F.

No: PSUR/Wockhardt/Hep-A/2016/08
Government of India
Directorate General of Health Service
Central Drug Standard Control Organization (HQ)
(AEFI/PSUR Division)

Subject: PSUR of Hepatitis A vaccine (Biovac A) of m/s Wockhardt Ltd, Mumbai

Reporting period 01-Aug-2013 to 31-Jan-2014

Report date 27-Feb-2014, Dy. No.: 8697
Date of launch 05-Aug-2013

The firm has submitted the following information:

1 Introduction The vaccine under consideration is a freeze-dried, live, H2
attenuated vaccine, developed by Zhejiang Pukang
Biotechnological Company Ltd., China. The H2 strain was
developed through the propagation of the virus in human
embryonic pulmonary diploid cells at 32°C and a series of tests
in rhesus. The vaccine is imported from China, where it has
been in use for more than a decade. Early epidemiological
studies conducted on this freeze-dried, live attenuated vaccine
(H2 strain) have demonstrated its efficacy and safety in high-
risk populations.
A freeze-dried live vaccine is a loose substance with cheese
colour and has a light red colour after dissolution in water.
After re-constituting in vial to form 1.0ml solution (one single
dose), the live vaccine content should not be less than 6.5
LgCCID50.
Injection for subcutaneous use in a single dose vial containing
freeze-dried lyophilized Hepatitis A powder with a 1 ml
ampoule of sterile water for reconstituting the vaccine.
Hepatitis a vaccine should be stored at to 2° to 8°C (35° to
46°F) in a dark place. Do not use vaccine beyond the expiry
date.
2 Current worldwide Biovac-A is registered in India Only.
market
authorization status
3 Update of actions There were no marketing authorization withdrawal or
taken for safety suspension, no failure to obtain marketing authorization
reasons renewal, no restrictions on distribution & no clinical trial
suspension occurred during the period covered by this report.
There were no dosage modifications, formulation changes,
changes in target population, or changes in indications.
4 Changes to The Package Insert (PI) is in effect at the beginning of the
reference safety period covered, and is used as reference for the prescribing
information information in India except for modification in statement of
dosage and addition of composition details. There is no change
in the reference safety information of Biovac – A ® based on
the experience accrued from clinical trials or any other sources.
6 Estimated patient An estimate of patient exposure is calculated based on per unit
exposure of Biovac - A® sold during the review period. The sales volume
of Biovac - A® during the review period was 207759. The
estimated exposure was 207759 patients.
7 Presentation of No cases involving other Adverse events of interest were
 individual case received from India during the reporting period.
histories
8 Studies There have been no studies completed during the period of this report that
highlight any significant safety issues.
There have been no targeted safety studies completed during the period of
this report. A full review of the literature was conducted during the
reporting period but no studies have been identified containing important
safety finding.
9 other information No new important safety information received

10 Overall safety There is no relevant safety data received for Biovac - A® from
evaluation clinical trial or post marketing experience to initiate overall
safety evaluation. No incidence of lack of efficacy, drug
interaction, drug abuse or misuse and positive or negative
experiences during pregnancy or lactation, experiences is
special patient groups, effects of long-term treatment was
reported by any reporter.
11 Conclusion There is no relevant safety data collected/ received from
different sources (studies, spontaneous, literature) for Biovac -
A® in the review period of this first periodic safety update
report. The previous cumulative experience with Biovac-A®
and its reference safety information remains consistent with the
information provided in its prescribing information/package
insert and supports the favorable benefit/risk profile. Hence no
action was recommended or initiated either by regulatory body
or by Wockhardt Ltd.
 F.No: PSUR/Wockhardt/Hep-A/2016/08
Government of India
Directorate General of Health Service
Central Drug Standard Control Organization (HQ)
(AEFI/PSUR Division)

Subject: PSUR of Hepatitis A vaccine (Biovac A) of m/s Wockhardt Ltd, Mumbai

Reporting period 01-Feb-2014 to 31-Jul-2014

Report date 27-Aug-2014, Dy. No.: 36469
Date of launch 05-Aug-2013

The firm has submitted the following information:

1 Introduction The vaccine under consideration is a freeze-dried, live, H2
attenuated vaccine, developed by Zhejiang Pukang
Biotechnological Company Ltd., China. The H2 strain was
developed through the propagation of the virus in human
embryonic pulmonary diploid cells at 32°C and a series of tests
in rhesus. The vaccine is imported from China, where it has
been in use for more than a decade. Early epidemiological
studies conducted on this freeze-dried, live attenuated vaccine
(H2 strain) have demonstrated its efficacy and safety in high-
risk populations.
A freeze-dried live vaccine is a loose substance with cheese
colour and has a light red colour after dissolution in water.
After re-constituting in vial to form 1.0ml solution (one single
dose), the live vaccine content should not be less than 6.5
LgCCID50.
Injection for subcutaneous use in a single dose vial containing
freeze-dried lyophilized Hepatitis A powder with a 1 ml
ampoule of sterile water for reconstituting the vaccine.
Hepatitis a vaccine should be stored at to 2° to 8°C (35° to
46°F) in a dark place. Do not use vaccine beyond the expiry
date.
2 Current worldwide Biovac-A is registered in India Only.
market
authorization status
3 Update of actions There were no marketing authorization withdrawal or
taken for safety suspension, no failure to obtain marketing authorization
reasons renewal, no restrictions on distribution & no clinical trial
suspension occurred during the period covered by this report.
There were no dosage modifications, formulation changes,
changes in target population, or changes in indications.
4 Changes to The Package Insert (PI) is in effect at the beginning of the
reference safety period covered, and is used as reference for the prescribing
information information in India except for modification in statement of
dosage and addition of composition details. There is no change
in the reference safety information of Biovac – A ® based on
the experience accrued from clinical trials or any other sources.
6 Estimated patient An estimate of patient exposure is calculated based on per unit
exposure of Biovac - A® sold during the review period. The sales volume
of Biovac - A® during the review period was 216279. The
estimated exposure was 216279 patients.
7 Presentation of No cases involving other Adverse events of interest were
 individual case received from India during the reporting period.
histories
8 Studies There have been no studies completed during the period of this report that
highlight any significant safety issues.
There have been no targeted safety studies completed during the period of
this report. A full review of the literature was conducted during the
reporting period but no studies have been identified containing important
safety finding.
9 other information No new important safety information received

10 Overall safety There is no relevant safety data received for Biovac - A® from
evaluation clinical trial or post marketing experience to initiate overall
safety evaluation. No incidence of lack of efficacy, drug
interaction, drug abuse or misuse and positive or negative
experiences during pregnancy or lactation, experiences is
special patient groups, effects of long-term treatment was
reported by any reporter.
11 Conclusion There is no relevant safety data collected/ received from
different sources (studies, spontaneous, literature) for Biovac -
A® in the review period of this periodic safety update report.
The previous cumulative experience with Biovac-A® and its
reference safety information remains consistent with the
information provided in its prescribing information/package
insert and supports the favorable benefit/risk profile. Hence no
action was recommended or initiated either by regulatory body
or by Wockhardt Ltd.
 F.No: PSUR/Wockhardt/Hep-A/2016/08
Government of India
Directorate General of Health Service
Central Drug Standard Control Organization (HQ)
(AEFI/PSUR Division)

Subject: PSUR of Hepatitis A vaccine (Biovac A) of m/s Wockhardt Ltd, Mumbai

Reporting period 01-Aug-2014 to 31-January-2015

Report date 25-Feb-2015, Dy. No.: 6113
Date of launch 05-Aug-2013

The firm has submitted the following information:

1 Introduction The vaccine under consideration is a freeze-dried, live, H2
attenuated vaccine, developed by Zhejiang Pukang
Biotechnological Company Ltd., China. The H2 strain was
developed through the propagation of the virus in human
embryonic pulmonary diploid cells at 32°C and a series of tests
in rhesus. The vaccine is imported from China, where it has
been in use for more than a decade. Early epidemiological
studies conducted on this freeze-dried, live attenuated vaccine
(H2 strain) have demonstrated its efficacy and safety in high-
risk populations.
A freeze-dried live vaccine is a loose substance with cheese
colour and has a light red colour after dissolution in water.
After re-constituting in vial to form 1.0ml solution (one single
dose), the live vaccine content should not be less than 6.5
LgCCID50.
Injection for subcutaneous use in a single dose vial containing
freeze-dried lyophilized Hepatitis A powder with a 1 ml
ampoule of sterile water for reconstituting the vaccine.
Hepatitis a vaccine should be stored at to 2° to 8°C (35° to
46°F) in a dark place. Do not use vaccine beyond the expiry
date.
2 Current worldwide Biovac-A is registered I India Only.
market
authorization status
3 Update of actions There were no marketing authorization withdrawal or
taken for safety suspension, no failure to obtain marketing authorization
reasons renewal, no restrictions on distribution & no clinical trial
suspension occurred during the period covered by this report.
There were no dosage modifications, formulation changes,
changes in target population, or changes in indications.
4 Changes to The Package Insert (PI) is in effect at the beginning of the
reference safety period covered, and is used as reference for the prescribing
information information in India except for modification in statement of
dosage and addition of composition details. There is no change
in the reference safety information of Biovac – A ® based on
the experience accrued from clinical trials or any other sources.
6 Estimated patient An estimate of patient exposure is calculated based on per unit
exposure of Biovac - A® sold during the review period. The sales volume
of Biovac - A® during the review period was 372344. The
estimated exposure was 372344 patients.
7 Presentation of No cases involving other Adverse events of interest were
 individual case received from India during the reporting period.
histories
8 Studies There have been no studies completed during the period of this report that
highlight any significant safety issues.
There have been no targeted safety studies completed during the period of
this report. A full review of the literature was conducted during the
reporting period but no studies have been identified containing important
safety finding.
9 other information No new important safety information received

10 Overall safety There is no relevant safety data received for Biovac - A® from
evaluation clinical trial or post marketing experience to initiate overall
safety evaluation. No incidence of lack of efficacy, drug
interaction, drug abuse or misuse and positive or negative
experiences during pregnancy or lactation, experiences is
special patient groups, effects of long-term treatment was
reported by any reporter.
11 Conclusion There is no relevant safety data collected/ received from
different sources (studies, spontaneous, literature) for Biovac -
A® in the review period of this periodic safety update report.
The previous cumulative experience with Biovac-A® and its
reference safety information remains consistent with the
information provided in its prescribing information/package
insert and supports the favorable benefit/risk profile. Hence no
action was recommended or initiated either by regulatory body
or by Wockhardt Ltd.
 F.No: PSUR/Wockhardt/Hep-A/2016/08
Government of India
Directorate General of Health Service
Central Drug Standard Control Organization (HQ)
(AEFI/PSUR Division)

Subject: PSUR of Hepatitis A vaccine (Biovac A) of m/s Wockhardt Ltd, Mumbai

Reporting period 01-Feb-2015 to 31-Jul-2015

Report date 28-Aug-2015, Dy. No.: 28551
Date of launch 05-Aug-2013

The firm has submitted the following information:

1 Introduction The vaccine under consideration is a freeze-dried, live, H2
attenuated vaccine, developed by Zhejiang Pukang
Biotechnological Company Ltd., China. The H2 strain was
developed through the propagation of the virus in human
embryonic pulmonary diploid cells at 32°C and a series of tests
in rhesus. The vaccine is imported from China, where it has
been in use for more than a decade. Early epidemiological
studies conducted on this freeze-dried, live attenuated vaccine
(H2 strain) have demonstrated its efficacy and safety in high-
risk populations.
A freeze-dried live vaccine is a loose substance with cheese
colour and has a light red colour after dissolution in water.
After re-constituting in vial to form 1.0ml solution (one single
dose), the live vaccine content should not be less than 6.5
LgCCID50.
Injection for subcutaneous use in a single dose vial containing
freeze-dried lyophilized Hepatitis A powder with a 1 ml
ampoule of sterile water for reconstituting the vaccine.
Hepatitis a vaccine should be stored at to 2° to 8°C (35° to
46°F) in a dark place. Do not use vaccine beyond the expiry
date.
2 Current worldwide Biovac-A is registered I India Only.
market authorization
status
3 Update of actions There were no marketing authorization withdrawal or
taken for safety suspension, no failure to obtain marketing authorization
reasons renewal, no restrictions on distribution & no clinical trial
suspension occurred during the period covered by this report.
There were no dosage modifications, formulation changes,
changes in target population, or changes in indications.
4 Changes to reference The Package Insert (PI) is in effect at the beginning of the
safety information period covered, and is used as reference for the prescribing
information in India except for modification in statement of
dosage and addition of composition details. There is no change
in the reference safety information of Biovac – A ® based on
the experience accrued from clinical trials or any other
sources.
6 Estimated patient An estimate of patient exposure is calculated based on per unit
exposure of Biovac - A® sold during the review period. The sales
volume of Biovac - A® during the review period was 298765.
The estimated exposure was 298765 patients.
7 Presentation of There were four cases reported during this period No fatal
individual case casewas received. Of the four cases, three were serious listed
histories and remaining one was serious unlisted. As per company
comments no action needed.
8 Studies There have been no studies completed during the period of this report
that highlight any significant safety issues.
There have been no targeted safety studies completed during the period
of this report. A full review of the literature was conducted during the
reporting period but no studies have been identified containing important
safety finding.
9 other information Two published studies were identified during the period.
Philibert C et al reported the case of a 29-year-old man who
developed cold urticaria associated with dizziness and
asthenia, while swimming in a river. A detailed history
revealed that 3 weeks before he had received hepatits A
vaccine inactivated [Havrix] and yellow fever vaccine
[Stamaril]. Additionally, he experienced similar episodes of
cold urticaria on exposed cutaneous areas following exposure
to cold rain or during ski excursion. His ice cube test was
positive in 10 minutes. He was treated with high doses of
antihistaminic drugs; however, his symptoms persisted.
Dalkan C et al reported the occurrence of afebrile convulsion
in a two-year old girl following a paediatric dose of hepatitis A
vaccination. A two-year-old girl developed of afebrile
generalised tonic clonic convulsion 48 hours after the
administration of inactivated hepatitis A vaccine (Havrix
720u® paediatric) as part of routine childhood vaccination
schedule. Prior to admission, she was admitted to a state
hospital with tonic-clonic seizures while there was no
predefined contraindication for administration of hepatitis A
vaccination. After that seizure, she had second generalised
tonic-clonic seizure in that hospital which lasted for 5 minutes
and resolved spontaneously without use of anticonvulsants.
Cranial magnetic resonance imaging, electroencephalography,
electrocardiography and electro encephalography (within 24
hours and 15 days after seizures) revealed no abnormal
findings. There was no past medical history of convulsion,
trauma or recent diseases or family history of seizures. No
further convulsion or other neurologic disorders were observed
to date during one-year follow-up period.

However, as per company comments no action needed.

10 Overall safety There is no relevant safety data received for Biovac - A® from
evaluation clinical trial or post marketing experience to initiate overall
safety evaluation. No incidence of lack of efficacy, drug
interaction, drug abuse or misuse and positive or negative
experiences during pregnancy or lactation, experiences is
special patient groups, effects of long-term treatment was
reported by any reporter.
11 Conclusion There is no relevant safety data collected/ received from
different sources (studies studies, spontaneous and literature)
for Biovac - A® in the review period of this periodic safety
update report. The previous cumulative experience with
Biovac - A® and its reference safety information remains
consistent with the information provided in its package
insert/prescribing information and supports the favorable
benefit/risk profile. There are no signals being monitored by
regulatory body or Wockhardt Ltd. Hence, no action is
recommended at the moment. The Company will continue to
monitor for any new safety information that may alter the
benefit-risk profile of Biovac - A® and duly take necessary
steps with any new specific information that may become
available.
 F.No: PSUR/Wockhardt/Hep-A/2016/08
Government of India
Directorate General of Health Service
Central Drug Standard Control Organization (HQ)
(AEFI/PSUR Division)
Subject: PSUR of Hepatitis A vaccine (Biovac A) of m/s Wockhardt Ltd, Mumbai
Reporting period 01-Aug-2015 to 31-Jul-2016
Report date 12-Sept-2016, Dy. No.: 27665
Date of launch 05-Aug-2013

The firm has submitted the following information:

1 Introduction The vaccine under consideration is a freeze-dried, live, H2
attenuated vaccine, developed by Zhejiang Pukang
Biotechnological Company Ltd., China. The H2 strain was
developed through the propagation of the virus in human
embryonic pulmonary diploid cells at 32°C and a series of tests
in rhesus. The vaccine is imported from China, where it has
been in use for more than a decade. Early epidemiological
studies conducted on this freeze-dried, live attenuated vaccine
(H2 strain) have demonstrated its efficacy and safety in high-
risk populations.
A freeze-dried live vaccine is a loose substance with cheese
colour and has a light red colour after dissolution in water.
After re-constituting in vial to form 1.0ml solution (one single
dose), the live vaccine content should not be less than 6.5
LgCCID50.
Injection for subcutaneous use in a single dose vial containing
freeze-dried lyophilized Hepatitis A powder with a 1 ml
ampoule of sterile water for reconstituting the vaccine.
Hepatitis a vaccine should be stored at to 2° to 8°C (35° to
46°F) in a dark place. Do not use vaccine beyond the expiry
date.
2 Current worldwide Biovac-A is registered I India Only.
market
authorization status
3 Update of actions There were no marketing authorization withdrawal or
taken for safety suspension, no failure to obtain marketing authorization
reasons renewal, no restrictions on distribution & no clinical trial
suspension occurred during the period covered by this report.
There were no dosage modifications, formulation changes,
changes in target population, or changes in indications.
4 Changes to The Package Insert (PI) is in effect at the beginning of the
reference safety period covered, and is used as reference for the prescribing
information information in India except for modification in statement of
dosage and addition of composition details. There is no change
in the reference safety information of Biovac – A ® based on
the experience accrued from clinical trials or any other sources.
6 Estimated patient An estimate of patient exposure is calculated based on per unit
exposure of Biovac - A® sold during the review period. The sales volume
of Biovac - A® during the review period was 644400. The
estimated exposure was 644400 patients.
7 Presentation of A total of nine cases were reported during the review period. Of
individual case these, eight cases were spontaneous reports and one report
 histories derived from the published literature. All of these reports were
medically confirmed. Two of these cases were serious unlisted,
two cases were serious listed, four cases were non-serious
unlisted and one cases was non-serious listed. No cases with a
fatal outcome were reported.
As per company comments no action needed.
8 Studies There have been no studies completed during the period of this report that
highlight any significant safety issues.
There have been no targeted safety studies completed during the period of
this report. A full review of the literature was conducted during the
reporting period but no studies have been identified containing important
safety finding.
9 other information Following published studies were identified during the period.
Bhave S et al1 conducted a study to assess the immunogenicity
of a single dose of live attenuated HAV in Indian children, ten
years after immunisation. The study initially was conducted in
Pune, India in 2004 to assess the safety and efficacy of single
dose of live attenuated Biovac A. The results of
immunogenicity in the children enrolled at Pune study centre in
2004 were evaluated ten years after vaccination. Seroprotection
rate was defined as proportion of subjects with total anti-HAV
antibody level ≥20 mIU/mL. Of the original 143 children who
received a single dose of live attenuated HAV vaccine in 2004,
121 subjects reported for 10-year follow-up assessment in 2014.
Of these, four who had received two doses of licensed
inactivated HAV vaccine, Havrix®, 2004 (vaccine failures) and
nine who had received a second dose of live HAV vaccine in
2007 for low titres (antibody levels <20 mIU/mL), were not
evaluated in the present analysis. Only two participants had anti-
HAV titres <20 mIU/mL (11.5 mIU/mL and 13.5 mIU/mL).
Anti-HAV IgM was negative in all the children studied. A
single dose of live attenuated HAV vaccine continued to show
excellent immunogenicity,10 years after immunisation, in most
of the Indian children.
Li KK et al2 described an outbreak of HAV linked to a nursery
which affected a total of 10 individuals. Active case finding,
using oral fluid testing, helped in the identification of
asymptomatic cases. Nucleotide sequencing showed that all
cases were caused by similar to HAV strains circulating in
Zimbabwe. An asymptomatic child had returned from visiting
family in that country. Standard infection control procedures
and vaccination of contacts successfully contained the outbreak.
Only one patient developed hepatitis A despite having been
vaccinated a week before symptoms began.
Ma F et al5 conducted a randomised, parallel controlled, phase
IV clinical trial with 6000 healthy children aged 18 months to
16 years to compare the safety and immunogenicity of live
attenuated and inactivated hepatitis A vaccine. The participants
were randomised in 1:1 ratio where one group received
intramuscular single dose live attenuated HAV vaccine and the
other received inactivated HAV vaccine in two doses with a 6-
month interval between doses. It included participants had no
prior history of hepatitis A infection nor received hepatitis A
vaccine. Follow-up assessments of adverse reactions were
performed from day 1 (date of vaccination) to 28th day. The
participants from both the groups experienced grade1 and grade
 2 fevers with slightly more participants from live attenuated
hepatitis A vaccine group, mild to moderate diarrhoea, mild
convulsions, mental reactions, cough, unusual crying,
vomiting, generalised skin reaction, injection site pain,
redness, rash and pruritus. No adverse reactions above grade
2 were reported within 28 days after administration.
However no action warranted as per company comments.
10 Overall safety An analysis of the cases and publications identified from the
evaluation literature was done. No new safety concern indicating a change
in the benefit-risk profile of Biovac A was identified. One
case of a patient with bilateral optic neuritis was reported in a
patient post vaccination However, concomitant administration
of typhoid vaccine and the underlying sarcoidosis were the
significant confounders. There were cases of administration
errors reported during the review period where one case
involved the administration of expired drug while in the other
case the wrong drug was administered. Both the cases were not
associated with any other adverse events. No new significant
information was identified on drug interaction, drug abuse or
misuse and negative experiences during pregnancy or lactation,
and experiences in special patient groups and effects of long-
term treatment. A review of the cases and publications during
the review period were mainly related to the occurrence of
injection site reactions as an adverse reaction and vaccination
failures. The vaccine provides high level of immunity even in
the long term with although isolated cases of vaccination failure
may occur. The use of the live attenuated hepatitis A vaccine is
justified at a population level the benefits of vaccination clearly
outweigh the risks incurred by infection. No change in the
known risks or significant increase in the frequency of listed
events was identified.
Cumulatively, there are 13 cases in the database till 31-Jul-
2016. The information derived in the current review period does
not indicate a change in the safety profile in view of the
cumulative experience. No new information was identified
indicating a change in the benefitrisk profile of Biovac A . The
safety information of Biovac A remains in accord with the
information in the Biovac A package insert and no actions are
needed.
11 Conclusion During the reporting review period of this PSUR, a total of nine
cases were reported. Eight of these reports were spontaneous
and one report was derived from the published literature. The
previous cumulative experience with Biovac A® and its
reference safety information remains consistent with the
information provided in its package insert and supports the
favourable benefit/risk profile. There are no signals being
monitored by regulatory body or Wockhardt Ltd for Biovac® A.
Hence, no action is recommended at the moment. The company
will continue to monitor for any new safety information that
may alter the benefit-risk profile of Biovac® A and duly take
necessary steps with any new specific information that may
become available.