REPEVAX SUSPENSION FOR INJECTION IN A PRE-FILLED SYRINGE

Active substance: TETANUS TOXOID ADSORDED PURIFIED

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sanofi Pasteur
310 – REPEVAX®

1.

DRAFT Summary of Product Characteristics
Version 6.2

NAME OF THE MEDICINAL PRODUCT
REPEVAX™
REPEVAX®, suspension for injection in a pre-filled syringe
Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated)
Vaccine (adsorbed, reduced antigen(s) content)

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
1 dose (0.5 mL) contains:
Diphtheria Toxoid.................................................... Not less than 2 IU* (2 Lf)
Tetanus Toxoid .................................................... Not less than 20 IU* (5 Lf)
Pertussis Antigens
Pertussis Toxoid............................................................................. 2.5 micrograms
Filamentous Haemagglutinin ......................................................... 5 micrograms
Pertactin ......................................................................................... 3 micrograms
Fimbriae Types 2 and 3.................................................................. 5 micrograms
Poliovirus (Inactivated)**
Type 1 .......................................................................................... 40 D antigen units
Type 2 ............................................................................................ 8 D antigen units
Type 3 .......................................................................................... 32 D antigen units
Adsorbed on aluminium phosphate ............................................... 1.5 mg (0.33 mg aluminium)
* As lower confidence limit (p = 0.95) of activity measured according to the assay described in the
European Pharmacopoeia.
** Produced in Vero cells.
REPEVAX may contain traces of formaldehyde, glutaraldehyde, streptomycin, neomycin,
polymyxin B and bovine serum albumin, which are used during the manufacturing process (see
sections 4.3 and 4.4).
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Suspension for injection in pre-filled syringe
REPEVAX appears as a uniform, cloudy, white suspension.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
REPEVAX is indicated for active immunization against diphtheria, tetanus, pertussis and
poliomyelitis in persons from 3 years of age as a booster following primary immunization.
The use of REPEVAX should be determined on the basis of official recommendations.

4.2

Posology and method of administration
Posology
A single injection of one (0.5 mL) dose is recommended in all indicated age groups.
REPEVAX is a vaccine containing low-dose diphtheria toxoid plus tetanus toxoid in combination
with pertussis and polio antigens for booster vaccinations.
Individuals with an incomplete, or no history of a primary series of diphtheria and tetanus toxoids or
polio vaccine should not be vaccinated with REPEVAX.
REPEVAX is not precluded in persons with an incomplete, or no history of previous pertussis
vaccination. However, a booster response will only be elicited in individuals who have been
previously primed by vaccination or by natural infection.
There are currently no data upon which to base a recommendation for the optimal interval for
administering subsequent booster doses with REPEVAX.
Repeat vaccination against diphtheria, tetanus, pertussis and/or poliomyelitis should be performed at
intervals according to official recommendations.
REPEVAX can be used in the management of tetanus prone injuries with or without concomitant
administration of Tetanus Immunoglobulin according to official recommendations.
Paediatric Population
REPEVAX should not be used in children under 3 years of age.
Children from the age of 3 years onwards and adolescents should receive the same dosage as adults.
Method of administration
A single injection of one dose (0.5 mL) of REPEVAX should be administered intramuscularly. The
preferred site is into the deltoid muscle.
Do not administer REPEVAX intravascularly. After insertion of the needle, aspirate to ensure that
the needle has not entered a blood vessel.
REPEVAX should not be administered into the gluteal area; intradermal or subcutaneous routes
should not be used (in exceptional cases the subcutaneous route may be considered, see section 4.4).
Precautions to be taken before handling or administering the medicinal product
For instructions on handling of the medicinal product before administration, see section 6.6.

4.3

Contraindications


REPEVAX should not be administered to persons with known hypersensitivity
-

to diphtheria, tetanus, pertussis or poliomyelitis vaccines

-

to any other component of the vaccine (see Section 6.1)

-

to any residual substances carried over from manufacture (formaldehyde, glutaraldehyde,
streptomycin, neomycin, polymyxin B and bovine serum albumin), which may be present in
undetectable trace amounts.




