REPEVAX, suspension for injection in pre-filled syringe

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

* As lower confidence limit (p equals 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 cloudy white suspension.

REPEVAX is indicated for active immunization against diphtheria,tetanus, pertussis and poliomyelitis in persons from the age of three years as a booster following primary immunization.

REPEVAX is not intended for primary immunization.

REPEVAX is not to be used for the treatment of disease caused by B. pertussis, C. diphtheriae or C. tetani or Poliomyelitis infections.

The use of REPEVAX should be determined on the basis of official recommendations.

Posology

The same dosage, a single 0.5 mL intramuscular dose, applies to all age groups.

REPEVAX may be administered from the age of three years onwards. 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.

REPEVAX should be administered in accordance with official recommendations and/or local practice regarding the use of vaccines that provide low-dose diphtheria toxoid plus tetanus toxoid in combination with pertussis and polio antigens.

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 subjects 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. Repeat vaccination against diphtheria and tetanus should be performed at intervals as per official recommendations. It is not necessary to re-commence primary vaccination, should the officially recommended inter-booster interval be exceeded.

There are currently no data upon which to base a recommendation for the optimal interval for administering subsequent booster doses with REPEVAX to maintain antibody levels against pertussis.There are no data on the duration of protection against pertussis following vaccination with REPEVAX.

REPEVAX has not been studied in subjects with tetanus-prone injuries and should not be used in these circumstances.

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. REPEVAX should not be administered into the gluteal area.

Do not administer intravascularly.

The subcutaneous route should not be used (for exception, see section 4.4).

• Hypersensitivity to the active substances, to any of the excipients or any residual component carried over from manufacture (formaldehyde, glutaraldehyde, streptomycin, neomycin and polymyxin B).

• Anaphylactic or other allergic reactions to a previous dose of a vaccine containing diphtheria or tetanus toxoids, poliomyelitis viruses or pertussis (acellular or whole cell).

• 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, or to persons with a progressive or unstable neurological disorder, uncontrolled seizures or progressive encephalopathy until a treatment regimen has been established and the condition has been stabilized.

• Vaccination should be deferred in the presence of any acute illness, including febrile illness. A minor afebrile illness such as mild upper respiratory infection is not usually a reason to defer immunization.

REPEVAX should not be used for primary immunization or for boosters in children less than 3 years of age.

Prior to administration of any dose of REPEVAX, the parent or guardian of the recipient or the adult recipient must be asked about personal history, family history and recent health status, including immunization history, current health status and any adverse event after previous immunizations. 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.

Do not administer by intravascular injection. After insertion of the needle, aspirate to ensure that the needle has not entered a blood vessel.

Fractional doses (doses <0.5 mL) should not be given. The effect of fractional doses on the frequency of serious adverse events and on efficacy has not been determined.

Regarding the interval preceding a booster dose of REPEVAX the local recommendations should be followed. However, in order to minimize the risk of adverse reactions, the interval between a booster dose of REPEVAX and preceding booster doses of diphtheria and tetanus containing vaccines (DT, Td) should be preferably at least five years.

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.

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.

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 administration of REPEVAX by deep subcutaneous injection may be considered, although there is a risk of increased local reactions.

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.

As with any vaccine, vaccination with REPEVAX may not protect 100% of susceptible individuals.

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 subjects or subjects with chronic immunodeficiency, such as AIDS, is recommended even if the antibody response might be limited.

A clinical study has shown that REPEVAX can be administered concomitantly with hepatitis B vaccine, using a separate limb 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, there is no theoretical reason why it should not be administered concomitantly with other vaccines or immunoglobulins at separate sites.

In the case of immunosuppressive therapy please refer to section 4.4.

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. Data on the use of vaccines containing acellular pertussis antigens in pregnant women are not available.

The use of this combined vaccine is not recommended during pregnancy.

Use in lactation

The vaccine is unlikely to produce an effect on the ability to drive or operate machinery.

Data from clinical trials

In clinical trials REPEVAX was given to a total of 1,384 children, adolescent and adult subjects. 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:

Adolescents and adults (994 subjects)

In clinical studies in which REPEVAX was administered to adolescents and adults, the most frequently reported adverse reactions occurring over all age groups during the first 24 hours after vaccination included the following:

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%.

Children 5 to 6 years old (240 subjects)

In a clinical study, 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 most frequently reported adverse reactions occurring during the first 24 hours included the following:

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 upper arm was reported in <1% of subjects.

Children 3 to 5 years old (150 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. The most frequently reported adverse reactions occurring during the first 7 days included the following:

Data from post-marketing experience

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

Blood and lymphatic disorders:

Lymphadenopathy

Immune system disorders:

Anaphylactic reactions, such as urticaria, face oedema and dyspnea

Nervous system disorders:

Convulsions, vasovagal syncope

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

Potential adverse events

Other adverse events not listed above have been reported with other similar vaccines and should be considered potential adverse reactions to REPEVAX.

Brachial neuritis and Guillain-Barré syndrome after administration of a tetanus toxoid containing vaccine.

No case of overdose has been reported

Pharmacotherapeutic Group: Vaccine against diphtheria, tetanus, pertussis and poliomyelitis

ATC Code: J07CA02

Immune responses of adults, adolescents and children 3 to 6 years of age one-month post vaccination with REPEVAX are shown in the table below.

Table 1 : Immune Responses 4 Weeks After Vaccination

The safety and immunogenicity profile 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 two separate pertussis efficacy trials conducted in Sweden between 1992 and 1996, where primary immunization with Sanofi Pasteur Limited's acellular pertussis infant DTaP formulations conferred a protective efficacy of 85% against pertussis disease, it was considered that REPEVAX had elicited protective immune responses.

Seroprotection rates 3 years post-vaccination with REPEVAX in adults and adolescents are shown in the table below.

Table 2 : Seroprotection Rates 3 Years Post-Vaccination with REPEVAX in Adults and Adolescents

There are currently no data available on the antibody levels to any of the antigens in REPEVAX beyond four weeks post-vaccination in children. Studies are on-going to collect these data.

As for all vaccines, pharmacokinetic data being non-relevant, no pharmacokinetic studies have been performed.

Preclinical data revealed no unexpected findings and no target organ 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.

0.5 mL of suspension in pre-filled syringe (type I 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 (type I 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 (type I 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 (type I 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.

Not all pack sizes may be marketed.

Instructions for Use

Parenteral biological products should be inspected visually for extraneous particulate matter and/or discoloration prior to administration. In the event of either being observed, discard the vaccine.

The vaccine's normal appearance is a 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 06745/0121

02 November 2001 / 15 December 2006

07/2008