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PBRER - Abiraterone - ABIR-2023-03-PER

This PBRER evaluates the current benefit risk balance of Abiraterone based on new information received during the reporting interval. Abiraterone is approved for prostate cancer indications. The cumulative exposure to Abiraterone is 555 patients from clinical trials. The post-authorization exposure is estimated at 21,507 patient years. No new safety issues were identified that impact the favorable benefit-risk balance.

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0% found this document useful (0 votes)

29 views64 pages

PBRER - Abiraterone - ABIR-2023-03-PER

Uploaded by

LUIS EMILIO ESPINOZA HILARIO

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Periodic Benefit-Risk Evaluation Report Abiraterone

05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER

Page 1 of 64

PERIODIC BENEFIT-RISK EVALUATION REPORT

ABIPRO 250 mg tablets

(Abiraterone Acetate 250 mg Tablets)

MARKETING AUTHORISATION NUMBER : EE-07755

DATE OF APPROVAL : 05 September 2019
DATE OF LAUNCH : August 2020
REPORTING INTERVAL : 05 September 2022 – 04 September 2023
DATE OF REPORT : 29 November 2023
PBRER NUMBER : ABIR-2023-03-PER

Sun Pharmaceutical Industries Ltd. 29/Nov/2023

Signature ………………………………...………
Andréa Lopes– RPP Region V

29/Nov/2023
Sun Pharmaceutical Industries Ltd. Signature ………………………………...………
Sara Flores – RPP Peru

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

This PBRER evaluates current benefit risk balance of Abiraterone taking into account new
or emerging information received by SPIL during the reporting interval 05 September 2022
– 04 September 2023 in the context of cumulative information on risks and benefits.
Pharmacotherapeutic Group: Endocrine treatment, hormone antagonists and related
agents, ATC code: L02BX03.
Abiraterone acetate (ABIPRO) is converted in vivo to abiraterone, an inhibitor of androgen
biosynthesis. Specifically, abiraterone is a selective inhibitor of the enzyme 17α-hydroxylase
/ C17,20-lyase (CYP17). Expression of this enzyme is necessary for androgen biosynthesis
in testicular, adrenal, and prostate tumor tissues. CYP17 catalyzes the conversion of
pregnenolone and progesterone to the precursors of testosterone, DHEA and
androstenedione, respectively, by 17α-hydroxylation and cleavage of the C17, 20 bond.
Inhibition of CYP17 also results in increased mineralocorticoid production by the glands
adrenals.
Androgen-sensitive carcinoma of the prostate responds to treatment that lowers androgen
levels. Androgen deprivation treatments, such as treatment with LHRH analogs or
orchiectomy, decrease androgen production in the testes, but do not affect androgen
production in the adrenal glands or in the tumor. Abiraterone Acetate treatment reduces
serum testosterone to undetectable levels (using commercial assays) when co-administered
with LHRH analogs (or orchiectomy).
The Abiraterone acetate reduces the serum concentration of testosterone and other
androgens to levels lower than those achieved with LHRH analogs alone or with
orchiectomy. This is a consequence of the selective inhibition of the CYP17 enzyme
necessary for androgen biosynthesis. PSA acts as a biomarker in prostate cancer patients.
In a phase III clinical study with patients who had failed previous chemotherapy with taxanes,
38% of the patients treated with abiraterone acetate, compared with 10% of those who
received placebo, recorded a reduction of at least 50% with respect to baseline PSA values.
Therapeutic indications
ABIPRO is indicated with prednisone or prednisolone for:
− 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 metastatic castration-resistant prostate cancer (mCRPC) in adult men
who are asymptomatic or mildly symptomatic after failure of androgen deprivation
therapy in whom chemotherapy is not yet clinically indicated.
− The treatment of mCRPC in adult men whose disease has progressed during or after a
docetaxel-based chemotherapy regimen.
SPIL’s Abiraterone is currently available as 125 mg, 250 mg and 500 mg tablets.
The cumulative subject exposure to Abiraterone in the completed interventional clinical trials
till DLP of this PBRER is 555.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 3 of 64
The cumulative worldwide post authorization patient exposure (till August 2023) to SPIL’s
Abiraterone, in terms of Patient Treatment Years (PTY) is estimated to be 21,507.
The worldwide post authorization patient exposure to SPIL’s Abiraterone during the reporting
interval, in terms of PTY is estimated to be 5,179.
Abiraterone, worldwide was first approved for SPIL in India on 29 December 2018. In Peru,
Abiraterone was first approved for SPIL on 05 September 2019 and is marketed in Peru
under the brand name of ABIPRO available in the strength of 250 mg tablets. Currently,
Abiraterone is approved in 18 countries for SPIL. SPIL has received new approvals in 05
countries for Abiraterone during this reporting interval.
During the reporting interval, no significant actions related to safety have been taken related
to investigational uses of Abiraterone, sponsors of clinical trial(s), data monitoring
committees, ethics committees or competent authorities that had either a significant
influence on the risk-benefit balance of the authorised medicinal product and/or an impact
on the conduct of a specific clinical trial(s) or on the overall clinical development programme.
During the reporting interval of this PBRER, for the marketed products, there have been no
failure to obtain or apply for a marketing authorisation renewal; withdrawal or suspension of
a marketing authorisation; suspension of supply by the marketing authorisation holder; risk
management activities (including significant restrictions on distribution or introduction of
other risk minimisation measures; significant safety-related changes in labelling documents
that could affect the development programme, including restrictions on use or population
treated; communications to health care professionals and new post-marketing study
requirement(s) imposed by competent authorities) due to safety related reasons. No safety
related actions were required to be taken due to any product defects and quality issues.
During the reporting interval, SPIL has submitted an updated RMP [ABIR-2022-02-PHI, DLP:
30-Aug-22] to Philippines FDA. The following safety concerns (important identified risks,
important potential risk, missing information), were identified.
All the adverse reactions and regulatory recommendations related to Abiraterone reviewed
as part of this PBRER were assessed against RSI and relevant corresponding information
is presented in section 16 of this PBRER.
Based upon the above presented review of Company’s safety database, published literature
articles, regulatory authority recommendations, RMPs and from previous periodic safety
reports, the safety concerns and safety issues as described in section 16.3.3 have been
identified with Abiraterone which would be monitored in future periodic safety reports. The
impact of these safety concerns and safety issues on benefit risk balance of Abiraterone
would be evaluated in future periodic safety reports.
SAFETY INFORMATION FOR UPDATE
No safety information has been identified from reported cases or published literature or
regulatory recommendations received during the reporting interval or previous safety issues
for update in the RSI.
The efficacy data for the reporting interval of this PBRER, as presented in section 17, was
analyzed and there is no significant change in the efficacy profile of Abiraterone.
Overall, based on this review, no new information has been identified which impacts the
benefit-risk balance of Abiraterone in approved indications. Thus, the existing benefit-risk
balance of Abiraterone remains favourable in approved indications.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

LIST OF ABBREVIATIONS
ADCO Addendum To Clinical Overview
ADRs Adverse Drug Reactions
ADE Adverse Drug Event
AE Adverse Event
DDD Defined Daily Dose
DE Drug Event
DLP Data-Lock Point
EMA European Medicines Agency
EU European Union
EURD European Union Reference Date
GVP Good Pharmacovigilance Practices
ICSRs Individual Case Safety Reports
MAH Market Authorization Holder
MedDRA Medical Dictionary For Regulatory Activities
PBRER Periodic Benefit-Risk Evaluation Report
PRR Proportional Reporting Ratio
PSUR Periodic Safety Update Report
RSI Reference Safety Information
SAE Serious Adverse Event
SDR Signal of Disproportionate Reporting
SmPC Summary Of Product Characteristics
SOC System Organ Class
SOP Standard Operating Procedure
SPIL Sun Pharmaceutical Industries Limited
WHO World Health Organization

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 5 of 64
TABLE OF CONTENTS
EXECUTIVE SUMMARY...................................................................................................................... 2
LIST OF ABBREVIATIONS ................................................................................................................. 4
TABLE OF CONTENTS ....................................................................................................................... 5
1 INTRODUCTION ......................................................................................................................... 7
2 WORLDWIDE MARKETING APPROVAL STATUS .................................................................. 9
3 ACTIONS TAKEN IN THE REPORTING INTERVAL FOR SAFETY REASONS ...................... 9
4 CHANGES TO REFERENCE SAFETY INFORMATION .......................................................... 10
5 ESTIMATED EXPOSURE AND USE PATTERNS ................................................................... 10
5.1 CUMULATIVE SUBJECT EXPOSURE IN CLINICAL TRIALS .............................................................. 10
5.2 CUMULATIVE AND INTERVAL PATIENT EXPOSURE FROM MARKETING EXPERIENCE ...................... 22
5.3 POST-APPROVAL USE IN SPECIAL POPULATIONS......................................................................... 24
6 DATA IN SUMMARY TABULATIONS ...................................................................................... 25
6.1 REFERENCE INFORMATION ....................................................................................................... 25
6.2 CUMULATIVE SUMMARY TABULATIONS OF SERIOUS ADVERSE EVENTS FROM CLINICAL TRIALS .... 25
6.3 CUMULATIVE AND INTERVAL SUMMARY TABULATIONS FROM POST-MARKETING DATA SOURCES .. 25
7 SUMMARIES OF SIGNIFICANT FINDINGS FROM CLINICAL TRIALS IN THE REPORTING
INTERVAL .......................................................................................................................................... 27
7.1 COMPLETED CLINICAL TRIALS ................................................................................................... 27
7.2 ONGOING CLINICAL TRIALS ....................................................................................................... 27
7.3 LONG-TERM FOLLOW-UP .......................................................................................................... 27
7.4 OTHER THERAPEUTIC USE OF MEDICINAL PRODUCT ................................................................. 27
7.5 NEW SAFETY DATA RELATED TO FIXED COMBINATION THERAPIES ................................................ 27
8 FINDINGS FROM NON-INTERVENTIONAL STUDIES ........................................................... 27
9 INFORMATION FROM OTHER CLINICAL TRIALS AND SOURCES .................................... 28
9.1 INFORMATION FROM OTHER CLINICAL TRIALS / STUDY SOURCES: ................................................ 28
9.2 MEDICATION ERRORS .............................................................................................................. 28
10 NON-CLINICAL DATA .............................................................................................................. 28
11 LITERATURE ............................................................................................................................ 28
11.1 LITERATURE ARTICLES ON PREGNANCY OUTCOMES (INCLUDING TERMINATION) WITH/ WITHOUT
ADVERSE OUTCOMES ........................................................................................................................ 28
11.2 LITERATURE ARTICLES WITH USE IN PAEDIATRIC POPULATIONS ............................................... 28
11.3 LITERATURE ARTICLES WITH COMPASSIONATE SUPPLY, NAMED PATIENT USE .......................... 29
11.4 LITERATURE ARTICLES ON LACK OF EFFICACY........................................................................ 29
11.5 LITERATURE ARTICLES ON ASYMPTOMATIC OVERDOSE, ABUSE OR MISUSE .............................. 29
11.6 LITERATURE ARTICLES WITH MEDICATION ERROR WHERE NO ADVERSE EVENTS OCCURRED ..... 29
11.7 LITERATURE ARTICLES WITH IMPORTANT NON-CLINICAL SAFETY RESULTS ............................... 29
11.8 OTHER RELEVANT LITERATURE ARTICLES .............................................................................. 29
12 OTHER PERIODIC REPORTS ................................................................................................. 31
13 LACK OF EFFICACY IN CONTROLLED CLINICAL TRIALS ................................................. 31
14 LATE-BREAKING INFORMATION ........................................................................................... 31
15 OVERVIEW OF SIGNALS: NEW, ONGOING OR CLOSED .................................................... 32
16 SIGNAL AND RISK EVALUATION .......................................................................................... 33
16.1 SUMMARIES OF SAFETY CONCERNS..................................................................................... 33
16.2 SIGNAL EVALUATION............................................................................................................ 34
16.3 EVALUATION OF RISKS AND NEW INFORMATION .................................................................... 34

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Appendices 60
Appendix-I Reference Safety Information 61
Appendix-II Cumulative summary tabulations of serious adverse events from clinical trials; 62
and cumulative and interval summary tabulations of serious and non-serious
adverse reactions from post-marketing data sources from Company safety
database
Appendix-III Signal Tabulation 63
Appendix-IV Worldwide Marketing Authorization Status 64

