Leaflet HEXYON suspension for injection in pre-filled syringe

Hexyon suspension for injection in pre-filled syringe

Hexyon suspension for injection

Diphtheria, tetanus, pertussis (acellular, component), hepatitis B (rDNA), poliomyelitis (inactivated)and Haemophilus influenzae type b conjugate vaccine (adsorbed).

One dose1 (0.5 mL) contains:

Diphtheria Toxoid not less than 20 IU2,4 (30 Lf)

Tetanus Toxoid not less than 40 IU3,4 (10 Lf)

Bordetella pertussis antigens

Pertussis Toxoid 25 micrograms

Filamentous Haemagglutinin 25 micrograms

Poliovirus (Inactivated)5

Type 1 (Mahoney) 29 D-antigen units6

Type 2 (MEF-1) 7 D-antigen units6

Type 3 (Saukett) 26 D-antigen units6

Hepatitis B surface antigen7 10 micrograms

Haemophilus influenzae type b polysaccharide 12 micrograms(Polyribosylribitol Phosphate)conjugated to Tetanus protein 22-36 micrograms1 Adsorbed on aluminium hydroxide, hydrated (0.6 mg Al3+)2 As lower confidence limit (p= 0.95) and not less than 30 IU as mean value3 As lower confidence limit (p= 0.95)4 Or equivalent activity determined by an immunogenicity evaluation5 Cultivated on Vero cells6 These antigen quantities are strictly the same as those previously expressed as 40-8-32 D-antigenunits, for virus type 1, 2 and 3 respectively, when measured by another suitable immunochemicalmethod7 Produced in yeast Hansenula polymorpha cells by recombinant DNA technology

The vaccine may contain traces of glutaraldehyde, formaldehyde, neomycin, streptomycin andpolymyxin B which are used during the manufacturing process (see section 4.3).

Phenylalanine……………85 micrograms(See section 4.4)

For the full list of excipients, see section 6.1.

Suspension for injection.

Hexyon is a whitish, cloudy suspension.

Hexyon (DTaP-IPV-HB-Hib) is indicated for primary and booster vaccination of infants and toddlersfrom six weeks of age against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasivediseases caused by Haemophilus influenzae type b (Hib).

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

The primary vaccination consists of 2 doses (with an interval of at least 8 weeks) or 3 doses (with aninterval of at least 4 weeks) in accordance with the official recommendations.

All vaccination schedules including the WHO Expanded Program on Immunisation (EPI) at 6, 10,14 weeks of age can be used whether or not a dose of hepatitis B vaccine has been given at birth.

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

- Hexyon can be used for supplementary doses of hepatitis B vaccine from the age of 6 weeks. Ifa second dose of hepatitis B vaccine is required before this age, monovalent hepatitis B vaccineshould be used.

- Hexyon can be used for a mixed hexavalent/pentavalent/hexavalent combined vaccineimmunisation schedule in accordance with official recommendations.

Booster vaccination

After a 2-dose primary vaccination with Hexyon, a booster dose must be given.

After a 3-dose primary vaccination with Hexyon, a booster dose should be given.

Booster doses should be given at least 6 months after the last priming dose and in accordance with theofficial recommendations. As a minimum, a dose of Hib vaccine must be administered.

In addition:

In the absence of hepatitis B vaccination at birth, it is necessary to give a hepatitis B vaccine boosterdose. Hexyon can be considered for the booster.

When a hepatitis B vaccine is given at birth, after a 3-dose primary vaccination, Hexyon or apentavalent DTaP-IPV/Hib vaccine can be administered for the booster.

Hexyon may be used as a booster in individuals who have previously been vaccinated with anotherhexavalent vaccine or a pentavalent DTaP-IPV/Hib vaccine associated with a monovalent hepatitis Bvaccine.

WHO-EPI schedule (6, 10, 14 weeks):

After a WHO-EPI schedule, a booster dose should be given

- As a minimum, a booster dose of polio vaccine should be given

- In absence of hepatitis B vaccine at birth, a hepatitis B vaccine booster must be given

- Hexyon can be considered for the booster

The safety and efficacy of Hexyon in infants less than 6 weeks of age have not been established. Nodata are available.

No data are available in older children (see sections 4.8 and 5.1)

Immunisation must be carried out by intramuscular (IM) injection. The recommended injection sitesare the antero-lateral area of the upper thigh (preferred site) or the deltoid muscle in older children(possibly from 15 months of age).

For instructions on handling, see section 6.6.

History of an anaphylactic reaction after a previous administration of Hexyon.

Hypersensitivity to the active substances, to any of the excipients listed in section 6.1, to traceresiduals (glutaraldehyde, formaldehyde, neomycin, streptomycin and polymyxin B), to any pertussisvaccine, or after previous administration of Hexyon or a vaccine containing the same components orconstituents.

Vaccination with Hexyon is contraindicated if the individual has experienced an encephalopathy ofunknown aetiology, occurring within 7 days following prior vaccination with a pertussis containingvaccine (whole cell or acellular pertussis vaccines).

In these circumstances pertussis vaccination should be discontinued and the vaccination course shouldbe continued with diphtheria, tetanus, hepatitis B, poliomyelitis and Hib vaccines.

Pertussis vaccine should not be administered to individuals with uncontrolled neurologic disorder oruncontrolled epilepsy until treatment for the condition has been established, the condition hasstabilised and the benefit clearly outweighs the risk.

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

Hexyon will not prevent disease caused by pathogens other than Corynebacterium diphtheriae,

Clostridium tetani, Bordetella pertussis, hepatitis B virus, poliovirus or Haemophilus influenzaetype 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.

Hexyon will not protect against hepatitis infection caused by other agents such as hepatitis A, hepatitis

C and hepatitis E or by other liver pathogens.

Because of the long incubation period of hepatitis B, it is possible for unrecognised hepatitis Binfection to be present at the time of vaccination. The vaccine may not prevent hepatitis B infection insuch cases.

Hexyon does not protect against infectious diseases caused by other types of Haemophilus influenzaeor against meningitis of other origins.

Prior to immunisation

Immunisation should be postponed in individuals suffering from moderate to severe acute febrileillness or infection. The presence of a minor infection and/or low-grade fever should not result in thedeferral of vaccination.

Vaccination should be preceded by a review of the person’s medical history (in particular previousvaccinations and possible adverse reactions). The administration of Hexyon must be carefullyconsidered in individuals who have a history of serious or severe reactions within 48 hours followingadministration of a vaccine containing similar components.

Before the injection of any biological medicinal product, the person responsible for administrationmust take all precautions known for the prevention of allergic or any other reactions. As with allinjectable vaccines, appropriate medical treatment and supervision should always be readily availablein case of an anaphylactic reaction following administration of the vaccine.

If any of the following events are known to have occurred after receiving any pertussis containingvaccine, the decision to give further doses of pertussis containing vaccine should be carefullyconsidered:

* Temperature of ≥40°C within 48 hours of vaccination not due to another identifiable cause;

* Collapse or shock-like state (hypotonic-hyporesponsive episode) within 48 hours ofvaccination;

* 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 some circumstances, such as high incidence of pertussis, when the potential benefitsoutweigh possible risks.

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 Hexyon. Individuals with a history of febrileconvulsions should be closely followed up as such adverse events may occur within 2 to 3 days postvaccination.

If Guillain-Barré syndrome or brachial neuritis has occurred following receipt of prior vaccinecontaining tetanus toxoid, the decision to give any vaccine containing tetanus toxoid should be basedon careful consideration of the potential benefits and possible risks, such as whether or not the primaryvaccination has been completed. Vaccination is usually justified for individuals whose primaryvaccination is incomplete (i.e. fewer than three doses have been received).

The immunogenicity of the vaccine may be reduced by immunosuppressive treatment orimmunodeficiency. It is recommended to postpone vaccination until the end of such treatment ordisease. Nevertheless, vaccination of individuals with chronic immunodeficiency such as HIVinfection is recommended even if the antibody response may be limited.