4.4

REPEVAX should not be administered to persons who experienced an encephalopathy of unknown
origin within 7 days of previous immunization with a pertussis-containing vaccine.
As with other vaccines, administration of REPEVAX should be postponed in persons suffering from
an acute severe febrile illness. The presence of a minor infection (e.g., mild upper respiratory
infection) is not a contraindication.

Special warnings and precautions for use
REPEVAX should not be used for primary immunization.
Regarding the interval between a booster dose of REPEVAX and preceding booster doses of
diphtheria and/or tetanus containing vaccines, the official recommendations should generally be
followed. Clinical data in adults have demonstrated that there was no clinically relevant difference in
rates of adverse reactions associated with administration of REPEVAX as early as 4 weeks,
compared to at least 5 years after a preceding dose of tetanus and diphtheria-containing vaccine.
Prior to immunization
Vaccination should be preceded by a review of the person’s medical history (in particular
previous vaccinations and possible adverse events). In persons who have a history of serious or
severe reaction within 48 hours of a previous injection with a vaccine containing similar
components, administration of REPEVAX vaccine must be carefully considered.
As with all injectable vaccines, appropriate medical treatment and supervision should be readily
available for immediate use in case of a rare anaphylactic reaction following the administration of
the vaccine.
If Guillain-Barré syndrome or brachial neuritis has occurred following receipt of prior vaccine
containing tetanus toxoid, the decision to give any vaccine containing tetanus toxoid should be
based on careful consideration of the potential benefits and possible risks.
REPEVAX should not be administered to individuals with a progressive or unstable neurological
disorder, uncontrolled epilepsy or progressive encephalopathy until a treatment regimen has
been established and the condition has stabilized.
The rates and severity of adverse events in recipients of tetanus toxoid antigen are influenced by the
number of prior doses and level of pre-existing antitoxins.
The immunogenicity of the vaccine could be reduced by immunosuppressive treatment or
immunodeficiency. It is recommended to postpone the vaccination until the end of such disease
or treatment if practical. Nevertheless, vaccination of HIV infected persons or persons with
chronic immunodeficiency, such as AIDS, is recommended even if the antibody response might
be limited.
Administration precautions
Intramuscular injections should be given with care in patients on anticoagulant therapy or
suffering from coagulation disorders because of the risk of haemorrhage. In these situations and
following official recommendations the administration of REPEVAX by deep subcutaneous
injection may be considered, although there is a risk of increased local reactions.
Other considerations

As with any vaccine, a protective immune response may not be elicited in all vaccinees (see section
5.1).
A persistent nodule at the site of injection may occur with all adsorbed vaccines, particularly if
administered into the superficial layers of the subcutaneous tissue.

4.5

Interaction with other medicinal products and other forms of interaction
REPEVAX may be administered concomitantly with a dose of inactivated influenza vaccine, based
on the results of a clinical trial conducted in persons 60 years of age and older.
REPEVAX may be administered concomitantly with a dose of hepatitis B vaccine.
REPEVAX may be administered concurrently with a dose of recombinant Human Papillomavirus
vaccine with no significant interference with antibody response to any of the components of either
vaccine. However, a trend of lower anti-HPV GMTs was observed in the concomitant group. The
clinical significance of this observation is not known. This is based on the results from a clinical trial
in which REPEVAX was administered concomitantly with the first dose of Gardasil (see section
4.8).
Separate limbs must be used for the site of injection. Interaction studies have not been carried out
with other vaccines, biological products or therapeutic medications. However, in accordance with
commonly accepted immunization guidelines, since REPEVAX is an inactivated product it may be
administered concomitantly with other vaccines or immunoglobulins at separate injection sites.
In the case of immunosuppressive therapy please refer to Section 4.4.

4.6

Pregnancy and lactation
Pregnancy
The effect of REPEVAX on embryo-foetal development has not been assessed. No
teratogenic effect of vaccines containing diphtheria or tetanus toxoids, or inactivated
poliovirus has been observed following use in pregnant women.
Limited post-marketing information is available on the safety of administering REPEVAX
to pregnant women.
The use of this combined vaccine is not recommended during pregnancy.
Breastfeeding
The effect of administration of REPEVAX during lactation has not been assessed.
Nevertheless, as REPEVAX contains toxoids or inactivated antigens, no risk to the breastfed
infant should be expected. The benefits versus the risk of administering REPEVAX to
breastfeeding women should be evaluated by the health-care providers.
Fertility
REPEVAX has not been evaluated in fertility studies.

4.7

Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been performed.

4.8

Undesirable effects
a. Summary of the safety profile
In clinical trials REPEVAX was given to a total of 1,384 children, adolescent and adults. Most
commonly reported reactions following vaccination included local reactions at the injection site
(pain, redness and swelling). These signs and symptoms usually were mild in intensity and occurred
within 48 hours following vaccination. They all resolved without sequelae.
There was a trend for higher rates of local and systemic reactions in adolescents than in adults. In
both age groups, injection site pain was the most common adverse reaction.
Late-onset local adverse reactions (i.e. a local adverse reaction which had an onset or increase in
severity 3 to 14 days post-immunization), such as injection site pain, erythema and swelling occurred
in less than 1.2%. Most of the reported adverse reactions occurred within 24 hours after the
vaccination.
In a clinical trial of 843 healthy adolescent males and females 11-17 years of age, administration of
the first dose of Gardasil concomitantly with REPEVAX showed that there was more injection-site
swelling and headache reported following concomitant administration. The differences observed
were < 10% and in the majority of subjects, the adverse events were reported as mild to moderate in
intensity.
b. Tabulated list of adverse reactions
Adverse reactions are ranked under headings of frequency using the following convention:
Very common
Common
Uncommon
Rare
Very rare
Not known

(≥1/10)
(≥1/100 to <1/10)
(≥1/1,000 to <1/100)
(≥1/10,000 to <1/1,000)
(<1/10,000), including individual cases
cannot be estimated from the available data

Table 1 presents adverse reactions observed in clinical trials and also includes additional adverse
events which have been spontaneously reported during the post-marketing use of REPEVAX
worldwide. Adverse events in children were collected from clinical trials conducted in 3 to 5 years of
age and 5 to 6 years of age. The highest frequency from either study is presented. Because postmarketing adverse events are reported voluntarily from a population of uncertain size, it is not
always possible to reliably estimate their frequency or establish a causal relationship to vaccine
exposure. Therefore, the frequency category “Not known” is assigned to these adverse events.

sanofi Pasteur
310 – REPEVAX®

DRAFT Summary of Product Characteristics
Version 6.2

Table 1: Adverse events from clinical trials and worldwide post marketing experience

System Organ Class

Frequency

Blood and Lymphatic
System Disorders

Not known

Nervous System
Disorders

Very
common

Adolescents and Adults
(994 Persons)

Not known

Immune System
Disorders

Children 3 to 6 years
(390 Persons)*

Lymphadenopathy†

Anaphylactic reactions, such as urticaria, face oedema and
dyspnea†

Headache

Common
Headache
Not known

Gastrointestinal
Disorders

Convulsions, Vasovagal Syncope, Guillain Barré syndrome,
Facial Palsy, Myelitis, Brachial Neuritis, Transient
paresthesia/hypoesthesia of vaccinated limb, Dizziness†

Very
common
Common

Skin and Subcutaneous
System Disorders

Diarrhoea, Vomiting,
Nausea

Very
common

Diarrhoea, Vomiting

Common

Musculoskeletal and
Connective Tissue
Disorders

Nausea

Rash
Arthralgia/joint swelling, Myalgia

Common
Arthralgia/joint swelling
Not known
Pain in vaccinated limb†
General Disorders and
Administration Site
Conditions

Very
common
Common

Fatigue/Asthenia,
Fever‡, Irritability

Fatigue/Asthenia, Chills

Fever‡

System Organ Class

Frequency

Children 3 to 6 years
(390 Persons)*

Adolescents and Adults
(994 Persons)

