4.1. Therapeutic indications

Infanrix hexa is indicated for primary and booster vaccination of infants from the age of 6 weeks and toddlers against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and disease caused by Haemophilus influenzae type b.

The use of Infanrix hexa should be in accordance with official recommendations.

4.2. Posology and method of administration

Posology

Primary vaccination

The primary vaccination schedule consists of two or three doses (of 0.5 ml) which should be administered according to official recommendations (see the table below in this section and section 5.1 for schedules evaluated in clinical trials).

The Expanded Program on Immunisation schedule (at 6, 10, 14 weeks of age) may only be used if a dose of hepatitis B vaccine has been given at birth.

Where a dose of hepatitis B vaccine is given at birth:

• Infanrix hexa can be used as a replacement for supplementary doses of hepatitis B vaccine from the age of six weeks. If a second dose of hepatitis B vaccine is required before this age, monovalent hepatitis B vaccine should be used.

• Infanrix hexa can be used for a mixed pentavalent/hexavelent vaccine primary immunisation schedule in accordance with official recommendations.

Locally established immunoprophylactic measures against hepatitis B should be maintained.

Infanrix hexa can be replaced by the adminstration of a pentavalent vaccine co-adminsitered with hepatitis B vaccine.

Booster vaccination

After a 2-dose or a 3-dose primary series vaccination with Infanrix hexa, a booster dose with Infanrix hexa should be given at least 6 months after the last priming dose (see the table below in this section and section 5.1 for schedules evaluated in clinical trials).

Infanrix hexa may be used as a booster in individuals who have previously been vaccinated with another

hexavalent vaccine or a pentavalent DTPa-IPV+Hib vaccine associated with a monovalent hepatitis B vaccine for their primary series.

When a booster dose with a hexavalent DTPa (diphtheria, tetanus, and acellular pertussis) containing vaccine is not available, a dose of Hib vaccine must be administered, as a minimum.

Paediatric population

The safety and efficacy of Infanrix hexa in children over 36 months of age have not been established.

No data are available.

Primary vaccination

Booster vaccination

General considerations

Full-term infants

3-dose

A booster dose must be given.

• There should be an interval of at least 1 month between primary doses.

• The booster dose should be given at least 6 months after the last priming dose and preferably before 18 months of age.

2-dose

A booster dose must be given.

• There should be an interval of at least 2 months between primary doses.

• The booster dose should be given at least 6 months after the last priming dose and preferably between 11 and 13 months of age.

Preterm infants born after at least 24 weeks of gestational age

3-dose

A booster dose must be given.

• There should be an interval of at least 1 month between primary doses.

• The booster dose should be given at least 6 months after the last priming dose and preferably before 18 months of age.

Method of administration

Infanrix hexa is for deep intramuscular injection, preferably at alternating sites for subsequent injections.

For instructions on reconstitution of the medicinal product 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, or formaldehyde, neomycin and polymyxin.

Hypersensitivity after previous administration of diphtheria, tetanus, pertussis, hepatitis B, polio or Hib vaccines.

Infanrix hexa is contraindicated if the infant or toddlers 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, hepatitis B, polio and Hib vaccines.

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

4.4. Special warnings and precautions for use

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.

As with any vaccine, a protective immune response may not be elicited in all vaccinees (see section 5.1).

Infanrix hexa will not prevent disease caused by pathogens other than Corynebacterium diphtheriae, Clostridium tetani, Bordetella pertussis, hepatitis B virus, poliovirus or Haemophilus influenzae type b. However, it can be expected that hepatitis D will be prevented by immunisation as hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection.

If any of the following events are known to have occurred in temporal relation to receipt of pertussis-containing vaccine, the decision to give further 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-hyporesponsive 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 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.

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

Infanrix hexa should be administered with caution to subjects with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects.

Do not administer the vaccine intravascularly or intradermally.

A history of febrile convulsions, a family history of convulsions or Sudden Infant Death Syndrome (SIDS) do not constitute a contraindication for the use of Infanrix hexa. Vaccinees with a history of febrile convulsions should be closely followed up as such adverse events may occur within 2 to 3 days post vaccination.

The physician should be aware that the rate of febrile reactions is higher when Infanrix hexa is co-administered with a pneumococcal conjugate vaccine (PCV7, PCV10, PCV13), or with a measles-mumps-rubella-varicella (MMRV) vaccine, compared to that occurring following the administration of Infanrix hexa alone. These reactions were mostly moderate (less than or equal to 39°C) and transient (see sections 4.5 and 4.8).

Increased reporting rates of convulsions (with or without fever) and hypotonic hyporesponsive episode (HHE) were observed with concomitant administration of Infanrix hexa and Prevenar 13 (see section 4.8).

Prophylactic administration of antipyretics before or immediately after vaccine administration can reduce the incidence and intensity of post-vaccination febrile reactions. Clinical data generated with paracetamol and ibuprofen suggest that the prophylactic use of paracetamol might reduce the fever rate, while prophylactic use of ibuprofen showed a limited effect in reducing fever rate.

The use of prophylactic antipyretic medicinal products is recommended for children with seizure disorders or with a prior history of febrile seizures.

Antipyretic treatment should be initiated according to local treatment guidelines.

Special populations

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

Clinical data indicate that Infanrix hexa can be given to preterm infants, however, as expected in this population, a lower immune response has been observed for some antigens (see section 4.8 and section 5.1).

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 preterm 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 these infants, vaccination should not be withheld or delayed.

Interference with laboratory testing

Since the Hib capsular polysaccharide antigen is excreted in the urine, a positive urine test can be observed within 1-2 weeks following vaccination. Other tests should be performed in order to confirm Hib infection during this period.

Excipients with known effect

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

The vaccine contains 0.0298 microgram 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.

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

The vaccine 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.

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

Infanrix hexa can be given concomitantly with pneumococcal conjugate vaccines (PCV7, PCV10 and PCV13), meningococcal serogroup C conjugate vaccine (CRM197 and TT conjugates), meningococcal serogroups A, C, W-135 and Y conjugate vaccine (TT conjugate), meningococcal serogroup B vaccine (MenB), oral rotavirus vaccine and measles-mumps-rubella-varicella (MMRV) vaccine.

Data have shown no clinically relevant interference in the antibody response to each of the individual antigens, although inconsistent antibody response to poliovirus type 2 in co-administration with Synflorix was observed (seroprotection ranging from 78% to 100%) and the immune response rates to the PRP (Hib) antigen of Infanrix hexa after 2 doses given at 2 and 4 months of age were higher if co-administered with a tetanus toxoid conjugate pneumococcal or meningococcal vaccine (see section 5.1). The clinical relevance of these observations remains unknown.

When Infanrix hexa was co-administered with MenB and pneumococcal conjugate vaccines, inconsistent results were seen across studies for responses to inactivated poliovirus type 2, pneumococcal conjugate serotype 6B antigen and to the pertussis pertactin antigen but these data do not suggest clinically significant interference.

Data from clinical studies indicate that, when Infanrix hexa is co-administered with pneumococcal conjugate vaccines, the rate of febrile reactions is higher compared to that occurring following the administration of Infanrix hexa alone. Data from one clinical study indicate that when Infanrix hexa is co-administered with MMRV vaccine, the rate of febrile reactions is higher compared to that occurring following the administration of Infanrix hexa alone and similar to that occurring following the administration of MMRV vaccine alone (see sections 4.4 and 4.8). The immune responses were unaffected.

Due to an increased risk of fever, pain at the injection site, loss of appetite and irritability when Infanrix hexa was co-administered with MenB vaccine and 7-valent pneumococcal conjugate vaccine, separate vaccinations can be considered when possible.

As with other vaccines it may be expected that in patients receiving immunosuppressive therapy, an adequate response may not be achieved.

4.6. Fertility, pregnancy and lactation

As Infanrix hexa is not intended for use in adults, adequate human data on use during pregnancy or lactation and adequate animal reproduction studies are not available.

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

Summary of the safety profile

As has been observed for DTPa and DTPa-containing combinations, an increase in local reactogenicity and fever was reported after booster vaccination with Infanrix hexa with respect to the primary course.

Tabulated summary of adverse reactions

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

Frequencies per dose are defined as follows:

Very common:

Common:

Uncommon:

Rare:

Very rare:

(≥1/10)

(≥1/100 to <1/10)

(≥1/1 000 to <1/100)

(≥1/10 000 to <1/1 000)

(<1/10 000)

The following drug-related adverse reactions were reported in clinical studies (data from more than 16,000 subjects) and during post-marketing surveillance.

System Organ Class

Frequency

Adverse reactions

Infections and infestations

Uncommon

Upper respiratory tract infection

Blood and lymphatic system disorders

Rare

Lymphadenopathy2, thrombocytopenia2

Immune system disorders

Rare

Anaphylactic reactions2, anaphylactoid reactions (including urticaria)2

Allergic reactions (including pruritus)2

Metabolism and nutrition disorders

Very common

Loss of appetite

Psychiatric disorders

Very common

Crying abnormal, irritability, restlessness

Common

Nervousness

Nervous system disorders

Very common

Somnolence

Rare

Collapse or shock-like state (hypotonic-hyporesponsive episode)2

Very rare

Convulsions (with or without fever)

Respiratory, thoracic and mediastinal disorders

Uncommon

Cough

Rare

Bronchitis, apnoea2 [see section 4.4 for apnoea in very preterm infants (≤ 28 weeks of gestation)]

Gastrointestinal disorders

Common

Diarrhoea, vomiting

Skin and subcutaneous tissue disorders

Rare

Rash, Angioedema2

Very rare

Dermatitis

General disorders and administration site conditions

Very common

Fever ≥ 38°C, pain, redness, local swelling at the injection site (≤ 50 mm)

Common

Fever >39.5°C, injection site reactions, including induration, local swelling at the injection site (> 50 mm)1

Uncommon

Diffuse swelling of the injected limb, sometimes involving the adjacent joint1, fatigue

Rare

Swelling of the entire injected limb1, 2, extensive swelling reactions2, injection site mass2, injection site vesicles2

1 Children primed with acellular pertussis vaccines are more likely to experience swelling reactions after booster administration in comparison with children primed with whole cell vaccines. These reactions resolve over an average of 4 days.

2 Adverse reactions from spontaneous reporting.

• Experience in co-administration:

Analysis of postmarketing reporting rates suggests a potential increased risk of convulsions (with or without fever) and HHE when comparing groups which reported use of Infanrix hexa with Prevenar 13 to those which reported use of Infanrix hexa alone.

In clinical studies in which some of the vaccinees received Infanrix hexa concomitantly with Prevenar (PCV7) as a booster (4th) dose of both vaccines, fever ≥ 38.0°C was reported in 43.4% of infants receiving Prevenar and Infanrix hexa at the same time as compared to 30.5% of infants receiving the hexavalent vaccine alone. Fever ≥39.5°C was observed in 2.6% and 1.5% of infants receiving Infanrix hexa with or without Prevenar, respectively (see sections 4.4 and 4.5). The incidence and severity of fever following co-administration of the two vaccines in the primary series was lower than that observed after the booster dose.

Data from clinical studies show similar incidences of fever when Infanrix hexa is co-administered with other pneumococcal saccharide conjugated vaccine.

In a clinical study in which some of the vaccinees received a booster dose of Infanrix hexa concomitantly with measles-mumps-rubella-varicella (MMRV) vaccine, fever ≥ 38.0°C was reported in 76.6% of children receiving MMRV vaccine and Infanrix hexa at the same time, as compared to 48% of children receiving Infanrix hexa alone and 74.7% of children receiving MMRV vaccine alone. Fever of greater than 39.5°C was reported in 18% of children receiving Infanrix hexa with MMRV vaccine, as compared to 3.3% of children receiving Infanrix hexa alone and 19.3% of children receiving MMRV alone (see sections 4.4 and 4.5).

• Safety in preterm infants:

Infanrix hexa has been administered to more than 1000 preterm infants (born after a gestation period of 24 to 36 weeks) in primary vaccination studies and in more than 200 preterm infants as a booster dose in the second year of life. In comparative clinical studies, similar rates of symptoms were observed in preterm and full-term infants (refer to section 4.4 for information on apnoea).

• Safety in infants and toddlers born to mothers vaccinated with dTpa during pregnancy

In two clinical studies, Infanrix hexa has been administered to more than 500 subjects born to mothers vaccinated with dTpa (n=341) or placebo (n=346) during the third trimester of pregnancy (see section 5.1). The safety profile of Infanrix hexa was similar regardless of exposure/non-exposure to dTpa during pregnancy.

• Experience with hepatitis B vaccine:

In extremely rare cases, allergic reactions mimicking serum sickness, paralysis, neuropathy, neuritis, hypotension, vasculitis, lichen planus, erythema multiforme, arthritis, muscular weakness, Guillain-Barré syndrome, encephalopathy, encephalitis and meningitis have been reported. The causal relationship to the vaccine has not been established.

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 viathe Yellow Card Scheme.

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

4.9. Overdose

No case of overdose has been reported.