Immunogenicity data are available for 105 preterm infants. These data support the use of Hexyon inpreterm infants. As expected in preterm infants, lower immune response has been observed for someantigens, when indirectly compared to term infants, although seroprotective levels have been achieved(see section 5.1). No safety data were collected in preterm infants (born ≤37 weeks of gestation) inclinical trials.

The potential risk of apnoea and the need for respiratory monitoring for 48 to 72 hours should beconsidered 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 ordelayed.

Immune responses to the vaccine have not been studied in the context of genetic polymorphism.

In individuals with chronic renal failure, an impaired hepatitis B response is observed andadministration of additional doses of hepatitis B vaccine should be considered according to theantibody level against hepatitis B virus surface antigen (anti-HBsAg).

Immunogenicity data in HIV-exposed infants (infected and uninfected) showed that Hexyon isimmunogenic in the potentially immunodeficient population of HIV-exposed infants whatever their

HIV status at birth (see section 5.1). No specific safety concern was observed in this population.

Precautions for use

Do not administer by intravascular, intradermal or subcutaneous injection.

As with all injectable vaccines, the vaccine must be administered with caution to individuals withthrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscularadministration.

Syncope can occur following, or even before, any vaccination as a psychogenic response to the needleinjection. Procedures should be in place to prevent falling and injury and to manage syncope.

Interference with laboratory testing

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

Hexyon contains phenylalanine, potassium and sodium

Hexyon contains 85 micrograms phenylalanine in each 0.5-mL dose. Phenylalanine may be harmfulfor individuals with phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds upbecause the body cannot remove it properly.

Hexyon contains less than 1 mmol potassium (39 mg) and less than 1 mmol sodium (23 mg) per dose,that is to say essentially “potassium-free” and “sodium-free”.

Hexyon can be administered simultaneously with a pneumococcal polysaccharide conjugate vaccine,measles, mumps, rubella (MMR) and varicella-containing vaccines, rotavirus vaccines, ameningococcal C conjugate vaccine or a meningococcal group A, C, W-135 and Y conjugate vaccine,as no clinically relevant interference in the antibody response to each of the antigens has been shown.

If co-administration with another vaccine is considered, immunisation should be carried out onseparate injection sites.

Hexyon must not be mixed with any other vaccines or other parenterally administered medicinalproducts.

No significant clinical interaction with other treatments or biological products has been reportedexcept in the case of immunosuppressive therapy (see section 4.4).

For interference with laboratory testing, see section 4.4.

Not applicable. This vaccine is not intended for administration to women of child-bearing age.

Not applicable.

In clinical studies in individuals who received Hexyon, the most frequently reported reactions includeinjection-site pain, irritability, crying, and injection-site erythema.

Slightly higher solicited reactogenicity was observed after the first dose compared to subsequentdoses.

The safety of Hexyon in children over 24 months of age has not been studied in clinical trials.

The following convention has been used for the classification of adverse reactions;

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)

Not known (cannot be estimated from available data)

Within each frequency grouping the adverse reactions are presented in the order of decreasingseriousness.

Table 1: Adverse Reactions from clinical trials and post marketing surveillance

System Organ Class Frequency Adverse Events

Immune system disorders Uncommon Hypersensitivity reaction

Rare Anaphylactic reaction*

Metabolism and nutrition Very common Anorexia (decreased appetite)disorders

Nervous system disorders Very common Crying, somnolence

Common Abnormal crying (prolonged crying)

Rare Convulsions with or without fever*

Very rare Hypotonic reactions or hypotonic-hyporesponsive episodes (HHE)

Gastrointestinal disorders Very common Vomiting

Common Diarrhoea

Skin and subcutaneous Rare Rashtissue disorders

General disorders and Very common Pyrexia (body temperature ≥38.0°C)administration site Irritabilityconditions Injection-site pain, injection-site erythema,injection-site swelling

Common Injection-site induration

Uncommon Pyrexia (body temperature ≥39.6°C)

Injection-site nodule

Rare Extensive limb swelling†

*Adverse reactions from spontaneous reporting.