Not known
Malaise, Pallor †
Injection site reactions

Very
common
Common

Pain, Swelling,
Erythema
Dermatitis, Bruising
Pruritus

Not known
Extensive limb swelling §, Injection site induration †

*

AEs observed within 24 h and 7 days following vaccination
Post marketing adverse events
Fever was measured as temperature ≥37.5°C in Children groups and measured as
temperature ≥38°C in Adolescents and Adults group
See section c)



§

c. Description of selected adverse reactions
Extensive limb swelling which may extend from the injection site beyond one or both joints and is
frequently associated with erythema, and sometimes with blisters has been reported following
administration of REPEVAX. The majority of these reactions appeared within 48 hours of
vaccination and spontaneously resolved over an average of 4 days without sequelae.
The risk appears to be dependent on the number of prior doses of d/DTaP vaccine, with a greater risk
following the 4th and 5th doses.

d. Paediatric population
The safety profile of REPEVAX in 390 children 3 to 6 years of age as presented in Table 1 is
derived from two clinical studies:
-

In a clinical study, 240 children were primed at 3, 5 and 12 months of age with a DTaP vaccine with
no additional dose in the second year of life. These children received REPEVAX at 5 to 6 years of
age.

-

One hundred and fifty children primed at 2, 3, and 4 months of age with a DTwP vaccine (with no
additional dose in the second year of life) received REPEVAX at 3 to 5 years of age.
In both studies the rates of most systemic adverse events within 7 to 10 days following vaccination
were less than 10%. Only fever (≥37.5°C) and fatigue were reported in more than 10 % of subjects 3
to 6 years of age. In addition, irritability was reported in more than 10% of subjects 3 to 5 years of
age. (See Table1).
Transient severe swelling of the injected upper arm was reported in <1% of children aged 5 to 6
years.

4.9

Overdose
Not-applicable.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic Group: Vaccine against diphtheria, tetanus, pertussis and poliomyelitis
ATC Code: J07CA02
Clinical trials
The immune responses of adults, adolescents and children 3 to 6 years of age one-month after
vaccination with REPEVAX are shown in the table below. The use of REPEVAX in children aged 3 to
5 years is based upon studies in which REPEVAX was given as the fourth dose (first booster) of
diphtheria, tetanus, pertussis and poliomyelitis vaccines.

Table 2: Immune responses 4 weeks after vaccination

Antigen

Diphtheria

Criteria

>0.1 IU/mL

Adults and
Adolescentsi
(n = 994)

Children
5-6 years oldii
(n = 240)

Children
3-5 years
oldiii
(n = 148)

92.8%

99.4%

100%

Tetanus

100%

99.5%

100%

Pertussis
Pertussis Toxoid
Filamentous
Haemagglutinin
Pertactin
Fimbriae Types 2 and 3

>5 U/mLv
>5EU/mLv
>5EU/mLv
>5EU/mLv

99.7%
99.9%
99.6%
99.8%

91.2%
99.1%
100%
99.5%

99.3%
99.3%
100%
100%

Polio 1
Polio 2
Polio 3
*


§
**

>0.1 IU/mLiv

>1:8 Dilution
>1:8 Dilution
>1:8 Dilution

99.9%
100%
100%

100%
100%
100%

100%
100%
100%

From the age of 10 years onwards
Primed with DTaP at 3 and 5 months with a booster at 12 months of age
Primed with DTwP at 2, 3 and 4 months of age
Measured by ELISA
EU = ELISA units: Antibody levels of >5 EU/mL were postulated as possible surrogate markers for
protection against pertussis by Storsaeter J. et al, Vaccine 1998;16:1907-16.

