Tell your doctor about all prescription, nonprescription, illegal, recreational, herbal, nutritional, or dietary drugs you're taking, especially:

• Certain antifungal drugs, such as Sporanox (itraconazole), Nizoral (ketoconazole), or Vfend (voriconazole)
• Biaxin (clarithromycin) or Prevpac (lansoprazole, amoxicillin, and clarithromycin)
• HIV protease inhibitors, such as Reyataz (atazanavir), Crixivan (indinavir), Viracept (nelfinavir), Norvir (ritonavir), Kaletra (lopinavir and ritonavir), or Fortovase or Invirase (saquinavir)
• Certain medications for seizures, such as Carbatrol, Epitol, or Tegretol (carbamazepine), Luminal (phenobarbital), or Dilantin or Phenytek (phenytoin)
• Nefazodone
• Mycobutin (rifabutin)
• Rifadin or Rimactane (rifampin), Rifater (rifampin, isoniazid, and pyrazinamide), or Rifamate (rifampin and isoniazid)
• Priftin (rifapentine)
• St. John's wort
• Ketek (telithromycin)
• Thioridazine

Abiraterone works by reducing androgen production in the body. Androgens are male hormones that can promote tumor growth in the prostate gland.

Abiraterone is used together with prednisone to treat prostate cancer that has spread to other parts of the body. This medicine is used in men whose prostate cancer cannot be treated with surgery or other medicines.

Abiraterone may also be used for purposes not listed in this medication guide.

You should not use this medicine if you have severe liver disease.

Abiraterone tablets should not be handled by a woman who is pregnant or who may become pregnant. This medicine can harm an unborn baby or cause birth defects.

Skip the missed dose and take the medicine the following day on an empty stomach (no food for at least 2 hours before or 1 hour after you take abiraterone). Do not take extra medicine to make up the missed dose.

Call your doctor for instructions if you miss more than one dose of abiraterone.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Abiraterone falls into category X. Do not take abiraterone if you are pregnant or may become pregnant. Abiraterone may harm your unborn baby. Women who are pregnant or who may become pregnant should not touch abiraterone without protection, such as gloves.

• Take abiraterone and prednisone exactly as your healthcare provider tells you.
• The usual dose of abiraterone is 4 tablets taken once daily.
• Your healthcare provider may change your dose if needed.
• Do not stop taking your prescribed dose of abiraterone or prednisone without talking with your healthcare provider first.
• Take abiraterone on an empty stomach. Do not take abiraterone with food. Taking abiraterone with food may cause more of the medicine to be absorbed by the body than is needed and this may cause side effects.
• No food should be eaten 2 hours before and 1 hour after taking abiraterone.
• Swallow abiraterone tablets whole.
• Take abiraterone tablets with water.
• Men who are sexually active with a pregnant woman must use a condom during and for one week after treatment with abiraterone. If their sexual partner may become pregnant, a condom and another form of birth control must be used during and for one week after treatment with abiraterone. Talk with your healthcare provider if you have questions about birth control.
• If you miss a dose of abiraterone or prednisone, take your prescribed dose the following day. If you miss more than 1 dose, tell your healthcare provider right away.
• Your healthcare provider will do blood tests to check for side effects.

• Store abiraterone at 59°F to 86°F (15°C to 30°C).
• Keep abiraterone and all medicines out of the reach of children.

Applies to abiraterone: oral tablet

Along with its needed effects, abiraterone may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking abiraterone:

• Bladder pain
• bloating or swelling of the face, arms, hands, lower legs, or feet
• bloody or cloudy urine
• blurred vision
• bone fracture
• chest pain or discomfort
• convulsions
• decreased urine
• difficult, burning, or painful urination
• dizziness
• dry mouth
• fainting
• fast, pounding, or irregular heartbeat or pulse
• feeling of warmth
• frequent urge to urinate
• headache
• increased need to urinate
• increased thirst
• increased urge to urinate during the night
• lightheadedness, dizziness, or fainting
• loss of appetite
• lower back or side pain
• mood changes
• muscle pain or cramps
• nausea or vomiting
• nervousness
• numbness or tingling in the hands, feet, or lips
• pain or swelling in the arms or legs without any injury
• passing urine more often
• pounding in the ears
• rapid weight gain
• redness of the face, neck, arms, and occasionally, upper chest
• slow heartbeat
• sudden sweating
• swelling
• swelling with pits or depressions on the skin
• unusual tiredness or weakness
• unusual weight gain or loss
• waking to urinate at night