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

This periodic benefit-risk evaluation report (PBRER) of Abiraterone has been compiled
by Sun Pharmaceutical Industries Ltd. to evaluate the current benefit risk balance of
Abiraterone on the basis of available information on safety, efficacy and effectiveness.
This PBRER evaluates current benefit risk balance of Abiraterone taking into account
new or emerging information received by SPIL during the reporting interval 05
September 2022 – 04 September 2023 in the context of cumulative information on
risks and benefits.
Pharmacotherapeutic Group: Endocrine treatment, hormone antagonists and related
agents, ATC code: L02BX03.
Abiraterone acetate (ABIPRO) is converted in vivo to abiraterone, an inhibitor of
androgen biosynthesis. Specifically, abiraterone is a selective inhibitor of the enzyme
17α-hydroxylase / C17,20-lyase (CYP17). Expression of this enzyme is necessary for
androgen biosynthesis in testicular, adrenal, and prostate tumor tissues. CYP17
catalyzes the conversion of pregnenolone and progesterone to the precursors of
testosterone, DHEA and androstenedione, respectively, by 17α-hydroxylation and
cleavage of the C17, 20 bond. Inhibition of CYP17 also results in increased
mineralocorticoid production by the glands adrenals.
Androgen-sensitive carcinoma of the prostate responds to treatment that lowers
androgen levels. Androgen deprivation treatments, such as treatment with LHRH
analogs or orchiectomy, decrease androgen production in the testes, but do not affect
androgen production in the adrenal glands or in the tumor. Abiraterone Acetate
treatment reduces serum testosterone to undetectable levels (using commercial
assays) when co-administered with LHRH analogs (or orchiectomy).
The Abiraterone acetate reduces the serum concentration of testosterone and other
androgens to levels lower than those achieved with LHRH analogs alone or with
orchiectomy. This is a consequence of the selective inhibition of the CYP17 enzyme
necessary for androgen biosynthesis. PSA acts as a biomarker in prostate cancer
patients. In a phase III clinical study with patients who had failed previous
chemotherapy with taxanes, 38% of the patients treated with abiraterone acetate,
compared with 10% of those who received placebo, recorded a reduction of at least
50% with respect to baseline PSA values.
Therapeutic indications
ABIPRO is indicated with prednisone or prednisolone for:
− 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 metastatic castration-resistant prostate cancer (mCRPC) in adult
men who are asymptomatic or mildly symptomatic after failure of androgen
deprivation therapy in whom chemotherapy is not yet clinically indicated.
− The treatment of mCRPC in adult men whose disease has progressed during or
after a docetaxel-based chemotherapy regimen.
Population(s) being treated and studied1:
Pediatric populations
The use of ABIPRO in the pediatric population is not relevant.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 8 of 64
The European Medicines Agency has exempted the holder from the obligation to
present the results of the trials carried out with Abiraterone Acetate in different groups
of the pediatric population in advanced prostate cancer.
Liver failure
No dose adjustment is necessary in patients with pre-existing mild hepatic impairment,
Child-Pugh Class A.
In patients who develop hepatotoxicity during treatment (elevation of alanine
aminotransferase [ALT] or elevation of aspartate aminotransferase [AST] more than 5
times the upper limit of normal [ULN]), treatment should be discontinued immediately.
Once the liver function tests return to the patient's baseline values, treatment can be
resumed with a reduced dose of 500 mg (two tablets) once daily. In patients who
resume treatment, serum transaminases should be monitored at least once every two
weeks for three months and thereafter once a month. If hepatotoxicity reappears with
the reduced dose of 500 mg daily, treatment should be discontinued.
If patients develop severe hepatotoxicity (ALT or AST 20 times ULN) at any time during
treatment, treatment should be discontinued and should not be resumed in these
patients.
Renal insufficiency
No dose adjustment is necessary in patients with renal impairment. However, there is
no clinical experience in patients with prostate cancer and severe renal impairment,
therefore caution is advised in these patients.
Fertility, pregnancy and lactation
Women of childbearing age
There are no data on the use of ABIPRO in pregnant women, therefore this medicine
should not be used in women of childbearing potential.
Contraception in men and women
It is unknown whether abiraterone or its metabolites are present in semen. If the patient
has sexual intercourse with a pregnant woman, he must use a condom. If the patient
has sexual intercourse with a woman of childbearing potential, he must use a condom
in conjunction with another effective contraceptive method. Studies in animals have
shown reproductive toxicity.
Pregnancy
ABIPRO must not be used in women and is contraindicated in pregnant or potentially
pregnant women.
Lactation
ABIPRO is not indicated in women.
Fertility
Abiraterone affected fertility in male and female rats, but these effects were fully
reversible.
Reference:
1. Prescribing Information for Abiraterone [ABIPRO 250 mg tablets (abiraterone acetate
tablets 250 mg); Sun Pharmaceuticals Industries Limited, dated: 06 September 2019].

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Abiraterone, worldwide was first approved for SPIL in India on 29 December 2018. In
Peru, Abiraterone was first approved for SPIL on 05 September 2019 and is marketed
in Peru under the brand name of ABIPRO available in the strength of 250 mg tablets.
Currently, Abiraterone is approved in 18 countries for SPIL. SPIL has received new
approvals in 05 countries for Abiraterone during this reporting interval.
SPIL’s Abiraterone is currently available as tablets 125 mg, 250 mg and 500 mg.
The worldwide marketing authorization status for Abiraterone is presented in Appendix-
IV.

3 ACTIONS TAKEN IN THE REPORTING INTERVAL FOR SAFETY REASONS

During the reporting interval, no significant actions related to safety have been taken
related to investigational uses of Abiraterone, sponsors of clinical trial(s), data
monitoring committees, ethics committees or competent authorities that had either a
significant influence on the risk-benefit balance of the authorised medicinal product
and/or an impact on the conduct of a specific clinical trial(s) or on the overall clinical
development programme.
During the reporting interval of this PBRER, for the marketed products, there have been
no failure to obtain a marketing authorisation renewal; withdrawal or suspension of a
marketing authorisation; suspension of supply by the marketing authorisation holder;
risk management activities (including significant restrictions on distribution or
introduction of other risk minimisation measures; significant safety-related changes in
labelling documents that could affect the development programme, including
restrictions on use or population treated; communications to health care professionals
and new post-marketing study requirement(s) imposed by competent authorities) due
to safety related reasons. No safety related actions were required to be taken due to
any product defects and quality issues.
During the reporting interval, SPIL has submitted an updated RMP [ABIR-2022-02-
PHI, DLP: 30-Aug-22] to Philippines FDA. The following safety concerns (important
identified risks, important potential risk, missing information), were identified.
❖ Important identified risks
• Hepatotoxicity
• Cardiac disorders
• Osteoporosis including osteoporosis-related fractures
• Rhabdomyolysis/Myopathy
• Allergic alveolitis
• Increased exposure with food
❖ Important potential risks
• Anaemia
• Cataract
• Drug-drug interaction (CYP2D6)

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 10 of 64
❖ Missing information
• Use in patients with active or symptomatic viral hepatitis
• Use in patients with moderate/severe hepatic impairment and chronic liver
disease
• Use in patients with severe renal impairment
• Use in patients with heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or
New York Heart Association Class III or IV heart disease or cardiac ejection
fraction measurement of <50%.

4 CHANGES TO REFERENCE SAFETY INFORMATION

The Prescribing Information (PI) for Abiraterone and [ABIPRO 250 mg tablets
(Abiraterone acetate tablets 250 mg); Sun Pharmaceuticals Industries Limited, dated:
06 September 2019] has been used as the RSI to determine whether the ADRs in this
report are “listed” or “unlisted”.
No safety related changes have been made to the RSI during the reporting interval.
The SmPC/PI used as the RSI is appended to the PBRER (Appendix-I).

5 ESTIMATED EXPOSURE AND USE PATTERNS

5.1 CUMULATIVE SUBJECT EXPOSURE IN CLINICAL TRIALS

The cumulative subject exposure to Abiraterone in the completed interventional clinical
trials till DLP of this PBRER is 555.
As per the available information, all 555 subjects were male; the age distribution of all
555 subjects enrolled was between 18-65 years. The racial distribution of subjects
enrolled were 325 Asian, 91 black, 136 Caucasian and 03 other.
The subject exposure for Abiraterone has been calculated on the basis of the number
of subjects exposed to Abiraterone, and is presented below in Table 1:

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 11 of 64
Table 1: Subject exposure to Abiraterone in clinical studies
Gender
distributio Age distribution
Racial distribution of subjects
No. of subjects enrolled n of of subjects
Molecu Stu enrolled
Active subjects enrolled
le/ Study Test product dy
Study Title comparat enrolled
Produc Number name siz
or name 18-
t e Test Active <18 >65
Plac Tot Ma Fem 65 Asi Bla Cauca Oth Unkn
Prod Compar yea yea
ebo al le ale yea an ck sian er own
uct ator rs rs
rs
A
randomized,
open label,
two
treatment,
two period,
two
sequence,
single dose,
crossover,
food effect
study of
abiraterone
acetate 25 Abiraterone
Abirater
PKD_15_362 mg Acetate 25 mg NA 30 60 NA 0 30 30 0 0 30 0 30 0 0 0 0
one
capsules of Capsules
sun
pharmaceuti
cal
industries
limited in 30
healthy
adult male
subjects
when
administere
dunder
fasting & fed
conditions.
Single dose
Abiraterone PrZytiga®
randomized,
Abirater ABT_500T_0 Acetate (abiratero
blinded, fully 42 84 84 0 42 64 0 0 64 0 64 0 0 0 0
one 781_18 tablets 500 ne
replicate
mg acetate
crossover

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this report are the confidential and proprietary information
of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 19 of 64
Gender
distributio Age distribution
Racial distribution of subjects
No. of subjects enrolled n of of subjects
Molecu Stu enrolled
Active subjects enrolled
le/ Study Test product dy
Study Title comparat enrolled
Produc Number name siz
or name 18-
t e Test Active <18 >65
Plac Tot Ma Fem 65 Asi Bla Cauca Oth Unkn
Prod Compar yea yea
ebo al le ale yea an ck sian er own
uct ator rs rs
rs
Open-label, SoluMatrix
randomized, Abiraterone
single-dose, Acetate Zytiga
4- 100 mg (1 x 1000 mg
Abirater CHL-AA-101 /
way 100 mg) (4 x 250 20 20^ 20^ 0 20 20 0 0 20 0 0 15 5 0 0
one Phase 1
crossover 200 mg (2 x mg)
study under 100 mg)
fasted 400 mg (4 x
conditions 100 mg)
Open-label, SoluMatrix
randomized, Abiraterone
single-dose, Acetate
Zytiga
4- 125 mg (1 x
Abirater CHL-AA-102 / 1000 mg
way 125 mg) 36 36^ 36^ 0 36 36 0 0 36 0 0 26 8 2 0
one Phase 1 (4 x 125
crossover 500 mg (4 x
mg)
study under 125 mg)
fasted 625 mg (5 x
conditions 125 mg)
Open-label,
randomized,
SoluMatrix
single-dose,
Abiraterone
Abirater CHL-AA-103 / crossover,
Acetate nav 25 25 0 0 25 25 0 0 25 0 1 14 10 0 0
one Phase 1 study under
500 mg (4 x
fed and
125 mg)
fasted
conditions
Open-label, SoluMatrix
randomized, Abiraterone Zytiga
single-dose, Acetate 1000 (4 x
crossover, 500 mg (4 x 125 mg)
Abirater CHL-AA-104 /
study 125 mg QD) plus 37 19 18 0 37 37 0 0 37 0 1 20 16 0 0
one Phase 1
on plus prednison
background methylpredn e (5 mg
of steady- isolone BID)
state (4 mg BID)

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this report are the confidential and proprietary information
of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 20 of 64
Gender
distributio Age distribution
Racial distribution of subjects
No. of subjects enrolled n of of subjects
Molecu Stu enrolled
Active subjects enrolled
le/ Study Test product dy
Study Title comparat enrolled
Produc Number name siz
or name 18-
t e Test Active <18 >65
Plac Tot Ma Fem 65 Asi Bla Cauca Oth Unkn
Prod Compar yea yea
ebo al le ale yea an ck sian er own
uct ator rs rs
rs
steroid
treatment
under fasted
conditions
Randomize
d, open-
label, Zytiga
active- SoluMatrix 1,000
controlled, Abiraterone mg (4 x
multi-center Acetate 125 mg
Abirater CHL-AA-201 /
study 500 mg (4 x QD) plus 53 24 29 0 53 53 0 0 53 0 1 11 40 1 0
one Phase 2
to evaluate 125 mg QD) prednison
serum plus e (5 mg
testosterone BID)
levels, 84
days of
treatment
SoluMatrix
Open-label,
Abiraterone
single-arm,
Acetate
multiple
500 mg (4 x
Abirater CHL-AA-202 / center
125 mg QD) nav 20 0 0 0 20 20 0 0 20 0 0 5 15 0 0
one Phase 2 extension
plus
study, one
methylpredn
year of
isolone
treatment
(4 mg BID)
Single dose Abiraterone Zytiga
fully Acetate (Abiratero
replicate tablets 250 ne
crossover mg, Acetate)
Abirater
comparative Manufactured 250 mg
one ABI03522 18 36 36 0 18 18 0 0 18 0 18 0 0 0 0
bioavailabilit by Sun film
Acetate
y study Pharmaceutic coated
on al tablets;
Abiraterone Industries Manufact
Acetate Limited, India ured by:

The cumulative worldwide post authorization patient exposure (till August 2023) to SPIL’s Abiraterone, in terms of Patient Treatment Years
(PTY) is estimated to be 21,507. (Table 2a).
The worldwide post authorization patient exposure to SPIL’s Abiraterone during the reporting interval, in terms of PTY is estimated to be
5,179. (Table 2b).
5.2.1 Cumulative Patient Exposure from Marketing Experience
The cumulative worldwide post authorization patient exposure (till August 2023) to SPIL’s Abiraterone, in terms of PTY is estimated to be
21,507. (Table 2a).
The patient exposure has been estimated on the basis of the SPIL’s global sales data for Abiraterone for the period till August 2023$ and is
presented below:
$
Sales are calculated month wise rather than day wise. Wherever, the date of start of cumulative period of a PBRER crosses mid of the month (15th) the sales of that month are excluded from
calculation. Similarly, wherever DLP of a PBRER crosses mid of the month (15th) the sales of that whole month are included in the calculation. Also, when the date of start of cumulative period
of a PBRER is before 15th of a month, entire month’s sale figure is taken.

Table 2a: Sales and Cumulative Estimated Patient Exposure to Abiraterone

Defined Patients Exposure in

Dosage Sales figure (units) Sales Units (mg) Total Patient
Molecule Strength Daily PTY
Form Exposure in PTY
Dose Peru Others Peru Others Peru Others
Abiraterone Tablets 125 mg 500 mg 0 35,39,665 0 44,24,58,150 0 2,424 2,424
1000
Abiraterone Tablets 250 mg 58,440 2,65,36,543 1,46,10,000 6,63,41,35,750 40 18,175 18,216
mg*
1000
Abiraterone Tablets 500 mg 0 6,33,000 0 31,65,00,000 0 867 867
mg*
Total 21,507
*DDD = Defined Daily Dose

The methodology used for calculating an estimate of patient exposure for Abiraterone is:

Patient Exposure = Volume sales in mg

(Patient Treatment Years) DDD X 365

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of Sun Pharmaceutical Industries Ltd.
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As per WHO Collaborating Centre for Drug Statistics Methodology, the Defined Daily Dose (DDD) of abiraterone is 1000 mg for oral
administration. For calculation of patient exposure for abiraterone 250 and 500 mg (strengths approved in ROW), DDD of 1000 mg has
been considered as average dose to be taken per day for abiraterone.
For 125 mg strength (Yonsa), as per the US PI, the recommended dose of YONSA is 500 mg (four 125 mg tablets) administered orally
once daily in combination with methylprednisolone 4 mg administered orally twice daily. Based upon this, the DDD of 500 mg has been
considered as the average daily dose for Yonsa.
Abiraterone is indicated in combination with a corticosteroid for the treatment of patients with metastatic castration-resistant prostate cancer.
Abiraterone is generally prescribed for long-term treatment; therefore, the patient exposure has been calculated in terms of Patient
Treatment Years (PTY).
5.2.2 Interval Patient Exposure from Marketing Experience
The worldwide post authorization patient exposure to SPIL’s Abiraterone during the reporting interval, in terms of PTY is estimated to be
5,179. (Table 2b).
The patient exposure has been estimated on the basis of the SPIL’s global sales data for Abiraterone for the period September 2022$ to
August 2023$ and is presented below:
$
Sales are calculated month wise rather than day wise. Wherever, the date of start of reporting interval of a PBRER crosses mid of the month (15th) the sales of that month are excluded from
calculation. Similarly, wherever DLP of a PBRER crosses mid of the month (15th) the sales of that whole month are included in the calculation. Also, when the date of start of reporting interval
of a PBRER is before 15th of a month, entire month’s sale figure is taken.

Table 2b: Interval sales and estimated patient exposure to Abiraterone

Total
Defined Sales figure (units) Sales Units (mg) Patients Exposure in PTY
Dosage Patient
Molecule Strength Daily Dose
Form Exposure in
(DDD) Peru Others Peru Others Peru Others PTY
Abiraterone Tablets 125 mg 500 mg 0 7,46,610 0 9,33,26,250 0 511 511
Abiraterone Tablets 250 mg 1000 mg* 18,120 59,69,143 45,30,000 1,49,22,85,750 12 4,088 4,101
Abiraterone Tablets 500 mg 1000 mg* 0 4,14,000 0 20,70,00,000 0 567 567
Total 5,179
*DDD = Defined Daily Dose.

The methodology used for calculation of patient exposure is same as illustrated in section 5.2A for cumulative patient exposure from
marketing experience.

Detailed usage data are not available therefore presentation of patient exposure by special populations is not possible. In an effort to report
patterns of use with Abiraterone in special populations in the absence of exposure data, ICSR data were extracted from the Safety database.
The ICSR data is reported below by percentage of cases in the cumulative (since 18 January 2016) period. These are the spontaneous cases
(reported by consumer) received by the company. The patterns of use presented below represent approximations of use in each population
and are limited by the accuracy and completeness of the ICSR data reported to SPIL. No pattern of use in special populations was identified
from post-marketing reporting.

❖ Pediatric

Individual case safety report data reported in patients less than 18 years of age or in the neonate, child or adolescent age group were extracted
from the Safety database and reviewed. Cumulatively, no spontaneous case with Abiraterone in paediatric population was received.

❖ Elderly

Individual case safety report data reported in patients more than 65 years of age group were extracted from the Safety database and reviewed.
Cumulatively, 110 spontaneous case with Abiraterone in elderly population was received. No new safety information or pattern was identified
from the analysis

❖ Pregnant or lactating women

Individual case safety report data reported in Pregnant or lactating women were extracted from the Safety database and reviewed.
Cumulatively, nospontaneous case with Abiraterone in pregnant or lactating women was received.

❖ OTHER POST-APPROVAL USE

SPIL has not become aware of any patterns of use Abiraterone beyond that recommended in the reference safety information, including
overdose, drug abuse and misuse considered relevant for the interpretation of safety data.

6 DATA IN SUMMARY TABULATIONS

The cumulative period for inclusion of safety information for Abiraterone has been
considered based upon the initial receipt date of the first individual case safety report
(ICSR) with Abiraterone as suspect in company safety database. Accordingly, the
cumulative period for inclusion of safety information for Abiraterone is considered from
18 January 2016 which is the initial receipt date of first ICSR in company safety
database. This approach ensured that all ICSRs relevant to Abiraterone have been
included for analysis on a cumulative basis.
COMPANY SAFETY DATABASE
A total of 220 cases were received from company safety database during the reporting
interval consisting of 410 ADRs. Out of these 220 cases, 28 were reported from
literature sources, 37 were reported from regulatory authorities, 98 were reported
spontaneously, 26 cases were reported from Post Marketing Surveillance and the
remaining 31 were reported from other study report (Cases which are from non-
company, non-interventional observational studies including reports published in
literature, reports from compassionate use programs, patient support programs, market
research programs, registries, surveys of patients). Of these 220 cases, 106 were
judged as serious and the remaining 114 were judged as non-serious by the reporter
or the MAH.

6.1 REFERENCE INFORMATION

All Adverse Drug Events are coded using the Medical Dictionary for Regulatory
Activities (MedDRA). The ADEs received during the reporting interval that was
analyzed as part of this PBRER are coded with MedDRA version 26.1.
6.2 CUMULATIVE SUMMARY TABULATIONS OF SERIOUS ADVERSE EVENTS FROM CLINICAL
TRIALS
A total 16 serious adverse events (SAEs) were received with abiraterone till the DLP,
from clinical studies on SPIL’s abiraterone.
The highest number of SAEs with use of abiraterone were reported from the ‘General
disorders and administration site conditions’ system organ class (SOC) with 05 ADRs
(31.25 %). These were Asthenia (02 ADRs) and Abasia, Chest pain and Non-cardiac
chest pain (01 ADR each).
The second highest number of SAEs was reported from ‘Infections and infestations’
SOCs with 04 ADRs each (25.00 %). These were Cellulitis, Pyelonephritis, Sepsis and
Septic shock (01 ADR each).
A cumulative summary tabulation, showing Serious Adverse Events reported in the
clinical studies as extracted from safety database, has been appended as Appendix-II
(Table A).

6.3 CUMULATIVE AND INTERVAL SUMMARY TABULATIONS FROM POST-MARKETING DATA

SOURCES

COMPANY SAFETY DATABASE

• Cumulative Summary Tabulations:

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❖ Serious And Non-Serious Adverse Drug Reactions From Spontaneous ICSRs,
Including Reports From Healthcare Professionals, Consumers, Scientific
Literature, And Regulatory Authorities
A total of 924 ADRs with Abiraterone consisting of 575 serious ADRs and 349 non-
serious ADRs were received cumulatively.
The highest number of ADRs with use of Abiraterone were reported from the ‘General
disorders and administration site conditions’ system organ class (SOC) with 219 ADRs
(23.70 %). Majority of these were Disease progression (34 ADRs) and Fatigue (33
ADRs).
The second highest number of ADRs were reported from ‘Injury, poisoning and
procedural complications’ SOC with 138 ADRs (14.94 %). Majority of these were
Product dose omission issue (42 ADRs) and Product use issue (25 ADRs).
❖ Serious Adverse Reactions from Non-Interventional Studies
A total of 52 serious ADRs were received cumulatively from non-interventional clinical
studies.
The highest number of serious ADRs were reported from the ‘General disorders and
administration site conditions’ SOC with 28 ADRs (53.85 %). Majority of these ADR
were Death (22 ADRs) & Drug ineffective (02 ADRs).
The second highest number of serious ADRs were reported from the ‘Infections and
infestations’ SOC with 06 ADRs (11.54 %). These were Urinary tract infection (02
ADRs), Cellulitis, Corona virus infection, Septic shock and Staphylococcal infection
(01 ADR each).
• Interval Summary Tabulations:
Serious And Non-Serious Adverse Drug Reactions From Spontaneous ICSRs,
Including Reports From Healthcare Professionals, Consumers, Scientific
Literature, And Regulatory Authorities
A total of 364 ADRs with Abiraterone consisting of 187 serious ADRs and 177 non-
serious ADRs were received during the reporting interval.
The highest number of ADRs with use of Abiraterone were reported from the ‘General
disorders and administration site conditions’ system organ class (SOC) with 93 ADRs
(25.55 %). Majority of these were Disease progression, Fatigue (17 ADRs each) and
Death (13 ADRs).
The second highest number of ADRs were reported from ‘Injury, poisoning and
procedural complications’ SOC with 86 ADRs (23.63 %). Majority of these were
Product dose omission issue (28 ADRs) and Product use issue (25 ADRs).

❖ Serious Adverse Reactions from Non-Interventional Studies

A total of 08 serious ADRs were received during the reporting interval from non-
interventional clinical studies.
The highest number of serious ADRs were reported from the ‘General disorders and
administration site conditions’ SOC with 04 ADRs (50 %). These ADR were Condition
aggravated, Death, Drug ineffective and Malaise (01 ADR).
The second highest number of serious ADRs were reported from the ‘Injury, poisoning
and procedural complications’ SOC with 03 ADRs (75 %). These ADRs were Fall (02
ADR each), Contusion (01 ADR).

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Page 27 of 64
The summary tabulation of serious and non-serious reactions with cumulative and
interval data (organised by MedDRA SOC) as extracted from company safety database
Appendix-II (Table B).

7 SUMMARIES OF SIGNIFICANT FINDINGS FROM CLINICAL TRIALS IN THE

REPORTING INTERVAL
No sponsored interventional trials were conducted with the primary aim of identifying,
characterising, or quantifying a safety hazard, confirming the safety profile of the
medicinal product, or measuring the effectiveness of risk minimisation measures that
were completed or ongoing during the reporting interval.
A summary of other clinical studies during the reporting interval is presented below.

7.1 COMPLETED CLINICAL TRIALS

No clinical studies with Abiraterone were completed during the reporting interval.

7.2 ONGOING CLINICAL TRIALS

There is no ongoing clinical trial with Abiraterone, conducted during the reporting
interval.

7.3 LONG-TERM FOLLOW-UP

No clinical trial with Abiraterone was conducted where information from long-term
follow-up of subjects from clinical trials was reported.

7.4 OTHER THERAPEUTIC USE OF MEDICINAL PRODUCT

No clinical trial on expanded access programmes, compassionate use programmes,

particular patient use and other organised data collection were conducted with
Abiraterone.

7.5 NEW SAFETY DATA RELATED TO FIXED COMBINATION THERAPIES

No clinical trials with Abiraterone in other combination were conducted during the
reporting interval.

8 FINDINGS FROM NON-INTERVENTIONAL STUDIES

There is one patient assistance programs (PAPs) is ongoing for abiraterone. The detail
of this PAP has been presented below.

Enrolment Significant
Study Date of
Country Study title (cumulative; till 23 safety
Type initiation
Apr 22) information

YONSA
USA YONSA PAP Sep 2018 240 None
PAP

No new relevant safety information or information with potential impact on the benefit
or risk evaluations, from SPIL-sponsored non-interventional studies has been identified
during the reporting interval.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

9.1 INFORMATION FROM OTHER CLINICAL TRIALS / STUDY SOURCES:

No information relevant to the benefit-risk assessment of the medicinal product were

received from other clinical trial/ study sources during the reporting interval with
Abiraterone (e.g. results from pool analysis or meta-analysis of randomised clinical
trials, safety information provided by co-development partners).
Following investigator-initiated trial (IIT) was terminated during the reporting interval of
this PBRER. The study was early terminated due to lack of efficacy. No significant
safety information from this study was reported. The details of this IIT has been
provided below.
Cumulative
Trial ID Description
enrollment
EudraCT A Phase I/II Trial of Abiraterone Acetate in Combination with
Number: 2019- Tildrakizumab (anti-IL 23 targeting monoclonal antibodies) in
Men with Metastatic Castration -Resistant Prostate cancer 13
003485-40)
titled ACTion (Action study)

9.2 MEDICATION ERRORS

Sixty-eight cases of medication error were received with the use of products
containing Abiraterone during the reporting interval. No new safety information has
been identified from these cases.

10 NON-CLINICAL DATA

No non-clinical study was conducted with Abiraterone during the reporting interval.

11 LITERATURE

A literature search for Abiraterone was conducted using public domain of Entrez-
Pubmed database. Literature search during the reporting interval yielded 347 articles.
Additional literature articles with Abiraterone were received from literature search
vendor. The literature published during the reporting interval has been reviewed for
inclusion in this PBRER as per the following criteria:

11.1 LITERATURE ARTICLES ON PREGNANCY OUTCOMES (INCLUDING TERMINATION) WITH/

WITHOUT ADVERSE OUTCOMES

No relevant literature article on pregnancy outcomes (including termination) with/

without adverse outcomes with Abiraterone was identified during the reporting interval.

11.2 LITERATURE ARTICLES WITH USE IN PAEDIATRIC POPULATIONS

No relevant literature article having safety issue with Abiraterone was identified with
use in pediatric populations.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

No relevant published literature article having significant safety issue has been
identified with Abiraterone compassionate supply, named patient use during the
reporting interval.

11.4 LITERATURE ARTICLES ON LACK OF EFFICACY

No relevant published literature article of lack of efficacy of Abiraterone has been

identified during the reporting interval.

11.5 LITERATURE ARTICLES ON ASYMPTOMATIC OVERDOSE, ABUSE OR MISUSE

No relevant published literature article having significant safety information on

asymptomatic overdose, abuse or misuse of Abiraterone has been identified during the
reporting interval.

11.6 LITERATURE ARTICLES WITH MEDICATION ERROR WHERE NO ADVERSE EVENTS OCCURRED

No relevant published literature article having significant safety information on

medication error where no adverse event occurred with Abiraterone has been identified
during the reporting interval.

11.7 LITERATURE ARTICLES WITH IMPORTANT NON-CLINICAL SAFETY RESULTS

No safety issues have been identified from analysis of these literature articles during
the reporting interval of the PBRER.

11.8 OTHER RELEVANT LITERATURE ARTICLES

A published literature search has been conducted using public domain of Entrez-
PubMed database to identify other unlisted adverse reactions with Abiraterone.
Following safety issues have been identified from analysis of these literature articles
during the reporting interval of the PBRER.
• Increased risk of cognitive toxic effects (including cognitive impairment) and
functional toxic effects following second-generation antiandrogens (AAs)
Nowakowska et al. [1] examined the evidence from randomized clinical trials (RCTs) in
prostate cancer for an association between second-generation AAs and cognitive or
functional toxic effects. The findings of this systematic review and meta-analysis
suggest that second-generation AAs carry an increased risk of cognitive and functional
toxic effects, including when added to traditional forms of hormone therapy.
Increased risk of cognitive toxic effects (including cognitive impairment) and functional
toxic effects following second-generation antiandrogens (AAs) is unlisted as per the
RSI & Innovator’s SmPC. In view of the literature details such events shall be
monitored in the future reports.
The abstract of this literature has been presented below:
Association of Second-generation Antiandrogens with Cognitive and Functional
Toxic Effects in Randomized Clinical Trials: A Systematic Review and Meta-
analysis.1

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IMPORTANCE: The use of second-generation antiandrogens (AAs) in the treatment
of prostate cancer is increasing. Retrospective evidence suggests an association
between second-generation AAs and adverse cognitive and functional outcomes, but
further data from prospective trials are needed.
OBJECTIVE: To examine whether evidence from randomized clinical trials (RCTs) in
prostate cancer supports an association between second-generation AAs and
cognitive or functional toxic effects.
DATA SOURCES: PubMed, EMBASE, and Scopus (inception to September 12, 2022).
STUDY SELECTION: Randomized clinical trials of second-generation AAs
(abiraterone, apalutamide, darolutamide, or enzalutamide) among individuals with
prostate cancer that reported cognitive toxic effects, asthenic toxic effects (eg, fatigue,
weakness), or falls were evaluated.
DATA EXTRACTION AND SYNTHESIS: Study screening, data abstraction, and bias
assessment were completed independently by 2 reviewers following the Preferred
Reporting Items for Systematic Reviews and Meta-analyses and Enhancing the Quality
and Transparency of Health Research reporting guidelines. Tabular counts for all-
grade toxic effects were determined to test the hypothesis formulated before data
collection.
MAIN OUTCOMES AND MEASURES: Risk ratios (RRs) and SEs were calculated for
cognitive toxic effects, asthenic toxic effects, and falls. Because fatigue was the
asthenic toxic effect extracted from all studies, data on fatigue are specified in the
results. Meta-analysis and meta-regression were used to generate summary statistics.
RESULTS: The systematic review included 12 studies comprising 13 524 participants.
Included studies had a low risk of bias. An increased risk of cognitive toxic effects (RR,
2.10; 95% CI, 1.30-3.38; P = .002) and fatigue (RR, 1.34; 95% CI, 1.16-1.54; P < .001)
was noted among individuals treated with second-generation AAs vs those in the
control arms. The findings were consistent in studies that included traditional hormone
therapy in both treatment arms for cognitive toxic effects (RR, 1.77; 95% CI, 1.12-2.79;
P = .01) and fatigue (RR, 1.32; 95% CI, 1.10-1.58; P = .003). Meta-regression
supported that, across studies, increased age was associated with a greater risk of
fatigue with second-generation AAs (coefficient, 0.75; 95% CI, 0.04-0.12; P < .001). In
addition, the use of second-generation AAs was associated with an increased risk of
falls (RR, 1.87; 95% CI, 1.27-2.75; P = .001).
CONCLUSIONS AND RELEVANCE: The findings of this systematic review and meta-
analysis suggest that second-generation AAs carry an increased risk of cognitive and
functional toxic effects, including when added to traditional forms of hormone therapy.

In another literature article, Huang et al.2 performed a network meta-analysis to

compare the risk of cognitive impairment across NHA types. Databases (PubMed,
Embase, Scopus, and Web of Science), trial registries (Clinicaltrial.gov), the European
Medicines Agency, and the US Food and Drug Administration drug safety reports were
searched from inception through July 30, 2021. From the study it was found that
treatments associated with cognitive impairment, from the most to the least, were
enzalutamide (OR, 3.66; 95% confidence interval [CI], 2.84-4.73), apalutamide (OR,
1.76; 95% CI, 1.08-2.87), abiraterone acetate (OR, 1.64; 95% CI, 1.01-2.45), and
darolutamide (OR, 1.11 95% CI, 0.51-2.39).
The abstract of this literature has been presented below:

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
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Risk of cognitive impairment in men with advanced prostate cancer treated with
NHAs: A systematic review and network meta-analysis2
Novel hormonal agents (NHAs) have significantly improved outcomes in men with
advanced prostate cancer. However, it remains unclear whether NHAs are associated
with subsequent cognitive impairment. Thus, we sought to perform a network meta-
analysis to compare the risk of cognitive impairment across NHA types. Databases
(PubMed, Embase, Scopus, and Web of Science), trial registries (Clinicaltrial.gov), the
European Medicines Agency, and the US Food and Drug Administration drug safety
reports were searched from inception through July 30, 2021. Eligible studies were
clinical trials evaluating the risk of cognitive impairment between NHAs and
placebo/standard care. Two independent investigators extracted the data and
performed quality assessments using the Cochrane Risk of Bias Tool and ROBINS-I.
We estimated the risk ratios by the frequentist approach and calculated the ranking
probabilities of all treatments with the surface under the cumulative ranking
probabilities. The primary outcome and secondary outcome were odds ratio (OR) and
incidence rate ratio of cognitive impairment, respectively. We identified 15 trials with
14,723 participants comparing HNAs with placebo/standard care. Treatments
associated with cognitive impairment, from the most to the least, were enzalutamide
(OR, 3.66; 95% confidence interval [CI], 2.84-4.73), apalutamide (OR, 1.76; 95% CI,
1.08-2.87), abiraterone acetate (OR, 1.64; 95% CI, 1.01-2.45), and darolutamide (OR,
1.11 95% CI, 0.51-2.39). After adjustment of treatment time duration, enzalutamide still
had the highest risk of cognitive impairment with an incidence rate ratio of 2.17 (95%
CI, 1.65-2.78). These findings suggest that NHAs, especially enzalutamide, may
increase the risk of cognitive impairment compared with placebo/standard care.
Reference
1. Nowakowska MK, Ortega RM, Wehner MR, Nead KT. Association of Second-generation
Antiandrogens with Cognitive and Functional Toxic Effects in Randomized Clinical Trials:
A Systematic Review and Meta-analysis. JAMA Oncol. 2023;9(7):930-7.
2. Huang SW, Chen LC, Tseng CS, Chen CH, Yuan LH, Shau WY, Pu YS. Risk of cognitive
impairment in men with advanced prostate cancer treated with NHAs: A systematic review
and network meta-analysis. Clin Transl Sci. 2023 Feb;16(2):313-325. doi:
10.1111/cts.13451. Epub 2022 Nov 20. PMID: 36369801; PMCID: PMC9926078.

12 OTHER PERIODIC REPORTS

No other PBRER for the products containing Abiraterone in fixed combination or

products with multiple indications and/or formulations was prepared during the
reporting interval.

13 LACK OF EFFICACY IN CONTROLLED CLINICAL TRIALS

No data was received from controlled clinical trials indicating lack of efficacy during the
reporting interval with Abiraterone.

14 LATE-BREAKING INFORMATION

No safety issue has been identified from the cases with Abiraterone received during
the late breaking information (LBI) period (i.e. 05 September 2023 to 23 November

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Page 32 of 64
2023) of this PBRER. No safety issue was identified from literature articles during the
LBI period.
During the period of preparation of this PBRER, no safety related actions have been
taken by SPIL. Further, no safety related actions have been taken by a competent
authority (worldwide) or data monitoring committee as communicated to SPIL.
No important safety, efficacy and effectiveness finding has been identified after the
data lock point and during the period of preparation of the PBRER.
There were no potentially important safety, efficacy, or effectiveness findings, nor
regulatory changes, that arose during the preparation of the PBRER after the DLP.

15 OVERVIEW OF SIGNALS: NEW, ONGOING OR CLOSED

15.1 BRIEF DESCRIPTION OF SIGNAL DETECTION METHOD

SPIL instituted a specific process of signal detection based on disproportionality
analysis of company database. This method is based on application of statistical tools
to the company database and review of ICSRs to detect safety signals.
The process included validation, analysis, prioritization and assessment. The process
is aligned with the Module IX – Signal Management. The identified signals are
characterized as valid and non- valid. Signals with either insufficient or inconclusive
information are characterized as non-valid signals. Other signals are characterized as
valid signal. Valid signals are further classified into Potential Risk (open signal) and
closed signals (identified or refuted signal).
SOURCES SCREENED FOR SIGNAL
All valid spontaneous, literature, regulatory authority and other post marketing ICSRs
(as applicable) available in the company safety database were analysed (statistically
and/or clinical review) for safety signals. The statistical tools were applied to the entire
safety database and clinical review was done for the ICSRs of applicable review
interval as identified with the help of referred statistical tools. This process was
supplemented by literature search for relevant Drug Event pairs.
15.2 SIGNAL TABULATIONS
The list of SPIL’S RSI and Innovator/comparator’s RSI used for the evaluation of ADE
cases (case occurrences) in the various review periods has been shown in Table 1 of
Appendix-III. In addition, all the identified signals were also assessed with the SPIL’s
and Innovator’s/Comparator’s RSI used for collation of PBRER with reporting interval
05 Sep 22 to 04 Sep 23 (SPIL SmPC, Abipro (abiraterone) 250 mg tablets, Sep 2019
and Comparator SmPC, Zytiga (abiraterone) 500 mg film-coated tablets, Janssen-Cilag
Ltd, Sep 2022).
The legacy signal data (data available before effective date of new signal process as
aligned with EMA GVP module VII and IX on PBRERs and signal management
respectively) was revisited and re-categorized. The periodic signal evaluation cycles
(review of ADE received during a particular period) are independent of the reporting
cycles of the periodic safety update reports and in line with module VII the signals
detected during the reporting interval of PBRER irrespective of signal evaluation cycles
have been considered for inclusion in PBRER and has been presented in Table 2 of
Appendix-III. In addition, signal evaluation data for abiraterone which pertained to the
reporting period of PBRER but was assessed outside the reporting period of PBRER
has also been presented in Table 2 (Appendix-III).

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

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Page 33 of 64
Corresponding to the reporting interval of this PBRER, 02 signal evaluation cycle was
conducted on company database with evaluation period of 01 Mar 2022 to 31 Aug 2022
and 01 Sep 2022 to 28 Feb 2023. From these evaluations, no validated signals were
identified for abiraterone.
Overall, in terms of unique data from all these evaluations, no validated signals were
identified for abiraterone on the basis of ADEs as available from 01 Mar 2022 to 28 Feb
2023.
All the SDRs with at least possible causal relationship with abiraterone were reassessed
with the company RSI and Innovator/comparator RSI used for the collation of this
PBRER. Following reassessment, listedness of none of the SDRs changed on this
assessment.
Based on the current review, none of the signals were deemed as potential risk/
identified risks/refuted signals.
Cumulatively, no potential risks were identified for abiraterone.
A tabulation of signals identified has been provided in Table 2 of Appendix-III.
A tabulation of prioritization of refuted signal or identified risk has been provided in Table
3 of Appendix-III.

16 SIGNAL AND RISK EVALUATION

16.1 SUMMARIES OF SAFETY CONCERNS

This is the third PBRER collated for submission in PERU. To arrive at comprehensive
information on safety concerns, primarily, last submitted PBRER was considered. No
potential risk and safety issues have been identified in the previous submitted periodic
safety report.

Safety Concerns from Risk Management Plan

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• Anaemia
• Cataract
• Drug-drug interaction (CYP2D6)
❖ Missing information
• Use in patients with active or symptomatic viral hepatitis
• Use in patients with moderate/severe hepatic impairment and chronic liver
disease
• Use in patients with severe renal impairment
• Use in patients with heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or
New York Heart Association Class III or IV heart disease or cardiac ejection
fraction measurement of <50%.

16.2 SIGNAL EVALUATION

Summaries of safety concerns identified from signal detection & evaluation

No validated signals were identified for Abiraterone pertaining to the reporting interval
of this PBRER.
All the SDRs with at least possible causal relationship with Abiraterone were reassessed
with the company RSI and Innovator/comparator RSI used for the collation of this
PBRER. Following reassessment, listedness of none of the SDRs changed on this
assessment.
Based on the current review, none of the signals were deemed as potential risk/
identified risks/refuted signals
16.2.1 Potential Risk:
No potential risks were identified corresponding to the review period of this PBRER.
16.2.2 False Signal:
No refuted signals were identified corresponding to the review period of this PBRER.

16.3 EVALUATION OF RISKS AND NEW INFORMATION

16.3.1 SUMMARIES OF SAFETY ISSUES/CONCERNS IDENTIFIED FROM IN HOUSE SAFETY DATABASE,

REGULATORY AUTHORITY RECOMMENDATIONS & PUBLISHED LITERATURE ARTICLES
RECEIVED DURING REPORTING INTERVAL

A total of 220 cases with Abiraterone have been received during the reporting interval.
The search for published literature articles on PubMed, corresponding to the reporting
interval of this PBRER yielded 347 articles. Based on the review of these ADR cases as
extracted from Company’s Safety database, regulatory authority recommendations &
review of published literature articles (Section 11), following safety concerns and safety
issues have been identified where there is some evidence of possible association but
the same is not conclusive.
These safety concerns and safety issues evaluated during the reporting interval are
presented below as an event-based approach:

• SAFETY ISSUES IDENTIFIED FROM REPORTED CASES

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Periodic Benefit-Risk Evaluation Report Abiraterone
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Page 35 of 64
Pancreatitis acute following abiraterone
Acute pancreatitis is a common disease and is the leading cause of hospitalization
among gastrointestinal disorders in the United States. It involves the acute inflammation
of the pancreas. The severity of acute pancreatitis varies widely, from mild conditions
needing conservative treatment to severe and complicated diseases with high morbidity
and mortality. The mortality of acute pancreas ranges from 3% in patients with mild
edematous pancreatitis to as high as 20% in patients with pancreatic necrosis. The
diagnosis of acute presentation is simple, but the major challenge is predicting the
progression of the disease course and outcome. The duration of the disease is essential
in determining the level of care.1
During the reporting interval, 01 case (2023R1-397204) of pancreatitis acute was
retrieved.
In case 2023R1-397204, the author stated, a 76-year-old male patient presented with
prostatism complaints and was diagnosed with prostate adenocarcinoma [Gleason
score (4 + 4 5 8)]. Total prostate specific antigen (PSA) was 5 mg/L; free PSA was 2.1
and was considered to be local disease. Radiotherapy for the prostate tissue and
luteinizing hormone-releasing hormone agonist treatment was initiated to the patient.
The patient presented with complaints of weight loss and widespread pain in the body 2
years later. Gallium-68 Positron emission tomography/computed tomography was
performed for staging, and involvement was detected in the prostate, bilateral iliac
wings, left femur, and bilateral inguinal lymph nodes. Total PSA was measured as 707.8
mg/L, and free PSA was 158.2 mg/L, and it was evaluated as metastatic disease, and
abiraterone acetate 1 3 1000 mg and prednisolone 5 mg were started. The patient
presented to the emergency department with complaints of abdominal pain, nausea, and
vomiting 1 week after the initiation of treatment. Biochemical parameters were
examined; ALT 15 U/L, AST 41 U/L, LDH 452 U/L, GGT 30 U/L, alkaline phosphatase
450 U/L, amylase 349 U/L, lipase 763 U/L, calcium 9.2 mg/ dL, and albumin was 4 g/L.
White blood cell count was within the normal range. Abdominal tomography was taken
for the patient. Liver size and parenchyma density are natural. No intrahepatic space-
occupying lesion was observed. The gall bladder wall and lumen were evaluated
naturally. Intrahepatic and extrahepatic bile ducts were not observed as dilated. The
spleen size is normal. Contamination in the mesentery around the head of the pancreas
was noticeable, and it was reported as suspicious for acute pancreatitis. The patient did
not use any drugs or alcohol, except for abiraterone acetate. He was hospitalized with
the diagnosis of acute pancreatitis, oral intake was discontinued, and hydration was
initiated. The patient whose complaints regressed on the third day of his hospitalization
and who tolerated oral intake was discharged. As stated in clinical studies, although the
use of abiraterone acetate is safe in the elderly, some side effects may be seen more
frequently in this patient group. In a meta-analysis including abiraterone acetate
registration studies, it was determined that abiraterone acetate poses an increased risk
for hepatobiliary side effects, but there are no data on the development of acute
pancreatitis. Abiraterone acetate was considered as a possible suspect for acute
pancreatitis in our case. The reporter assessed the causality for the events (Pancreatitis
acute) as related to abiraterone.
The event Acute pancreatitis is unlisted as per RSI and innovator's SmPC. In this case,
patient developed acute pancreatitis one week after starting therapy with abiraterone
acetate and prednisolone. No information regarding the action taken with the suspect
medication is mentioned. However, considering the plausible temporal relation and
author's comment causality cannot be excluded.
On literature search, no relevant supporting article was found.

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Page 36 of 64
In light of the available details, more data is needed to establish the causal relationship
for this event. Hence, pancreatitis acute following abiraterone would be monitored in
future periodic safety reports.
Reference:
1. Gapp J, Tariq A, Chandra S. Acute Pancreatitis. [Updated 2023 Feb 9]. In: StatPearls
[Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK482468/

Fanconi Syndrome following abiraterone

Fanconi syndrome is a defect of proximal tubule leading to malabsorption of
various electrolytes and substances that are usually absorbed by the proximal tubule. It
could be an inherited or acquired condition.(1) The main pathogenic feature is a
generalized reabsorption defect, leading to the wasting of phosphate, amino acids,
glucose, and bicarbonate in erratic degrees.(2)
During the reporting interval one case (2023R1-402045) of Fanconi Syndrome and was
reported.
In case 2023R1-402045, A 65-year-old patient with a history of metastatic prostate
cancer and no history of kidney disease was started on abiraterone. Over the first month
of his treatment with abiraterone, he developed mild hypokalemia requiring 40 mEq oral
potassium chloride supplementation. He then presented to emergency department for
altered mental status and was found to have severe hypokalemia (2.5 mmol/L) and
severe hypophosphatemia (1.6 mg/dL). Abiraterone was stopped. 24 hours urine
collection revealed a phosphate excretion of 544mg/day and potassium excretion of
142mmol/day; consistent with renal wasting. Patient initially received up to 280 mEq/day
of intravenous potassium and 60 mmol/day of phosphate to maintain appropriate serum
levels. Over the course of 2 weeks after the discontinuation of Abiraterone, the
replacement requirements for both potassium and phosphate declined to zero. Normal
potassium and phosphate concentrations were maintained without the need for
supplementation. Abiraterone uncommonly causes proximal tubulopathy resembling a
Fanconi syndrome which is reversible with discontinuation of therapy.
The event hypokalaemia is listed while hypophosphatemia and fanconi syndrome are
unlisted as per RSI and innovator's SmPC. Fanconi syndrome is a defect of proximal
tubule leading to malabsorption of various electrolytes and can present with
hypokalaemia and hypophosphatemia. Considering the plausible temporal relation and
positive dechallenge, causality of the event Fanconi syndrome with drug abiraterone
cannot be excluded.
On literature search, no relevant supporting article was found.
In light of the available details, more data is needed to establish the causal relationship
for this event. Hence, Fanconi Syndrome would be monitored in future periodic safety
reports.
References:
1. Keefe P, Bokhari SRA. Fanconi Syndrome. [Updated 2023 Jul 4]. In: StatPearls [Internet].
Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from:
https://www.ncbi.nlm.nih.gov/books/NBK534872/
2. Karatzas A, Paridis D, Kozyrakis D, Tzortzis V, Samarinas M, Dailiana Z, Karachalios T.
Fanconi syndrome in the adulthood. The role of early

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

• Increased risk of cognitive toxic effects (including cognitive impairment) and

functional toxic effects following second-generation antiandrogens (AAs)

• SAFETY ISSUES IDENTIFIED FROM REGULATORY RECOMMENDATIONS

• None

• SAFETY CONCERNS FROM RMPS

The following Risk Management Plans for abiraterone have been submitted by SPIL.
SPIL has submitted updated Risk Management Plan (RMP) (ABIR-2022-02-PHI;
Version 0.2; DLP: 30 August 2022; Dated:14 October 2022) to Philippines MOH, RMP
[ABIR-2022-01-MOR; DLP: 15-Jan-2022 version 0.1; Dated: 07 June 2022] to Morocco
MOH, RMP [RMP/SOU/ABI/1; DLP: 31 July 2019; Dated: 08 November 2019] to South
African Agency and RMP [ABIR-2021-vs 0.1; DLP: 4-Mar-2021; Dated: 26-Mar-2021] to
European agency. The safety concerns identified in these RMPs are as follows:
❖ Important identified risks
• Hepatotoxicity
• Cardiac disorders
• Osteoporosis including osteoporosis-related fractures
• Rhabdomyolysis/Myopathy
• Allergic alveolitis
• Increased exposure with food
❖ Important potential risks
• Anaemia
• Cataract
• Drug-drug interaction (CYP2D6)
❖ Missing information
• Use in patients with active or symptomatic viral hepatitis
• Use in patients with moderate/severe hepatic impairment and chronic liver
disease
• Use in patients with severe renal impairment
• Use in patients with heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or
New York Heart Association Class III or IV heart disease or cardiac ejection
fraction measurement of <50%.
Comments: As per RMP commitment, SPIL will continue to monitor above events in
future periodic reports. The characterization of these safety concerns has been
provided in section 16.4 of this PBRER.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 38 of 64
16.3.2 EVALUATION OF NEW INFORMATION AVAILABLE DURING THE REPORTING INTERVAL
RELEVANT TO PREVIOUSLY IDENTIFIED SAFETY CONCERNS/ SAFETY ISSUES:

No potential risk and safety issues have been identified in the previous submitted
periodic safety report. The safety concerns identified in RMPs submitted prior to
reporting interval has been mentioned above.
16.3.3 SUMMARY OF SAFETY CONCERNS/ IDENTIFIED RISKS/POTENTIAL RISK/ SAFETY ISSUES:
Based upon the above presented review of Company’s safety database, published
literature articles, regulatory authority recommendations, risk management plan (RMP)
and from previous periodic safety reports, the following safety concerns and safety
issues have been identified with Abiraterone which would be monitored in future
periodic safety reports. The impact of these safety concerns and safety issues on
benefit risk balance of Abiraterone would be evaluated in future periodic safety reports.

Safety Issues:
• Pancreatitis acute following abiraterone
• Fanconi Syndrome following abiraterone
• Increased risk of cognitive toxic effects (including cognitive impairment) and
functional toxic effects following second-generation antiandrogens (AAs)

Safety Concerns from Risk Management Plan:

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
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Page 39 of 64
• Use in patients with moderate/severe hepatic impairment and chronic liver
disease
• Use in patients with severe renal impairment
• Use in patients with heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or
New York Heart Association Class III or IV heart disease or cardiac ejection
fraction measurement of <50%.
SAFETY INFORMATION FOR UPDATE
No safety information has been identified from reported cases or published literature
or regulatory recommendations received during the reporting interval or previous safety
issues for update in the RSI.

16.4 CHARACTERISATION OF RISKS

The detailed characterisation of the important identified risks, important potential

risk or missing information identified from RMP are presented below:

Important Hepatotoxicity
Identified Risk

Frequency/ Cases of hepatotoxicity were searched in the safety database. A total of

Number of cases/ 25 cases were received (relevant PTs: Hepatic enzyme abnormal,
Extent of use Hepatotoxicity, Transaminases increased, Hypertransaminasaemia,
Hepatitis fulminant, Acute hepatic failure, Drug-induced liver injury,
Aspartate aminotransferase increased, Alanine aminotransferase
increased, Liver function test abnormal, Hepatic failure,
hyperbilirubinemia, Blood bilirubin increased, liver disorder) during the
cumulative period of this report. The age of the patients ranged between
31 to 86 years.

Estimate of relative NA
risk

Estimate of A total of 25 cases of hepatotoxicity with relevant to hepatotoxicity were

absolute risk received during cumulative period with an estimated patient exposure
of 21,507 during the cumulative period of this PBRER. Accordingly, the
frequency of this event with abiraterone reported is 1/ 860 patients. The
absolute risk for this event is 0.12% and was calculated against the
patient exposure to abiraterone

Impact on Serum aminotransferase elevations occur in up to 13% of patients

individual patient treated with abiraterone compared with 1% to 8% receiving placebo, but
the abnormalities are generally mild, transient and not associated with
symptoms or jaundice. ALT elevations above 5 times the upper limit of
normal (ULN) occur in 6% of abiraterone treated vs <1% of placebo
treated subjects. Nevertheless, clinically apparent liver injury with
jaundice was not reported in the preregistration trials of abiraterone,
although such cases including examples of acute liver failure have been
reported to the sponsor since its licensure and more widespread use. [3]

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Hepatotoxicity
Identified Risk

Considering the preventability and reversibility as described below, the

impact on individual patient is moderate.

Public health Alanine aminotransferase increased and/or aspartate aminotransferase

impact increased are reported very common. Rarely hepatitis fulminant and
acute hepatic failure have been reported. The impact on public health
is moderate.

Risk factors • Elderly patients

• Obesity
• Patients with comorbid conditions
• Infections
• Pre-existing hepatic conditions (including congenital anomalies,
infections etc)
• Chronic alcoholism
• Concomitant use of hepatotoxic agents.
• Genetic predisposition [1,2]

Preventability For patients who develop hepatotoxicity during treatment (alanine

aminotransferase [ALT] increases or aspartate aminotransferase [AST]
increases above 5 times the upper limit of normal [ULN]), treatment
should be withheld immediately. Re-treatment following return of liver
function tests to the patient's baseline may be given at a reduced dose
of 500 mg (one tablet) once daily. For patients being re-treated, serum
transaminases should be monitored at a minimum of every two weeks
for three months and monthly thereafter. If hepatotoxicity recurs at the
reduced dose of 500 mg daily, treatment should be discontinued.
If patients develop severe hepatotoxicity (ALT or AST 20 times the ULN)
anytime while on therapy, treatment should be discontinued and
patients should not be re-treated. [4]

Reversibility Upon analysis of the cases retrieved from the safety database,
significant improvement and/or complete recovery were evidenced in 09
cases (resolved) upon initiation of remedial measures (including dose
reduction, drug discontinuation etc).

Potential The cause of hepatic injury from abiraterone is unknown, but may relate
mechanisms to its mechanism of action in inhibition of CYP17. In addition,
abiraterone is metabolized in the liver by the cytochrome P450 system,
predominantly CYP 3A4 and 2D6, which may lead to formation of a toxic
or immunogenic intermediate. Abiraterone is susceptible to drug-drug
interactions with inhibitors, inducers or substrates of the CYP 3A4 or
2D6 microsomal enzymes. [1]

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Hepatotoxicity
Identified Risk

Strength of Details on this safety concern are provided under the following sections
evidence of SmPC:
• Section 4.4 Special warnings and precautions for use-information
pertaining to Hepatotoxicity and hepatic impairment is provided:
Marked increases in liver enzymes leading to treatment
discontinuation or dose modification occurred in controlled clinical
studies. Serum transaminase levels should be measured prior to
starting treatment, every two weeks for the first three months of
treatment, and monthly thereafter. If clinical symptoms or signs
suggestive of hepatotoxicity develop, serum transaminases
should be measured immediately. If at any time the ALT or AST
rises above 5 times the ULN, treatment should be interrupted
immediately and liver function closely monitored. Re-treatment
may take place only after return of liver function tests to the
patient's baseline and at a reduced dose level.
If patients develop severe hepatotoxicity (ALT or AST 20 times
the ULN) anytime while on therapy, treatment should be
discontinued and patients should not be re-treated.
Patients with active or symptomatic viral hepatitis were excluded
from clinical trials; thus, there are no data to support the use of
ZYTIGA in this population.
There are no data on the clinical safety and efficacy of multiple
doses of abiraterone acetate when administered to patients with
moderate or severe hepatic impairment (Child-Pugh Class B or
C). The use of ZYTIGA should be cautiously assessed in patients
with moderate hepatic impairment, in whom the benefit clearly
should outweigh the possible risk. ZYTIGA should not be used in
patients with severe hepatic impairment.
There have been rare post-marketing reports of acute liver failure
and hepatitis fulminant, some with fatal outcome.
• Section 4.8 Undesirable effects under Hepatobiliary disorders
relevant PTs (e.g. Alanine aminotransferase increased and/or
aspartate aminotransferase increased, hepatitis fulminant, acute
hepatic failure). [4]

Impact on benefit- Considering the significant clinical benefit that patients can obtain from
risk balance this treatment, preventability, reversibility and moderate impact on the
patient with this risk, the benefit is considered as outweighing the risk.

References:
1. Mayoral W; Lewis JH; Zimmerman H, Drug-induced liver disease, Curr Opin Gastroenterol.
1999; 15(3):208-16
2. Larrey D; Pageaux GP, Genetic predisposition to drug-induced hepatotoxicity, J Hepatol.
1997; 26 Suppl 2:12-21
3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda
(MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Abiraterone.
[Updated 2017 Jul 5]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548136/

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 42 of 64
4. SmPC of ZYTIGA 500 mg film-coated tablets. By Janssen-Cilag International NV. Last
updated Sep 2022.

Important Cardiac disorders

identified risk

Frequency/ Cases of Cardiac disorders (Events reported from Cardia disorder SOC)
Number of cases/ were searched in the safety database. A total of 26 cases were received
Extent of use during the cumulative period of this report. The age of the patients
ranged between 62 to 89 years.

Estimate of relative NA
risk

Estimate of A total of 26 cases of Cardiac disorders were received during cumulative

absolute risk period with an estimated patient exposure of 21,507 during the
cumulative period of this PBRER. Accordingly, the frequency of this
event with abiraterone reported is 1/ 827 patients. The absolute risk for
this event is 0.12 % and was calculated against the patient exposure to
abiraterone.

Impact on Cardiac failure, angina pectoris, atrial fibrillation, tachycardia have been
individual patient reported with abiraterone. [1] Considering the preventability and
reversibility as described below, the impact on individual patient is
moderate.

Public health The following are the frequencies of the reported cardiac events:
impact
• Common: cardiac failure, angina pectoris, atrial fibrillation,
tachycardia.
• Uncommon: other arrhythmias.
• Not known: myocardial infarction, QT prolongation. [1]

The impact on public health is moderate.

Risk factors Patients with a history of cardiovascular disease. [1]

Preventability The drug should be used with caution in patients with a history of
cardiovascular disease. Before treating patients with a significant risk
for congestive heart failure (e.g.a history of cardiac failure, uncontrolled
hypertension, or cardiac events such as ischaemic heart disease),
consider obtaining an assessment of cardiac function (e.g.
echocardiogram). Before treatment with abiraterone, cardiac failure
should be treated and cardiac function optimised. Hypertension,
hypokalaemia and fluid retention should be corrected and controlled.
During treatment, blood pressure, serum potassium, fluid retention
(weight gain, peripheral oedema), and other signs and symptoms of
congestive heart failure should be monitored every 2 weeks for 3
months, then monthly thereafter and abnormalities corrected. QT
prolongation has been observed in patients experiencing hypokalaemia
in association with abiraterone treatment. Assess cardiac function as

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Cardiac disorders

identified risk

clinically indicated, institute appropriate management and consider

discontinuation of this treatment if there is a clinically significant
decrease in cardiac function. [1]

Reversibility Upon analysis of the cases retrieved from the safety database,
significant improvement and/or complete recovery were evidenced in 04
cases upon initiation of remedial measures (including dose reduction,
drug discontinuation etc).

Potential Cardiotoxicity due to abiraterone occurs as a result of excess

mechanisms meineralocorticoids. [1]

Strength of Cardiovascular reactions: The three Phase 3 studies excluded patients

evidence with uncontrolled hypertension, clinically significant heart disease as
evidenced by myocardial infarction, or arterial thrombotic events in the
past 6 months, severe or unstable angina, or NYHA Class III or IV heart
failure (study 301) or Class II to IV heart failure (studies 3011 and 302)
or cardiac ejection fraction measurement of < 50%. All patients enrolled
(both active and placebo-treated patients) were concomitantly treated
with androgen deprivation therapy, predominantly with the use of LHRH
analogues, which has been associated with diabetes, myocardial
infarction, cerebrovascular accident and sudden cardiac death. The
incidence of cardiovascular adverse reactions in the Phase 3 studies in
patients taking abiraterone acetate versus patients taking placebo were
as follows: atrial fibrillation 2.6% vs. 2.0%, tachycardia 1.9% vs. 1.0%,
angina pectoris 1.7% vs. 0.8%, cardiac failure 0.7% vs. 0.2%, and
arrhythmia 0.7% vs. 0.5%. [1]

References:
1. SmPC of ZYTIGA 500 mg film-coated tablets. By Janssen-Cilag International NV. Last
updated sep 2022.

Important Osteoporosis including osteoporosis-related fractures

identified risk

Frequency/
No cases of Osteoporosis including osteoporosis-related fractures were
Number of cases/
retrieved during the cumulative period of this PBRER.
Extent of use

Estimate of relative
NA
risk

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Osteoporosis including osteoporosis-related fractures

identified risk

Estimate of
NA
absolute risk

Impact on Fractures including osteoporosis have been reported with abiraterone.

[1]
individual patient
Considering that some studies [2] reported very low risk of fracture with
abiraterone and preventability as described below, the impact on
individual patient is moderate.

Public health Fractures are reported commonly. Fractures includes osteoporosis and
impact all fractures with the exception of pathological fractures. [1] The impact
on public health is moderate.

Risk factors Combination of abiraterone and prednisone/prednisolone with radium

(Ra-223)

Preventability It is recommended that subsequent treatment with Ra-223 is not

initiated for at least 5 days after the last administration of Abiraterone in
combination with prednisone/prednisolone. [1]

Reversibility Not available.

Potential Not available.

mechanisms

Strength of Caffo O et al evaluated the fracture risk and survival outcomes in

evidence patients with metastatic castration-resistant prostate cancer (mCRPC)
who received sequentially abiraterone acetate (AA) and radium 223
[223Ra] RaCl2 in the daily clinical practice. As per the study results,
treatment with [223Ra] RaCl2 immediately after AA was active and safe
with a very low risk of a fracture. Thus, the present observational report
makes a valuable contribution to the current debate concerning the risks
and benefits of including [223Ra] RaCl2 in the therapeutic algorithm. [2]

Impact on benefit- As per some studies, treatment with [223Ra] RaCl2 immediately after
risk balance AA was active and safe with a very low risk of a fracture. Considering
the significant clinical benefit that patients can obtain from this
treatment, preventability, reversibility and moderate impact on the
patient with this risk, the benefit is considered as outweighing the risk.

References:
1. SmPC of ZYTIGA 500 mg film-coated tablets. By Janssen-Cilag International NV. Last
updated Sep 2022.
2. Caffo O, Frantellizzi V, Tucci M, Galli L, Monari F, Baldari S, et al. Fracture risk and survival
outcomes in metastatic castration-resistant prostate cancer patients sequentially treated with

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 45 of 64
abiraterone acetate and RADIUM-223. Eur J Nucl Med Mol Imaging. 2020 Oct;47(11):2633-
2638.

Important Rhabdomyolysis/Myopathy
identified risk

Frequency/ A total of 07 cases of rhabdomyolysis/myopathy were retrieved during

Number of cases/ the cumulative period of this report. The age of the patients ranges
Extent of use between 74 to 89 years.

Estimate of relative
NA
risk

Estimate of A total of 07 cases of rhabdomyolysis/myopathy were received during

absolute risk cumulative period with an estimated patient exposure of 21,507 during
the cumulative period of this PBRER. Accordingly, the frequency of this
event with abiraterone reported is 1/ 3072 patients. The absolute risk for
this event is 0.033 % and was calculated against the patient exposure
to abiraterone.

Impact on Cases of myopathy and rhabdomyolysis have been reported in patients

individual patient treated with abiraterone. [1] Considering the preventability and
reversibility as described below, the impact on individual patient is mild.

Public health Myopathy and rhabdomyolysis have been reported uncommonly. [1] The
impact impact on public health is mild.

Risk factors • Concomitantly treated with medicinal products known to be

associated with myopathy/rhabdomyolysis. [1]
• chronic kidney disease, age >65 years, and concurrent statin
therapy [2]

Preventability Caution is recommended in patients concomitantly treated with

medicinal products known to be associated with
myopathy/rhabdomyolysis. [1]
Strict monitoring should be employed in patients started on abiraterone
who have additional risk factors for developing rhabdomyolysis. [2]

Reversibility Most cases developed within the first 6 months of treatment and
recovered after abiraterone withdrawal. [1]

Potential Dineen et al reported a case of rhabdomyolysis in a patient treated with

mechanisms rosuvastatin and abiraterone. Both abiraterone and rosuvastatin
metabolism is dependent on the hepatic system. The hepatic enzyme
CYP3A4 is a known major substrate for abiraterone metabolism and is
responsible for the formation of N-oxide abiraterone sulphate, an
inactive metabolite.8 In the setting of hepatotoxicity, metabolism of
abiraterone and rosuvastatin may be diminished resulting in an
increased serum concentration of the drug with increased risk of

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Rhabdomyolysis/Myopathy
identified risk

adverse effects, including rhabdomyolysis. There is no known drug

interaction between abiraterone and rosuvastatin; however, both can
cause hepatotoxicity resulting in increased exposure to both drugs. [2]

Strength of Rhabdomyolysis / myopathy have been reported with abiraterone at a

evidence frequency of ≥ 1/1,000 to < 1/100. [1]

Impact on benefit- Considering the significant clinical benefit that patients can obtain from
risk balance this treatment, preventability, reversibility and mild impact on the patient
with this risk, the benefit is considered as outweighing the risk.

References:
1. SmPC of ZYTIGA 500 mg film-coated tablets. By Janssen-Cilag International NV. Last
updated Sep 2022.
2. Dineen M, Hansen E, Guancial E, Sievert L, Sahasrabudhe D. Abiraterone-induced
rhabdomyolysis resulting in acute kidney injury: A case report and review of the literature. J
Oncol Pharm Pract. 2018 Jun;24(4):314-8.

Important Allergic alveolitis

identified risk

Frequency/
Number of cases/ No cases were retrieved during the cumulative period of this PBRER.
Extent of use

Estimate of relative
NA
risk

Estimate of
NA
absolute risk

Impact on Allergic alveolitis has been reported in patients treated with

individual patient abiraterone.[1] Considering the rare frequency of occurrence of this risk
with abiraterone and lack of adequate evidence to relate the risk, the
impact on individual patient is mild.

Public health Allergic alveolitis has been reported rarely. [1] The impact on public
impact health is mild.

Risk factors Not available.

Preventability Not available.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Allergic alveolitis

identified risk

Reversibility Most cases developed within the first 6 months of treatment and
recovered after abiraterone withdrawal. [1]

Potential The pathogenesis of extrinsic allergic alveolitis (EAA) involves repeated

mechanisms antigen exposure, immunological sensitization of the host to the antigen
and immune inflammatory response causing pulmonary and systemic
symptoms. The immune response is characterized by interstitial and
alveolar inflammation with granuloma formation. This appears to involve
a combination of type III hypersensitivity reactions and delayed type IV
hypersensitivity reactions to the inhaled antigens. The delay in the onset
of symptoms after antigen exposure and the high levels of antigen-
specific IgG in the serum and BAL supports the role of type III
hypersensitivity immune complex-mediated response. However, the
appearance of granuloma in the lungs and asymptomatic individuals
with a positive antibody response suggests the involvement of type IV
hypersensitivity cell-mediated response in the pathogenesis of EAA. [2]

Strength of Allergic alveolitis has been reported with abiraterone at a rare

evidence frequency. [1]

Impact on benefit- Considering the significant clinical benefit that patients can obtain from
risk balance this treatment, rare frequency of occurrence and mild impact on the
patient with this risk, the benefit is considered as outweighing the risk.

References:
1. SmPC of ZYTIGA 500 mg film-coated tablets. By Janssen-Cilag International NV. Last
updated sep 2022.
2. Ismail T, McSharry C, Boyd G. Extrinsic allergic alveolitis. Respirology. 2006 May;11(3):262-
8. doi: 10.1111/j.1440-1843.2006.00839.x. PMID: 16635083.

Important Increased exposure with food

identified risk

Frequency/
One case of food interaction has been retrieved during the cumulative
Number of cases/
period of this PBRER.
Extent of use

Estimate of relative
NA
risk

Estimate of A total of 01 cases of food interaction was received during cumulative

absolute risk period with an estimated patient exposure of 21,507 during the
cumulative period of this PBRER. Accordingly, the frequency of this
event with abiraterone reported is 1/ 21,507 patients. The absolute risk
for this event is 0.005 % and was calculated against the patient
exposure to abiraterone.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Increased exposure with food

identified risk

Impact on The impact on individual patient is mild considering the preventability of

individual patient this risk.

Public health
The impact on public health is mild.
impact

Risk factors Co- administration with food. [1]

Preventability The efficacy and safety when given with food have not been established
therefore this medicinal product must not be taken with food. [1]

Reversibility Not available

Potential The mechanism responsible for the food effect on abiraterone

mechanisms bioavailability appears to depend on changes in drug solubility and
absorption process. In a relative bioavailability study (COU-AA-010),
systemic exposure to abiraterone following 1000 mg of AA as an oral
liquid olive oil formulation given under fasted conditions was
approximately 4.5-fold higher relative to a tablet formulation. These
results suggest that the food effect on abiraterone is mainly attributed to
its poor solubility and a solubilization effect produced by the lipid content
in the food. [2]

Strength of Groenland et al. evaluated whether pharmacokinetically (PK) guided

evidence abiraterone acetate dosing with a food intervention is feasible and
results in an increased percentage of patients with concentrations
above the target.Administration with food significantly increases the
absorption of abiraterone acetate. As per study results, in total, 32
evaluable patients were included, of which 20 patients (63%) had a
Cmin < 8.4 ng/mL at a certain time point during treatment. These
patients were recommended to take abiraterone acetate concomitantly
with food, after which Cmin increased from 6.9 ng/mL to 27 ng/mL (p <
0.001) without additional toxicities. This intervention led to adequate
exposure in 28 patients (87.5%). This intervention led to adequate
exposure in 28 patients (87.5%). As per the authors’ conclusion,
concomitant intake with food resulted in a significant increase in Cmin
and offers a cost-neutral opportunity to optimise exposure in patients
with low Cmin. [3]

Impact on benefit- Considering the significant clinical benefit that patients can obtain from
risk balance this treatment, preventability and mild impact on the patient with this
risk, the benefit is considered as outweighing the risk.

References:
1. SmPC of ZYTIGA 500 mg film-coated tablets. By Janssen-Cilag International NV. Last
updated Sep 2022.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 49 of 64
2. Chien, C., Smith, M, & Porre, P. D. Effect of food on abiraterone pharmacokinetics: a review.
International Journal of Pharmacokinetics;2017; 2(3), 183–193.
3. Groenland, S. L., Van Nuland, M., Bergman, A. M., de Feijter, J. M., Dezentje, V. O., Rosing,
H., Steeghs, N. (2020). Concomitant intake of abiraterone acetate and food to increase
pharmacokinetic exposure: real life data from a therapeutic drug monitoring programme.
European Journal of Cancer.2020; 130:32-38.

Important Anemia
potential risk

Frequency/ A total of 10 cases of anemia were retrieved during the cumulative

Number of cases/ period of this report. The age of all the patients were unknown to 73
Extent of use years.

Estimate of relative
NA
risk

Estimate of A total of 10 cases of anemia were received during cumulative period

absolute risk with an estimated patient exposure of 21,507 during the cumulative
period of this PBRER. Accordingly, the frequency of this event with
abiraterone reported is 1/ 2151 patients. The absolute risk for this event
is 0.046 % and was calculated against the patient exposure to
abiraterone.

Impact on Anemia in men with advanced prostate cancer may be caused by

individual patient several factors, including androgen deprivation, nutritional decline, bone
marrow infiltration, treatment-related toxicity, and the chronic
inflammatory state. Castration is a well-documented cause of anemia,
as testosterone is required for the enhancement of erythropoietin
formation in the kidney, as well as for the marrow action of
erythropoiesis. It has been demonstrated that, after castration, red blood
cell mass decreases 10%, red blood cell diameter decreases 40%, and
osmotic fragility increases. [1] Considering that anemia in prostate
cancer has multiple other etiologies and that there is lack of sufficient
data to relate the risk with abiraterone, the impact on individual patient
is mild.

Public health The impact on public health is mild considering the lack of adequate
impact evidence.

Risk factors Etiology of anemia in Men With Advanced Prostate Cancer includes:
• Androgen deprivation
• Marrow replacement
• Radiation therapy
• Radiopharmaceuticals
• Chemotherapeutics
• Anemia of chronic disease

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Anemia
potential risk

• Inflammatory cytokines
• Hematuria
• Poor nutrition [1]

Preventability Not available.

Reversibility Upon analysis of the cases retrieved from the safety database,
significant improvement and/or complete recovery were evidenced in 01
case upon initiation of remedial measures (including dose reduction,
drug discontinuation etc).

Potential Currently there is lack of adequate data to relate the risk with
mechanisms abiraterone

Strength of Anemia may occur in men with metastatic prostate cancer including
evidence those undergoing treatment with abiraterone. [2]

Impact on benefit- Presently, a causal relationship between the risk and the drug treatment
risk balance has not been confirmed and therefore, this risk has no impact on benefit-
risk balance.

References:
1. Nalesnik JG, Mysliwiec AG, Canby-Hagino E. Anemia in men with advanced prostate cancer:
incidence, etiology, and treatment. Rev Urol. 2004;6(1):1-4.
2. SmPC of ZYTIGA 500 mg film-coated tablets. By Janssen-Cilag International NV. Last
updated sep 2022.

Important Cataract
potential risk

Frequency/
Number of cases/ No cases were retrieved during the cumulative period of this report.
Extent of use

Estimate of relative
NA
risk

Estimate of
NA
absolute risk

Impact on In non- clinical toxicological studies, cataracts were observed in rats. [1]
individual patient Considering the lack of sufficient data to relate the risk with abiraterone,
the impact on individual patient is mild.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Cataract
potential risk

Public health The impact on public health is mild considering the lack of adequate
impact evidence.

Risk factors Risk factors associated with cataract includes:

• Educational status
• Smoking
• Diabetes
• Sunlight exposure
• Body mass index
• Drug use
• Estrogen replacement therapy [2]

Preventability Not available.

Reversibility Not available.

Potential Currently there is lack of adequate data to relate the risk with
mechanisms abiraterone.

Strength of In non-clinical toxicology studies, a dose dependent increase in

evidence cataracts was observed in rats at 26 weeks starting at >50 mg/kg/day
(1.14X the human clinical exposure based on AUC). However, in the 39-
week monkey study, no cataracts were observed at higher doses (2X
the clinical exposure based on AUC). [1]

Impact on benefit- Presently, a causal relationship between the risk and the drug treatment
risk balance has not been confirmed and therefore, this risk has no impact on benefit-
risk balance.

References:
1. SmPC of ZYTIGA 500 mg film-coated tablets. By Janssen-Cilag International NV. Last
updated sep 2022.
2. Chang JR, Koo E, Agrón E, Hallak J, Clemons T, Azar D, Sperduto RD, Ferris FL 3rd, Chew
EY; Age-Related Eye Disease Study Group. Risk factors associated with incident cataracts
and cataract surgery in the Age-related Eye Disease Study (AREDS): AREDS report number
32. Ophthalmology. 2011 Nov;118(11):2113-9. doi: 10.1016/j.ophtha.2011.03.032. PMID:
21684602; PMCID: PMC3178670.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Drug-drug interaction (CYP2D6)

potential risk

Frequency/ Number A total of 09 cases were retrieved with drug interaction during the
of cases/ Extent of cumulative period of this report. No cases of drug interaction-drug
use interaction (CYP2D6)* were received during the cumulative period of
this report.

Estimate of relative
NA
risk

Estimate of
NA
absolute risk

Impact on individual
NA
patient

Public health Impact on public health is mild considering the reversibility and
impact preventability.

Risk factors Concomitant administration with medicinal products metabolised by

CYP2D6. [1]

Preventability • 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). [1]

Reversibility Drug interactions are generally reversible on withdrawal of the suspect

drugs and dose modification.

Potential Abiraterone is an inhibitor of the hepatic drug-metabolising enzymes

mechanisms CYP2D6. [1]

Strength of In a study to determine the effects of abiraterone acetate (plus

evidence 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%.
[1]

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Important Drug-drug interaction (CYP2D6)

potential risk

Impact on benefit- Considering the significant clinical benefit that patients can obtain from
risk balance this treatment, reversibility, preventability and mild impact on the patient
with this risk, the benefit is considered as outweighing the risk.

*In previous PBRER, all cases of drug interaction were considered.

References:
1. SmPC of ZYTIGA 500 mg film-coated tablets. By Janssen-Cilag International NV. Last
updated Sep 2022.
Missing information
1. Use in patients with active or symptomatic viral hepatitis
No cases of use in patients with active or symptomatic viral hepatitis were retrieved
during the cumulative period of this PBRER.
As per RSI, “Patients with active or symptomatic viral hepatitis were excluded from
clinical trials; thus, there are no data to support the use of abiraterone in this
population.”
2. Use in patients with moderate/severe hepatic impairment and chronic liver
disease
A total of 02 cases of use in patients with hepatic impairment were retrieved during the
cumulative period of this PBRER. No safety information has been identified from these
cases.
As per RSI, “There are no data on the clinical safety and efficacy of multiple doses of
abiraterone acetate when administered to patients with moderate or severe hepatic
impairment (Child-Pugh Class B or C). No dose adjustment can be predicted.
Abiraterone should be used with caution in patients with moderate hepatic impairment
only if the benefit clearly outweighs the possible risk. Abiraterone should not be used
in patients with severe hepatic impairment.”
3. Use in patients with severe renal impairment
A total of 08 cases of use in patients with renal impairment were retrieved during the
cumulative period of this PBRER. No safety information has been identified from these
cases.
As per RSI, “Administration in patients with renal impairment, including severe renal
impairment, does not require dose reduction. However, there is no clinical experience
in patients with prostate cancer and severe renal impairment. Caution is advised in
these patients.”
4. Use in patients with heart disease as evidenced by myocardial infarction, or
arterial thrombotic events in the past 6 months, severe or unstable angina, or
New York Heart Association Class III or IV heart disease or cardiac ejection
fraction measurement of <50%.
A total of 22 cases of use in patients with cardiac disorders or arterial thrombotic events
were retrieved during the cumulative period of this PBRER. No safety information has
been identified from these cases.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 54 of 64
As per RSI, “Abiraterone should be used with caution in patients with a history of
cardiovascular disease. The phase 3 studies conducted with abiraterone excluded
patients with uncontrolled hypertension, clinically significant heart disease as
evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months,
severe or unstable angina, or New York Heart Association (NYHA) Class III or IV heart
failure (Study 301) or Class II to IV heart failure (Study 302) or cardiac ejection fraction
measurement of < 50%. In Study 302 patients with atrial fibrillation, or other cardiac
arrhythmia requiring medical therapy were excluded. Safety in patients with left
ventricular ejection fraction (LVEF) < 50% or NYHA Class III or IV heart failure (in Study
301) or NYHA Class II to IV heart failure (in Study 302) was not established. Before
treating patients with a significant risk for congestive heart failure (e.g.a history of
cardiac failure, uncontrolled hypertension, or cardiac events such as ischaemic heart
disease), consider obtaining an assessment of cardiac function (e.g. echocardiogram).
Before treatment with abiraterone, cardiac failure should be treated and cardiac
function optimised. Hypertension, hypokalemia and fluid retention should be corrected
and controlled. During treatment, blood pressure, serum potassium, fluid retention
(weight gain, peripheral oedema), and other signs and symptoms of congestive heart
failure should be monitored every 2 weeks for 3 months, then monthly thereafter.
Assess cardiac function as clinically indicated, institute appropriate management and
consider discontinuation of abiraterone treatment if there is a clinically significant
decrease in cardiac function.”
Based upon RMP commitment, these risks will be monitored in future PBRERs.

16.5 EFFECTIVENESS OF RISK MINIMISATION (IF APPLICABLE)

No additional risk minimisation activities for Abiraterone have been performed during
the current reporting interval.

17 BENEFIT EVALUATION

17.1 IMPORTANT BASELINE EFFICACY AND EFFECTIVENESS INFORMATION

Therapeutic indications
➢ ABIPRO is indicated with prednisone or prednisolone for:
− 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 metastatic castration-resistant prostate cancer (mCRPC) in adult
men who are asymptomatic or mildly symptomatic after failure of androgen
deprivation therapy in whom chemotherapy is not yet clinically indicated.
− The treatment of mCRPC in adult men whose disease has progressed during or
after a docetaxel-based chemotherapy regimen.
Epidemiology:
Prostate cancer is the second most commonly diagnosed malignancy in men around
the world with an estimated 1,111,700 new cases and 307,500 deaths per year.
Metastatic prostate cancer is characterized by a period during which suppression of
serum testosterone with androgen deprivation therapy (ADT) is sufficient to control
disease. Unfortunately, this period is followed by transition to castration resistance,

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

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Periodic Benefit-Risk Evaluation Report Abiraterone
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Page 55 of 64
during which progression occurs despite continued suppression of testosterone. This
is referred to as metastatic castration-resistant prostate cancer (mCRPC). Formerly,
this disease state was known as hormone-refractory prostate cancer. As it is now
known that androgen receptor (AR) signaling remains critical to disease progression in
castration-resistant disease, this term is no longer used. That prostate-specific antigen
(PSA) rises in the setting of progression in mCRPC exemplifies this point as PSA is an
androgen-regulated gene. The clinical relevance of targeting androgen signaling in
mCRPC is demonstrated by the survival advantage of both abiraterone acetate and
enzalutamide in this disease state.1
Metastatic castration-resistant prostate cancer (mCRPC) typically confers a poor
prognosis with a median survival of approximately 2 years. Docetaxel with prednisone
was the first approved treatment for mCRPC, and until now, treatment options for
patients progressing on or after docetaxel were limited. However, development of
biomarkers for monitoring disease response and progression has recently helped to
improve survival.2 Metastatic castration. -resistant prostate cancer (mCRPC) accounts
for approximately 3% of all new prostate-cancer diagnoses in the United States.3
In April 2011, the Food and Drug Administration approved abiraterone acetate for the
treatment of patients with mCRPC following initial docetaxel treatment. This approval
extended for chemotherapy-naive patients as well in December 2012. Abiraterone, a
potential androgen synthesis blocker, inhibits androgen biosynthesis from adrenal and
intratumoral sources. This potent agent irreversibly inhibits Cytochrome P450 17alpha
hydroxylase/17.20 lyase (CYP17), a dual function enzyme that is necessary for
testosterone synthesis, thereby blocking androgen synthesis by the adrenal glands and
testes as well as within the prostate tumor. It is currently recommended for
chemotherapy-naive patients and after progression on chemotherapy.3
Efficacy:
Abiraterone acetate (a prodrug of abiraterone, which is a selective inhibitor of androgen
biosynthesis) combined with prednisone/prednisolone (AA+P) and enzalutamide (ENZ)
(an androgen-receptor–signalling inhibitor) have proven survival benefit in men with
metastatic castration resistant prostate cancer (mCRPC) in chemo naïve and prior
chemo patients.4
Boegemann M (2019) et al conducted a retrospective, observational study which
collected the data from chemotherapy-naïve metastatic castration-resistant prostate
cancer (mCRPC) patients treated with abiraterone acetate plus prednisone (AAP) from
four European countries. Kaplan-Meier curves were used to estimate time to treatment
failure (TTF), progression-free survival (PFS), and time to first skeletal-related event.
The impact of baseline characteristics on TTF and PFS was explored using univariate
and multivariate Cox proportional hazard models. Log-rank test was used to assess
the potential role of duration of response to ADT in predicting response to AAP
treatment. Data from 481 eligible patients (Belgium: 68; France: 61; Germany: 150;
UK: 202) were analysed. At AAP initiation, the median age of patients was 75.0 years
(interquartile range [IQR]: 69.0–81.0), and the median PSA was 56.2 ng/mL (IQR:
22.2–133.1), with over 50% of patients presenting an ECOG score of 0 or 1. Visceral
metastases were present in 7.5% of patients; an exclusion criterion in the COU-AA-
302 clinical trial. The median TTF with AAP was 10.0 months (95%CI: 9.2–11.1) and
the median PFS was 10.8 months (95%CI: 9.6–11.8). Shorter TTF was significantly
associated with higher ALP (> 119 units/L), higher PSA (> 56.2 ng/mL), or poorer
ECOG PS scores at AAP initiation (p < 0.05). Patients with longer duration of response
to ADT (≥12 months) presented longer TTF and longer time to progression (p
< 0.0001). This European real-world study provides valuable insights into the

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
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Page 56 of 64
characteristics, treatment, and outcomes of chemotherapy-naïve patients with mCRPC
who received AAP in routine clinical practice. Treatment effectiveness of AAP in the
real-world is maintained despite patients having poorer clinical features at initiation
than those observed in the COU-AA-302 trial population.5
Fizazi K (2017) et al conducted a double-blind, placebo-controlled, phase 3 trial
assigning 1,199 patients to receive either androgen-deprivation therapy plus
abiraterone acetate (1000 mg daily, given once daily as four 250-mg tablets) plus
prednisone (5 mg daily) (the abiraterone group) or androgen-deprivation therapy plus
dual placebos (the placebo group). The two primary end points were overall survival
and radiographic progression-free survival. After a median follow-up of 30.4 months at
a planned interim analysis (after 406 patients had died), the median overall survival
was significantly longer in the abiraterone group than in the placebo group (not reached
vs. 34.7 months) (hazard ratio for death, 0.62; 95% confidence interval [CI], 0.51 to
0.76; P<0.001). The median length of radiographic progression-free survival was 33.0
months in the abiraterone group and 14.8 months in the placebo group (hazard ratio
for disease progression or death, 0.47; 95% CI, 0.39 to 0.55; P<0.001). Significantly
better outcomes in all secondary end points were observed in the abiraterone group,
including the time until pain progression, next subsequent therapy for prostate cancer,
initiation of chemotherapy, and prostate-specific antigen progression (P<0.001 for all
comparisons), along with next symptomatic skeletal events (P=0.009). These findings
led to the unanimous recommendation by the independent data and safety monitoring
committee that the trial be unblinded and crossover be allowed for patients in the
placebo group to receive abiraterone. Rates of grade 3 hypertension and hypokalemia
were higher in the abiraterone group. The addition of abiraterone acetate and
prednisone to androgen-deprivation therapy significantly increased overall survival and
radiographic progression-free survival in men with newly diagnosed, metastatic,
castration-sensitive prostate cancer.2
Abiraterone acetate (AA) has a specific activity blocking the conversion of cholesterol
to testosterone by interfering with the CYP17 system. In combination with prednisone,
AA has shown activity in patients with mCRPC who have received docetaxel-based
chemotherapy with an improvement in median overall survival compared with
prednisone alone. Side effects were mild and treatment was supported well. It was
shown that AA can be safely used in patients with renal insufficiency, while in patients
with severe liver disease its use should be further studied. There are also possible
drug–drug interactions and the combination with drugs metabolized by the same
enzyme systems should be used with caution. The drug has been registered in the
United States of America (USA), Europe and other regions for the treatment of patients
with mCRPC who have received chemotherapy containing docetaxel and a study in
chemotherapy-naive patients has been completed. AA is an important addition to the
treatment of patients with prostate cancer.6
References:
1. Benjamin A. Gartrell and Fred Saad. Abiraterone in the management of castration-resistant
prostate cancer prior to chemotherapy. Ther Adv Urol. 2015 Aug; 7(4): 194–202.
2. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY et al. Abiraterone
plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med 2017;
377:352-360.
3. Yasar Ahmed1, Nemer Osman1, Rizwan Sheikh2, Sarah Picardo1, Geoffrey Watson. Real-
world experience with abiraterone in metastatic castration-resistant prostate cancer.
4. Das P, Price J, Jones M, Martin-Fernandez C, Ali A, Mugunthan T et al. Abiraterone acetate
plus prednisone/prednisolone compared with enzalutamide in metastatic castration

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 57 of 64
resistant prostate cancer before or after chemotherapy: A retrospective study of real-world
data (ACES). Journal of Clinical Oncology, 37(7).
5. Boegemann M, Khaksar S, Bera G, Birtle A, Dopchie C, Dourthe LM, et al. Abiraterone
acetate plus prednisone for the Management of Metastatic Castration-Resistant Prostate
Cancer (mCRPC) without prior use of chemotherapy: report from a large, international, real-
world retrospective cohort study. BMC Cancer volume 19, Article number: 60 (2019).
6. D Schrijvers. Abiraterone acetate in the treatment of metastatic castration-resistant prostate
cancer: review of clinical data. Clin. Invest. (2012) 2(7), 707–713.

17.2 NEWLY IDENTIFIED INFORMATION ON EFFICACY AND EFFECTIVENESS

During the reporting interval, no literature relevant for efficacy or effectiveness of

Abiraterone in authorised indications (as per current version of RSI) was received.

17.3 CHARACTERISATION OF BENEFITS

Based on the information presented in section 17.1 & 17.2, no significant change in the
baseline benefit profile of Abiraterone in the authorised indications has been identified
in the reporting interval. The efficacy & effectiveness profiles of the Abiraterone are
expected to be similar to those already established as described in section 17.1 of this
PBRER.

18 INTEGRATED BENEFIT-RISK ANALYSIS FOR AUTHORISED INDICATIONS

No significant changes in the benefit or risk profile of Abiraterone has been identified
during the reporting interval.
A total of 220 cases consisting of 410 ADRs were received against patient exposure of
5,179 for Abiraterone in terms of Patient Treatment Years (PTY).
Majority of the ADRs received with Abiraterone use were Product dose omission issue
(28 ADRs) and Product use issue (25 ADRs). No safety issue has been identified from
the analysis of cases with reported ADRs.

18.1 BENEFIT-RISK CONTEXT – MEDICAL NEED AND IMPORTANT ALTERNATIVES

Castrate-resistant prostate cancer is prostate cancer that stops responding to hormone

therapy. Hormone therapy, also called androgen deprivation therapy (ADT),
dramatically lowers testosterone levels in the body. The testosterone levels are
comparable to levels in men who have had their testicles surgically removed.1 Prostate
cancer (PCa) is one of the most prevalent malignancies in the world and the third most
common cause of male cancer-related death in the USA.2
In 2019 Prostate cancer (PCa) accounts for nearly 1 in 5 new diagnoses of cancer in
men in the USA.1 In the last several years the overall prostate cancer (PCa) incidence
rate declined by approximately 7% per year.1 The sharp drop in incidence has been
commonly attributed to decreased PSA testing from 2008 to 2013. Regardless of the
treatment given, approximately 20%-30% of patients with localized PCa progress to
metastatic disease, commonly treated with hormonal therapy. This can be given
through surgical castration (bilateral orchiectomy) or through medical castration using
ADT. Both methods achieve a castrate level of serum testosterone which is regarded
as the standard of care for treating metastatic hormone-sensitive PCa (mHSPC).
However, mHSPC is destined to progress to metastatic castrate-resistant prostate

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Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 58 of 64
cancer (mCRPC). The castrate-resistant prostate cancer (CRPC) state is defined as
disease progression despite reaching castrate testosterone levels (serum testosterone
< 50 ng/dL or 1.7 nmol/L), and can present as either a continuous rise in serum PSA
levels, progression of pre-existing disease, and/or the appearance of new metastases.
CRPC has a median survival of approximately three years and is associated with a
significant deterioration of quality of life. The exact mechanism of transition from
mHSPC to mCRPC is still unclear. However, it is known that despite castrate levels of
androgens, the androgen receptor (AR) remains active and continues to drive PCa
progression in CRPC. This has led to the development of novel agents aimed at further
decreasing androgen production or blocking AR function. However, there are other
biologic pathways that function independently of androgen signaling and also result in
CRPC.3
In the past 15 years, several new treatment options for mCRPC have been approved
including docetaxel, cabazitaxel, abiraterone, enzalutamide and radium-223. Recently,
major shifts in the treatment of metastatic prostate cancer have occurred, since
substantial survival benefit has been obtained with docetaxel and abiraterone in
addition to the standard of ADT in metastatic castration-naïve prostate cancer
(mCNPC). The challenge is now to identify the mCNPC patients who will benefit most
from combination strategies (ADT+docetaxel or ADT+abiraterone/prednisone). Trials
have been conducted in slightly different patient populations. Unfortunately, no
biomarkers are available, leaving the treatment choice based on clinical symptoms,
patients’ preference, experience, toxicity and costs; however, stratification of patients
by disease burden seems to be a possible factor for treatment selection, since the
recently published post-hoc analysis of the STAMPEDE abiraterone trial showed a
survival benefit in low-volume (LV) mCNPC patients, which has not been substantially
established by the addition of docetaxel.4
Currently, cytotoxic chemotherapy agents, AR blocking agents, immunotherapies, and
radiopharmaceuticals represent effective therapeutic strategies for MCRPC treatment.
Taxane chemotherapy (docetaxel and cabazitaxel) is the standard for MCRPC
treatment. Abiraterone and enzalutamide represent significant breakthroughs in the
treatment of MCRPC and bestow significant survival benefits. Sipuleucel-T, a novel
active cellular immunotherapy, can prolong the overall survival (OS) of men with
MCRPC. Radium-223 (Ra 223) dichloride targets bone metastases with high-energy,
short-range a-particles, improves OS, and is a good treatment option for patients with
CRPC and symptomatic bone metastases. Denosumab, a human anti-RANKL
monoclonal antibody, can delay bone metastasis in men with PCa. According to recent
guidelines, the first-line treatments for MCRPC include abiraterone acetate plus
prednisone (AA/P), enzalutamide, radium 223, docetaxel, and sipuleucel-T.
Cabazitaxel, AA/P, enzalutamide, and radium have been approved as second-line
treatments for CRPC following docetaxel treatment.2
References
1. Healthline.com [Internet]. What Is Castration-Resistant Prostate Cancer and Is It Treatable?.
Accessed on 18 Nov 2020. Available at: https://www.healthline.com/health/prostate-
cancer/castration-resistant-prostate-cancer.
2. He Lugeng, Fang Hui, Chen Chao, Wu Yanqi, Wang Yuyong, Ge Hongwei et al. Metastatic
castration-resistant prostate cancer: Academic insights and perspectives through
bibliometric analysis. Medicine: April 2020 - Volume 99 - Issue 15 - p e19760.
3. Urotoday.com [internet]. First-line Treatment for Metastatic Castrate-resistant Prostate
Cancer. Accessed on 18 Nov 2020. Available at: https://www.urotoday.com/library-
resources/mcrpc-treatment/114581-first-line-treatment-for-metastatic-castrate-resistant-
prostate-cancer.html

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of Sun Pharmaceutical Industries Ltd.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER
Page 59 of 64
4. Belderbos BPS, Wit RD, Lolkema MPJ, Mathijssen RHJ and van Soest RJ. Novel treatment
options in the management of metastatic castration-naïve prostate cancer; which treatment
modality to choose?. Reviews, volume 30, issue 10, p1591-1600, October 01, 2019.

18.2 BENEFIT-RISK ANALYSIS EVALUATION

Based on the information presented in section 18, no significant change in the baseline
benefit profile of Abiraterone in the authorized indications has been identified in the
reporting interval.
Based upon the above presented review of Company’s safety database, published
literature articles, regulatory authority recommendations, RMPs and from previous
periodic safety reports, the safety concerns and safety issues as described in section
16.3.3 have been identified with Abiraterone which would be monitored in future
periodic safety reports.
No significant changes in the benefit or risk balance of Abiraterone in the approved
indications were identified.
Therefore, it is apparent that when used according to the labelling in the respective
SmPC, the benefit/risk evaluation for Abiraterone remains favourable.

19 CONCLUSIONS AND ACTIONS

Based upon the above presented review of Company’s safety database, published
literature articles, regulatory authority recommendations, RMPs and from previous
periodic safety reports, the safety concerns and safety issues as described in section
16.3.3 have been identified with Abiraterone which would be monitored in future
periodic safety reports. The impact of these safety concerns and safety issues on
benefit risk balance of Abiraterone would be evaluated in future periodic safety reports.
SAFETY INFORMATION FOR UPDATE
No safety information has been identified from reported cases or published literature
or regulatory recommendations received during the reporting interval or previous safety
issues for update in the RSI.
The efficacy data for the reporting interval of this PBRER, as presented in section 17,
was analyzed and there is no significant change in the efficacy profile of Abiraterone.
Overall, based on this review, no new information has been identified which impacts
the benefit-risk balance of Abiraterone in approved indications. Thus, the existing
benefit-risk balance of Abiraterone remains favourable in approved indications.

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Appendices

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Appendix-I
Reference Safety Information

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of SUN Pharmaceutical Industries
Limited.
Periodic Benefit-Risk Evaluation Report Abiraterone
05 September 2022 – 04 September 2023 PBRER No.: ABIR-2023-03-PER

Page 62 of 64

Appendix-II
Cumulative Summary Tabulations of Serious Adverse Events from
Clinical Trials and Cumulative Summary Tabulation of Serious and
Non-Serious Adverse Reactions from Post-Marketing Data
Sources from Company safety database

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Page 63 of 64

Appendix-III
Signal Tabulation

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

Page 64 of 64

Appendix-IV
Worldwide Marketing Authorization Status

PROPRIETARY INFORMATION: CONFIDENTIAL. The data and conclusions included in this

report are the confidential and proprietary information of SUN Pharmaceutical Industries
Limited.

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