Consumer medicine information

Bexsero

Meningococcal group B multicomponent vaccine

BRAND INFORMATION

Brand name

Bexsero

Active ingredient

Meningococcal group B multicomponent vaccine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bexsero.

What is in this leaflet

Read all of this leaflet carefully before you are vaccinated.

This leaflet answers some common questions about BEXSERO.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up-to-date information on the medicine. You can also download the most up-to-date leaflet from http://www.ebs.tga.gov.au/. Those updates may contain important information about the medicine and its use of which you should be aware.

All medicines, including vaccines, have risks and benefits. Your doctor has weighed the risks of you or your child having BEXSERO against the benefits they expect it will have for you.

If you have any concerns about this medicine, ask your doctor, nurse or pharmacist.

Keep this leaflet. You may need to read it again.

What BEXSERO is used for

BEXSERO is a meningococcal group B vaccine.

BEXSERO is given to individuals from 2 months of age and older to help protect against disease caused by bacteria called Neisseria meningitidis group B. These bacteria can cause serious, and sometimes life-threatening, infections such as meningitis (inflammation of the covering of the brain and spinal cord) and sepsis (blood poisoning).

The vaccine works by specifically stimulating the body's natural defense system of the vaccinated person. This results in protection against this disease.

The use of this vaccine should be in accordance with the official recommendations.

Please note that BEXSERO can only protect you or your child from meningitis caused by Neisseria meningitidis group B.

BEXSERO is not expected to provide protection against all circulating meningococcal group B types.

How BEXSERO works

BEXSERO works by causing you or your child's body to produce its own protection (or antibodies), against the meningococcal group B bacteria. Your or your child's body usually takes a couple of weeks after vaccination to develop protection against Neisseria meningitidis group B.

If a vaccinated person comes into contact with Neisseria meningitidis group B, the body is usually able to destroy it. However, as with all vaccines, 100% protection cannot be guaranteed.

As with all vaccines, occasionally, individuals may react unfavourably to the vaccine.

The chance of a severe reaction from BEXSERO is very small, but the risks from not being vaccinated against meningococcal disease may be very serious.

BEXSERO should not be given to a person who has:

  • allergy (hypersensitivity) to the active substances or any of the other ingredients of BEXSERO listed at the end of this leaflet. Signs of an allergic reaction may include:
    - shortness of breath, wheezing or difficulty breathing,
    - swelling of the face, lips, tongue or other parts of the body,
    - skin rash, itching or hives

In addition, BEXSERO should not be administered if:

  • the expiry date printed on the pack has passed
  • the packaging is torn or shows signs of tampering.

If you are not sure whether you or your child should have BEXSERO, talk to your doctor, nurse or pharmacist.

Before you or your child receives BEXSERO

Tell your doctor or pharmacist if you have/your child has allergies to:

  • active substances or any of the other ingredients of BEXSERO
  • the antibiotic kanamycin. If present, the kanamycin level in the vaccine is low
  • latex. Although no natural rubber latex is detected in the syringe tip cap, the safe use of BEXSERO in latex-sensitive individuals has not been established.

Tell your doctor if in the past you or your child have/has reacted to any vaccination with any of the following:

  • severe allergic reaction
  • difficulty breathing
  • swelling of the throat

Tell your doctor if you have/your child has a severe infection with a high temperature. If this is the case, then vaccination will be postponed. The presence of a minor infection, such as a cold, should not require postponement of the vaccination, but talk to your doctor first.

Tell your doctor if you receive treatment that blocks the part of the immune system known as complement activation, such as eculizumab. Even if you have been vaccinated with BEXSERO you remain at increased risk of disease caused by the Neisseria meningitidis group B bacteria.

If your child was born prematurely (before or at 28 weeks of pregnancy), particularly if they had breathing difficulties, please tell your doctor. Stopping breathing or irregular breathing for a short time may be more common in the first three days following vaccination in these babies and they may need special monitoring.

Fainting, feeling faint or other stress-related reactions can occur as a response to any needle injection.

Tell your doctor or nurse if you have experienced this kind of reaction previously

Tell your doctor if you or your child have or have had any medical conditions especially the following:

  • an immune deficiency condition. Little is known about the effectiveness of BEXSERO when administered to individuals with weakened immunity due to the use of immunosuppressive medications, or HIV infection, or hereditary defects of the body's natural defence system. It is possible the effectiveness of BEXSERO could be reduced in such individuals.