• Abdominal or stomach pain or tenderness
• arm, back, or jaw pain
• chest tightness or heaviness
• clay colored stools
• cool, sweaty skin
• dark urine
• decreased appetite
• decreased urine output
• difficulty with breathing
• dilated neck veins
• extreme fatigue
• fever
• headache
• irregular breathing
• itching skin or rash
• sweating
• swelling of the face, fingers, feet, or lower legs
• weakness
• weight gain
• yellow eyes or skin

• Darkening of the skin
• diarrhea
• mental depression

Some side effects of abiraterone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Acid or sour stomach
• belching
• body aches or pain
• chills
• cough
• difficulty with moving
• ear congestion
• heartburn
• indigestion
• joint pain
• loss of voice
• muscle cramps or spasms
• muscle or bone pain
• muscle stiffness
• nasal congestion
• runny nose
• sneezing
• sore throat
• stomach discomfort or upset
• swelling or stiffness of the joints

Applies to abiraterone: oral tablet

Endocrine

Uncommon (0.1% to 1%): Adrenocortical insufficiency[Ref]

Hepatic

Very common (10% or more): Elevated ALT (up to 41.9%), elevated AST (up to 37.3%)
Common (1% to 10%): Elevated total bilirubin
Postmarketing reports: Fulminant hepatitis, acute liver failure and death[Ref]

Cardiovascular

Very common (10% or more): Hot flush (up to 22.3%), hypertension (up to 21.6%)
Common (1% to 10%): Arrhythmia, chest pain/chest discomfort, angina pectoris, atrial fibrillation, tachycardia, myocardial infarction/ischemia, cardiac failure (e.g., congestive heart failure, left ventricular dysfunction, decreased ejection fraction)
Frequency not reported: QT prolongation[Ref]

Musculoskeletal

Very common (10% or more): Joint swelling/discomfort (up to 30.3%), muscle discomfort (up to 26.2%), contusion (up to 13.3%)
Common (1% to 10%): Groin pain, fractures, falls
Postmarketing reports: Rhabdomyolysis, myopathy[Ref]

Hematologic

Very common (10% or more): Lymphopenia (up to 38.2%), anemia[Ref]

Metabolic

Very common (10% or more): Hypertriglyceridemia (up to 62.5%), hyperglycemia (up to 56.6%), hypernatremia (up to 32.8%), hypokalemia (up to 28.3%), fluid retention/edema (up to 26.7%), hypophosphatemia (up to 23.8%), elevated alkaline phosphatase, hypercholesterolemia[Ref]

Renal

Frequency not reported: Renal failure[Ref]

Other

Very common (10% or more): Fatigue (up to 39.1%)
Common (1% to 10%): Sepsis, pyrexia[Ref]

Respiratory

Very common (10% or more): Cough (up to 17.3%), upper respiratory tract infection (up to 12.7%), dyspnea (up to 11.8%), nasopharyngitis (up to 10.7%)
Postmarketing reports: Non-infectious pneumonitis, allergic alveolitis[Ref]

Genitourinary

Very common (10% or more): Urinary tract infection (up to 12%), hematuria (up to 10.3%)
Common (1% to 10%): Urinary frequency, nocturia[Ref]

Psychiatric

Very common (10% or more): Insomnia (up to 13.5%)[Ref]

Gastrointestinal

Very common (10% or more): Constipation (up to 23.1%), diarrhea (up to 21.6%), dyspepsia (up to 11.1%), vomiting[Ref]

Dermatologic

Common (1% to 10%): Rash[Ref]

Some side effects of abiraterone may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

No adjustment recommended

-This drug can cause fetal harm based on its mechanism of action and animal studies. -It is not indicated for use in women, and is contraindicated in women who are or may become pregnant. AU TGA pregnancy category: D US FDA pregnancy category: X Comments: -Females of reproductive potential should be advised to avoid becoming pregnant during treatment, and apprised of the potential hazard to the fetus and the potential risk for pregnancy loss if pregnancy occurs while taking this drug. -Male patients should be advised to use a condom and another effective method of birth control during treatment and for one week following treatment cessation if having sex with a pregnant woman or a woman of child-bearing potential as it is unknown whether this drug or its metabolites are present in semen.

Animal studies revealed evidence of developmental toxicity at systemic exposures that were lower than in patients receiving the recommended human dose. Findings included embryofetal lethality, fetal developmental delay, decreased fetal body weight, urogenital effects, and maternal toxicity. Animal studies also showed this drug has potential to impair reproductive function and fertility in humans. Observed effects include atrophy, aspermia/hypospermia, reduced organ weights of the reproductive system, altered sperm morphology, and decreased fertility in males; increased pre-implantation loss and reduced number of corpora lutea, implantations, and live embryos in females. Fertility effects were reversible in female animals after 4 weeks and in male animals after 16 weeks from the last drug dose. There are no controlled data in human pregnancy. AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details. US FDA pregnancy category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess

Abiraterone acetate may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Clinical Pharmacology (12.1)]. 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 acetate [see Adverse Reactions (6)].

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 acetate with caution in patients with a history of cardiovascular disease. The safety of Abiraterone acetate 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 [see Clinical Studies (14)]. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month. Control hypertension and correct hypokalemia before and during treatment with Abiraterone acetate.

Adrenocortical Insufficiency

Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking Abiraterone acetate and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving Abiraterone acetate 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 acetate. 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 [see Warnings and Precautions (5.1)].

Hepatotoxicity

In postmarketing experience, there have been Abiraterone acetate-associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths [see Adverse Reactions (6.2)].

In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5× ULN) were reported in 4% of patients who received Abiraterone acetate, 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 liver enzyme increases occurred in 1% of patients taking Abiraterone acetate. No deaths clearly related to Abiraterone acetate were reported due to hepatotoxicity events.

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with Abiraterone acetate, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced Abiraterone acetate 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 acetate treatment and closely monitor liver function.

Re-treatment with Abiraterone acetate 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 2.5× ULN and total bilirubin less than or equal to 1.5× ULN [see Dosage and Administration (2.2)].

Permanently discontinue Abiraterone acetate for patients who develop a concurrent elevation of ALT greater than 3 × ULN and total bilirubin greater than 2 × ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation [see Dosage and Administration (2.2)].

The safety of Abiraterone acetate re-treatment of 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.

The following are discussed in more detail in other sections of the labeling:

• Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess [see Warnings and Precautions (5.1)].
• Adrenocortical Insufficiency [see Warnings and Precautions (5.2)].
• Hepatotoxicity [see Warnings and Precautions (5.3)].

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 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 acetate 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 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× ULN in the absence of liver metastases. Patients with liver metastases were excluded if AST and/or ALT >5× ULN.

Table 1 shows adverse reactions on the Abiraterone acetate 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 acetate was 8 months.

Table 2 shows laboratory abnormalities of interest from Study 1. Grade 3–4 low serum phosphorus (7%) and low potassium (5%) occurred at a greater than or equal to 5% rate in the Abiraterone acetate 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 ≥2.5× ULN and patients were excluded if they had liver metastases.

Table 3 shows adverse reactions on the Abiraterone acetate arm in Study 2 that occurred with a ≥2% absolute increase in frequency compared to placebo. The median duration of treatment with Abiraterone acetate was 13.8 months.

Table 4 shows laboratory abnormalities that occurred in greater than 15% of patients, and more frequently (>5%) in the Abiraterone acetate arm compared to placebo in Study 2. Grade 3–4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the Abiraterone acetate arm.

Cardiovascular Adverse Reactions:

In the combined data for studies 1 and 2, cardiac failure occurred more commonly in patients treated with Abiraterone acetate compared to patients on the placebo arm (2.1% versus 0.7%). Grade 3–4 cardiac failure occurred in 1.6% of patients taking Abiraterone acetate and led to 5 treatment discontinuations and 2 deaths. Grade 3–4 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 acetate arms and no deaths in the placebo arms. There were 7 (0.5%) deaths due to cardiorespiratory arrest in the Abiraterone acetate 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 acetate arms.

Postmarketing Experience

The following additional adverse reactions have been identified during post approval use of Abiraterone acetate. 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.

Musculoskeletal and Connective Tissue Disorders: myopathy, including rhabdomyolysis.

Hepatobiliary Disorders: fulminant hepatitis, including acute hepatic failure and death.

Drugs that Inhibit or Induce CYP3A4 Enzymes

Based on in vitro data, Abiraterone acetate 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 acetate treatment. If a strong CYP3A4 inducer must be co-administered, increase the Abiraterone acetate dosing frequency [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

Effects of Abiraterone on Drug Metabolizing Enzymes

Abiraterone acetate is an inhibitor of the hepatic drug-metabolizing enzymes CYP2D6 and CYP2C8. 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 [see Clinical Pharmacology (12.3)].

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone (CYP2C8 substrate) was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg Abiraterone acetate. Therefore, patients should be monitored closely for signs of toxicity related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly with Abiraterone acetate [see Clinical Pharmacology (12.3)].

Human experience of overdose with Abiraterone acetate is limited.

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

Mechanism of Action

Abiraterone acetate is converted in vivo to Abiraterone, an androgen biosynthesis inhibitor, that inhibits 17 α-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 17α-hydroxy derivatives by 17α-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 [see Warnings and Precautions (5.1)].

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 acetate 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 acetate 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.

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 (<0.2 ng/mL) in >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. In healthy subjects Abiraterone Cmax and AUC0–∞ were approximately 7- and 5-fold higher, respectively, when a single dose of Abiraterone acetate was administered with a low-fat meal (7% fat, 300 calories) and approximately 17- and 10-fold higher, respectively, when a single dose of Abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal compared to overnight fasting. Abiraterone AUC0–∞ was approximately 7-fold or 1.6-fold higher, respectively, when a single dose of Abiraterone acetate was administered 2 hours after or 1 hour before a medium fat meal (25% fat, 491 calories) compared to overnight fasting.

Systemic exposures of Abiraterone in patients with metastatic CRPC, after repeated dosing of Abiraterone acetate were similar when Abiraterone acetate was taken with low-fat meals for 7 days and increased approximately 2-fold when taken with high-fat meals for 7 days compared to when taken at least 2 hours after a meal and at least 1 hour before a meal for 7 days.

Given the normal variation in the content and composition of meals, taking Abiraterone acetate 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 acetate is taken and for at least one hour after the dose of Abiraterone acetate is taken. The tablets should be swallowed whole with water [see Dosage and Administration (2.1)].

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.

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 [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

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 acetate 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 [see Use in Specific Populations (8.7)].

Drug Interactions

In vitro studies with human hepatic microsomes showed that Abiraterone has the potential to inhibit CYP1A2, CYP2D6, CYP2C8 and to a lesser extent 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 [see Drug Interactions (7.2)].

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% [see Drug Interactions (7.1)].

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 [see Drug Interactions (7.1)].

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% when pioglitazone was given together with a single dose of 1,000 mg Abiraterone acetate [see Drug Interactions (7.2)].

In vitro, Abiraterone and its major metabolites were shown to inhibit the hepatic uptake transporter OATP1B1. There are no clinical data available to confirm transporter based interaction.

QT Prolongation

In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received Abiraterone acetate 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.

NDC 57894-155-12

Abiraterone Acetate
tablets

250 mg

Each tablet contains:
Abiraterone acetate 250 mg

Warning: Women who are or may be
pregnant should not handle
Abiraterone acetate without gloves
(see package insert).

Rx only
120 TABLETS