Xbira.in

Abiraterone Acetate Tablets 250 mg
XBIRA
COMPOSITION
Each tablet contains:
Abiraterone Acetate ……… 250 mg
Excipients……………………….q.s.
DOSAGE FORM
Tablet

PHARMACOLOGY
Pharmacodynamics
Mechanism of Action
Abiraterone acetate is converted in vivo to abiraterone, an androgen biosynthesis
inhibitor, that inhibits 17alpha-hydroxylase/C17,20-lyase (CYP17). This enzyme is
expressed in testicular, adrenal and prostatic tumour tissues and is required for
androgen biosynthesis.
Cytochrome (CY) P17 catalyses two sequential reactions: 1) the conversion of
pregnenolone and progesterone to their 17alpha-hydroxy derivatives by 17alpha-
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 gonadotropin-releasing
hormone (GnRH) agonists or orchiectomy, decrease androgen production in the testes
but do not affect androgen production by the adrenals or in the tumour.
Abiraterone acetate decreased serum testosterone and other androgens in patients in
the placebo-controlled Phase 3 clinical trial. It is not necessary to monitor the effect of
abiraterone acetate on serum testosterone levels.
Changes in serum prostate-specific antigen (PSA) levels may be observed, but have
not been shown to correlate with clinical benefit in individual patients.
Pharmacokinetics
Following administration of abiraterone acetate, the pharmacokinetics of abiraterone
and abiraterone acetate have been studied in healthy subjects and in patients with
metastatic castration-resistant prostate cancer (CRPC). In vivo, abiraterone acetate is
converted to abiraterone. In clinical studies, abiraterone acetate plasma concentrations
were below detectable levels (<0.2 ng/mL) in >99% of the analysed 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 the steady state,
with a 2-fold higher exposure (steady-state area under the concentration curve [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 ± S.D.) of the Cmax were 226 ± 178 ng/mL and of the AUC were 1173 ± 690
ng.hr/mL. No major deviation from dose proportionality was observed in the dose range
of 250 mg to 1,000 mg.
Systemic exposure of abiraterone is increased when abiraterone acetate is
administered with food. Abiraterone Cmax and AUC0-∞were approximately 7- and 5-fold
higher, respectively, when abiraterone acetate was administered with a low-fat meal
(7% fat, 300 calories) and approximately 17- and 10-fold higher, respectively, when
abiraterone acetate was administered with a high-fat (57% fat, 825 calories) meal.
Given the normal variation in the content and composition of meals, taking abiraterone
acetate with meals has the potential to result in increased and highly variable
exposures. Therefore, no food should be consumed for at least 2 hours before the dose
of abiraterone acetate is taken and for at least 1 hour after the dose of abiraterone
acetate is taken.

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 ± S.D.) is 19,669 ± 13,358 L. In vitro studies show that at
clinically relevant concentrations, abiraterone acetate and abiraterone are not
substrates of P-glycoprotein (P-gp) and that abiraterone acetate is an inhibitor of P-gp.
No studies have been conducted with other transporter proteins.

Metabolism: Following oral administration of 14C-abiraterone acetate as capsules,
abiraterone acetate is hydrolysed 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 ± S.D.) is 12 ± 5 hours. Following oral administration of 14C-
abiraterone acetate, approximately 88% of the radioactive dose is recovered in faeces
and approximately 5% in urine. The major compounds present in faeces are unchanged
abiraterone acetate and abiraterone (approximately 55% and 22% of the administered
dose, respectively).
Pharmacokinetics in special populations:
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. Abiraterone acetate has not
been studied in patients with baseline severe hepatic impairment (Child-Pugh Class C).

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 ESRD on dialysis, compared to subjects with normal renal function.
INDICATIONS
XBIRA is a CYP17 inhibitor indicated in combination with prednisone for the treatment
of patients with metastatic CRPC who have received prior chemotherapy containing
docetaxel.
DOSAGE AND ADMINISTRATION
The recommended dose of XBIRA tablets is 1,000 mg (four 250 mg tablets)
administered orally once daily in combination with prednisone 5 mg administered orally
twice daily. XBIRA tablets must be taken on an empty stomach. No food should be
consumed for at least 2 hours before the dose of XBIRA tablet is taken and for at least
1 hour after the dose of XBIRA tablet is taken. The tablets should be swallowed whole
with water. Do not crush or chew the tablets.

Special Populations
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 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 alanine aminotransferase (ALT), aspartate
aminotransferase (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.
Avoid abiraterone acetate in patients with baseline severe hepatic impairment (Child-
Pugh Class C), as abiraterone acetate has not been studied in this population, and no
dose adjustment can be predicted.

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.
CONTRAINDICATIONS
XBIRA tablets are contraindicated in women who are or may become pregnant. XBIRA
tablets can cause foetal harm when administered to a pregnant woman. XBIRA tablets
are not indicated for use in women. 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 foetus and the potential risk for pregnancy loss.
WARNINGS AND PRECAUTIONS
General
Abiraterone acetate must be taken on an empty stomach. No food should be consumed
for at least 2 hours before the dose of abiraterone acetate is taken and for at least 1
hour after the dose of abiraterone acetate is taken. Abiraterone Cmax and AUC0-∞
(exposure) were increased up to 17- and 10-fold higher, respectively, when a single
dose of abiraterone acetate was administered with a meal compared to a fasted state.
The safety of these increased exposures when multiple doses of abiraterone acetate
are taken with food has not been assessed.
Drug Interactions
Effects of Abiraterone on Drug-Metabolizing Enzymes
In vitro studies with human hepatic microsomes showed that abiraterone is a strong
inhibitor of CYP1A2, CYP2D6 and CYP2C8, a moderate inhibitor of CYP2C9, CYP2C19
and CYP3A4/5. In a CYP2D6 drug–drug interaction trial, the Cmax and AUC of
dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively,
when dextromethorphan 30 mg was given with abiraterone acetate 1,000 mg daily and
prednisone 5 mg twice daily. The AUC for dextrorphan, the active metabolite of
dextromethorphan, increased by approximately 1.3-fold. Avoid co-administration of
abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g.
thioridazine). If alternative treatments cannot be used, exercise caution and consider a
dose reduction of the concomitant CYP2D6 substrate drug.
In vitro, abiraterone acetate inhibits CYP2C8. There are no clinical data on the use of
abiraterone acetate with drugs that are substrates of CYP2C8. However, patients
should be monitored closely for signs of toxicity related to the CYP2C8 substrate if used
concomitantly with abiraterone acetate.
In a clinical study to determine the effects of abiraterone acetate 1,000 mg daily (plus
prednisone 5 mg twice daily) on a single 100 mg dose of the CYP1A2 substrate
theophylline, no increase in systemic exposure of theophylline was observed.

Drugs that Inhibit or Induce CYP3A4 Enzymes
Based on in vitro data, abiraterone acetate is a substrate of CYP3A4. The effects of
strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir,
nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or
inducers (e.g. phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital)
on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use
with caution, strong inhibitors and inducers of CYP3A4 during abiraterone acetate
treatment.

Hypertension, Hypokalaemia and Fluid Retention Due to Mineralocorticoid
Excess
Abiraterone acetate may cause hypertension, hypokalaemia 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 hypokalaemia in 4% of patients, and grade 3 to 4 oedema 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, hypokalaemia 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, hypokalaemia,
and fluid retention at least once a month. Control hypertension and correct
hypokalaemia 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 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 2 weeks for the first 3 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 2 weeks for the following 2
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.
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 2 weeks
for 3 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.
QT Prolongation
In a multicentre, open-label, single-arm trial, 33 patients with metastatic CRPC received
abiraterone acetate orally at a dose of 1,000 mg once daily at least 1 hour before or 2
hours after a meal in combination with prednisone 5 mg orally twice daily. Assessments
up to day 2 of cycle 2 showed no large changes in the QTc interval (i.e. >20 ms) from
baseline. However, small increases in the QTc interval (i.e. <10 ms) due to abiraterone
acetate cannot be excluded due to study design limitations.

Bone Density
Decreased bone density may occur in men with metastatic advanced prostate cancer
(castration resistant prostate cancer). The use of abiraterone acetate in combination
with a glucocorticoid could increase this effect.
Hyperglycaemia
The use of glucocorticoids could increase hyperglycaemia; therefore blood sugar should
be measured frequently in patients with diabetes.
Use with Chemotherapy
The safety and efficacy of concomitant use of abiraterone acetate with cytotoxic
chemotherapy has not been established.
Effects on Ability to Drive and Use Machines
Abiraterone acetate has no or negligible influence on the ability to drive or use
machines.

Information for Patients
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 must not be taken with food and that no food should be consumed for at least 2 hours before the dose of abiraterone acetate is taken and for at least 1 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 the recommended dosage of abiraterone acetate is once daily while prednisone is taken twice daily, and they should be taken 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 oedema, hypokalaemia, hypertension, elevated liver function tests, and urinary tract infection. Patients should be advised that their liver function will be monitored using blood Patients should be informed that abiraterone acetate may harm a developing foetus; 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 childbearing potential. These measures are required during and for 1 week after treatment with abiraterone acetate.
Renal Impairment
In a dedicated renal impairment trial, the mean pharmacokinetic parameters were
comparable between healthy subjects with normal renal function (N=8) and those with
end-stage renal disease (ESRD) on haemodialysis (N=8) after a single oral 1,000 mg
dose of abiraterone acetate. 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 ESRD on dialysis, compared to subjects with normal renal function. No
dosage adjustment is necessary for patients with renal impairment.

Hepatic Impairment
The pharmacokinetics of abiraterone were examined in subjects with baseline mild
(N=8) or moderate (N=8) hepatic impairment (Child-Pugh Class A and B, respectively)
and in 8 healthy control subjects with normal hepatic function. The systemic exposure
(AUC) of abiraterone after a single oral 1,000 mg dose of abiraterone acetate given
under fasting conditions 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. 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.

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. A once-daily dose of
250 mg in patients with moderate hepatic impairment is predicted to result in an 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
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.
The safety of abiraterone acetate in patients with baseline severe hepatic impairment
(Child-Pugh Class C) has not been studied. Hence, avoid abiraterone acetate in these
patients and no dose adjustment can be predicted.

Pregnancy
Pregnancy Category X
Abiraterone acetate can cause foetal 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 the maternal use
of a CYP17 inhibitor could affect development of the foetus. 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 foetus and the potential risk for pregnancy loss. Advise
females of reproductive potential to avoid becoming pregnant during treatment with
abiraterone acetate.
In an embryo-foetal 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-foetal lethality (increased post-implantation loss and resorptions, and
decreased number of live foetuses), foetal developmental delay (skeletal effects) and
urogenital effects (bilateral ureter dilation) at doses ≥10 mg/kg/day, decreased foetal
ano-genital distance at ≥30 mg/kg/day, and decreased foetal 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.
Lactation
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.

Paediatric Use
Safety and effectiveness of abiraterone acetate in paediatric patients have not been
established.

Geriatric Use
Of the total number of patients receiving abiraterone acetate in Phase 3 trials, 73% of
patients were aged 65 years and over and 30% were aged 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.
UNDESIRABLE EFFECTS
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, multicentre clinical trials enrolled patients who had
metastatic CRPC who were using a 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 drug reactions (≥10%) reported in the two randomized
clinical trials that occurred more commonly (>2%) in the abiraterone acetate arm were
fatigue, joint swelling or discomfort, oedema, hot flush, diarrhoea, vomiting, cough,
hypertension, dyspnoea, 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
anaemia, elevated alkaline phosphatase, hypertriglyceridaemia, lymphopenia,
hypercholesterolaemia, hyperglycaemia, elevated AST, hypophosphataemia, elevated
ALT and hypokalaemia.

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 ≥2.5X ULN in the absence
of liver metastases. Patients with liver metastases were excluded if AST and/or ALT
>5X ULN.
Table 1 shows the adverse reactions in 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

Abiraterone Acetate with
System/Organ
Prednisone
Placebo with Prednisone
All Grades1
Grade 3-4
All Grades
Grade 3-4
Musculoskeletal
and Connective
Tissue Disorders
Joint swelling/
Disorders
Oedema4
Vascular
Disorders
Hot flush
Gastrointestinal
Disorders
Diarrhoea
Infections and
Infestations
Urinary tract
tract infection
Respiratory,
Thoracic and
Mediastinal
Disorders
Cough
Renal and Urinary
Disorders
Urinary frequency
Injury, Poisoning
and Procedural
Complications
Fractures5
Cardiac Disorders
1 Adverse events graded according to CTCAE version 3.0. 2 Includes the terms, arthritis, arthralgia9, joint swelling and joint stiffness. 3 Includes the terms, muscle spasms, musculoskeletal pain, myalgia, musculoskeletal discomfort and musculoskeletal stiffness. 4 Includes the terms, oedema, oedema peripheral, pitting oedema and generalized oedema. 5 Includes all fractures with the exception of pathological fracture. 6 Includes the terms, arrhythmia, tachycardia, atrial fibrillation, supraventricular tachycardia, atrial tachycardia, ventricular tachycardia, atrial flutter, bradycardia, atrioventricular block complete, conduction disorder and bradyarrhythmia. 7 Includes the 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 the 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

Abiraterone Acetate (N=791)
Placebo (N=394)
Laboratory
All Grades
Grade 3–4
All Grades
Grade 3–4
Abnormality

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 the adverse reactions in 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 in the Abiraterone Acetate Arm in
Study 2
Abiraterone Acetate with
System/Organ
Placebo with Prednisone
Prednisone
All Grades1
Grade 3–4
All Grades
Grade 3–4
Disorders
Fatigue
Musculoskeletal
and Connective
Tissue Disorders
Joint swelling/
Gastrointestinal
Disorders
Constipation
Vascular
Disorders
Hot flush
Respiratory,
Thoracic and
Mediastinal
Disorders
Cough
Psychiatric
Disorders
Insomnia
Injury, Poisoning
and Procedural
Complications
Contusion
Infections and
Infestations
Upper respiratory
Renal and
Urinary
Disorders
Haematuria
Subcutaneous
Tissue Disorders
Rash

1 Adverse events graded according to CTCAE version 3.0
2 Includes the terms, oedema peripheral, pitting oedema and generalized oedema
3 Includes the terms, arthritis, arthralgia, joint swelling and joint stiffness
Table 4 shows the 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%), hyperglycaemia (7%) and high ALT
(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

Abiraterone Acetate (N=542)
Placebo (N=540)
Laboratory
Grade 1–4
Grade 3–4
Grade 1–4
Grade 3–4
Abnormality
Haematology
Chemistry
1Based 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 in 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 Studies 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 ischaemia or myocardial infarction led to death in 3 patients
in the placebo arms and 2 deaths in the abiraterone acetate arms.
OVERDOSAGE
There have been no reports of overdose of abiraterone acetate during clinical studies.
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.

SHELF-LIFE
See on pack.

STORAGE AND HANDLING INSTRUCTIONS
Store below 25°C.

PACKAGING INFORMATION
XBIRA 250 mg Tablets . 120 tablets in a sealed container
Last Updated: May 2013
Last Reviewed: May 2013

Source: http://xbira.in/xbira.pdf