The safety and efficacy of BEXSERO in adults above 50 years of age have not been established. There are limited data on the use in patients with chronic medical conditions.

Tell your doctor if you are pregnant or intend to become pregnant soon. Your doctor will discuss the possible risks and benefits of receiving BEXSERO vaccine during pregnancy. Your doctor may still recommend that you receive BEXSERO if you are at risk of exposure to meningococcal infection.

Tell your doctor if you are breastfeeding. Your doctor will discuss the possible risks and benefits of receiving BEXSERO vaccine during breastfeeding.

Tell your doctor or pharmacist if you or your child are taking, or have recently taken, any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Having other vaccines

Tell your doctor if you or your child has had any vaccines recently.

BEXSERO may be given at the same time as other vaccinations.

When given at the same time as other vaccines, BEXSERO must be administered at a separate injection site. BEXSERO can be given at the same time as any of the following vaccines components:
diphtheria, tetanus, whooping cough (pertussis), Haemophilus influenzae type b, polio, hepatitis B, pneumococcus, measles, mumps, rubella, chickenpox and meningococcus C.

Your doctor may ask you to give your child medicines that lower fever after BEXSERO has been given. This will help to reduce some of the side effects of BEXSERO.

Your doctor or pharmacist may have more information on medicines and vaccines that require special precautions or should be avoided during vaccination with BEXSERO.

How BEXSERO is given

How it is given

BEXSERO is given as an injection, usually into your or your child's arm or leg muscle.

It is important to follow the instructions from your doctor or nurse so that you or your child completes the course of injections.

If you have any concerns about how this vaccine is to be given, talk to your doctor, nurse or pharmacist.

How much is given

The dose is 0.5 mL given by injection.

You or your child may be given more than one single dose of BEXSERO. Please talk to your doctor, nurse or pharmacist to get more information.

You should keep a record of your/ your child's vaccinations.

Side effects

Tell your doctor or pharmacist as soon as possible if you or your child does not feel well after having BEXSERO.

Like all vaccines, BEXSERO can cause side effects, although not everybody gets them.

When BEXSERO is given to you or your child, the most common side effects that you may get are:

  • pain at the injection site, redness at the injection site, swelling of skin at the injection site, hardness of skin at the injection site, generally feeling unwell, headache, fever (38°C or higher) and feeling irritable.

The following side effects may occur after receiving this vaccine:

Infants, toddlers and children (up to 10 years of age)

Very common:

  • fever (38°C or higher), loss of appetite, tenderness or discomfort to touch at the injection site (including severe tenderness at injection site resulting in crying when injected limb was moved), redness of skin at the injection site, skin rash in toddlers (uncommon after booster), hardness of skin at the injection site, swelling of skin at the injection site, sleepiness, feeling irritable, unusual crying, vomiting (uncommon after booster), diarrhea, headache, painful joints.

Common:

  • skin rash in infants and children aged 2 to 10 years, fever (39.5°C or higher).

The incidence of fever may be decreased by the use of paracetamol. Before you or your child receives vaccination, ask your doctor about the risks of fever and how to treat it, including what to do if fever does not respond to initial treatment.

Uncommon:

  • high fever (40°C or higher), seizures (including febrile seizures due to fever), dry skin, paleness (rare after booster).

Rare:

  • Kawasaki disease which may include symptoms such as fever that lasts for more than five days, associated with a rash on the trunk of the body, and sometimes followed by a peeling of the skin on the hands and fingers, swollen glands in the neck, red eyes, lips, throat and tongue.
  • Itchy rash, skin rash.

Adolescents (from 11 years of age) and Adults

Very common:

  • pain at the injection site (including severe pain at injection site resulting in inability to perform normal daily activity), redness of skin at the injection site, swelling of skin at the injection site, hardness of skin at the injection site, painful muscles and joints, nausea, generally feeling unwell, headache.

Other side effects reported during marketed use include:

  • allergic reactions that may include severe swelling of the lips, mouth, throat (which may cause difficulty in swallowing), difficulty breathing with wheezing or coughing, rash, loss of consciousness and very low blood pressure
  • collapse (sudden onset of muscle floppiness), less responsive than usual or lack of awareness, and paleness or bluish skin discolouration in young children
  • skin rash (adolescents from 11 years of age and adults)
  • feeling faint or fainting
  • fever (adolescents from 11 years of age and adults), injection site reactions like extensive swelling of the vaccinated limb, blisters at or around the injection site and hard lump at the injection site (which may persist for more than one month)

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

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

However, some of the side effects mentioned under section Side Effects may temporarily affect the ability to drive or use machines.

Ask your doctor or pharmacist to answer any questions you may have.

Storing BEXSERO

  • Keep BEXSERO away from light.
  • Keep it in the refrigerator (between 2°C and 8°C).
  • Do not freeze BEXSERO.
  • Do not use BEXSERO after the expiry date which is stated on the carton.
  • Keep out of the reach and sight of children.

Medicines should not be disposed of in wastewater or household waste. Ask your doctor how to dispose of medicines that are out of date or no longer required. These measures will help to protect the environment.

Product description

What it looks like

BEXSERO is a white, opalescent liquid suspension for injection, supplied in a pre-filled syringe providing 1 dose of 0.5 ml.

Ingredients

The active ingredients are:

50 micrograms of Neisseria meningitidis Group B Neisseria Heparin Binding Antigen fusion protein (rbe); 50 micrograms of Neisseria meningitidis Group B Neisseria Adhesin A protein (rbe);

50 micrograms of Neisseria meningitidis Group B Factor H Binding Protein fusion protein (rbe); 25 micrograms of Outer Membrane Vesicles from Neisseria meningitidis group B strain NZ98/254.

Antigens are adsorbed on aluminium hydroxide hydrate (0.5 mg aluminium).

The other ingredients are: sodium chloride, histidine, sucrose and water for injections.

BEXSERO is supplied in packs of 1 or 10 syringes, supplied with or without needles.

Not all pack sizes may be marketed.

BEXSERO does not contain lactose, gluten, thiomersal (organic mercurials), tartrazine or any other azodyes.

Sponsor

GlaxoSmithKline Australia Pty Ltd
Level 4, 436 Johnston Street
Abbotsford, Victoria, 3067

Australian Registration Numbers:

BEXSERO pre-filled syringe without needle (AUST R 190718)

BEXSERO pre-filled syringe with needle (AUST R 190719)

This leaflet was prepared on 31 March 2020.

Trade marks are owned by or licensed to the GSK group of companies.

©2020 GSK group of companies or its licensor.

Version: 7.0

Published by MIMS September 2020

BRAND INFORMATION

Brand name

Bexsero

Active ingredient

Meningococcal group B multicomponent vaccine

Schedule

S4

 

1 Name of Medicine

Multicomponent meningococcal group B vaccine (recombinant, adsorbed).

2 Qualitative and Quantitative Composition

Bexsero is a multicomponent meningococcal group B vaccine presented as a suspension for injection in a prefilled syringe containing purified recombinant meningococcal protein antigens expressed in E. coli and outer membrane vesicles (OMV) derived from N. meningitidis group B. Bactericidal antibodies directed against components of the bacterium protect against invasive meningococcal disease (IMD).
1 dose (0.5 mL) of Bexsero contains:
Neisseria meningitidis group B Neisseria heparin binding antigen fusion protein1,2 (rbe) - 50 microgram;
Neisseria meningitidis group B Neisseria adhesin A protein1,2 (rbe) - 50 microgram;
Neisseria meningitidis group B factor H binding protein fusion protein1,2 (rbe) - 50 microgram;
Outer membrane vesicles (OMV) from Neisseria meningitidis group B strain NZ98/254 measured as amount of total protein containing the PorA P1.42 - 25 microgram.
1 Produced in E. coli cells by recombinant DNA technology. The NHBA (Neisseria heparin binding antigen) is derived from strain NZ98/254 and is fused with accessory protein 953, derived from strain 2996; NadA (Neisseria adhesin A) is derived from strain 2996; fHBP (factor H binding protein) is derived from strain MC58 and is fused with accessory protein 936, derived from strain 2996.
2 Adsorbed on aluminium hydroxide hydrate (0.5 mg Al3+).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

White opalescent liquid suspension.
Bexsero is supplied in a 1.0 mL (Type I glass) pre-filled syringe. Syringes are sealed with a plunger stopper (Type I bromobutyl rubber) and with a protective tip cap (Type II rubber).

