Hexyon (diphtheria toxoid/ tetanus toxoid/ two-component...) – Summary of product characteristics - J07CA09

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1.NAME OF THE MEDICINAL PRODUCT

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).

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

1Adsorbed on aluminium hydroxide, hydrated (0.6 mg Al3+)

2As lower confidence limit (p= 0.95)

3Produced on Vero cells

4Or equivalent antigenic quantity determined by a suitable immunochemical method

5Produced in yeast Hansenula polymorpha cells by recombinant DNA technology

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

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Suspension for injection.

Hexyon is a whitish, cloudy suspension.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

Hexyon (DTaP-IPV-HB-Hib) is indicated for primary and booster vaccination of infants and toddlers from six weeks of age against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and invasive

diseases caused by Haemophilus influenzae type b (Hib).

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

4.2Posology and method of administration

Posology

Primary vaccination:

The primary vaccination consists of two doses (with an interval of at least 8 weeks) or three doses (with an interval 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 six weeks. If a second dose of hepatitis B vaccine is required before this age, monovalent hepatitis B vaccine should be used.

When a dose of hepatitis B vaccine is given at birth, the sequential infant primary vaccination hexavalent/pentavalent/hexavalent schedule with Hexyon and a pentavalent DTaP-IPV/Hib vaccine can be used 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 the official recommendations. At the very least, 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 booster dose. Hexyon can be considered for the booster.

After a 3-dose WHO EPI schedule with Hexyon (6, 10, 14 weeks) and in the absence of hepatitis B vaccination at birth, a hepatitis B vaccine booster must be given. At the very least, a booster dose of polio vaccine should be given. Hexyon can be considered for the booster.

When a hepatitis B vaccine is given at birth, after a 3-dose primary vaccination, Hexyon or a pentavalent 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 another hexavalent vaccine or a pentavalent DTaP-IPV/Hib vaccine associated with a monovalent hepatitis B vaccine.

Other paediatric population:

The safety and efficacy of Hexyon in infants less than 6 weeks of age have not been established. No data are available.

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

Method of administration

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

For instructions on handling see section 6.6.

4.3Contraindications

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 trace residuals (glutaraldehyde, formaldehyde, neomycin, streptomycin and polymyxin B), to any pertussis vaccine, or after previous administration of Hexyon or a vaccine containing the same components or constituents.

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

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

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

4.4Special warnings and precautions for use

Hexyon 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.

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 B infection to be present at the time of vaccination. The vaccine may not prevent hepatitis B infection in such cases.

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

Prior to immunisation

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

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

Before the injection of any biological, the person responsible for administration must take all precautions known for the prevention of allergic or any other reactions. As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in 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 containing vaccine, the decision to give further doses of pertussis containing vaccine should be carefully considered:

•Temperature of ≥ 40°C within 48 hours 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 some circumstances, such as high incidence of pertussis, when the potential benefits outweigh 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 febrile convulsions should be closely followed up as such adverse events may occur within 2 to 3 days post vaccination.

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

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

Special populations

No data are available for premature infants. However, a lower immune response may be observed and the level of clinical protection is unknown.

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 and administration of additional doses of hepatitis B vaccine should be considered according to the antibody level against hepatitis B virus surface antigen (anti-HBsAg).

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 with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration.

The potential risk of apnoea and the need for respiratory monitoring for 48 to 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.

Interference with laboratory testing

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

4.5Interaction with other medicinal products and other forms of interaction

Data on concomitant administration of Hexyon with a pneumococcal polysaccharide conjugate vaccine have shown no clinically relevant interference in the antibody response to each of the antigens.

Data on concomitant administration of a booster dose of Hexyon with measles-mumps-rubella vaccines have shown no clinically relevant interference in the antibody response to each of the antigens. There may be a clinically relevant interference in the antibody response of Hexyon and a varicella vaccine and these vaccines should not be administered at the same time.

Data on concomitant administration of rotavirus vaccines have shown no clinically relevant interference in the antibody response to each of the antigens.

Data on concomitant administration of Hexyon with a meningococcal C conjugate vaccine or a meningococcal group A, C, W-135 and Y conjugate vaccine have shown no clinically relevant interference in the antibody response to each of the antigens.

If co-administration with another vaccine is considered, immunisation should be carried out on separate injections sites.

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

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

Interference with laboratory testing: see section 4.4.

4.6Fertility, pregnancy and lactation

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

4.7Effects on ability to drive and use machines

Not applicable.

4.8Undesirable effects

a- Summary of the safety profile

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

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

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

b- Tabulated list of adverse reactions

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)

Table 1: Adverse Reactions from clinical trials and reported during commercial use

* Adverse reactions from spontaneous reporting.

† See section c

c- Description of selected adverse reactions

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

d- Potential adverse events (i.e. adverse events which have been reported with other vaccines containing one or more of the components or constituents of Hexyon and not directly with Hexyon)

Nervous system disorders

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

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

-Encephalopathy/encephalitis

Respiratory, thoracic and mediastinal disorders

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

General disorders and administration site conditions

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 primary injections and within the first few hours following vaccination. Associated symptoms may include cyanosis, redness, transient purpura and severe crying. All events should resolve spontaneously without sequel within 24 hours.

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 national reporting system listed in Appendix V.

4.9Overdose

No cases of overdose have been reported.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

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 clinical trials.

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 or 3 doses of Hexyon

*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 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 <8 EU/ml, then the post-vaccination antibody concentration 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

*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-booster antibody 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 2 doses in a subset of subjects receiving Hexyon (N=148) at 2, 4, 6 months of age. The immune responses to PRP, PT and FHA antigens one month after 2 doses given at 2 and 4 months of age were similar 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 and 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 / toddler primary series and following Hepatitis B vaccine given at birth or not have shown maintenance of levels above the recognized protective levels or antibody thresholds for the vaccine antigens (see Table 3).

In addition, immunity against the hepatitis B component of the vaccine has been shown to persist up to 9 years of age after a primary series consisting of one dose of Hepatitis B vaccine given at birth followed by a 3-dose infant series at 2, 4, and 6 months of age without a toddler booster where 49.3% of vaccinees had antibodies ≥ 10 mIU/ml with geometric mean concentrations at 13.3 (95% CI: 8.82 – 20.0) mIU/ml. Immune memory against Hepatitis B had been demonstrated by the presence of an anamnestic response to a challenge Hepatitis B vaccination at the age of 9 years in 93% of vaccinees with development of geometric mean concentrations at 3692 (95% CI: 1886 – 7225) mIU/ml after vaccination.

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

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 have been analysed

e: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

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 randomised double-blind study among infants with a 3 dose primary series using a DTaP vaccine in a highly endemic 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 reduce pertussis incidence and control pertussis disease in the childhood has been demonstrated in a 10-year national pertussis surveillance on pertussis disease in Sweden with the pentavalent DTaP-IPV/Hib vaccine using a 3, 5, 12 months schedule. Results of long term follow-up demonstrated a dramatic reduction 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 been demonstrated in Germany via an extensive (over five years follow-up period) post-marketing surveillance study. The vaccine effectiveness was of 96.7% for the full primary series, and 98.5% for booster dose (irrespective of priming).

5.2Pharmacokinetic properties

No pharmacokinetic studies have been performed.

5.3Preclinical safety data

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

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

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Disodium hydrogen phosphate

Potassium dihydrogen phosphate

Trometamol

Saccharose

Essential amino acids including L-phenylalanine

Water for injections.

For adsorbent: see section 2.

6.2Incompatibilities

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

6.3Shelf life

3 years.

6.4Special precautions for storage

Store in a refrigerator (2 C – 8 C).

Do not freeze.

Keep the container in the outer carton in order to protect from 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 guide healthcare professionals in case of temporary temperature excursion only.

6.5Nature and contents of container

Hexyon in pre-filled syringes

0.5 ml suspension in pre-filled syringe (type I glass) with plunger stopper (halobutyl) and tip cap (halobutyl), without needle.

0.5 ml suspension in pre-filled syringe (type I glass) with plunger stopper (halobutyl) and tip cap (halobutyl), with 1 separate needle.

0.5 ml suspension in pre-filled syringe (type I glass) with plunger stopper (halobutyl) and tip cap (halobutyl), with 2 separate needles.

Pack size of 1 or 10 pre-filled syringes with or without needle. Pack size of 50 pre-filled syringes without needle.

Multipack of 50 (5 packs of 10) pre-filled syringes without needle.

Hexyon in vials

0.5 ml suspension in vial (type I glass) with a stopper (halobutyl). Pack size of 10.

Not all pack sizes may be marketed.

6.6Special precautions for disposal and other handling

Hexyon in pre-filled syringes

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

The suspension should be visually inspected prior to administration. In the event of any foreign particulate matter and/or variation of physical aspect being observed, discard the pre-filled syringe.

For syringes without an attached needle, the needle must be fitted firmly to the syringe, rotating it by a one-quarter turn.

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

Hexyon in vials

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

The suspension should be visually inspected prior to administration. In the event of any foreign particulate 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 local requirements.

7.MARKETING AUTHORISATION HOLDER

Sanofi Pasteur Europe, 2 Avenue Pont Pasteur, 69007 Lyon, France

8.MARKETING AUTHORISATION NUMBER(S)

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

Hexyon in vials

EU/1/13/829/001

9.DATE OF FIRST AUTHORISATION / RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 April 2013

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu