REPEVAX^®, suspension for injection, in pre-filled syringe

Diphtheria, Tetanus, Pertussis (acellular, component) and Poliomyelitis (inactivated) Vaccine (adsorbed, reduced antigen(s) content)

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

Poliovirus (Inactivated)**

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.

For a full list of excipients, see section 6.1.

Suspension for injection in pre-filled syringe

REPEVAX appears as a uniform, cloudy, white suspension.

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.

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.

• 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.

• 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.

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.

REPEVAX may be administered concurrently with a dose of hepatitis B vaccine.

REPEVAX may be administered concurrently with a dose of recombinant Human Papillomavirus 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.

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.

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

Clinical Trials

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.

Adverse reactions are ranked under headings of frequency using the following convention:

Children

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.

The rates of general symptoms after the first day but within 10 days after vaccination were low; only fever (38.0°C) and fatigue were reported in >10% of subjects. Transient severe swelling of the injected upper arm was reported in <1% of subjects.

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.

* AEs observed within 7 days following vaccination

† AEs observed within 24 hours following vaccination

‡ Fever was measured as temperature 38°C in the group “children 5 to 6 years” and measured as temperature ≥37.5°C in the groups “Children 3 to 5 years”

Adolescents (11 years of age and older) and Adults

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.

Data from Post-Marketing Experience

The following additional adverse events have been spontaneously reported during the post-marketing use of REPEVAX worldwide. Because these 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.

Blood and Lymphatic Disorders

Lymphadenopathy

Immune System Disorders

Anaphylactic reactions, such as urticaria, face oedema and dyspnea

Nervous System Disorders

Convulsions, vasovagal syncope, Guillain-Barré syndrome, facial palsy, myelitis, brachial neuritis, transient paresthesia / hypoesthesia of vaccinated limb, dizziness.

Musculoskeletal and Connective Tissue Disorders

Pain in vaccinated limb

General Disorders and Administrative Site Conditions

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 4^th and 5^th doses.

Malaise, pallor, injection site induration

Not applicable.

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 1: Immune Responses 4 Weeks after Vaccination

* 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.

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.

Evaluation of pharmacokinetic properties is not required for vaccines.

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

Phenoxyethanol

Polysorbate 80

Water for injections

In the absence of compatibility studies, REPEVAX must not be mixed with other medicinal products.

3 years.

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.

0.5 mL of suspension in pre-filled syringe (glass) with a plunger stopper (chlorobromobutyl or bromobutyl or chlorobutyl 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 or bromobutyl or chlorobutyl 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 or bromobutyl or chlorobutyl 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.

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 product or waste material should be disposed of in accordance with local requirements.

Needles should not be recapped.

Sanofi Pasteur MSD Ltd

Mallards Reach

Bridge Avenue

Maidenhead, Berkshire

SL6 1QP

PL 06745/121

02 November 2001 / 15 December 2006

21/12/2011