†See section Description of selected adverse reactions

Extensive limb swelling: Large injection-site reactions (>50 mm), including extensive limb swellingfrom the injection site beyond one or both joints, have been reported in children. These reactions startwithin 24-72 hours after vaccination, may be associated with erythema, warmth, tenderness or pain atthe injection site and resolve spontaneously within 3-5 days. The risk appears to be dependent on thenumber of prior doses of acellular pertussis containing vaccine, with a greater risk following the 4thdose.

Potential adverse events

These are adverse events that have been reported with other vaccines containing one or more of thecomponents or constituents of Hexyon and not directly with Hexyon.

- Brachial neuritis and Guillain-Barré Syndrome have been reported after administration of a tetanustoxoid-containing vaccine

- Peripheral neuropathy (polyradiculoneuritis, facial paralysis), optic neuritis, central nervous systemdemyelination (multiple sclerosis) have been reported after administration of a hepatitis Bantigen-containing vaccine

- Encephalopathy/encephalitis

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

Oedematous reaction affecting one or both lower limbs may occur following vaccination with

Haemophilus influenzae type b-containing vaccines. If this reaction occurs, it is mainly after primaryinjections and within the first few hours following vaccination. Associated symptoms may includecyanosis, redness, transient purpura, and severe crying. All events should resolve spontaneouslywithout sequel within 24 hours.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No cases of overdose have been reported.

Pharmaco-therapeutic group: Vaccines, bacterial and viral vaccines combined, ATC code: J07CA09

The immunogenicity of Hexyon in children over 24 months of age has not been studied in clinicaltrials.

Results obtained for each of the components are summarised in the tables below:

Table 1: Seroprotection/Seroconversion rates* one month after a primary vaccination with 2 or3 doses of Hexyon

Antibody Thresholds Two doses Three doses3-5 6-10-14 2-3-4 2-4-6

Months Weeks Months Months

N=249** N=123 to N=934 to

N=322††220† 1270‡% % % %

Anti-diphtheria99.6 97.6 99.7 97.1(0.01 IU/mL)

Anti-tetanus100.0 100.0 100.0 100.0(0.01 IU/mL)

Anti PT(Seroconversion‡‡) 93.4 93.6 88.3 96.0(Vaccine response§) 98.4 100.0 99.4 99.7

Anti FHA(Seroconversion‡‡) 92.5 93.1 90.6 97.0(Vaccine response§) 99.6 100.0 99.7 99.9

With hepatitis B

Anti-HBs vaccination at birth/99.0/99.7(10

Without hepatitis BmIU/mL) 97.2vaccination at birth 95.7 96.8 98.8

Anti-Polio type 190.8 100.0 99.4 99.9(8 (1/dilution))

Anti-Polio type 295.0 98.5 100.0 100.0(8 (1/dilution))

Anti-Polio type 396.7 100.0 99.7 99.9(8 (1/dilution))

Anti-PRP71.5 95.4 96.2 98.0(0.15 µg/mL)

* Generally accepted surrogates (PT, FHA) or correlates of protection (other components)

N = Number of individuals analysed (per protocol set)

** 3, 5 months without hepatitis B vaccination at birth (Finland, Sweden)† 6, 10, 14 weeks with and without hepatitis B vaccination at birth (Republic of South Africa)†† 2, 3, 4 months without hepatitis B vaccination at birth (Finland)‡ 2, 4, 6 months without hepatitis B vaccination at birth (Argentina, Mexico, Peru) and with hepatitis Bvaccination at birth (Costa Rica and Colombia)‡‡ Seroconversion: minimum 4-fold increase compared to pre-vaccination level (pre-dose 1)§ Vaccine response: If pre-vaccination antibody concentration <8 EU/mL, then the post-vaccination antibodyconcentration should be ≥8 EU/mL. Otherwise, post-vaccination antibody concentration should be ≥ pre-immunisation level.

Table 2: Seroprotection/Seroconversion rates* one month after booster vaccination with Hexyon

Booster

Antibody Thresholdsvaccination at

Booster vaccination during the11-12 monthssecond year of life following aof age after athree-dose primary coursetwo-doseprimary course3-5 6-10-14 2-3-4 2-4-6

Months Weeks Months Months

N=249** N=204† N=178†† N=177 to396‡% % % %

Anti-diphtheria100.0 100.0 100.0 97.2(0.1 IU/mL)

Anti-tetanus100.0 100.0 100.0 100.0(0.1 IU/mL)

Anti-PT(Seroconversion‡‡) 94.3 94.4 86.0 96.2(Vaccine response§) 98.0 100.0 98.8 100.0

Anti-FHA(Seroconversion‡‡) 97.6 99.4 94.3 98.4(Vaccine response§) 100.0 100.0 100.0 100.0

With hepatitis B/ 100.0/99.7

Anti-HBs vaccination at birth(10 mIU/mL) Without hepatitis B96.4 98.5 99.4vaccination at birth 98.9

Anti-Polio type 1100.0 100.0 98.9 100.0(8 (1/dilution))

Anti-Polio type 2100.0 100.0 100.0 100.0(8 (1/dilution))

Anti-Polio type 399.6 100.0 100.0 100.0(8 (1/dilution))

Anti-PRP93.5 98.5 98.9 98.3(1.0 µg/mL)

* Generally accepted surrogates (PT, FHA) or correlates of protection (other components)

N = Number of individuals analysed (per protocol set)

** 3, 5 months without hepatitis B vaccination at birth (Finland, Sweden)† 6, 10, 14 weeks with and without hepatitis B vaccination at birth (Republic of South Africa)†† 2, 3, 4 months without hepatitis B vaccination at birth (Finland)‡ 2, 4, 6 months without hepatitis B vaccination at birth (Mexico) and with hepatitis B vaccination at birth (Costa

Rica and Colombia)‡‡ Seroconversion: minimum 4-fold increase compared to pre-vaccination level (pre-dose 1)§ Vaccine response: If pre-vaccination antibody concentration (pre-dose 1) <8 EU/mL, then the post-boosterantibody concentration should be ≥8 EU/mL. Otherwise, post-booster antibody concentration should be ≥pre-immunisation level (pre-dose 1)

Immune responses to Hib and pertussis antigens after 2 doses at 2 and 4 months of age

The immune responses to Hib (PRP) and pertussis antigens (PT and FHA) were evaluated after 2doses in a subset of subjects receiving Hexyon (N=148) at 2, 4, 6 months of age. The immuneresponses to PRP, PT and FHA antigens one month after 2 doses given at 2 and 4 months of age weresimilar to those observed one month after a 2-dose priming given at 3 and 5 months of age:

- anti-PRP titers ≥0.15 µg/mL were observed in 73.0% of individuals,

- anti-PT vaccine response in 97.9% of individuals,

- anti-FHA vaccine response in 98.6% of individuals.

Persistence of immune response

Studies on long-term persistence of vaccine induced antibodies following varying infant/toddlerprimary series and following Hepatitis B vaccine given at birth or not have shown maintenance oflevels above the recognized protective levels or antibody thresholds for the vaccine antigens (see

Table 3).

Table 3: Seroprotection ratesa at the age of 4.5 years old after vaccination with Hexyon

Antibody Thresholds Primary 2-4-6 months

Primary 6-10-14 weeks and booster atand booster at15-18 months12-24 months

Without hepatitis B With hepatitis B With hepatitis B atat birth at birth birth

N=173b N=103b N=220c% % %

Anti-diphtheria(0.01 IU/mL) 98.2 97 100(0.1 IU/mL) 75.3 64.4 57.2

Anti-tetanus(0.01 IU/mL) 100 100 100(0.1 IU/mL) 89.5 82.8 80.8

Anti-PTe(8 EU/mL) 42.5 23.7 22.2

Anti-FHAe(8 EU/mL) 93.8 89.0 85.6

Anti-HBs(10 mIU/mL) 73.3 96.1 92.3

Anti-Polio type 1(8 (1/dilution)) NAd NAd 99.5

Anti-Polio type 2(8 (1/dilution)) NAd NAd 100

Anti-Polio type 3(8 (1/dilution)) NAd NAd 100

Anti-PRP(0.15 µg/mL) 98.8 100 100

N = Number of individuals analysed (per protocol set)a Generally accepted surrogates (PT, FHA) or correlates of protection (other components)b 6, 10, 14 weeks with and without hepatitis B vaccination at birth (Republic of South Africa)c 2, 4, 6 months with hepatitis B vaccination at birth (Colombia)d Due to an OPV National Immunisation Days in the country, Polio results have not been analysede 8 EU/mL corresponds to 4 LLOQ (Lower Limit Of Quantification in enzyme-linked immunosorbent assay

ELISA)

LLOQ value for anti-PT and anti-FHA is 2 EU/mL

The persistence of the immune responses against the hepatitis B component of Hexyon was evaluatedin infants primed from two different schedules.

For a 2-dose primary infant series at 3 and 5 months of age without hepatitis B at birth, followed by atoddler booster at 11-12 months of age, 53.8% of children were seroprotected (anti-HBsAg≥10 mIU/mL) at 6 years of age, and 96.7% presented an anamnestic response after a challenge dosewith a standalone Hepatitis B vaccine.

For a primary series consisting of one dose of hepatitis B vaccine given at birth followed by a 3-doseinfant series at 2, 4, and 6 months of age without a toddler booster, 49.3% of children wereseroprotected (anti-HBsAg ≥10 mIU/mL) at 9 years of age, and 92.8% presented an anamnesticresponse after a challenge dose with a standalone Hepatitis B vaccine.

These data support persisting immune memory induced in infants primed with Hexyon.

Immune responses to Hexyon in preterm infants

Immune responses to Hexyon antigens in preterm (105) infants (born after a gestation period of 28 to36 weeks), including 90 infants born to women vaccinated with Tdap vaccine during pregnancy and15 to women not vaccinated during pregnancy, were evaluated following a 3-dose primary vaccinationcourse at 2, 3, and 4 months of age, and a booster dose at 13 months of age.

One month after primary vaccination, all subjects were seroprotected against diphtheria(≥0.01 IU/mL), tetanus (≥0.01 IU/mL), and poliovirus types 1, 2 and 3 (≥8 (1/dilution)); 89.8% ofsubjects were seroprotected against hepatitis B (≥10 IU/mL) and 79.4% were seroprotected against

Hib invasive diseases (≥0.15 µg/mL).

One month after the booster dose, all subjects were seroprotected against diphtheria (≥0.1 IU/mL),tetanus (≥0.1 IU/mL), and poliovirus types 1, 2 and 3 (≥8 (1/dilution)); 94.6% of subjects wereseroprotected against hepatitis B (≥10 IU/mL) and 90.6% were seroprotected against Hib invasivediseases (≥1 µg/mL).

Regarding pertussis, one month after primary vaccination 98.7% and 100% of subjects developedantibodies ≥8 EU/mL against PT and FHA antigens, respectively. One month after the booster dose,98.8% of subjects developed antibodies ≥8 EU/mL against both PT and FHA antigens. Pertussisantibody concentrations increased by 13-fold after primary vaccination and by 6- to 14-fold after thebooster dose.

Immune responses to Hexyon in infants born to women vaccinated with Tdap during pregnancy

Immune responses to Hexyon antigens in term (109) and preterm (90) infants born to womenvaccinated with Tdap vaccine during pregnancy (between 24 and 36 weeks of gestation) wereevaluated following a 3-dose primary vaccination course at 2, 3, and 4 months of age, and a boosterdose at 13 (preterm infants) or 15 (term infants) months of age.

One month after primary vaccination, all subjects were seroprotected against diphtheria(≥0.01 IU/mL), tetanus (≥0.01 IU/mL), and poliovirus types 1 and 3 (≥8 (1/dilution)); 97.3% ofsubjects were seroprotected against poliovirus type 2 (≥8 (1/dilution)); 94.6% of subjects wereseroprotected against hepatitis B (≥10 IU/mL) and 88.0% were seroprotected against Hib invasivediseases (≥0.15 µg/mL).

One month after the booster dose, all subjects were seroprotected against diphtheria (≥0.1 IU/mL),tetanus (≥0.1 IU/mL), and poliovirus types 1, 2 and 3 (≥8 (1/dilution)); 93.9% of subjects wereseroprotected against hepatitis B (≥10 IU/mL) and 94.0% were seroprotected against Hib invasivediseases (≥1 µg/mL).

Regarding pertussis, one month after primary vaccination 99.4% and 100% of subjects developedantibodies ≥8 EU/mL against PT and FHA antigens, respectively. One month after the booster dose,99.4% of subjects developed antibodies ≥8 EU/mL against both PT and FHA antigens. Pertussisantibody concentrations were increased by 5- to 9-fold after primary vaccination, and by 8- to 19-foldafter the booster dose.

Immune responses to Hexyon in HIV-exposed infants

Immune responses to Hexyon antigens in 51 HIV-exposed infants (9 infected and 42 uninfected) wereevaluated following a 3-dose primary vaccination course at 6, 10, and 14 weeks of age, and a boosterdose at 15 to 18 months of age.

One month after primary vaccination, all infants were seroprotected against diphtheria (≥0.01 IU/mL),tetanus (≥0.01 IU/mL), poliovirus types 1, 2, and 3 (≥8 (1/dilution), hepatitis B (≥10 IU/mL), andmore than 97.6% for Hib invasive diseases (≥0.15 µg/mL).

One month after the booster dose, all subjects were seroprotected against diphtheria (≥0.1 IU/mL),tetanus (≥0.1 IU/mL), poliovirus types 1, 2 and 3 (≥8 (1/dilution), hepatitis B (≥10 IU/mL), and morethan 96.6% for Hib invasive diseases (≥1 µg/mL).

Regarding pertussis, one month after primary vaccination, 100% of subjects developed antibodies≥8 EU/mL against both PT and FHA antigens. One month after the booster dose, 100% of subjectsdeveloped antibodies ≥8 EU/mL against both PT and FHA antigens. Seroconversion rates defined asminimum 4-fold increase compared to pre-vaccination level (pre-dose 1) were 100% in the

HIV-exposed and infected group for anti-PT and anti-FHA; and 96.6% for anti-PT, and 89.7% foranti-FHA in the HIV-exposed and uninfected group.

Efficacy and effectiveness in protecting against pertussis

Vaccine efficacy of the acellular pertussis (aP) antigens contained in Hexyon against the most severe

WHO-defined typical pertussis (21 days of paroxysmal cough) is documented in a randomiseddouble-blind study among infants with a 3-dose primary series using a DTaP vaccine in a highlyendemic country (Senegal). The need for a toddler booster dose was seen in this study.

The long-term capability of the acellular pertussis (aP) antigens contained in Hexyon to reducepertussis incidence and control pertussis disease in childhood has been demonstrated in a 10-yearnational pertussis surveillance on pertussis disease in Sweden with the pentavalent DTaP-IPV/Hibvaccine using a 3, 5, 12 months schedule. Results of long-term follow-up demonstrated a dramaticreduction of the pertussis incidence following the second dose regardless of the vaccine used.

Effectiveness in protecting against Hib invasive disease

The vaccine effectiveness against Hib invasive disease of DTaP and Hib combination vaccines(pentavalent and hexavalent including vaccines containing the Hib antigen from Hexyon) has beendemonstrated in Germany via an extensive (over five years follow-up period) post-marketingsurveillance study. The vaccine effectiveness was of 96.7% for the full primary series, and 98.5% forthe booster dose (irrespective of priming).

No pharmacokinetic studies have been performed.

Non-clinical data reveal no special hazard for humans based on conventional repeat dose toxicity andlocal tolerance studies.

At the injection sites, chronic histological inflammatory changes were observed that are expected tohave a slow recovery.

Disodium hydrogen phosphate

Potassium dihydrogen phosphate

Trometamol

Sucrose

Essential amino acids including L-phenylalanine

Sodium hydroxide, acetic acid or hydrochloric acid (for pH adjustment)

Water for injections.

For adsorbent: see section 2.

In the absence of compatibility studies, this vaccine must not be mixed with other vaccines ormedicinal products.

4 years.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Keep the container in the outer carton in order to protect it from the light.

Stability data indicate that the vaccine components are stable at temperatures up to 25°C for 72 hours.

At the end of this period, Hexyon should be used or discarded. These data are intended to guidehealthcare professionals in case of temporary temperature excursion only.

Hexyon in pre-filled syringes0.5 mL of suspension in pre-filled syringe (type I glass) equipped with a plunger stopper (halobutyl)and a Luer lock adaptor with a tip cap (halobutyl + polypropylene).

Pack of 1, 10 or 50 or Multipack of 50 (5 packs of 10) pre-filled syringe(s) without needle(s).

Pack of 1 or 10 pre-filled syringe(s) with separate needle(s) (stainless steel).

Pack of 1 or 10 pre-filled syringe(s) with separate needle(s) (stainless steel) with safety shield(polycarbonate).

Hexyon in vials0.5 mL suspension in vial (type I glass) with a stopper (halobutyl).

Pack size of 10 vials.

Not all pack sizes may be marketed.

Hexyon in pre-filled syringes

Prior to administration, the pre-filled syringe should be shaken in order to obtain a homogeneous,whitish, cloudy suspension.

Preparation for administration

The syringe with suspension for injection should be visually inspected prior to administration. In theevent of any foreign particulate matter, leakage, premature activation of the plunger or faulty tip seal,discard the pre-filled syringe.

The syringe is intended for single use only and must not be reused.

Instructions for use of Luer Lock pre-filled syringe

Picture A: Luer Lock syringe with Rigid Tip Cap

Step 1: Holding the Luer Lock adapter inone hand (avoid holding the syringeplunger or barrel), unscrew the tip cap bytwisting it.

Step 2: To attach the needle to thesyringe, gently twist the needle into the

Luer Lock adapter of the syringe untilslight resistance is felt.

Instructions for use of safety needle with Luer Lock pre-filled syringe

Picture B: Safety Needle (inside case) Picture C: Safety Needle Components (prepared foruse)

Follow Step 1 and 2 above to prepare the Luer Lock syringe and needle for attachment.

Step 3: Pull the safety needle’s casestraight off. The needle is covered by thesafety shield and protector.

Step 4:

A: Move the safety shield away from theneedle and toward the syringe barrel to theangle shown.

B: Pull the protector straight off.

Step 5: After injection is complete, lock(activate) the safety shield using one of thethree (3) one-handed techniquesillustrated: surface, thumb or fingeractivation.

Note: Activation is verified by an audibleand/or tactile “click.”

Step 6: Visually inspect the safety shieldactivation. The safety shield should be fullylocked (activated) as shown in Figure C.

Note: When fully locked (activated), theneedle should be at an angle to the safetyshield.

Figure D shows the safety shield is NOTfully locked (not activated).

Caution: Do not attempt to unlock (deactivate) the safety device by forcing the needle out ofthe safety shield.

Hexyon in vials

The vial is intended for single use only and must not be reused.

Prior to administration, the vial should be shaken in order to obtain a homogeneous, whitish, cloudysuspension.

The suspension should be visually inspected prior to administration. In the event of any foreignparticulate matter and/or variation of physical aspect being observed, discard the vial.

A dose of 0.5 mL is withdrawn using a syringe for injection.

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

Sanofi Winthrop Industrie, 82 Avenue Raspail, 94250 Gentilly, France

Hexyon in vials

EU/1/13/829/001

Hexyon in pre-filled syringes

EU/1/13/829/002

EU/1/13/829/003

EU/1/13/829/004

EU/1/13/829/005

EU/1/13/829/006

EU/1/13/829/007

EU/1/13/829/008

EU/1/13/829/009

EU/1/13/829/010

EU/1/13/829/011

Date of first authorisation: 17 April 2013

Date of latest renewal: 08 January 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu