PEDIACEL

Suspension for Injection

Diphtheria, tetanus, five component acellular pertussis, inactivated poliomyelitis and Haemophilus influenzae type b conjugate vaccine (adsorbed).

Each 0.5 millilitre dose contains:

For excipients, see 6.1.

* As lower confidence limit (p=0.95) of activity measured according to the assay described in the European Pharmacopoeia

** or equivalent antigenic quantity determined by a suitable immunochemical method.

Active components of the vaccine are inactivated with either formaldehyde or glutaraldehyde.

Inactivated poliovirus components are produced using the Vero cell line.

Suspension for injection in a vial.

PEDIACEL is a sterile, uniform, cloudy, white to off-white suspension.

PEDIACEL is indicated for the active immunisation of infants against diphtheria, tetanus, pertussis, poliomyelitis and invasive infections caused by Haemophilus influenzae type b.

PEDIACEL may also be administered as a single dose to children who have previously completed a primary immunisation series with diphtheria, tetanus, pertussis, polio and Hib antigens (see sections 4.8 and 5.1), in accordance with the applicable official recommendations.

Primary Immunisation Series in Infancy

The primary immunisation series in infancy may be commenced from two months of age according to applicable official recommendations. A single 0.5 millilitre dose should be given on three separate occasions with at least one month between doses.

There are no data regarding the administration of PEDIACEL for one or two doses and use of different vaccine(s) for other dose(s). Therefore, it is recommended that infants who receive PEDIACEL for the first dose should also receive this vaccine for the second and third doses of the primary immunisation series.

Booster Dose

After completion of the primary series, a booster dose of Hib conjugate vaccine should be administered. The timing of this Hib conjugate booster dose should be in accordance with official recommendations.

A single 0.5 millilitre dose of PEDIACEL may be used to provide the Hib booster dose if it is officially recommended to boost responses to all other antigens in the vaccine at the same time.

Based on safety and immunogenicity data from clinical studies, PEDIACEL should preferably be given to children who received this same vaccine in infancy. However, if necessary, PEDIACEL may be given at this age to children who received other vaccines in infancy.

PEDIACEL should not be administered to children after reaching the fourth birthday.

Method of Administration

PEDIACEL should be administered intramuscularly. The recommended injection sites are the anterolateral aspect of the thigh in infants and the deltoid region in older children.

PEDIACEL should not be given to children who:

• Are known to be hypersensitive to any component of the vaccine (including neomycin, streptomycin and polymyxin B which may be present in trace amounts).

• Have had a previous severe local or general reaction to this vaccine or to any other vaccine that contains one or more of the antigenic components.

• Have experienced encephalopathy (e.g., coma, decreased level of consciousness, prolonged seizures) within 7 days of a previous dose of a pertussis-containing vaccine that is not attributable to another identifiable cause.

• Have a progressive neurologic disorder, uncontrolled epilepsy, or progressive encephalopathy. Pertussis vaccine should not be administered to individuals with these common conditions until the treatment regimen has been established, the condition has stabilized, and the benefit clearly outweighs the risk.

• Have a fever or acute severe systemic illness. In this case vaccination should be postponed until the child has recovered. Minor infections without fever or systemic upset are not reasons to postpone vaccination.

As with all vaccines, appropriate facilities and medication such as epinephrine (adrenaline) should be readily available for immediate use in case of anaphylaxis or hypersensitivity following injection.

If any of the following events are known to have occurred in temporal relation to a previous dose of a pertussis-containing vaccine, the decision to give further doses of pertussis-containing vaccines should be carefully considered:

• Temperature of 40°C within 48 hours, not due to another identifiable cause.

• Hypotonic hyporesponsive episode (HHE): a syndrome characterised by acute diminution of sensory awareness or loss of consciousness, accompanied by pallor and muscle hypotonicity. The onset is usually 1-12 hours after vaccination and the episode may last from a few minutes up to 36 hours. Recovery is complete with no persistent sequelae.

• Persistent, inconsolable crying lasting more than 3 hours occurring within 48 hours of vaccination.

• Convulsions with or without fever occurring within 3 days of vaccination.

In children with a progressive, evolving or unstable neurological condition (including seizures), immunisation should be deferred until the condition is corrected or stable.

