Components:
Abiraterone
Method of action:
Endocrine Therapy
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Name of the medicinal product

Abiraterone acetate

Qualitative and quantitative composition

Abiraterone

Pharmaceutical form

Substance-powder

Therapeutic indications

The information provided in Therapeutic indications of Abiraterone acetate is based on data of another medicine with exactly the same composition as the Abiraterone acetate of the medicine (Abiraterone). Be careful and be sure to specify the information on the section Therapeutic indications in the instructions to the drug Abiraterone acetate directly from the package or from the pharmacist at the pharmacy.
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Abiraterone acetate is a CYP17 inhibitor indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer.

Dosage (Posology) and method of administration

The information provided in Dosage (Posology) and method of administration of Abiraterone acetate is based on data of another medicine with exactly the same composition as the Abiraterone acetate of the medicine (Abiraterone). Be careful and be sure to specify the information on the section Dosage (Posology) and method of administration in the instructions to the drug Abiraterone acetate directly from the package or from the pharmacist at the pharmacy.
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Recommended Dosage

The recommended dose of Abiraterone acetate is 1,000 mg (four 250 mg tablets) administered orally once daily in combination with prednisone 5 mg administered orally twice daily. Abiraterone acetate must be taken on an empty stomach. 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. Do not crush or chew tablets.

Dose Modification Guidelines In Hepatic Impairment And Hepatotoxicity

Hepatic Impairment

In patients with baseline moderate hepatic impairment (Child-Pugh Class B), reduce the recommended dose of Abiraterone acetate 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 acetate and do not re-treat patients with Abiraterone acetate .

Do not use Abiraterone acetate in patients with baseline severe hepatic impairment (Child-Pugh Class C).

Hepatotoxicity

For patients who develop hepatotoxicity during treatment with Abiraterone acetate (ALT and/or AST greater than 5X ULN or total bilirubin greater than 3X ULN), interrupt treatment with Abiraterone acetate . 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 acetate. The safety of Abiraterone acetate 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.

Permanently discontinue Abiraterone acetate for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation .

Dose Modification Guidelines For Strong CYP3A4 Inducers

Avoid concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) during Abiraterone acetate 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 acetate 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 .

Contraindications

The information provided in Contraindications of Abiraterone acetate is based on data of another medicine with exactly the same composition as the Abiraterone acetate of the medicine (Abiraterone). Be careful and be sure to specify the information on the section Contraindications in the instructions to the drug Abiraterone acetate directly from the package or from the pharmacist at the pharmacy.
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Pregnancy

Abiraterone acetate can cause fetal harm when administered to a pregnant woman. Abiraterone acetate is not indicated for use in women. Abiraterone acetate 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 .

Special warnings and precautions for use

The information provided in Special warnings and precautions for use of Abiraterone acetate is based on data of another medicine with exactly the same composition as the Abiraterone acetate of the medicine (Abiraterone). Be careful and be sure to specify the information on the section Special warnings and precautions for use in the instructions to the drug Abiraterone acetate directly from the package or from the pharmacist at the pharmacy.
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WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 . 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 .

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 . 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 .

Hepatotoxicity

In postmarketing experience, there have been Abiraterone acetate-associated severe hepatic toxicity,including fulminant hepatitis, acute liver failure and deaths .

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 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 2.5X ULN and total bilirubin less than or equal to 1.5X ULN .

Permanently discontinue Abiraterone acetate for patients who develop a concurrent elevation of ALT greater than 3 x ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other causes responsible for the concurrent elevation .

The safety of Abiraterone acetate 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.

Patient Counseling Information

See FDA-approved patient labeling (PATIENT INFORMATION)

  • Patients should be informed that Abiraterone acetate 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 acetate and prednisone.
  • Patients should be informed that Abiraterone acetate should not be taken with food and that 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. They should be informed that the tablets should be swallowed whole with water without crushing or chewing. Patients should be informed that taking Abiraterone acetate with food causes increased exposure and this may result in adverse reactions.
  • Patients should be informed that Abiraterone acetate 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 acetate 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 acetate, including peripheral edema, hypokalemia, hypertension, elevated liver function tests, and urinary tract infection. Direct the patient to a complete list of adverse reactions in PATIENT INFORMATION.
  • Patients should be advised that their liver function will be monitored using blood tests.
  • Patients should be informed that Abiraterone acetate may harm a developing fetus; thus, women who are pregnant or women who may be pregnant should not handle Abiraterone acetate 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 acetate.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, And Impairment Of Fertility

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 acetate 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.

Use In Specific Populations

Pregnancy

Pregnancy Category X .

Abiraterone acetate 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 acetate in pregnant women and Abiraterone acetate 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 acetate 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 acetate.

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 6-17). 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.

Nursing Mothers

Abiraterone acetate 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 acetate, 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

Safety and effectiveness of Abiraterone acetate in pediatric patients have not been established.

Geriatric Use

Of the total number of patients receiving Abiraterone acetate 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.

Patients With Hepatic Impairment

The pharmacokinetics of abiraterone were examined in subjects with baseline mild (N=8) or moderate (N=8) hepatic impairment (Child-Pugh 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 acetate 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 acetate to 250 mg once daily. Do not use Abiraterone acetate 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 acetate treatment .

For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required .

Patients With 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 acetate. No dosage adjustment is necessary for patients with renal impairment .

Undesirable effects

The information provided in Undesirable effects of Abiraterone acetate is based on data of another medicine with exactly the same composition as the Abiraterone acetate of the medicine (Abiraterone). Be careful and be sure to specify the information on the section Undesirable effects in the instructions to the drug Abiraterone acetate directly from the package or from the pharmacist at the pharmacy.
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The following are discussed in more detail in other sections of the labeling:

  • Hypertension, Hypokalemia, and Fluid Retention due to Mineralocorticoid Excess .
  • Adrenocortical Insufficiency .
  • Hepatotoxicity .

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 ≥ 2.5X ULN 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 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 1: Adverse Reactions due to Abiraterone acetate in Study 1

System/Organ Class Adverse reaction Abiraterone acetate with Prednisone
(N=791)
Placebo with Prednisone
(N=394)
All Grades1% Grade 3-4% All Grades% Grade 3-4%
Musculoskeletal and connective tissue disorders
  Joint swelling/discomfort2 29.5 4.2 23.4 4.1
  Muscle discomfort3 26.2 3.0 23.1 2.3
General disorders
  Edema4 26.7 1.9 18.3 0.8
Vascular disorders
  Hot flush 19.0 0.3 16.8 0.3
  Hypertension 8.5 1.3 6.9 0.3
Gastrointestinal disorders
  Diarrhea 17.6 0.6 13.5 1.3
  Dyspepsia 6.1 0 3.3 0
Infections and infestations
  Urinary tract infection 11.5 2.1 7.1 0.5
  Upper respiratory tract infection 5.4 0 2.5 0
Respiratory, thoracic and mediastinal disorders
  Cough 10.6 0 7.6 0
Renal and urinary disorders
  Urinary frequency 7.2 0.3 5.1 0.3
  Nocturia 6.2 0 4.1 0
Injury, poisoning and procedural complications
  Fractures5 5.9 1.4 2.3 0
Cardiac disorders
  Arrhythmia6 7.2 1.1 4.6 1.0
  Chest pain or chest discomfort7 3.8 0.5 2.8 0
  Cardiac failure8 2.3 1.9 1.0 0.3
1 Adverse events graded according to CTCAE version 3.0.
2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.
3 Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness.
4 Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema.
5 Includes all fractures with the exception of pathological fracture.
6 Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia.
7 Includes terms Angina pectoris, Chest pain, and Angina unstable. Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the Abiraterone acetate arm (1.3% vs. 1.1% respectively).
8 Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased.

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.

Table 2: Laboratory Abnormalities of Interest in Study 1

Laboratory Abnormality Abiraterone
(N=791)
Placebo
(N=394)
All Grades (%) Grade 3-4 (%) All Grades (%) Grade 3-4 (%)
Hypertriglyceridemia 62.5 0.4 53.0 0
High AST 30.6 2.1 36.3 1.5
Hypokalemia 28.3 5.3 19.8 1.0
Hypophosphatemia 23.8 7.2 15.7 5.8
High ALT 11.1 1.4 10.4 0.8
High Total Bilirubin 6.6 0.1 4.6 0
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 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 3: Adverse Reactions in ≥ 5% of Patients on the Abiraterone acetate Arm in Study 2

System/Organ Class Adverse reaction Abiraterone acetate with Prednisone
(N=542)
Placebo with Prednisone
(N=540)
All Grades1% Grade 3-4% All Grades% Grade 3-4%
General disorders
  Fatigue  39.1 2.2 34.3 1.7
  Edema2 25.1 0.4 20.7 1.1
  Pyrexia 8.7 0.6 5.9 0.2
Musculoskeletal and connective tissue disorders
  Joint swelling/discomfort3 30.3 2.0 25.2 2.0
  Groin pain 6.6 0.4 4.1 0.7
Gastrointestinal disorders
  Constipation 23.1 0.4 19.1 0.6
  Diarrhea 21.6 0.9 17.8 0.9
  Dyspepsia 11.1 0.0 5.0 0.2
Vascular disorders
  Hot flush 22.3 0.2 18.1 0.0
  Hypertension 21.6 3.9 13.1 3.0
Respiratory, thoracic and mediastinal disorders
  Cough 17.3 0.0 13.5 0.2
  Dyspnea 11.8 2.4 9.6 0.9
Psychiatric disorders
  Insomnia 13.5 0.2 11.3 0.0
Injury, poisoning and procedural complications
  Contusion 13.3 0.0 9.1 0.0
  Falls 5.9 0.0 3.3 0.0
Infections and infestations
  Upper respiratory tract infection 12.7 0.0 8.0 0.0
  Nasopharyngitis 10.7 0.0 8.1 0.0
Renal and urinary disorders
  Hematuria 10.3 1.3 5.6 0.6
Skin and subcutaneous tissue disorders
  Rash 8.1 0.0 3.7 0.0
1 Adverse events graded according to CTCAE version 3.0.
2 Includes terms Edema peripheral, Pitting edema, and Generalized edema.
3 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.

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.

Table 4: Laboratory Abnormalities in > 15% of Patients in the Abiraterone acetate Arm of Study 2

Laboratory Abnormality Abiraterone
(N=542)
Placebo
(N=540)
Grade 1-4 % Grade 3-4 % Grade 1-4 % Grade 3-4 %
Hematology
  Lymphopenia 38.2 8.7 31.7 7.4
Chemistry
  Hyperglycemia1 56.6 6.5 50.9 5.2
  High ALT 41.9 6.1 29.1 0.7
  High AST 37.3 3.1 28.7 1.1
  Hypernatremia 32.8 0.4 25.0 0.2
  Hypokalemia 17.2 2.8 10.2 1.7
1 Based on non-fasting blood draws.
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.

Overdose

The information provided in Overdose of Abiraterone acetate is based on data of another medicine with exactly the same composition as the Abiraterone acetate of the medicine (Abiraterone). Be careful and be sure to specify the information on the section Overdose in the instructions to the drug Abiraterone acetate directly from the package or from the pharmacist at the pharmacy.
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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.

Pharmacokinetic properties

The information provided in Pharmacokinetic properties of Abiraterone acetate is based on data of another medicine with exactly the same composition as the Abiraterone acetate of the medicine (Abiraterone). Be careful and be sure to specify the information on the section Pharmacokinetic properties in the instructions to the drug Abiraterone acetate directly from the package or from the pharmacist at the pharmacy.
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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 .

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 .

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 .