4.1. Therapeutic indications

Bexsero is indicated for active immunisation of individuals from 2 months of age and older against invasive meningococcal disease caused by Neisseria meningitidis group B. The impact of invasive disease in different age groups as well as the variability of antigen epidemiology for group B strains in different geographical areas should be considered when vaccinating. See section 5.1 for information on protection against specific group B strains. The use of this vaccine should be in accordance with official recommendations.

4.2. Posology and method of administration

Posology

Table 1. Summary of posology

Age at first dose

Primary Immunisation

Intervals between Primary Doses

Booster

Infants, 2 months to 5 months a

Three doses each of 0.5 ml

Not less than 1 month

Yes, one dose between 12 and 15 months of age with an interval of at least 6 months between the primary series and booster dose b, c

Two doses each of 0.5 ml

Not less than 2 months

Infants, 6 months to 11 months

Two doses each of 0.5 ml

Not less than 2 months

Yes, one dose in the second year of life with an interval of at least 2 months between the primary series and booster dose c

Children, 12 months to 23 months

Two doses each of 0.5 ml

Not less than 2 months

Yes, one dose with an interval of 12 months to 23 months between the primary series and booster dose c

Children, 2 years to 10 years

Two doses each of 0.5 ml

Not less than 1 month

A booster dose should be considered in individuals at continued risk of exposure to meningococcal disease, based on official recommendations d

Adolescents (from 11 years) and adults*

a The first dose should be given no earlier than 2 months of age. The safety and efficacy of Bexsero in infants less than 8 weeks of age has not yet been established. No data are available.

b In case of delay, the booster should not be given later than 24 months of age.

c See section 5.1. The need for and timing of further booster doses has not yet been determined.

d See section 5.1.

* There are no data in adults above 50 years of age.

Method of administration

The vaccine is given by deep intramuscular injection, preferably in the anterolateral aspect of the thigh in infants or in the deltoid muscle region of the upper arm in older subjects.

Separate injection sites must be used if more than one vaccine is administered at the same time.

The vaccine must not be injected intravenously, subcutaneously or intradermally and must not be mixed with other vaccines in the same syringe.

For instructions on the handling of the vaccine before administration, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

As with other vaccines, administration of Bexsero should be postponed in subjects suffering from an acute severe febrile illness. However, the presence of a minor infection, such as cold, should not result in the deferral of vaccination.

Do not inject intravascularly.

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

Anxiety-related reactions, including vasovagal reactions (syncope), hyperventilation or stress-related reactions may occur in association with vaccination as a psychogenic response to the needle injection (see section 4.8). It is important that procedures are in place to avoid injury from fainting.

This vaccine should not be given to individuals with thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection, unless the potential benefit clearly outweighs the risk of administration.

As with any vaccine, vaccination with Bexsero may not protect all vaccine recipients.

Bexsero is not expected to provide protection against all circulating meningococcal group B strains (see section 5.1).

As with many vaccines, healthcare professionals should be aware that a temperature elevation may occur following vaccination of infants and children (less than 2 years of age). Prophylactic administration of antipyretics at the time of and closely after vaccination can reduce the incidence and intensity of post-vaccination febrile reactions. Antipyretic medication should be initiated according to local guidelines in infants and children (less than 2 years of age).

Individuals with impaired immune responsiveness, whether due to the use of immunosuppressive therapy, a genetic disorder, or other causes, may have reduced antibody response to active immunisation.

Immunogenicity data are available in individuals with complement deficiencies, asplenia, or splenic dysfunctions (see section 5.1).

Individuals with familial complement deficiencies (for example, C3 or C5 deficiencies) and individuals receiving treatments that inhibit terminal complement activation (for example, eculizumab) are at increased risk for invasive disease caused by Neisseria meningitidis group B, even if they develop antibodies following vaccination with Bexsero.

There are no data on the use of Bexsero in subjects above 50 years of age and limited data in patients with chronic medical conditions.

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

Kanamycin is used in early manufacturing process and is removed during the later stages of manufacture. If present, kanamycin levels in the final vaccine are less than 0.01 micrograms per dose.

The safe use of Bexsero in kanamycin-sensitive individuals has not been established.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

Use with other vaccines

Bexsero can be given concomitantly with any of the following vaccine antigens, either as monovalent or as combination vaccines: diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b, inactivated poliomyelitis, hepatitis B, heptavalent pneumococcal conjugate, measles, mumps, rubella, varicella, and meningococcal groups A, C, W, Y conjugate.

Clinical studies demonstrated that the immune responses of the co-administered routine vaccines were unaffected by concomitant administration of Bexsero, based on non-inferior antibody response rates to the routine vaccines given alone. Inconsistent results were seen across studies for responses to inactivated poliovirus type 2 and pneumococcal conjugate serotype 6B and lower antibody titers to the pertussis pertactin antigen were also noted, but these data do not suggest clinically significant interference.

Due to an increased risk of fever, tenderness at the injection site, change in eating habits and irritability when Bexsero was co-administered with the above vaccines, separate vaccinations can be considered when possible. Prophylactic use of paracetamol reduces the incidence and severity of fever without affecting the immunogenicity of either Bexsero or routine vaccines. The effect of antipyretics other than paracetamol on the immune response has not been studied.

Concomitant administration of Bexsero with vaccines other than those mentioned above has not been studied.

When given concomitantly with other vaccines Bexsero must be administered at separate injection sites (see section 4.2).

4.6. Fertility, pregnancy and lactation

Pregnancy

Insufficient clinical data on exposed pregnancies are available.