sanofi Pasteur
310 – REPEVAX®

DRAFT Summary of Product Characteristics
Version 6.2

The safety and immunogenicity of REPEVAX in adults and adolescents was shown to be comparable
to that observed with a single booster dose of Td adsorbed or Td Polio adsorbed vaccines containing a
similar amount of tetanus and diphtheria toxoids and inactivated poliovirus types 1, 2 and 3.
The lower response to diphtheria toxoid in adults probably reflected the inclusion of some participants
with an uncertain or incomplete immunization history.
Serological correlates for protection against pertussis have not been established. On comparison with
data from the Sweden I pertussis efficacy trials conducted between 1992 and 1996, where primary
immunization with Sanofi Pasteur Limited’s acellular pertussis infant DTaP formulation confirmed a
protective efficacy of 85% against pertussis disease, it is considered that REPEVAX had elicited
protective immune responses.
In a subsequent study, robust immune responses were observed following a single dose of REPEVAX
in UK children 3.5 to 4.0 years of age previously primed with either an acellular pertussis combination
vaccine (DTaP-IPV-Hib) or whole cell pertussis combination vaccine (DTwP//Hib) and OPV.
Serology follow-up studies were conducted in children adolescents and adults immunized with a single
booster dose of REPEVAX.
At the 5-year follow-up time point, seroprotective antibody levels ( 0.01IU/ml) were maintained in
100% of participants of all age groups, for tetanus, and in 96-100% of the children and adolescent and
>79% of the adults, for diphtheria.



For poliovirus, the seroprotective levels ( 1:8 dilution) for each type (1, 2 and 3) were maintained for
95-100% of the children, adolescents and adults at the 5-year follow-up time point.



GMTs for all pertussis antigens at 5 years remained several fold higher than pre-immunization levels,
indicating a sustained long-term immune response for all age groups.

5.2

Pharmacokinetic properties
Evaluation of pharmacokinetic properties is not required for vaccines.

5.3

Preclinical safety data
Non-clinical data revealed no special hazard for humans based on conventional studies of repeated
doses toxicity.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients
Phenoxyethanol
Polysorbate 80
Water for injections

6.2.

Incompatibilities
In the absence of compatibility studies, REPEVAX® must not be mixed with any vaccine or
other medicinal products.

6.3.

Shelf life
3 years.

6.4

Special precautions for storage
Store in a refrigerator at 2°C to 8°C.
Do not freeze. Discard the vaccine if it has been frozen.
Keep the container in the outer carton in order to protect from light.

6.5

Nature and contents of container
0.5 mL of suspension in pre-filled syringe (glass) with a plunger stopper (chlorobromobutyl
elastomer), without attached needle, with a tip-cap (chlorobromobutyl elastomer) - pack size
of 1, 10 or 20.
0.5 mL of suspension in pre-filled syringe (glass) with a plunger stopper (chlorobromobutyl
elastomer), without attached needle, with a tip-cap (chlorobromobutyl elastomer) and 1 or 2
separate needles - pack size of 1 or 10.
0.5 mL of suspension in pre-filled syringe (glass) with a plunger stopper (chlorobromobutyl
elastomer) with attached needle and needle guard (elastomer) - pack size of 1, 10 or 20.
0.5 mL of suspension in pre-filled syringe (glass) with a plunger stopper (chlorobromobutyl
elastomer) with attached needle and needle guard (translucent polypropylene rigid safeshield
and polyisoprene) - pack size of 1, 10 or 20.
The stoppers, plunger stoppers and caps for all presentations of REPEVAX are latex-free.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Instructions for use
Parenteral products should be inspected visually for extraneous particulate matter and/or
discoloration prior to administration. In the event of either being observed, discard the medicinal
product.
The normal appearance of the vaccine is a uniform cloudy, white suspension which may sediment
during storage. Shake the prefilled syringe well to uniformly distribute the suspension before
administering the vaccine.

For needle free syringes, the needle should be pushed firmly on to the end of the prefilled syringe
and rotated through 90 degrees.
Disposal
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.
Needles should not be recapped.

7.

MARKETING AUTHORISATION HOLDER
Sanofi Pasteur MSD Ltd.,
Mallards Reach
Bridge Avenue
Maidenhead
Berkshire
SL6 1QP.
United Kingdom

8.

MARKETING AUTHORISATION NUMBER(S)
PL 06745/0121

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
15/12/2006

10

DATE OF REVISION OF THE TEXT
10/09/2012

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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