The immunogenicity of the vaccine may be reduced by immunosuppressive treatment or immunodeficiency. It is recommended to postpone vaccination until the end of such treatment or the resolution of disease. Nevertheless, vaccination of subjects with chronic immunodeficiency (such as those with HIV infection or on long-term immunosuppressive therapy) is recommended even though the immunological response may be impaired and the degree of protection may be limited.

Intramuscular injections should be given with care in patients with thrombocytopenia or bleeding disorders due to the risk of haemorrhage.

The vaccine should be given intramuscularly since subcutaneous administration increases the chances of an injection site reaction. Do not administer by intradermal or intravenous injection.

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, such as whether or not the primary immunization schedule has been completed.

PEDIACEL does not protect against infectious diseases caused by Haemophilus influenzae other than type b, or against meningitis caused by other organisms.

As with any vaccine, immunisation with PEDIACEL may not protect all recipients from the infections that it is intended to prevent.

Applicable official recommendations for childhood immunisations should be consulted before administering this vaccine to children in or after the second year of life since this exact combination of antigens may not be considered appropriate and/or necessary after completion of the infant immunisation series.

The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be considered when administering the primary immunization series to very premature infants (born 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. As the benefit of vaccination is high in this group of infants, vaccination should not be withheld or delayed.

PEDIACEL may be administered at the same time as, but as a separate injection to, meningococcal group C conjugate vaccines or hepatitis B vaccines. Injections should be made into separate sites and, preferably, into separate limbs.

Antibody responses to the Hib component of PEDIACEL (PRP conjugated to tetanus toxoid; see section 2) were lower when a meningococcal group C CRM₁₉₇ conjugate vaccine was co-administered as a separate injection than when a meningococcal group C tetanus toxoid conjugate vaccine was co-administered as a separate injection at 2, 3 and 4 months of age (see section 5.1). The clinical significance of these observations is unknown but the findings relating to meningococcal group C CRM₁₉₇ conjugate vaccine may have implications for the timing of and need for a Hib conjugate booster dose.

The type of meningococcal conjugate vaccine that is co-administered may also affect responses to the diphtheria and tetanus components of PEDIACEL. Anti-diphtheria responses were higher when a meningococcal group C CRM₁₉₇ conjugate was co-administered with PEDIACEL and anti-tetanus responses were higher when a meningococcal group C tetanus toxoid conjugate was co-administered. However, responses to both these antigens were satisfactory regardless of the type of meningococcal group C conjugate that was given (see section 5.1).

PEDIACEL did not affect the proportions of infants with meningococcal group C serum bactericidal antibody (SBA) titres of at least 1:8 (measured with rabbit complement) when co-administered with either a CRM₁₉₇ conjugate or a tetanus toxoid conjugate vaccine. However, the SBA geometric mean titres (GMTs) were numerically lower after co-administration with PEDIACEL than were seen when these same meningococcal group C conjugate vaccines were co-administered with a whole cell pertussis (as DTwP) vaccine. Also, the SBA GMT when PEDIACEL was co-administered with a meningococcal group C tetanus toxoid conjugate vaccine was significantly lower than that seen after co-administration with a CRM₁₉₇ conjugate (see section 5.1). However, the clinical significance of the lower SBA GMTs is unknown.

There are currently no data on the concomitant use of PEDIACEL and pneumococcal conjugate vaccine. However, concomitant use may be considered if medically important or in accordance with applicable official recommendations.

There are no data on immune responses to hepatitis B vaccines when co-administered with PEDIACEL. However, there are no safety concerns regarding co-administration.

Except for immunosuppressive therapy (see 4.4), no significant interaction with other treatments or biological products is anticipated.

As PEDIACEL is not intended for use in adults, or in children above the age of 4 years, information on the safety of the vaccine when used in pregnancy or lactation is not available.

Not applicable. This vaccine is intended for paediatric use.

In controlled clinical studies performed with PEDIACEL, 71% of 451 infants immunised at 2, 4 and 6 months experienced a reaction (pain, erythema or oedema) at the injection site within the first 24 hours after vaccination. In 16% of infants the reaction was of moderate to severe intensity. Also, 64% of infants experienced a systemic reaction, which was of moderate to severe intensity in 16%.

There was a trend for an increased frequency of injection site reactions when a fourth dose of PEDIACEL was given to 401 children in the second year of life. Pain was reported in 33%, erythema in 23% and oedema in 16% compared to rates of 18%, 11% and 11%, respectively, during the primary series. The frequency of systemic reactions was similar whether PEDIACEL was administered in infancy or in the second year of life.

The reactions observed were as follows:

Large injection site reactions (>50 mm), including extensive limb swelling from the injection site beyond one or both joints, have been reported following administration of acellular-pertussis contained in PEDIACEL. These reactions start within 24-72 hours after vaccination, may be associated with erythema, warmth, tenderness or pain at the injection site and resolve spontaneously within 3-5 days. The risk appeared to be dependent on the number of prior doses of acellular pertussis containing vaccine, with a greater risk following the 4th and 5th doses.

In a controlled clinical study of PEDIACEL, administered concomitantly with meningococcal group C conjugate vaccine, 71% of 121 infants immunised at 2, 3 and 4 months experienced a reaction (pain, erythema or oedema) at the PEDIACEL injection site within the first seven days after vaccination. Also, 92% of infants experienced a systemic reaction within the first seven days after vaccination. The rates of moderate to severe reactions were similar to those described at 2, 4 and 6 months.

Acute allergic reactions have been reported after diphtheria, tetanus and/or pertussis vaccines. Manifestations include dyspnoea, cyanosis, urticaria, angioneurotic oedema, hypotension and, rarely, anaphylaxis.

A persistent nodule at the site of vaccination may occur with all adsorbed vaccines, particularly if administered into the superficial layers of the subcutaneous tissue. Rarely aseptic abscesses have been reported.

Oedematous reaction affecting one or both lower limbs may occur following vaccination with Haemophilus Influenza type b containing vaccines. If this reaction occurs, it does so mainly after primary injections and is observed within the first few hours following vaccination. Associated symptoms may include cyanosis, redness, transient purpura and severe crying. All events resolve spontaneously without sequelae within 24 hours.

Data from Post Marketing Surveillance

Based on spontaneous reporting, the following additional adverse events have been reported during the commercial use of PEDIACEL. These events have been very rarely reported (<0.01%); however, the exact incidence rates cannot precisely be calculated.

Nervous system disorders

Afebrile convulsions.

General disorders and administration site conditions

Pallor

Somnolence

Additional Information on Special Populations

Apnoea in very premature infants (28 weeks of gestation). (See section 4.4.)

Since PEDIACEL is presented in single dose vials, it is very unlikely that overdose might occur.

Therapeutic classification: Bacterial and viral vaccines combined, ATC codes J07CA02 and J07AG01.

Immunogenicity

Antibody responses at one month after completion of a primary series of PEDIACEL given at 2, 4 and 6 months to 339 infants are summarised in the table below.

^†GMT Geometric mean titre; PT Pertussis toxoid; FHA Filamentous haemagglutinin

^‡PRP Polyribosyl Ribitol Phosphate

Antibody responses were also assessed one month after completion of a primary series of PEDIACEL, administered concomitantly with meningococcal group C conjugate vaccine, given at 2, 3 and 4 months to 121 infants. Serological responses were generally similar to those summarised above and to those seen in the comparator group who received diphtheria, tetanus, whole cell pertussis and PRP-T Hib combination vaccine and oral polio vaccine. These data are summarised in the table below.

^† Meningococcal group C tetanus toxoid conjugate vaccine

^‡ Meningococcal group C CRM₁₉₇ conjugate vaccine

^§ Vaccine studied was Act-HIB^® DTP

Concomitant administration of meningococcal group C conjugate vaccine influenced the response to the PRP-T Hib component of PEDIACEL, dependent upon the type of conjugate protein. The Hib response in infants who received PEDIACEL and concomitant meningococcal group C tetanus conjugate vaccine was comparable to that observed in the whole cell pertussis comparator group. The mean anti-PRP antibody levels were 3.67 μg/mL and 4.01 μg/mL, respectively, with 98.1% and 100% achieving a level 0.15 μg/mL. However, Hib antibody levels were lower in infants who received PEDIACEL and a concomitant meningococcal group C CRM₁₉₇ conjugate vaccine (mean anti-PRP antibody level of 1.26 μg/mL with 88.0% achieving a level 0.15 μg/mL). Hib antibody levels were also lower in infants who received the whole cell pertussis comparator and concomitant meningococcal group C CRM₁₉₇ conjugate vaccine (mean anti-PRP antibody level of 2.57 μg/mL) compared to those who received concomitant meningococcal group C tetanus conjugate vaccine (GMT 4.01 μg/mL).

The type of meningococcal conjugate vaccine also affected responses to the diphtheria and tetanus components of PEDIACEL. Anti-diphtheria responses were higher when a meningococcal group C CRM₁₉₇ conjugate was co-administered with PEDIACEL and anti-tetanus responses were higher when a meningococcal group C tetanus toxoid conjugate was co-administered. However, responses to both these antigens were satisfactory regardless of the type of meningococcal group C conjugate that was given.

Concomitant administration of PEDIACEL and meningococcal group C conjugate vaccine also influenced the meningococcal group C SBA GMTs, dependent upon the type of conjugate protein. However, the seroprotection rates were unaffected, remaining at 98-100%. The antibody levels in infants who received PEDIACEL and concomitant meningococcal group C CRM₁₉₇ conjugate vaccine were comparable to those observed in the whole cell pertussis comparator group. Meningococcal group C antibody levels were lower in infants receiving PEDIACEL and concomitant meningococcal group C tetanus conjugate vaccine compared to those receiving PEDIACEL and concomitant meningococcal group C CRM₁₉₇ conjugate vaccine (SBA GMTs of 690 and 2165 respectively).

When PEDIACEL was administered to children in the second year of life who had completed a primary immunisation series with all antigens, an anamnestic response was observed for all antigens. The interval between the completion of the primary series and the booster was not less than 10 months.

Efficacy

The efficacy of the acellular pertussis component of PEDIACEL was assessed when given in combination with the diphtheria and tetanus toxoids to more than 18,000 Swedish infants at 3, 5 and 12 months. The acellular pertussis component of PEDIACEL demonstrated protective efficacy similar to a whole cell DTP vaccine with regard to protection against mild (culture-confirmed pertussis with or without cough) or serious (culture-confirmed pertussis with paroxysmal cough for 21 days) pertussis disease.

Immunogenicity data were obtained from 80 out of another 2,500 infants who were given the acellular pertussis component of PEDIACEL at 2, 4 and 6 months in this study, and were compared with data from 58 infants immunised at 3, 5 and 12 months. The GMTs at one month after the third dose of each regimen were generally comparable for antibody to each of PT, FHA, pertactin and fimbrial agglutinogens.

GMTs seen in response to pertussis components in the same amounts as in PEDIACEL were also found to be generally comparable with those recorded in a previous Swedish study, in which the same antigens (but with a lower dose of PT and FHA) were shown to be efficacious.

These data have also been compared with GMTs obtained after administration of three doses of PEDIACEL to Canadian infants at 2, 4 and 6 months and found to be of the same order. Therefore, an extrapolation from the efficacy of the pertussis component in the Swedish trials appears to be supported.

Not applicable.

Limited pre-clinical testing of PEDIACEL and closely related products, mainly single dose rodent toxicity studies, revealed no special hazards for human health in addition to those identified in controlled clinical trials.

Aluminium phosphate

2-phenoxyethanol

Polysorbate 80

Water for Injections

The vaccine should not be mixed with other vaccines or parenterally administered substances.

48 months.

Store between +2°C and +8°C. Do not freeze; vaccine which has been frozen must not be used.

PEDIACEL is supplied in a Type I (Ph. Eur.) glass tubing vial with bromobutyl stopper (latex free).

Available in unit packs of one vial or packs of 10 vials.

Not all pack sizes may be marketed.

The vaccine should be used as supplied; no dilution or reconstitution is necessary.

Shake well immediately before use.

Parenteral drug products should be inspected visually for extraneous particulate matter and discolouration prior to administration.

It is important to use a separate sterile syringe and needle for each individual to prevent transmission of infections from one person to another.

Sanofi Pasteur MSD Ltd

Mallards Reach

Bridge Avenue

Maidenhead

Berkshire, SL6 1QP

UK

PL 06745/0120

16-10-2002 / 15-10-2007

06-2008