Boostrix-IPV suspension for injection in pre-filled syringe

Boostrix-IPV is indicated for booster vaccination against diphtheria, tetanus, pertussis and poliomyelitis of individuals from the age of three years onwards (see section 4.2).

Boostrix-IPV is also indicated for passive protection against pertussis in early infancy following maternal immunisation during pregnancy (see sections 4.2, 4.6 and 5.1).

The administration of Boostrix-IPV should be based on official recommendations.

Posology

A single 0.5 ml dose of the vaccine is recommended.

Boostrix-IPV may be administered from the age of three years onwards.

Boostrix-IPV contains reduced content of diphtheria, tetanus and pertussis antigens in combination with poliomyelitis antigens. Therefore, Boostrix-IPV should be administered in accordance with official recommendations and/or local practice.

Boostrix-IPV can be administered to pregnant women during the second or the third trimester in accordance with official recommendations (see sections 4.1, 4.6 and 5.1).

Boostrix-IPV may also be administered to adolescents and adults with unknown vaccination status or incomplete vaccination against diphtheria, tetanus and pertussis as part of an immunisation series against diphtheria, tetanus, pertussis and poliomyelitis. Based on data in adults, two additional doses of a diphtheria and tetanus containing vaccine are recommended one and six months after the first dose to maximize the vaccine response against diphtheria and tetanus (see section 5.1).

Boostrix-IPV can be used in the management of tetanus prone injuries in persons who have previously received a primary vaccination series of tetanus toxoid vaccine and for whom a booster against diphtheria, pertussis and poliomyelitis is indicated. Tetanus immunoglobulin should be administered concomitantly in accordance with official recommendations.

Repeat vaccination against diphtheria, tetanus, pertussis and poliomyelitis should be performed at intervals as per official recommendations.

Paediatric population

The safety and efficacy of Boostrix-IPV in children below 3 years of age have not been established.

Method of administration

Boostrix-IPV is for deep intramuscular injection preferably in the deltoid region (see section 4.4).

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or neomycin, polymyxin or formaldehyde.

Hypersensitivity after previous administration of diphtheria, tetanus, pertussis or poliomyelitis vaccines.

Boostrix-IPV is contraindicated if the subject has experienced an encephalopathy of unknown aetiology, occurring within 7 days following previous vaccination with pertussis-containing vaccine. In these circumstances, pertussis vaccination should be discontinued and the vaccination course should be continued with diphtheria, tetanus and poliomyelitis vaccines.

Boostrix-IPV should not be administered to subjects who have experienced transient thrombocytopenia or neurological complications (for convulsions or hypotonic-hyporesponsive episodes, see section 4.4) following an earlier immunisation against diphtheria and/or tetanus.

As with other vaccines, administration of Boostrix-IPV should be postponed in subjects suffering from acute severe febrile illness. The presence of a minor infection is not a contraindication.

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

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

- Temperature of ≥ 40.0° C within 48 hours of vaccination, not due to another identifiable cause.

- Collapse or shock-like state (hypotonic-hyporesponsiveness episode) within 48 hours of vaccination.

- Persistent, inconsolable crying lasting ≥ 3 hours, occurring within 48 hours of vaccination.

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

There may be circumstances, such as a high incidence of pertussis, when the potential benefits outweigh possible risks.

As for any vaccination, the risk-benefit of immunising with Boostrix-IPV or deferring this vaccination should be weighed carefully in a child suffering from a new onset or progression of a severe neurological disorder.

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

Boostrix-IPV should be administered with caution to subjects with thrombocytopenia (see section 4.3) or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects. If in accordance with official recommendations, the vaccine may be administered subcutaneously to these subjects. With both routes of administration, firm pressure should be applied to the injection site (without rubbing) for at least two minutes.

Boostrix-IPV should in no circumstances be administered intravascularly.

A history of febrile convulsions, a family history of convulsions and a family history of an adverse event following DTP vaccination do not constitute contraindications.

Human Immunodeficiency Virus (HIV) infection is not considered as a contraindication. The expected immunological response may not be obtained after vaccination of immunosuppressed patients.

Syncope (fainting) can occur following, or even before, any vaccination especially in adolescents as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints.

As with any vaccine, a protective immune response may not be elicited in all vaccinees.

Excipients with known effect

Boostrix-IPV contains para-aminobenzoic acid. It may cause allergic reactions (possibly delayed), and exceptionally, bronchospasm.

This medicine contains 0.0298 micrograms phenylalanine in each dose. Phenylalanine may be harmful if you have phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.

This medicine contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially 'potassium- free'.

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

Use with other vaccines or immunoglobulins

Boostrix-IPV may be administered concomitantly with any of the following monovalent or combination vaccines: measles, mumps, rubella, varicella (MMR/V) and human papilloma virus (HPV) vaccine with no clinically relevant interference with antibody response to any of the components of either vaccine (see section 4.8).

Concomitant administration of Boostrix-IPV with other vaccines or with immunoglobulins has not been studied.

It is unlikely that co-administration will result in interference with the immune responses.

According to generally accepted vaccine practices and recommendations, if concomitant administration of Boostrix-IPV with other vaccines or immunoglobulins is considered necessary, the products should be given at separate sites.

Use with immunosuppressive treatment

As with other vaccines, patients receiving immunosuppressive therapy may not achieve an adequate response.

Pregnancy

Boostrix-IPV can be used during the second or third trimester of pregnancy in accordance with official recommendations.

For data relating to the prevention of pertussis disease in infants born to women vaccinated during pregnancy, see section 5.1.

Safety data from a randomised controlled clinical trial (341 pregnancy outcomes) and from a prospective observational study (793 pregnancy outcomes), where Boostrix (dTpa component of Boostrix-IPV) was administered to pregnant women during the third trimester, have shown no vaccine related adverse effect on pregnancy or on the health of the foetus/newborn child.

Safety data from prospective clinical studies on the use of Boostrix-IPV or Boostrix during the first and second trimester of pregnancy are not available.

Data from passive surveillance where pregnant women were exposed to Boostrix-IPV or to Boostrix in the 3^rd or 2^nd trimester have shown no vaccine-related adverse effect on pregnancy or on the health of the foetus/newborn child.

As with other inactivated vaccines, it is not expected that vaccination with Boostrix-IPV harms the foetus at any trimester of pregnancy.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or post-natal development (see section 5.3).

Breastfeeding

The effect of administration of Boostrix-IPV during lactation has not been assessed. Nevertheless, as Boostrix-IPV contains toxoids or inactivated antigens, no risk to the breastfed infant should be expected. The benefits versus the risk of administering Boostrix-IPV to breastfeeding women should carefully be evaluated by the healthcare providers.

Fertility

No human data from prospective clinical studies are available. Animal studies do not indicate direct or indirect harmful effects with respect to female fertility (see section 5.3).

The vaccine is unlikely to produce an effect on the ability to drive and use machines.

Summary of the safety profile

The safety profile presented in Table 1 is based on data from clinical trials where Boostrix-IPV was administered to 908 children (from 4 to 8 years of age) and 955 adults, adolescents and children (from 10 to 93 years of age).

The most common events occurring after Boostrix-IPV administration in both groups were local injection site reactions (pain, redness and swelling) reported by 31.3 – 82.3% of subjects overall. These usually had their onset within the first 48 hours after vaccination. All resolved without sequelae.

Tabulated list of adverse reactions

Adverse reactions reported are listed according to the following frequency:

• Clinical trials

Table 1: Adverse reactions reported in clinical trials with Boostrix-IPV

Coadministration with MMR/V vaccines in children aged 3-6 years

Boostrix-IPV was coadministered with MMR/V vaccines in 2 clinical studies with 406 children aged 3-6 years. In these studies, upper respiratory tract infection and rash were commonly reported. Fever, irritability, fatigue, loss of appetite and gastrointestinal disorders (including diarrhoea and vomiting) were reported with a higher frequency (very common) when compared to Table 1 while all other adverse reactions occurred at the same or lower frequency.

Adverse reactions additionally reported during clinical studies with Boostrix (dTpa component of Boostrix-IPV), administered to 839 children (from 4 to 8 years of age) and 1931 adults, adolescents and children (from 10 to 76 years of age), are listed in Table 2.

Table 2: Adverse reactions reported in clinical trials with Boostrix

Reactogenicity after repeat dose

Data suggest that in subjects primed with DTP in childhood a second booster dose might give an increase of local reactogenicity.

Subjects aged 15 years onwards without recent vaccination for diphtheria, tetanus, pertussis and poliomyelitis, who received a dose of Boostrix-IPV or another reduced-antigen content vaccine, followed by an additional dose of Boostrix-IPV 10 years after, showed no increased reactogenicity after this second dose compared to the first one.

• Post-marketing surveillance

Because these events were reported spontaneously, it is not possible to reliably estimate their frequency.

Table 3: Adverse reactions reported with Boostrix-IPV during post-marketing surveillance

Following administration of tetanus toxoid containing vaccines, there have been very rare reports of adverse reactions on the central or peripheral nervous systems, including ascending paralysis or even respiratory paralysis (e.g. Guillain-Barré syndrome).

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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Cases of overdose have been reported during post-marketing surveillance. Adverse events following overdosage, when reported, were similar to those reported with normal vaccine administration.

Pharmacotherapeutic group: Bacterial and viral vaccines combined, ATC code: J07CA02

Immune response

The immune responses to Boostrix-IPV were evaluated in clinical trials carried out in subjects of different ages having different vaccination histories (see section 4.8).

The following immune responses were observed across studies one month post vaccination with Boostrix-IPV in children, adolescents and adults (Table 4).

Table 4: Immune response in children, adolescents and adults

N=number of subjects

⁽¹⁾ Percentage of subjects with antibody concentrations associated with protection against disease (≥ 0.1 IU/ml by ELISA assay or ≥ 0.016 IU/ml by an in-vitro Vero-cell neutralisation assay).

⁽²⁾ This assay was not performed in study HPV-042.

⁽³⁾ Booster response defined as:

- for initially seronegative subjects, antibody concentrations at least four times the cut-off (post-vaccination concentration ≥ 20 El.U/ml);

- for initially seropositive subjects with Pre booster vaccination concentration ≥ 5 El.U/ml and < 20 El.U/ml: an increase in antibody concentrations of at least four times the Pre booster vaccination concentration.

- for initially seropositive subjects with Pre booster vaccination concentration ≥ 20 El.U/ml: an increase in antibody concentrations of at least two times the Pre booster vaccination concentration

As with other adult-type Td vaccines, Boostrix-IPV induces higher seroprotection rates and higher titres of both anti-D and anti-T antibodies in children and adolescents as compared to adults.

Persistence of the immune response

The following seroprotection/seropositivity rates were observed five years after vaccination with Boostrix-IPV in children and 10 years after vaccination with Boostrix-IPV in adolescents and adults (Table 5).

Table 5: Persistence of immune response in children, adolescents and adults

*98.2% of subjects with antibody concentrations associated with protection against disease ≥ 0.016 IU/ml by an in-vitro Vero-cell neutralisation assay.

**92.1% of subjects with antibody concentrations associated with protection against disease ≥ 0.01 IU/ml by an in-vitro Vero-cell neutralisation assay.

Immune response after a repeat dose

The immunogenicity of Boostrix-IPV, administered 5 years after a first booster dose of Boostrix-IPV at 4 to 8 years of age, has been evaluated. One month post vaccination, > 99 % of subjects were seropositive against pertussis and seroprotected against diphtheria, tetanus and all three poliovirus types.

In adults, one dose of Boostrix-IPV administered 10 years after the previous dose, elicited a protective immune response in > 96.8% of the subjects (for the diphtheria antigen) and in 100% of the subjects (for the tetanus and polio antigens). The booster response against the pertussis antigens was between 74.2 and 98.4%.

Immune response in subjects without prior or with unknown vaccination history

After administration of one dose of Boostrix (dTpa component of Boostrix-IPV) to 83 adolescents aged from 11 to 18 years, without previous pertussis vaccination and no vaccination against diphtheria and tetanus in the previous 5 years, all subjects were seroprotected against tetanus and diphtheria. The seropositivity rate after one dose varied between 87% and 100% for the different pertussis antigens.

After administration of one dose of Boostrix-IPV to 140 adults ≥ 40 years of age (including those who have never been vaccinated or whose vaccination status was unknown), that had not received any diphtheria and tetanus containing vaccine in the past 20 years, more than 96.4% of adults were seropositive for all three pertussis antigens and 77.7% and 95.7% were seroprotected against diphtheria and tetanus respectively.

Immune response and safety profile in subjects on active treatment for obstructive airway diseases

The safety and immunogenicity of Boostrix have been evaluated in a descriptive meta-analysis study combining data from 222 subjects ≥ 18 years of age vaccinated with Boostrix while on active treatment for obstructive airway disease such as asthma or Chronic Obstructive Pulmonary Disease (COPD). One month after Boostrix vaccination, the immune responses against diphtheria and tetanus antigens in terms of seroprotective rates (≥ 0.1 IU/mL) were respectively 89.0% and 97.2%, and against pertussis in terms of booster responses these were 78.3 %, 96.1 % and 92.2 % against pertussis toxoid [PT], filamentous haemagglutinin [FHA] and pertactin [PRN], respectively. These results are consistent with the responses obtained in the general adult population and with a similar safety profile.

Efficacy in protecting against pertussis

The pertussis antigens contained in Boostrix-IPV are an integral part of the paediatric acellular pertussis combination vaccine (Infanrix), for which efficacy after primary vaccination has been demonstrated in a household contact efficacy study. The antibody titres to all three pertussis components following vaccination with Boostrix-IPV are at least as high or higher than those observed during the household contact efficacy trial. Based on these comparisons, Boostrix-IPV would provide protection against pertussis, however the degree and duration of protection afforded by the vaccine are undetermined.

Passive protection against pertussis in infants (below 3 months of age) born to mothers vaccinated during pregnancy

In a randomised, cross-over, placebo-controlled study, higher pertussis antibody concentrations were demonstrated at delivery in the cord blood of babies born to mothers vaccinated with Boostrix (dTpa group; N=291) versus placebo (control group; N=292) at 27-36 weeks of pregnancy. The cord blood geometric mean concentrations of antibodies against the pertussis antigens PT, FHA and PRN were 46.9, 366.1 and 301.8 IU/ml in the dTpa group, and 5.5, 22.7 and 14.6 IU/ml in the control group. This corresponds to antibody titres that are 8, 16 and 21 times higher in the cord blood of babies born to vaccinated mothers versus controls. These antibody titres may provide passive protection against pertussis as shown by observational effectiveness studies.

Immunogenicity in infants and toddlers born to mothers vaccinated during pregnancy

The immunogenicity of Infanrix hexa (diphtheria, tetanus, pertussis, hepatitis B, inactivated poliovirus, Haemophilus influenzae type b conjugate vaccine) in infants and toddlers born to healthy mothers vaccinated with Boostrix at 27-36 weeks of pregnancy was evaluated in two clinical studies.

Infanrix hexa was co-administered with a 13-valent pneumococcal conjugate vaccine to infants for primary vaccination (n=268); and to the same infants/toddlers from 11 to 18 months as booster dose (n=229).

Post-primary and post-booster vaccination, immunological data did not show clinically relevant interference of maternal vaccination with Boostrix on the infant's and toddler's responses to diphtheria, tetanus, hepatitis B, inactivated poliovirus, Haemophilus influenzae type b or pneumococcal antigens.

Lower antibody concentrations against pertussis antigens post-primary (PT, FHA and PRN) and post-booster (PT, FHA) vaccination were observed in infants and toddlers born to mothers vaccinated with Boostrix during pregnancy. The fold-increases of anti-pertussis antibody concentrations from the pre-booster to the 1-month post-booster time point were in the same range for infants and toddlers born to mothers vaccinated with Boostrix or with placebo, demonstrating effective priming of the immune system. In the absence of correlates of protection for pertussis, the clinical relevance of these observations remains to be fully understood. However, current epidemiological data on pertussis disease following the implementation of dTpa maternal immunisation do not suggest any clinical relevance of this immune interference.

Effectiveness in the protection against pertussis disease in infants born to women vaccinated during pregnancy

Boostrix or Boostrix-IPV vaccine effectiveness (VE) was evaluated in three observational studies, in UK, Spain and Australia. The vaccine was used during the third trimester of pregnancy to protect infants below 3 months of age against pertussis disease, as part of a maternal vaccination programme.

Details of each study design and results are provided in Table 6.

Table 6: VE against pertussis disease for infants below 3 months of age born to mothers vaccinated during the third trimester of pregnancy with Boostrix/Boostrix-IPV

CI: confidence interval

If maternal vaccination occurs within two weeks before delivery, vaccine effectiveness in the infant may be lower than the figures in the table.

Evaluation of pharmacokinetic properties is not required for vaccines.

Reproductive toxicology

Fertility

Non-clinical data obtained with Boostrix-IPV reveal no specific hazard for humans based on conventional studies of female fertility in rats and rabbits.

Pregnancy

Non-clinical data obtained with Boostrix-IPV reveal no specific hazard for humans based on conventional studies of embryo-foetal development in rats and rabbits, and also of parturition and postnatal toxicity in rats (up to the end of the lactation period).

Animal toxicology and/or pharmacology

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

Medium 199 (as stabilizer containing amino acids (including phenylalanine), mineral salts (including sodium and potassium), vitamins (including para-aminobenzoic acid) and other substances)

Sodium chloride

Water for injections

For adjuvants, see section 2.

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

3 years

Store in a refrigerator (2° C – 8° C).

Upon removal from the refrigerator, the vaccine is stable for 8 hours at 21° C. Discard the vaccine if it was not used during this period. This information is intended to guide healthcare professionals in case of temporary temperature excursion only.

Do not freeze.

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

0.5 ml of suspension in a pre-filled syringe (type I glass) with a plunger stopper (butyl rubber) and with a rubber tip cap.

Pack sizes of 1 and 10, with or without needles.

The tip cap and rubber plunger stopper of the pre-filled syringe are made with synthetic rubber.

Not all pack sizes may be marketed.

Prior to use, the vaccine should be at room temperature, and well shaken in order to obtain a homogeneous turbid white suspension. Prior to administration, the vaccine should be visually inspected for any foreign particulate matter and/or variation of physical aspect. In the event of either being observed, do not administer the vaccine.

Instructions for the pre-filled syringe

Disposal:

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