Abiraterone Acetate SPC is a CYP17 inhibitor indicated in combination with prednisone for:

-  The treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

-  The treatment of newly diagnosed high risk metastatic hormone sensitive prostate cancer (mHSPC) in adult men in combination with androgen deprivation therapy (ADT).

-  The treatment of mCRPC in adult men whose disease has progressed on or after a docetaxel‑based chemotherapy regimen..

Posology

The recommended dose is 1,000 mg (two 500 mg tablets) as a single daily dose that must not be taken with food (see “Method of administration” below). Taking the tablets with food increases systemic exposure to abiraterone (see sections 4.5 and 5.2).

 

 

Recommended Dosage

The recommended dose of Abiraterone Acetate SPC is 1,000 mg (four 250 mg tablets) administered orally once daily in combination with:

•          Prednisone 5 mg administered orally once a day for mHSPC or

•          Prednisone 5 mg administered orally twice a daily for mCRPC.

Abiraterone Acetate SPC tablets must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of Abiraterone Acetate SPC tablet is taken and for at least one hour after the dose of Abiraterone Acetate SPC tablet 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 SPC 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 SPC tablets and do not re- treat patients with Abiraterone Acetate SPC tablets.

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

 

Hepatotoxicity

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

 

 

Renal impairment

No dose adjustment is necessary for patients with renal impairment (see section 5.2). However, there is no clinical experience in patients with prostate cancer and severe renal impairment. Caution is advised in these patients (see section 4.4).

 

Pediatric population

There is no relevant use of Abiraterone Acetate SPC in the pediatric population.

 

Method of administration

Abiraterone Acetate SPC is for oral use.

The tablets should be taken at least one hour before or at least two hours after eating. for at least one hour after taking the tablets. These should be swallowed whole with water.

 

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. • Women who are or may potentially be pregnant (see section 4.6). • Severe hepatic impairment [Child-Pugh Class C (see sections 4.2, 4.4 and 5.2)] • Abiraterone Acetate SPC with prednisone or prednisolone is contraindicated in combination with Ra-223.

Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess

Abiraterone Acetate SPC 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 SPC.

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 SPC with caution in patients with a history of cardiovascular disease. The safety of Abiraterone Acetate SPC 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 & 3) 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 SPC tablets.

 

Adrenocortical Insufficiency

Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients taking Abiraterone Acetate SPC tablets and in 0.2% of patients taking placebo. Adrenocortical insufficiency was reported in patients receiving Abiraterone Acetate SPC 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 SPC. 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 post-marketing experience, there have been Abiraterone Acetate associated severe hepatic toxicity, including fulminant hepatitis, acute liver failure and deaths.

In the three randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) were reported in 6% of patients who received Abiraterone Acetate SPC, 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 SPC or abnormal hepatic function were reported in 1.1%. No deaths clearly related to Abiraterone Acetate SPC were reported due to hepatotoxicity events.

 

Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with Abiraterone Acetate SPC, 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 SPC 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 SPC treatment and closely monitor liver function.

Re-treatment with Abiraterone Acetate SPC 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 SPC 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 SPC 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.

 

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 SPC 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 SPC to 250 mg once daily. Do not use Abiraterone Acetate SPC 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 SPC treatment.

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

 

Pediatric Use

Safety and effectiveness of Abiraterone Acetate SPC tablets 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 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 SPC. No dosage adjustment is necessary for patients with renal impairment.

 

Corticosteroid withdrawal and coverage of stress situations

Caution is advised and monitoring for adrenocortical insufficiency should occur if patients are withdrawn from prednisone or prednisolone. If Abiraterone Acetate SPC is continued after corticosteroids are withdrawn, patients should be monitored for symptoms of mineralocorticoid excess (see information above).

In patients on prednisone or prednisolone who are subjected to unusual stress, an increased dose of corticosteroids may be indicated before, during and after the stressful situation.

 

Bone density

Decreased bone density may occur in men with metastatic advanced prostate cancer. The use of Abiraterone Acetate SPC in combination with a glucocorticoid could increase this effect.

 

Prior use of ketoconazole

Lower rates of response might be expected in patients previously treated with ketoconazole for prostate cancer.

 

Hyperglycemia

The use of glucocorticoids could increase hyperglycemia, therefore blood sugar should be measured frequently in patients with diabetes.

 

Use with chemotherapy

The safety and efficacy of concomitant use of Abiraterone Acetate SPC with cytotoxic chemotherapy has not been established (see section 5.1).

 

Intolerance to excipients

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicinal product also contains more than 1.18 mmol (or 27 mg) sodium per dose of two tablets. To be taken into consideration by patients on a controlled sodium diet.

 

Potential risks

Anaemia and sexual dysfunction may occur in men with metastatic prostate cancer including those undergoing treatment with Abiraterone Acetate SPC.

 

Skeletal muscle effects

Cases of myopathy have been reported in patients treated with Abiraterone Acetate SPC. Most cases developed within the first month of treatment and recovered after Abiraterone Acetate SPC withdrawal. Caution is recommended in patients concomitantly treated with medicinal products known to be associated with myopathy/rhabdomyolysis.

 

Interactions with other medicinal products

Strong inducers of CYP3A4 during treatment are to be avoided unless there is no therapeutic alternative, due to risk of decreased exposure to abiraterone (see section 4.5).

 

Combination of abiraterone and prednisone/prednisolone with Ra-223

 

Treatment with abiraterone and prednisone/prednisolone in combination with Ra-223 is contraindicated (see section 4.3) due to an increased risk of fractures and a trend for increased mortality among asymptomatic or mildly symptomatic prostate cancer patients as observed in clinical trials.

 

It is recommended that subsequent treatment with Ra-223 is not initiated for at least 5 days after the last administration of Abiraterone Acetate in combination with prednisone/prednisolone.

Effect of food on abiraterone acetate

Administration with food significantly increases the absorption of abiraterone acetate. The efficacy and safety when given with food have not been established therefore this medicinal product must not be taken with food.

 

Interactions with other medicinal products

Potential for other medicinal products to affect abiraterone exposures

In a clinical pharmacokinetic interaction study of healthy subjects pretreated with a strong CYP3A4 inducer rifampicin, 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%.

Strong inducers of CYP3A4 (e.g., phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John's wort [Hypericum perforatum]) during treatment are to be avoided, unless there is no therapeutic alternative.

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.

Combination of abiraterone and prednisone/prednisolone with Ra-223.

 

Treatment with abiraterone and prednisone/prednisolone in combination with Ra-223 is contraindicated due to an increased risk of fractures and a trend for increased mortality among asymptomatic or mildly symptomatic prostate cancer patients as observed in clinical trials.

 

It is recommended that subsequent treatment with Ra-223 is not initiated for at least 5 days after the last administration of ZYTIGA in combination with prednisone/prednisolone.

 

Potential to affect exposures to other medicinal products

Abiraterone is an inhibitor of the hepatic drug-metabolising enzymes CYP2D6 and CYP2C8.

In a study to determine the effects of Abiraterone Acetate (plus prednisone) on a single dose of the CYP2D6 substrate dextromethorphan, the systemic exposure (AUC) of dextromethorphan was increased approximately

2.9 fold. The AUC24 for dextrorphan, the active metabolite of dextromethorphan, increased approximately 33%.

Caution is advised when administering with medicinal products activated by or metabolised by CYP2D6, particularly with medicinal products that have a narrow therapeutic index. Dose reduction of medicinal products with a narrow therapeutic index that are metabolised by CYP2D6 should be considered. Examples of medicinal products metabolised by CYP2D6 include metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol (the latter three medicinal products requiring CYP2D6 to form their active analgesic metabolites).

In a CYP2C8 drug-drug interaction trial in healthy subjects, the AUC of pioglitazone was increased by 46% and the AUCs for M-III and M-IV, the active metabolites of pioglitazone, each decreased by 10% when pioglitazone was given together with a single dose of 1,000 mg Abiraterone Acetate. Although these results indicate that no clinically meaningful increases in exposure are expected when Abiraterone Acetate is combined with medicinal products that are predominantly eliminated by CYP2C8, patients should be monitored for signs of toxicity  related to a CYP2C8 substrate with a narrow therapeutic index if used concomitantly.

 

In vitro, the major metabolites abiraterone sulphate and N-oxide abiraterone sulphate were shown to inhibit the hepatic uptake transporter OATP1B1 and as a consequence it may increase the concentrations of medicinal products eliminated by OATP1B1. There are no clinical data available to confirm transporter- based interaction.

 

Use with products known to prolong QT interval

Since androgen deprivation treatment may prolong the QT interval, caution is advised when administering Abiraterone Acetate SPC with medicinal products known to prolong the QT interval or medicinal products able to induce torsades de pointes such as class IA (e.g. quinidine, disopyramide) or class III (e.g. amiodarone, sotalol, dofetilide, ibutilide) antiarrhythmic medicinal products, methadone, moxifloxacin, antipsychotics, etc.

 

Use with Spironolactone

Spironolactone binds to the androgen receptor and may increase prostate specific antigen (PSA) levels. Use with Abiraterone Acetate SPC is not recommended

Women of childbearing potential

There are no human data on the use of Abiraterone Acetate SPC in pregnancy and this medicinal product is not for use in women of childbearing potential.

 

Contraception in males and females

It is not known whether abiraterone or its metabolites are present in semen. A condom is required if the patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sex with a woman of childbearing potential, a condom is required along with another effective contraceptive method.

Studies in animals have shown reproductive toxicity.

 

Pregnancy

Abiraterone Acetate SPC is not for use in women and is contraindicated in women who are or may potentially be pregnant

 

 

Breast-feeding

Abiraterone Acetate SPC is not for use in women.

 

 

Fertility

Abiraterone affected fertility in male and female rats, but these effects were fully reversible

Abiraterone has no or negligible influence on the ability to drive and use machines.

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 1,195 patients with metastatic CRPC who had received prior docetaxel chemotherapy. Patients were not eligible if AST and/or ALT ≥2.5 X 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 to 4 %	All Grades %	Grade 3 to 4 %
Musculoskeletal and connective tissue disorders
Joint swelling/discomfort2	29.5	4.2	23.4	4.1
Muscle discomfort3	26.2	3	23.1	2.3
General disorders
Edema4	26.7	1.9	18.3	0.8
Vascular disorders
Hot flush	19	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
Chest pain or chest discomfort7	3.8	0.5	2.8	0
Cardiac failure8	2.3	1.9	1	0.3

 

1Adverse events graded according to CTCAE version 3.

2 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness.

3Includes   terms   Muscle   spasms,   Musculoskeletal   pain,   Myalgia,   Musculoskeletal   discomfort,                  and Musculoskeletal stiffness.

4Includes terms Edema, Peripheral Edema, Pitting edema, and Generalized edema. 5Includes all fractures with the exception of pathological fracture

6Includes 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 tablets arm (1.3% vs. 1.1% respectively).

8Includes 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 to 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)
	l Grades (%)	de 3 to 4 (%)	l Grades (%)	Grade 3 to 4 (%)
Hypertriglyceridemia	62.5	0.4	53	0
High AST	30.6	2.1	36.3	1.5
Hypokalemia	28.3	5.3	19.8	1
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 1,088 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	terone Acetate with Prednisone (N=542)		with Prednisone (N=540)
	All Grades1 %	Grade 3 to 4 %	All Grades %	Grade 3 to 4 %
General disorders
Fatigue Edema2	39.1 25.1	2.2 0.4	34.3 20.7	1.7 1.1
Pyrexia	8.7	0.6	5.9	0.2
Musculoskeletal and connective
tissue disorders
Joint swelling/discomfort3	30.3	2	25.2	2
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	5	0.2
Vascular disorders
Hot flush	22.3	0.2	18.1	0
Hypertension	21.6	3.9	13.1	3
Respiratory, thoracic and
mediastinal disorders
Cough	17.3	0	13.5	0.2
Dyspnea	11.8	2.4	9.6	0.9
Psychiatric disorders
Insomnia	13.5	0.2	11.3	0
Injury, poisoning and procedural
complications
Contusion	13.3	0	9.1	0
Falls	5.9	0	3.3	0
Infections and infestations
Upper respiratory tract infection	12.7	0	8	0
Nasopharyngitis	10.7	0	8.1	0
Renal and urinary disorders Hematuria	10.3	1.3	5.6	0.6
Skin and subcutaneous tissue
disorders Rash	8.1	0	3.7	0

 

1Adverse events graded according to CTCAE version 3.

2Includes terms Edema peripheral, Pitting edema, and Generalized edema. 3Includes 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 to 4 lymphopenia (9%), hyperglycemia (7%) and high alanine aminotransferase (6%) occurred at a greater than 5% rate in the Abiraterone Acetate SPC 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)
	de 1 to 4 (%)	de 3 to 4 (%)	de 1 to 4 (%)	Grade 3 to (%) 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	0.2
Hypokalemia	17.2	2.8	10.2	1.7

1 Based on non-fasting blood draws.

Study 3: Patients with Newly Diagnosed High Risk mHSPC

 

Study 3 enrolled 1199 patients and the median age of enrolled patients was 67 years. The number of patients treated with Abiraterone Acetate by racial group was Caucasian 832 (69.4%), Asian 246 (20.5%), Black or African American 25 (2.1%), other 80 (6.7%), unknown/not reported 13 (1.1%), and American Indian or Alaska Native 3 (0.3%). The ECOG performance status was 0 or 1 for 97% of patients. Patients with known brain metastasis, uncontrolled hypertension, significant heart disease, or NYHA Class II-IV heart failure were excluded. Patients that were treated with prior pharmacotherapy, radiation therapy, or surgery for metastatic prostate cancer were excluded with the exception of up to 3 months of ADT or 1 course of palliative radiation or surgical therapy to treat symptoms resulting from metastatic disease. Co-primary efficacy endpoints were overall survival (OS) and radiographic progression-free survival (rPFS). The median baseline pain score, as measured by the Brief Pain Inventory Short Form (BPI-SF) was 2.0 in both the treatment and Placebo groups. In addition to the co- primary endpoint measures, benefit was also assessed using time to skeletal-related event (SRE), time to subsequent therapy for prostate cancer, time to initiation of chemotherapy, time to pain progression, and time to PSA progression. Treatment continued until disease progression, withdrawal of consent, the occurrence of unacceptable toxicity, or death.

 

Radiographic progression-free survival was defined as the time from randomization to the occurrence of radiographic progression or death from any cause. Radiographic progression included progression by bone scan (according to modified PCWG2) or progression of soft tissue lesions by CT or MRI (according to RECIST 1.1).

 

A significant difference in rPFS between treatment groups was observed (see Table 2 and Figure 1 in eMC)

 

 

 

Subgroup analyses consistently favor treatment with abiraterone acetate. The treatment effect of AA-P on rPFS and OS across the pre-specified subgroups was favorable and consistent with the overall study population, except for the subgroup of ECOG score of 2 where no trend towards benefit was observed, however the small sample size (n=40) limits drawing any meaningful conclusion.

 

In addition to the observed improvements in overall survival and rPFS, benefit was demonstrated for abiraterone acetate vs. placebo treatment in all prospectively-defined secondary endpoint measures as follows:

 

Time to skeletal-related event (SRE): There was a 30% reduction in the risk of skeletal-related events (HR = 0.703; 95% CI: [0.539, 0.916], p = 0.0086). The median time to SRE has not been reached for the abiraterone acetate or placebo study arm.

 

Time to PSA progression based on PCWG2 criteria: The median time to PSA progression was 33.2 months for patients receiving abiraterone acetate and 7.4 months for patients receiving placebo (HR = 0.299; 95% CI: [0.255, 0.352], p <0.0001).

 

Time to subsequent therapy: The median time to subsequent therapy at the time of interim analysis was not reached for patients receiving abiraterone acetate and was 21.6 months for patients receiving placebo (HR = 0.415; 95% CI: [0.346, 0.497], p <0.0001).

 

Time to initiation of chemotherapy: The median time to initiation of chemotherapy was not reached for patients receiving abiraterone acetate and was 38.9 months for patients receiving placebo (HR = 0.443; 95% CI: [0.349, 0.561], p < 0.0001).

 

Time to pain progression: The median time to pain progression was not reached for patients receiving abiraterone acetate and was 16.6 months for patients receiving placebo (HR = 0.695; 95% CI: [0.583, 0.829], p <0.0001).

 

The majority of exploratory endpoints favored treatment with abiraterone acetate and prednisone (AA-P) over Placebo.

 

Cardiovascular Adverse Reactions:

In the three studies ( 1, 2 and 3), then make the required changes if you find, 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 to 4 cardiac failure occurred in 1.6% of patients taking Abiraterone Acetate and led to 5 treatment discontinuations and 2 deaths. Grade 3 to 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 clinical trials, then make the required changes if you find., 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.

 

Post-marketing Experience

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

There is no specific antidote. In the event of an overdose, administration should be withheld and general supportive measures undertaken, including monitoring for arrhythmias, hypokalemia and for signs and symptoms of fluid retention. Liver function also should be assessed.

Abiraterone Acetate SPC 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.

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.

 

Pharmacodynamic effects

Abiraterone Acetate SPC decreases serum testosterone and other androgens to levels lower than those achieved by the use of LHRH analogues alone or by orchiectomy. This results from the selective inhibition of the CYP17 enzyme required for androgen biosynthesis. PSA serves as a biomarker in patients with prostate cancer. In a Phase 3 clinical study of patients who failed prior chemotherapy with taxanes, 38% of patients treated with Abiraterone Acetate, versus 10% of patients treated with placebo, had at least a 50% decline from baseline in PSA levels.

 

Clinical studies

The efficacy and safety of Abiraterone Acetate in patients with mHSPC and mCRPC that has progressed on androgen deprivation therapy was demonstrated in three 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. Concurrent use of spironolactone was not allowed during the study period.

 

 

Study 1 Patients with metastatic CRPC who had received prior docetaxel chemotherapy:

A total of 1,195 patients were randomized 2:1 to receive either Abiraterone Acetate 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 39 to 95) 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 0 to 1 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 (OS) in patients treated with Abiraterone Acetate 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 withthose from the interim analysis (Table 5).

Table 5: Overall Survival of Patients Treated with Either Abiraterone Acetate or Placebo in Combination with Prednisone in Study 1 (Intent-to-Treat Analysis)

 

 

 

Figure 1: Kaplan-Meier Overall Survival Curves in Study 1 (Intent-to-Treat Analysis)

 

 

 

 

Study 2: Patients with metastatic CRPC who had not received prior cytotoxic chemotherapy

In Study 2, 1,088 patients were randomized 1:1 to receive either Abiraterone Acetate 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 Acetate 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 0 to 1 (asymptomatic) in 66% of patients and 2 to 3 (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.

The planned final analysis for OS, conducted after 741 deaths (median follow up of 49 months) demonstrated a statistically significant OS improvement in patients treated with Abiraterone Acetate compared to those treated with placebo (Table 6 and Figure 2). Sixty-five percent of patients on the Abiraterone Acetate arm and 78% of patients on the placebo arm used subsequent therapies that may prolong OS in metastatic CRPC. Abiraterone Acetate was used as a subsequent therapy in 13% of patients on the Abiraterone Acetate arm and 44% of patients on the placebo arm.

 

Table 6: Overall Survival of Patients Treated with Either Abiraterone Acetate or Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis)

Overall Survival	Abiraterone Acetate (N=546)	Placebo (N=542)
Deaths	354 (65%)	387 (71%)
Median survival (months) (95% CI)	34.7 (32.7, 36.8)	30.3 (28.7, 33.3)
p-value1	0.0033
Hazard ratio2 (95% CI)	0.81 (0.70, 0.93)

 

1 p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1).

2Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors Abiraterone Acetate SPC.

Figure 2: Kaplan Meier Overall Survival Curves in Study 2

 

 

 

 

At the pre-specified rPFS analysis, 150 (28%) patients treated with Abiraterone Acetate 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).

 

Table 7: Radiographic Progression-free Survival of Patients Treated with Either Abiraterone Acetate or Placebo in Combination with Prednisone in Study 2 (Intent-to-Treat Analysis)

 

Radiographic Progression-free Survival	Abiraterone Acetate (N=546)	Placebo (N=542)
Progression or death	150 (28%)	251 (46%)
Median rPFS (months) (95% CI)	NR (11.66, NR)	8.28 (8.12, 8.54)
p-value1	<0.0001
Hazard ratio2 (95% CI)	0.425 (0.347, 0.522)

NR=Not reached.

1p-value is derived from a log-rank test stratified by ECOG performance status score (0 vs. 1).

2Hazard Ratio is derived from a stratified proportional hazards model. Hazard ratio <1 favors Abiraterone Acetate SPC.

Figure 3: Kaplan Meier Curves of Radiographic Progression-free Survival in Study 2 (Intent-to- Treat Analysis)

 

 

 

 

 

 

 

 

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 Acetate and 16.8 months for patients receiving placebo (HR=0.580; 95% CI: [0.487, 0.691], p < 0.0001).

The median time to opiate use for prostate cancer pain was not reached for patients receiving Abiraterone Acetate and was 23.7 months for patients receiving placebo (HR=0.686; 95% CI: [0.566, 0.833], p=0.0001). The time to opiate use result was supported by a delay in patient reported pain progression favoring the Abiraterone Acetate arm.

 

QT Prolongation

In a multi-center, open-label, single-arm trial, 33 patients with metastatic CRPC received Abiraterone Acetate tablets 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 SPC cannot be excluded due to study design limitations.

Following administration of Abiraterone Acetate SPC, 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 SPC 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 SPC.

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 SPC 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 SPC 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 SPC 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 SPC 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 SPC were similar when Abiraterone Acetate SPC 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 SPC tablets 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 SPC tablets is taken and for at least one hour after the dose of Abiraterone Acetate SPC tablets 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 SPC and abiraterone are not substrates of P- glycoprotein (P-gp) and that Abiraterone Acetate SPC is an inhibitor of P-gp.

 

Metabolism

Following oral administration of 14C- Abiraterone Acetate SPC as capsules, Abiraterone Acetate SPC 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 SPC, 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 SPC 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 SPC 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 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 SPC 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 SPC 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 SPC 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.

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 SPC.

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

Animal Toxicology and/or Pharmacology

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 SPC 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 anti-androgenic pharmacological activity of Abiraterone Acetate SPC. 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 SPC reversed or were partially resolved after a 4-week recovery period.

 

Carcinogenesis, Mutagenesis, and Impairment of Fertility

A two-year carcinogenicity study was conducted in rats at oral Abiraterone Acetate SPC doses of 5, 15, and 50 mg/kg/day for males and 15, 50, and 150 mg/kg/day for females. Abiraterone Acetate SPC 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 SPC was not carcinogenic in female rats at exposure levels up to 0.8 times the human clinical exposure based on AUC. Abiraterone Acetate SPC 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.

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