4 Clinical Particulars

4.1 Therapeutic Indications

Bexsero is indicated for active immunisation against invasive disease caused by N. meningitidis group B strains. For information on protection against specific group B strains, see Section 5.1 Pharmacodynamic Properties.
Bexsero is indicated for vaccination of individuals from 2 months of age and older.

4.2 Dose and Method of Administration

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. Bexsero can be given at the same time as other immunisations, provided that the vaccine is administered either at a different site or away from the injection site of the other vaccine, according to local guidelines.

Infants 2 months to 5 months of age at the time of the first dose.

The primary infant vaccination schedule consists of two or three doses, each of 0.5 mL, with an interval not less than 2 months between doses (2-dose primary schedule) or 1 month between doses (3-dose primary schedule). 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. A booster dose is recommended in the second year of life, from the age of 12 months or later, with an interval of at least 6 months between the primary series and booster dose (see Section 5.1, Clinical trials).

Infants 6 months to 11 months of age at the time of the first dose.

The vaccination schedule consists of two doses, each of 0.5 mL, with an interval not less than 2 months between doses. A booster dose is recommended in the second year of life with an interval of at least 2 months between the primary series and booster dose (see Section 5.1, Clinical trials).

Toddlers 12 months to 23 months of age at the time of the first dose.

The vaccination schedule consists of two doses, each of 0.5 mL, with an interval not less than 2 months between doses. The need for a booster dose after this vaccination schedule has not been established (see Section 5.1, Clinical trials).

Children 2 years to 10 years of age at the time of the first dose.

The vaccination schedule consists of two doses, each of 0.5 mL, with an interval not less than 1 month between doses. The need for a booster dose after this vaccination schedule has not been established (see Section 5.1, Clinical trials).

Adolescents and adults from 11 years of age at the time of first dose.

Two doses, each of 0.5 mL, with an interval of at least 1 month between doses. The need for a booster dose after this vaccination schedule has not been established (see Section 5.1, Clinical trials).
The safety and efficacy of Bexsero in individuals above 50 years of age have not been established. See Table 1.
Sufficient data are not available on the safety and effectiveness of using Bexsero and other meningococcal group B vaccines interchangeably to complete the vaccination series. Therefore, it is recommended that subjects who receive a first dose of Bexsero, complete the vaccination course with Bexsero.
Further guidance regarding the use of vaccines can be found in the Australian Immunisation Handbook.

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. Administer in accordance with local guidelines.
The vaccine must not be injected intravenously, subcutaneously or intradermally and must not be mixed with other vaccines in the same syringe.
Bexsero is for single use in one patient only.
Upon storage of the suspension, a fine off-white deposit may form. Shake the vaccine well before use to form a homogeneous suspension. The vaccine should be visually inspected for particulate matter and discoloration prior to administration. In the event of any foreign particulate matter and/or variation of physical aspect being observed, do not administer the vaccine.
Any unused product or waste material should be disposed of in accordance with local requirements.

4.3 Contraindications

Hypersensitivity to the active substances (see Section 2 Qualitative and Quantitative Composition) or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

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 Adverse Effects (Undesirable Effects)). It is important that procedures are in place to avoid injury from fainting.
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 Pharmacodynamic Properties).
As with many vaccines, health care professionals should be aware that a temperature elevation may occur following vaccination of infants and toddlers. Accordingly, patients and/or their care givers should be made aware of the risks and management of fever and its sequelae. In infant study V72P13, fever ≥ 38.0°C was reported by 78%, 84% and 73% of participants after dose 1, 2 and 3, respectively, in the Bexsero vaccine group, compared with 44%, 59% and 50% of participants receiving the routine vaccines alone. In the same study, fever ≥ 39.5°C was reported by 5%, 7% and 4% of participants after dose 1, 2 and 3, respectively, in the Bexsero vaccine group, compared with 1%, 1% and 2% of participants receiving the routine vaccines alone. The rate of fever was decreased by the use of prophylactic antipyretics (as demonstrated in study V72P16). Prophylactic administration of antipyretics at the time of and closely after vaccination can reduce the incidence and intensity of postvaccination febrile reactions. Antipyretic medication should be initiated according to local guidelines in infants and toddlers.
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 dysfunction (see Section 5.1, Clinical trials).
Individuals receiving treatment that inhibits terminal complement activation (for example, eculizumab) remain at increased risk of invasive disease caused by Neisseria meningitidis group B even following vaccination with Bexsero.
Although no natural rubber latex is detected in the syringe tip cap, the safe use of Bexsero in latex-sensitive individuals has not been established.
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 microgram per dose. The safe use of Bexsero in kanamycin sensitive individuals has not been established.

Use in the elderly.

The safety and efficacy of Bexsero in individuals above 50 years of age have not been established. There are limited data in patients with chronic medical conditions.

Paediatric use.

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.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 group C-CRM conjugate.
Clinical studies demonstrated that the immune responses of the coadministered routine vaccines were unaffected by concomitant administration of Bexsero. Inconsistent results were seen across studies for responses to inactivated poliovirus type 2 and pneumococcal conjugate serotype 6B, but these data do not suggest clinically significant interference.
The safety profiles of the coadministered vaccines were unaffected by concomitant administration of Bexsero with the exception of more frequent occurrence of fever, tenderness at the injection site, change in eating habits and irritability. 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 Dose and Method of Administration).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on fertility in humans.
There were no effects on the mating performance or fertility of female rabbits in a reproductive and developmental toxicity study in which rabbits were intramuscularly injected with the clinical dose of Bexsero 35, 21, and 7 days prior to mating and on gestation days 7 and 20. Male fertility has not been assessed in animals.
(Category B1)
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.
A reproductive and developmental toxicity study has been performed in female rabbits intramuscularly injected 35, 21, and 7 days prior to mating and on gestation days 7 and 20 with the clinical dose of Bexsero (approximately 10 times the human dose based on body weights). There was no evidence of maternal, foetal, or postnatal developmental effects due to Bexsero. Vaccine specific antibodies were detected in rabbit foetuses and kits.
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 vaccine specific antibodies were detected in the offspring, but antibody levels in milk were not determined.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.
However, some of the effects mentioned (see Section 4.8 Adverse Effects (Undesirable Effects)) may temporarily affect the ability to drive or use machines.

4.8 Adverse Effects (Undesirable Effects)

Adverse reactions from clinical studies with the Bexsero are described below.
The safety of Bexsero was evaluated in 13 studies including 9 randomised controlled clinical trials with 7802 participants (from 2 months of age) who received at least one dose of Bexsero and in a subsequent study in 974 young adults. Among Bexsero recipients, 5849 were infants and toddlers (less than 2 years of age), 250 were children (2 to 10 years of age) and 2677 were adolescents and adults. Of the participants who received primary infant series of Bexsero, 3285 received a booster dose in the second year of life. Data for 988 infants and children (less than 2 years of age) and 801 children (2 to 10 years of age) exposed to Bexsero in subsequent studies have additionally been evaluated.
In infants and toddlers 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, fever occurred more frequently when Bexsero was coadministered with routine vaccines (containing the following antigens: pneumococcal 7 valent conjugate, diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliomyelitis and Haemophilus influenzae type b) than when it was given 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.
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 (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infants, toddlers, and children (up to 10 years of age).

Metabolism and nutrition disorders.

Very common: eating disorders.

Nervous system disorders.

Very common: sleepiness, unusual crying, headache. Uncommon: seizures (including febrile seizures).

Vascular disorders.

Uncommon: pallor (rare after booster). Rare: Kawasaki syndrome.

Gastrointestinal disorders.

Very common: diarrhea, vomiting (uncommon after booster).

Skin and subcutaneous tissue disorders.

Very common: rash (toddlers) (uncommon after booster). Common: rash (infants and children 2 to 10 years of age). Uncommon: eczema. Rare: urticaria.

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. Common: fever (≥ 39.5°C). Uncommon: fever (≥ 40°C).

Musculoskeletal and connective tissue disorders.

Very common: arthralgia.

Adolescents (from 11 years of age) and adults.

Nervous system disorders.

Very common: headache.

Gastrointestinal disorders.

Very common: nausea.

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.

Musculoskeletal and connective tissue disorders.

Very common: myalgia, arthralgia.

Adverse reactions from postmarketing spontaneous reports.

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

General disorders and administration site conditions.

Fever (adolescents from 11 years of age and adults).
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).

Immune system disorders.

Allergic reactions (including anaphylactic reactions), rash.

Nervous system disorders.

Hypotonic-hyporesponsive episode.
Syncope or vasovagal responses to injection.

Skin and subcutaneous tissue disorders.

Rash (adolescents from 11 years of age and adults).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Experience of overdose is limited. In the event of overdose, monitoring of vital functions and possible symptomatic treatment is recommended.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Meningococcal vaccines, ATC code: J07AH09.

Mechanism of action.

Immunisation with Bexsero is intended to stimulate the production of bactericidal antibodies against the vaccine antigens (NHBA, NadA, fHBP, and PorA P1.4 (the immunodominant antigen present in the OMV component)). The resultant antibodies are expected to be protective against invasive meningococcal disease (IMD). As these antigens are variably expressed by different strains, meningococci that express these antigens at sufficient levels are susceptible to killing by vaccine elicited antibodies. The vaccine antigens present in Bexsero are also expressed by strains belonging to meningococcal groups other than group B. Limited data suggest protection against some non-group B strains, however, the extent is not yet determined.

Epidemiological data.

Invasive meningococcal disease (IMD) is an important cause of meningitis and septicemia, which can lead to mortality (8.1% in Europe), or permanent sequelae (11-19%). According to the Australian Department of Health, the most common serogroups causing IMD in Australia are B, W and Y. However, trends in the incidence of meningococcal disease are hard to predict over time due to natural fluctuations in disease. According to the National Notifiable Diseases Surveillance System in 2016, the highest incidence of IMD occurs in children under 4 years of age (3.5 notifications per 100,000 population), followed by a peak in children from 15 to 19 years of age (2.5 notifications per 100,000 population).
Group B has caused prolonged outbreaks due to hypervirulent strains in New Zealand, with high incidences in infants (less than 1 year: 124 cases per 100,000), and children (1 to 4 years: 60 cases per 100,000).
Protection from meningococcal disease correlates with the presence of serum antibodies able to kill the bacteria in the presence of human complement. The potential of Bexsero to induce antibodies able to kill diverse strains of invasive meningococcal group B bacteria was studied using a novel typing method, the Meningococcal Antigen Typing System (MATS). MATS was developed to relate antigen profiles of different strains of meningococcal group B bacteria to killing of the strains in the serum bactericidal assay with human complement (hSBA) by pooled serum from 13 month old infants immunized at 2, 4 and 6 months of age with a booster at 12 months of age. A survey of 520 invasive meningococcal group B isolates collected between January 2007 and December 2011 from six Australian states and two territories showed that 75% (95% confidence interval: 61%-86%) of meningococcal group B isolates were predicted to be killed in hSBA based on their MATS vaccine antigen type.

Clinical trials.

The efficacy of Bexsero has been inferred by measuring bactericidal antibody responses to each of the vaccine antigens NadA, fHBP, NHBA and PorA P1.4, using a set of four meningococcal group B reference strains (5/99, 44/76, M10713 and NZ98/254). Bactericidal antibodies against these strains were measured by the serum bactericidal assay using human serum as the source of complement (hSBA). Strain H44/76 measured bactericidal antibody directed against fHBP; strain 5/99 measured bactericidal antibody directed against NadA; strain M10713 measured bactericidal antibody directed against NHBA; and strain NZ98/254 measured bactericidal antibody directed against PorA P1.4 in the OMV vaccine component. Data are not available from all vaccine schedules using strain M10713.

Immunogenicity.

The primary immunogenicity endpoint was measured as the proportion of participants with hSBA equal to or above the threshold of 1:4 against each of the meningococcal group B reference strains. This threshold, used in early stage clinical studies (V72P6, V72P9, V72P4, V72P5 and V72P10), is an accepted correlate of protection. Based on the intermediate precision of the validated assay a threshold of 1:5 was then set to ensure 95% certainty of a true response of 1:4. This cut-off was used to define seropositive responses in late stage clinical studies in infants and children (V72P13, V72P12, V72P12E1, V72P13E1, V72P16, V72P13E2, V72P6E1, V72P9E1, V72_28, V72_28E1 and V72P10E1). Immunogenicity was evaluated in randomised, multicentre, clinical trials that enrolled infants, children, adolescents and adults.

Immunogenicity in infants 2 months to 5 months of age.

Three dose primary schedule followed by a booster.

In infant studies V72P13, V72P12 and V72P16, participants received three doses of Bexsero either at 2, 4 and 6 or 2, 3 and 4 months of age with concomitant routine vaccines and a booster dose in their second year of life, as early as 12 months of age. Control groups received only routine childhood vaccinations. Sera were obtained before vaccination, one month after the third vaccination (Table 2) and one month after booster vaccination (Table 3).
Across these studies, baseline geometric mean titres (GMTs) against all four reference strains were uniformly low ranging from 1.02 to 3.28 in the Bexsero groups and 1.01 to 4.08 in the controls.
One month after the third Bexsero vaccination, bactericidal responses against the meningococcal reference strains fHPB, NadA, PorA P1.4 and NHBA antigens were high for both schedules. For NHBA antigen, the bactericidal responses were higher in infants vaccinated at the 2, 4, 6 month schedule than for those vaccinated on the 2, 3, 4 month schedule. The clinical consequence of the reduced immunogenicity of the NHBA antigen following the 2, 3, 4 month schedule is not known. Following routine childhood vaccination in the control group the mean hSBA GMTs against meningococcal reference strains remained low ranging from 1.04 to 2.24.
Table 3 summarises antibody persistence pre-booster dose 8 months after primary vaccination at 2, 3 and 4 months of age and at 6 months after vaccination at 2, 4 and 6 months of age. Table 3 also summarises an antibody response for both regimens one month after a booster dose administered at 12 months of age, and antibody persistence 12 months after the booster dose for the 2, 4 and 6 month regimen. Seroprotection rates and hSBA GMTs one month following the fourth dose at 12 months were indicative of a booster response for both regimens.

Two dose primary schedule followed by a booster.

The immunogenicity after two doses (at 3 and a half and 5 months of age) or three doses (at 2 and a half, 3 and a half and 5 months of age) of Bexsero, followed by a booster, has been evaluated in an additional phase 3 clinical study (V72_28). The percentages of seropositive subjects (i.e. achieving an hSBA of at least 1:4 to the fHPB, NadA, PorA P1.4 and/or NHBA antigens) ranged from 44% to 100% one month after the second dose and from 55% to 100% one month after the third dose. At one month following a booster administered 6 months after the last dose, the percentages of seropositive to the fHPB, NadA, PorA P1.4 and/or NHBA antigens ranged from 87% to 100% for the two-dose schedule, and from 83% to 100% for the three-dose schedule.
Antibody persistence was evaluated in an extension study in children 3 to 4 years of age (V72_28E1). Comparable percentages of subjects were seropositive at 2 to 3 years after being previously vaccinated in infancy with either two doses followed by a booster of Bexsero at 11 months (ranging from 35% to 91%) or three doses in infancy followed by a booster at 11 months (ranging from 36% to 84%). In the same study the response to an additional dose administered 2 to 3 years after the 11 month booster was indicative of immunological memory as shown by a robust antibody response against all 4 Bexsero antigens, ranging from 81% to 100% and from 70% to 99%, respectively. These observations are consistent with adequate priming in infancy with both a two-dose and a three-dose primary series followed by a booster of Bexsero.

Immunogenicity in infants 6 to 11 months of age and children 12 to 23 months of age.

Bactericidal responses following two doses administered two months apart to children 6 months to 23 months of age were investigated in two studies (V72P9 and V72P13E1). Baseline GMTs were uniformly low against all reference strains in each study, ranging from 1.00 to 2.32. After the two-dose series seropositivity rates and hSBA GMTs were high against each of the vaccine antigens and were similar for infants vaccinated at 6 and 8 months of age and toddlers vaccinated at 13 and 15 months of age (see Table 4). Data on antibody persistence one year after the two doses at 13 and 15 months of age are also summarized in Table 4 (V72P13E2).
An increase in hSBA titres for the four reference strains was recorded in an additional group of 43-68 children evaluated after vaccination with Bexsero at 12 and 14 months of age in study V72P13E1. Post-vaccination seropositivity rates were: 100% for strain 44/76 and strain 5/99; 96% for strain NZ98/254; and 74% for strain M10713.

Immunogenicity in children 2 to 10 years of age.

The immunogenicity after two doses of Bexsero administered either one or two months apart in children 2 to 10 years of age has been evaluated in two phase 3 clinical studies (V72_28 and V72_28E1). In the first study (V72_28), whose results are summarised in Table 5, participants received two doses of Bexsero two months apart. The seroresponse rates and hSBA GMTs were high after the two-dose schedule in children against each of the vaccine antigens (Table 5).
High percentages of subjects aged 3-10 years were seropositive in the second study (V72_28E1), in which two doses of Bexsero were administered one month apart. An early immune response after the first dose was also evaluated. The percentages of seropositive subjects (i.e. achieving an hSBA of at least 1:4) against fHPB, NadA, PorA P1.4 and/or NHBA antigens ranged from 46% to 95% at one month after the first dose and from 69% to 100% at one month after the second dose.

Immunogenicity in adolescents (from 11 years of age) and adults.

Participants aged 11 to 17 years (study V72P10) received two doses of Bexsero with a 1, 2 or 6 month interval between doses. Baseline GMTs ranged from 2.64 to 4.11. As early as one month after the first dose, percentages of participants who achieved an hSBA ≥ 1:4 ranged from 90% to 97%. Antibody persistence was demonstrated 18-23 months after the second dose (see Table 6). Independent of pre-vaccination seropositivity status, a high percentage of participants were seropositive and achieved 4-fold increases in hSBA titres post vaccination (see Table 7).
In studies of adults aged 18 to 50 years (V72P4) and 18 to 40 years (V72P5), data were obtained after the two doses of Bexsero with a 1 month or 2 month interval between doses (see Table 8). Baseline GMTs against reference strains ranged from 1.71 to 4.06. Responses in adults were similar to those of adolescents.

Immunogenicity in special populations.

Children and adolescents with complement deficiencies, asplenia, or splenic dysfunction.

In a phase 3 clinical study, children and adolescents 2 to 17 years of age with complement deficiencies (40), with asplenia or splenic dysfunction (107), and age-matched healthy participants (85) received two doses of Bexsero two months apart. At 1 month following the 2-dose vaccination course, the percentages of participants with hSBA ≥ 1:5 in individuals with complement deficiencies and asplenia or splenic dysfunction were 87% and 97% for antigen fHbp, 95% and 100% for antigen NadA, 68% and 86% for antigen PorA P1.4, 73% and 94% for antigen NHBA, respectively, indicating an immune response in these immunocompromised participants. The percentages of healthy participants with hSBA ≥ 1:5 were 98% for antigen fHbp, 99% for antigen NadA, 83% for antigen PorA P1.4, and 99% for antigen NHBA.

Effectiveness.

In the UK, Bexsero has been introduced into the national immunisation programme (NIP) in September 2015 using a two dose schedule in infants (at 2 and 4 months of age) followed by a booster (at 12 months of age). Public Health England is conducting a 3 year observational study at the national level covering the entire birth cohort.
In the ongoing study, the first 10 months data showed a 50% reduction in cases of IMD caused by Neisseria meningitidis group B [Incidence Rate Ratio 0.50 (95% CI: 0.36; 0.71)] in vaccine-eligible infants, irrespective of the infants' vaccination status or predicted meningococcal group B strain coverage. Two years after the introduction of Bexsero into the NIP, data showed sustained reductions in cases of IMD caused by Neisseria meningitidis group B in vaccine-eligible infants, irrespective of vaccine coverage in the population.
Two years after the introduction of Bexsero into the NIP, vaccine effectiveness after at least one dose was 43% (95% CI: -11; 69), after at least two doses was 64% (95% CI: 4; 84) and after the booster (third) dose at 12 months of age was 82% (95% CI: -81; 97).

5.2 Pharmacokinetic Properties

Not applicable for vaccines.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies have not been performed with Bexsero.

Carcinogenicity.

Carcinogenicity studies have not been performed with Bexsero.

6 Pharmaceutical Particulars

6.1 List of Excipients

Bexsero contains the excipients sodium chloride, histidine, sucrose, and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

3 years.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C - 8°C). Do not freeze. Protect from light.

6.5 Nature and Contents of Container

Bexsero is presented as a 0.5 mL suspension in a pre-filled syringe (Type I glass) with a plunger stopper (Type I bromobutyl rubber) and with a protective tip cap (Type II rubber).
Bexsero is supplied in packs of 1 syringe with or without needle or packs of 10 syringes without needles.
Not all pack sizes may be distributed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Not applicable for vaccines.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes