Menitorix – Powder and solvent for solution for injection

Haemophilus type b and Meningococcal group C conjugate vaccine

After reconstitution, each 0.5 ml dose contains:

Haemophilus type b polysaccharide

Excipients:

This product contains sodium 75 micromol per dose (see section 4.4)

For a full list of excipients, see section 6.1.

Powder and solvent for solution for injection

White powder and a clear colourless solvent.

Active immunization of infants from the age of 2 months and toddlers up to the age of 2 years for the prevention of invasive diseases caused by Haemophilus influenzae type b (Hib) and Neisseria meningitidis group C (MenC).

See also section 4.4.

Posology

Primary vaccination in infants from 2 months up to 12 months of age:

Three doses, each of 0.5 ml, should be given with an interval of at least 1 month between doses.

There are no data on the use of Menitorix for one or two doses of the primary vaccination course and other Hib and/or MenC conjugate vaccines for other dose(s). It is recommended that infants who receive Menitorix for the first dose should also receive this vaccine for the second and third doses of the primary vaccination course.

Booster vaccination:

After primary vaccination in infancy, booster doses of Hib and MenC must be administered. In children who received an acellular pertussis combination vaccine containing Hib in the primary infant immunisation series the Hib booster dose should be given before the age of 2 years.

A single (0.5 ml) dose of Menitorix may be used to boost immunity to Hib and MenC in children who have previously completed a primary immunisation series with Menitorix or with other Hib or MenC conjugate vaccines (see section 5.1). The timing of the booster dose should be in accordance with available official recommendations and should usually be from the age of 12 months onwards and before the age of 2 years.

Menitorix is not recommended for use in children above 2 years of age due to lack of data on safety and efficacy.

Method of administration

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Menitorix should be given by intramuscular injection only, preferably in the anterolateral thigh region. In children 12 to 24 months of age, the vaccine may be administered in the deltoid region. (see also sections 4.4 and 4.5)

Menitorix should under no circumstances be administered intravascularly, intradermally or subcutaneously.

Hypersensitivity to the active substances, including tetanus toxoid, or to any of the excipients (see sections 2 and 6.1).

Hypersensitivity reaction after previous administration of Menitorix.

Acute severe febrile illness. The presence of a minor infection is not a contraindication for vaccination.

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of a rare anaphylactic event following the administration of the vaccine.

Vaccination should be preceded by a review of the medical history (especially with regard to previous vaccination and possible occurrence of undesirable events) and a clinical examination.

The vaccine should be given with caution to individuals with thrombocytopenia or any coagulation disorder. No data are available on subcutaneous administration of Menitorix, therefore the possibility of any toxicity or reduced efficacy that might occur with this route of administration is unknown.

Menitorix will only confer protection against Haemophilus influenzae type b and Neisseria meningitidis group C. As for any vaccine, Menitorix may not completely protect against the infections it is intended to prevent in every vaccinated individual. There are no data available on administration of Menitorix in toddlers not already primed with Hib and MenC conjugates.

No data are available on the use of Menitorix in immunodeficient subjects. In individuals with impaired immune responsiveness (whether due to the use of immunosuppressive therapy, a genetic defect, human immunodeficiency virus (HIV) infection, or other causes) a protective immune response to Hib and MenC conjugate vaccines may not be obtained. Individuals with complement deficiencies and individuals with functional or anatomical asplenia may mount an immune response to Hib and MenC conjugate vaccines; however the degree of protection that would be afforded is unknown.

There are no data available on the use of Menitorix in infants who were born prematurely. Therefore the degree of protection that would be afforded is unknown.

Although symptoms of meningism such as neck pain/stiffness or photophobia have been reported following administration of other MenC conjugate vaccines, there is no evidence that MenC conjugate vaccines cause meningitis. Clinical alertness to the possibility of co-incidental meningitis should be maintained.

The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be considered when administering the primary immunisation 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 the vaccination is high in this group of infants, vaccination should not be withheld or delayed.

Immunisation with this vaccine does not substitute for routine tetanus immunisation.

Since Hib capsular polysaccharide antigen is excreted in the urine, a positive urine antigen test can be observed within 1-2 weeks following vaccination. Other diagnostic tests, not based on the detection of the capsular antigen in urine, should be used to confirm Hib disease during this period.

The solvent of the vaccine contains less than 1mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

Menitorix must not be mixed with any other vaccine in the same syringe.

Different injectable vaccines should always be given at different injection sites.

In various studies with licensed monovalent meningococcal group C conjugate vaccines, concomitant administration with combinations containing diphtheria, tetanus and acellular pertussis components (with or without inactivated polio viruses, hepatitis B surface antigen or Hib conjugate [e.g. DTPa-HBV-IPV-Hib*]), has been shown to result in lower serum bactericidal antibody (SBA) geometric mean titres (GMT) compared to separate administrations or to co-administration with whole cell pertussis vaccines. The proportions reaching SBA titres of at least 1:8 are not affected. At present, the potential implications of these observations for the duration of protection are not known.

In clinical trials of primary vaccination series, Menitorix was administered concomitantly (into opposite thighs) with a DTPa-HBV-IPV vaccine. Responses to all the co-administered antigens were satisfactory and were similar to those achieved in control groups that received DTPa-HBV-IPV-Hib* concomitantly with a MenC conjugate vaccine (MenCC) or DTPa-HBV-IPV* concomitantly with a Hib conjugate vaccine and no MenCC. The immune response to the Hib and MenC components of Menitorix was only assessed in primary vaccination clinical studies that employed co-administration with DTPa-IPV* or DTPa-HBV-IPV* vaccines.

In a trial of primary vaccination, concomitant administration of an investigational vaccine containing the same amount of conjugated Hib and MenC saccharides as in Menitorix with DTPa-HBV-IPV* and a licensed pneumococcal saccharide conjugated vaccine (the three injections were made into anatomically distant sites) gave similar immune responses to the seven pneumococcal serotypes as achieved in a group that received DTPa-HBV-IPV* concomitantly with Hib (conjugated to tetanus toxoid) and a licensed pneumococcal saccharide conjugated vaccine.

There are no data on concomitant use of Menitorix with whole cell pertussis and oral poliomyelitis vaccines, however, no interference is expected.

In a trial of booster vaccination against Hib and MenC, Menitorix was administered concomitantly (into opposite thighs) with a first dose of combined measles, mumps and rubella (MMR) vaccine. Compared to the two control groups that received either Menitorix or MMR alone the immune responses to the antigens in both vaccines were not affected by concomitant administration. See sections 4.8 and 5.1.

*GlaxoSmithKline combination vaccine

Menitorix is not intended for use in adults. Information on the safety of the vaccine when used during pregnancy or lactation is not available.

Not relevant.

• Clinical trials

In clinical trials, Menitorix has been administered as a 3-dose primary series (N=1,171) or as a booster (N=991) dose. When Menitorix was administered as a 3-dose primary vaccination course, a DTPa-HBV-IPV* vaccine (N=796) or a DTPa-IPV* vaccine (N=375) was administered concomitantly.

Adverse reactions occurring during these studies were mostly reported within 48 hours following vaccination.

In two clinical trials (N=578), Menitorix was administered concomitantly with Measles, Mumps, Rubella (MMR) vaccine. In one of these trials, the incidences of adverse reactions observed in subjects (N=102) who received Menitorix concomitantly with MMR* were similar to those observed in the group who received MMR alone (N=91) or Menitorix alone (N=104). (see sections 4.5 and 5.1)

Adverse reactions considered as being at least possibly related to vaccination have been categorised by frequency as follows.

Very common (>1/10)

Common (>1/100, <1/10)

Uncommon (>1/1,000, <1/100)

Rare (>1/10,000, <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Psychiatric disorders:

very common: irritability

uncommon: crying

Nervous system disorders:

very common: drowsiness

Gastrointestinal disorders:

very common: appetite lost

uncommon: diarrhoea, vomiting

Skin and subcutaneous tissue disorders:

uncommon: dermatitis atopic

rare: rash

General disorders and administration site conditions:

very common: fever (rectal 38°C), swelling, pain, redness

common: injection site reaction

uncommon: fever (rectal > 39.5°C), malaise

• Post-marketing experience

The following adverse events have been reported after administration of Menitorix:

Blood and lymphatic system disorders:

Lymphadenopathy

Immune system disorders:

Allergic reactions (including urticaria and anaphylactoid reactions)

Nervous system disorders:

Febrile seizures, hypotonia, headache, dizziness

Respiratory, thoracic and mediastinal disorders:

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

• Other possible side effects:

The following have not been reported in association with administration of Menitorix but have occurred very rarely during routine use of licensed meningococcal group C conjugate vaccines:

Severe skin reactions), collapse or shock-like state (hypotonic-hyporesponsiveness episode), faints, seizures in patients with pre-existing seizure disorders, hypoaesthesia, paraesthesia, relapse of nephrotic syndrome, arthralgia, petechiae and/or purpura.

*GlaxoSmithKline combination vaccine

No case of overdose has been reported.

Pharmacotherapeutic group: bacterial vaccines ATC code: J07AG53

Antibody against Haemophilus influenzae type b (anti- polyribosylribitol phosphate [anti-PRP]) was measured with an enzyme-linked immunosorbent assay (ELISA). Antibody against Neisseria meningitidis serogroup C was measured by a serum bactericidal activity assay using rabbit complement (rSBA-MenC).

Primary vaccination course

Clinical trials have evaluated the antibody responses at one month after two doses and after completion of a 3-dose primary vaccination course of Menitorix (co-administered with DTPa-HBV-IPV or DTPa-IPV vaccines) given at approximately 2, 3, 4 months or 2, 4, 6 months to 814 infants.

Percentages of subjects with antibody titres assay cut-off one month after primary vaccination with Menitorix co-administered with GlaxoSmithKline combined DTPa-IPV or DTPa-HBV-IPV vaccines were as follows:

N= number of subjects with available results

%= percentage of subjects with titres equal to or above the cut-off

GMC or GMT= geometric mean antibody concentration or titre

†= subjects 18 weeks of age at time of third Menitorix dose

N= number of subjects with available results

%= percentage of subjects with titres equal to or above the cut-off

GMC or GMT= geometric mean antibody concentration or titre

Booster vaccination

Immune responses to a booster dose of Menitorix may vary according to the vaccines used for the primary series. It is not known if the differences that have been observed are of any clinical significance. See also below regarding antibody persistence after booster doses.

In four clinical studies, antibody responses were evaluated one month after a booster vaccination with Menitorix in children who had received three doses of Menitorix, Menjugate or Meningitec or two doses of NeisVac-C in infancy. The rSBA-MenC immune response to a booster dose of Menitorix was lower after a three-dose course of a MenC-CRM197 conjugate vaccine in infancy (i.e. Menjugate or Meningitec) compared to administration of a MenC-TT conjugate vaccine in infancy (i.e. two doses of NeisVac-C or three doses of Menitorix). It should be noted that immune responses to a booster dose of Menitorix after administration of two doses of a MenC-CRM197 vaccine in infancy have not been documented and that responses may differ from the data shown in the table.

Percentages of subjects with antibody titres assay cut-off one month after booster vaccination with Menitorix administered alone or co-administered with GlaxoSmithKline combined DTPa-HBV-IPV vaccine were as follows:

N= number of subjects with available results

GMC or GMT= geometric mean antibody concentration or titre

%= percentage of subjects with titres equal to or above the cut-off

*= co-administered with GlaxoSmithKline combined DTPa-HBV-IPV

**= co-administered with DTPa-Hib containing vaccines

All subjects received Hib-TT containing vaccine.

In two clinical studies, the antibody responses were also evaluated one month after a booster vaccination with Menitorix co-administered with measles-mumps-rubella vaccine in subjects primed with Menitorix or Meningitec or Menjugate.

Percentages of subjects with antibody titres assay cut-off one month after booster vaccination with Menitorix co-administered with measles-mumps-rubella GlaxoSmithKline combined vaccine (MMR) were as follows:

N= number of subjects with available results

GMC or GMT= geometric mean antibody concentration or titre

%= percentage of subjects with titres equal to or above the cut-off

*= co-administered with GlaxoSmithKline combined DTPa-IPV vaccines

**= co-administered with DTPa-Hib-TT containing vaccines

Antibody persistence

Antibody persistence without a booster dose:

Antibody persistence has been demonstrated for Hib in three clinical trials (N=217) with 98.2% of subjects having an anti-PRP concentration of 0.15 micrograms/ml at 11-18 months of age i.e. at 7-14 months following completion of a 3-dose primary series with Menitorix.

In three clinical trials (N=209), 92.3% of subjects had an SBA-MenC titre 1/8 at 11–18 months of age, i.e. at 7-14 months following completion of a 3-dose primary series with Menitorix. All subjects responded immunologically to a challenge dose of 10 µg of unconjugated group C meningococcal polysaccharide with a thirty-three-fold increase in SBA titres demonstrating the immune memory induced by the primary vaccination course.

Antibody persistence after a booster dose:

Antibody persistence was evaluated in subjects primed either with Menitorix or with co-administration of licensed meningococcal C conjugate and Hib containing vaccines and boosted with Menitorix.

In a first study, the antibody responses were evaluated in subjects primed either with Menitorix or with Meningitec both given as a three dose primary schedule and boosted with Menitorix.

The results in the comparator group may not predict what would be seen with a 2 dose primary schedule of Meningitec followed by a booster dose of Menitorix.

The antibody responses at month 1 post-booster and at the Month 12 and Month 24 post-booster persistence time-points were as follows:

N= number of subjects with available results

GMC or GMT= geometric mean antibody concentration or titre

%= percentage of subjects with titres equal to or above the cut-off

¹ co-administered with GlaxoSmithKline combined DTPa-IPV

² co-administered with DTPa-IPV/Hib-TT

³ co-administered with GlaxoSmithKline combined MMR

In another study, the subjects were primed either with 3 doses of Menitorix or with 2 doses of Neis Vac-C. All subjects were boosted with Menitorix.

The antibody responses at the Month 18, Month 30 and Month 42 post-booster persistence time-points were as follows:

N= number of subjects with available results

GMC or GMT= geometric mean antibody concentration or titre

%= percentage of subjects with titres equal to or above the cut-off

¹ co-administered with GlaxoSmithKline combined DTPa-HBV-IPV

² co-administered with DTPa-HBV-IPV/Hib-TT (2, 4, 6 months) or with DTPa-HBV-IPV/Hib-TT (2, 6 months) and DTPa-IPV/Hib-TT (4 months) (GlaxoSmithKline combined vaccines)

Post-marketing surveillance following an immunisation campaign in the UK

Estimates of vaccine effectiveness from the UK's routine immunisation programme (using various quantities of three meningococcal group C conjugate vaccines) covering the period from introduction at the end of 1999 to March 2004 demonstrated the need for a booster dose after completion of the primary series (three doses administered at 2, 3 and 4 months). Within one year of completion of the primary series, vaccine effectiveness in the infant cohort was estimated at 93% (95% confidence intervals 67-99). However, more than one year after completion of the primary series, there was clear evidence of waning protection.

Up to 2007, the overall estimates of effectiveness in age cohorts from 1-18 years that received a single dose of meningococcal group C conjugate vaccine during the initial catch-up vaccination programme in the UK fall between 83 and 100%. The data show no significant fall in effectiveness within these age cohorts when comparing time periods less than a year or one year or more since immunisation.

Evaluation of pharmacokinetic properties is not required for vaccines.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and single and repeated dose toxicity studies.

Powder:

Trometamol

Sucrose

Solvent:

Sodium chloride

Water for injections

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

3 years.

After reconstitution, the vaccine should be administered promptly or kept in the refrigerator (2°C – 8°C). If it is not used within 24 hours, it should be discarded.

Experimental data show that the reconstituted vaccine could also be kept to 24 hours at ambient temperature (25°C). If it is not used within 24 hours, it should be discarded.

Store in a refrigerator (2°C – 8°C).

Do not freeze

Store in the original package in order to protect from light.

For storage conditions of the reconstituted medicinal product, see section 6.3.

Powder in a vial (type I glass) with a stopper (butyl rubber),

0.5 ml of solvent in a pre-filled syringe (type I glass) with a plunger stopper (butyl rubber) with or without separate needles in the following pack sizes:

- pack size of 1 vial of powder plus 1 pre-filled syringe of solvent with 2 separate needles or without needles

- pack size of 10 vials of powder plus 10 pre-filled syringes of solvent with 20 separate needles or without needles

Not all pack sizes may be marketed.

The reconstituted vaccine should be inspected visually for any foreign particulate matter and/or variation of physical aspect prior to administration. In the event of either being observed, discard the vaccine.

The vaccine must be reconstituted by adding the entire contents of the pre-filled syringe of solvent to the vial containing the powder. After the addition of the solvent, the mixture should be well shaken until the powder is completely dissolved in the solvent.

The reconstituted vaccine is a clear and colourless solution. Inject the entire contents of the vial.

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

SmithKline Beecham plc

Trading as:

GlaxoSmithKline UK

Stockley Park West, Uxbridge

Middlesex, UB11 1BT

PL 10592/0217

19 December 2005

19 December 2010