The potential risk for pregnant women is unknown. Nevertheless, vaccination should not be withheld when there is a clear risk of exposure to meningococcal infection.

There was no evidence of maternal or foetal toxicity, and no effects on pregnancy, maternal behaviour, female fertility, or postnatal development in a study in which female rabbits received Bexsero at approximately 10 times the human dose equivalent based on body weights.

Breast-feeding

Information on the safety of the vaccine to women and their children during breast-feeding is not available. The benefit-risk ratio must be examined before making the decision to immunise during breast-feeding.

No adverse reactions were seen in vaccinated maternal rabbits or in their offspring through day 29 of lactation. Bexsero was immunogenic in maternal animals vaccinated prior to lactation, and antibodies were detected in the offspring, but antibody levels in milk were not determined.

Fertility

There are no data on fertility in humans.

There were no effects on female fertility in animal studies.

4.7. Effects on ability to drive and use machines

Bexsero has no or negligible influence on the ability to drive and use machines. However, some of the effects mentioned under section 4.8 “Undesirable effects” may temporarily affect the ability to drive or use machines.

4.8. Undesirable effects

Summary of the safety profile

The safety of Bexsero was evaluated in 17 studies including 10 randomised controlled clinical trials with 10 565 subjects (from 2 months of age) who received at least one dose of Bexsero. Among Bexsero recipients, 6 837 were infants and children (less than 2 years of age), 1 051 were children (2 to 10 years of age) and 2 677 were adolescents and adults. Of the subjects who received primary infant series of Bexsero, 3 285 received a booster dose in the second year of life.

In infants and children (less than 2 years of age) the most common local and systemic adverse reactions observed in clinical trials were tenderness and erythema at the injection site, fever and irritability.

In clinical studies in infants vaccinated at 2, 4 and 6 months of age, fever (≥ 38 °C) was reported by 69% to 79% of subjects when Bexsero was co-administered with routine vaccines (containing the following antigens: pneumococcal 7-valent conjugate, diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b) compared with 44% to 59% of subjects receiving the routine vaccines alone. Higher rates of antipyretic use were also reported for infants vaccinated with Bexsero and routine vaccines. When Bexsero was given alone, the frequency of fever was similar to that associated with routine infant vaccines administered during clinical trials. When fever occurred, it generally followed a predictable pattern, with the majority resolving by the day after vaccination.

In adolescents and adults, the most common local and systemic adverse reactions observed were pain at the injection site, malaise and headache.

No increase in the incidence or severity of the adverse reactions was seen with subsequent doses of the vaccination series.

Tabulated list of adverse reactions

Adverse reactions (following primary immunisation or booster dose) considered as being at least possibly related to vaccination have been categorised by frequency.

Frequencies are defined as follows:

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)

(cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

In addition to reports in clinical trials, worldwide voluntary reports of adverse reactions received for Bexsero since market introduction are included in the list. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency and they are consequently listed with the frequency unknown.

Infants and children (up to 10 years of age)

Blood and lymphatic system disorders

Not known: lymphadenopathy

Immune system disorders

Not known: allergic reactions (including anaphylactic reactions)

Metabolism and nutrition disorders

Very common: eating disorders

Nervous system disorders

Very common: sleepiness, unusual crying, headache

Uncommon: seizures (including febrile seizures)

Not known: hypotonic-hyporesponsive episode, meningeal irritation (signs of meningeal irritation, such as neck stiffness or photophobia, have been sporadically reported shortly after vaccination. These symptoms have been of mild and transient nature)

Vascular disorders

Uncommon: pallor (rare after booster)

Rare: Kawasaki syndrome

Gastrointestinal disorders

Very common: diarrhoea, vomiting (uncommon after booster)

Skin and subcutaneous tissue disorders

Very common: rash (children aged 12 to 23 months) (uncommon after booster)

Common: rash (infants and children 2 to 10 years of age)

Uncommon: eczema

Rare: urticaria

Musculoskeletal and connective tissue disorders

Very common: arthralgia

General disorders and administration site conditions

Very common: fever (≥ 38 °C), injection site tenderness (including severe injection site tenderness defined as crying when injected limb is moved), injection site erythema, injection site swelling, injection site induration, irritability

Uncommon: fever (≥ 40 °C)

Not known: injection site reactions (including extensive swelling of the vaccinated limb, blisters at or around the injection site and injection site nodule which may persist for more than one month)

Adolescents (from 11 years of age) and adults

Blood and lymphatic system disorders

Not known: lymphadenopathy

Immune system disorders

Not known: allergic reactions (including anaphylactic reactions)

Nervous system disorders

Very common: headache

Not known: syncope or vasovagal responses to injection, meningeal irritation (signs of meningeal irritation, such as neck stiffness or photophobia, have been sporadically reported shortly after vaccination. These symptoms have been of mild and transient nature)

Gastrointestinal disorders

Very common: nausea

Skin and subcutaneous tissue disorders

Not known: rash

Musculoskeletal and connective tissue disorders

Very common: myalgia, arthralgia

General disorders and administration site conditions

Very common: injection site pain (including severe injection site pain defined as unable to perform normal daily activity), injection site swelling, injection site induration, injection site erythema, malaise

Not known: fever, injection site reactions (including extensive swelling of the vaccinated limb, blisters at or around the injection site and injection site nodule which may persist for more than one month)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Experience of overdose is limited. In the event of overdose, monitoring of vital functions and possible symptomatic treatment is recommended.