Diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis, hepatitis B (recombinant) and

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 0.5 ml adjuvanted dose contains: Active substances: Purified diphtheria toxoid ....................................................... equal to or greater than 20 IU * (30 Lf) Purified tetanus toxoid ............................................................ equal to or greater than 40 IU * (10 Lf) Purified pertussis toxoid ......................................................... 25 micrograms Purified pertussis filamentous haemagglutinin ...................... 25 micrograms Hepatitis B surface antigen * * ................................................ 5.0 micrograms Inactivated type 1 poliovirus (Mahoney)................................ D antigen ^: 40 units+ Inactivated type 2 poliovirus (MEF 1) ................................... D antigen ^: 8 units+ Inactivated type 3 poliovirus (Saukett) ................................... D antigen ^: 32 units+

type b polysaccharide (polyribosylribitol phosphate) 12 micrograms conjugated to tetanus toxoid (24 micrograms)

* * Surface antigen of hepatitis B virus produced from recombinant strain 2150-2-3 of the yeast

Saccharomyces cerevisiae. ^ Quantity of antigen in the final bulk product, according to W.H.O. (TRS 673, 1992)

PHARMACEUTICAL FORM

Suspension for injection in pre-filled syringe HEXAVAC is a slightly opaque white suspension

CLINICAL PARTICULARS

Posology and method of administration

The primary vaccination schedule consists of two or three doses of 0.5 ml administered within the first year of life according to official recommendations. There should be an interval of at least 1 month between doses : such as 2 , 3, 4 months; 2, 4, 6 months; 3, 5 months.

Booster : After a primary vaccination with 2 doses of HEXAVAC (i.e. 3, 5 months), a booster dose must be given between 11 and 13 months of age; after a primary vaccination with 3 doses of Hexavac (e.g. 2, 3, 4 months; 2, 4, 6 months), a booster dose must be given between 12 and 18 months of age, according to official recommendations. HEXAVAC can be used for the booster dose provided the toddler has received a full primary vaccination course of each of the antigens contained in HEXAVAC regardless of whether they were administered as monovalent or combination vaccines produced by Sanofi Pasteur MSD.

HEXAVAC should be administered intramuscularly into the quadriceps or deltoid preferably at alternating sites for subsequent injections. This vaccine should not be used in newborns, adolescents or adults.

Contraindications

Known hypersensitivity to any component of the vaccine or severe reaction after previous administration of the vaccine. Encephalopathy within 7 days of administration of a previous dose of any vaccine containing pertussis antigens (whole cell or acellular pertussis vaccines). In these circumstances the vaccination course should be continued with vaccine not containing a pertussis component. Vaccination should be postponed in the case of fever or acute disease.

Special warnings and special precautions for use

This vaccine should not be used in newborns, adolescents or adults. Infants born of hepatitis B virus surface antigen (HBsAg)-positive mothers should receive Hepatitis B Immune Globulin (HBIG) and Hepatitis B Vaccine (Recombinant) at birth and should complete the hepatitis B vaccination series. The subsequent administration of HEXAVAC for completion of the hepatitis B vaccination series in infants who were born of HBsAg-positive mothers and received HBIG or infants born of mothers of unknown status has not been studied. HEXAVAC should not be used as the birth dose or subsequent doses during the first year of life for children born to HbsAg- positive mothers. HEXAVAC should be administered with caution to subjects with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects. HEXAVAC should under no circumstances be administered intravascularly. The intradermal or subcutaneous routes must not be used either. If any of the following events are known to have occurred in temporal relation to receipt of the vaccine, the decision to give further doses of pertussis-containing vaccines should be carefully considered: Temperature of 3 40.0 degC within 48 hours, not due to another identifiable cause. Collapse or shock-like state (hypotonic-hyporesponsiveness episode) within 48 hours of vaccination. Persistent, inconsolable crying lasting 3 3 hours, occurring within 48 hours of vaccination. Convulsions with or without fever, occurring within 3 days of vaccination. Antipyretic treatment should be initiated according to local guidelines. As with all injectable vaccines, appropriate medical treatment and supervision should be readily available for immediate use in case of a rare anaphylactic reaction following the administration of vaccine. In subjects who have a history of a severe reaction within 48 hours of a previous injection with a vaccine containing similar components, the course of vaccination should be carefully considered. Because of the long incubation period of hepatitis B, it is possible for unrecognised hepatitis B infection to be present at the time of immunisation. The vaccine may not prevent hepatitis B infection in such cases. HEXAVAC will not prevent hepatitis infection caused by other agents such as hepatitis A, hepatitis C and hepatitis E or by other liver pathogens. HEXAVAC does not protect against invasive diseases due to serotypes other than Haemophilus influenzae type b or against meningitis of other origins. As each dose may contain undetectable traces of neomycin, streptomycin and polymyxin B, caution should be exercised when the vaccine is administered to subjects with hypersensitivity to these antibiotics. The immunogenicity of HEXAVAC could be reduced by immunosuppressive treatment or immunodeficiency. In such cases it is recommended to postpone the vaccination until the end of the disease or treatment. Nevertheless, vaccination of subjects with chronic immunodeficiency such as HIV infection is recommended even if the antibody response might be limited.

There are currently no sufficient data available regarding immunogenicity of the concomitant administration of HEXAVAC with PREVENAR (pneumococcal polysaccharide conjugated vaccine, adsorbed). However when HEXAVAC was co-administered with PREVENAR (pneumococcal polysaccharide conjugated vaccine, adsorbed) in clinical studies, the rate of febrile reactions was higher compared to that occurring following the administration of hexavalent vaccines alone. These reactions were mostly moderate (less than or equal to 39deg C) and transient. HEXAVAC must not be mixed in the same syringe with other vaccines or other parenterally administered drugs.

Interaction with other medicinal products and other forms of interaction

Except in the case of immunosuppressive therapy (see 4.4 Special warnings and special precautions for use), no significant clinical interaction with other treatments or biological products has been documented. There are no data in regards to the efficacy and safety of concomitant administration of HEXAVAC with Measles, Mumps and Rubella Virus Vaccine, live. There are currently no sufficient data available regarding immunogenicity of the concomitant administration of HEXAVAC with PREVENAR (pneumococcal polysaccharide conjugated vaccine, adsorbed).

Pregnancy and lactation

Effects on ability to drive and use machines

Undesirable effects

Clinical trials experience

In clinical trials, more than 3,900 infants and 4,400 toddlers (from 12 to 20 months of age) have received HEXAVAC. Commonly reported reactions included redness and/or induration/swelling/pain at the injection site, fever equal to or greater than 38 degC, irritability, drowsiness, loss of appetite, insomnia, diarrhoea and vomiting. Less commonly, fever equal to or greater than 40 degC, tenderness at the injection site, prolonged inconsolable crying and redness and/or induration > 7 cm at the injection site or swelling of the entire limb have been reported. Febrile convulsion and high-pitched crying have been reported rarely. A single bilateral oedematous reaction of the lower limbs and a single, hypotonic hypo- responsive episode have been reported. These signs and symptoms usually occurred within 48 hours following the vaccination. They were mostly mild, generally lasting for up to 72 hours and resolved spontaneously. No increase in the number of undesirable reactions was noted between first, second and third doses of the primary series except for an increase in the rate of fever equal to or greater than 38 degC after the second dose in the primary series. The rate of fever equal to or greater than 40 degC increased after booster immunisation but remained

Medicinal product no longer authorised

< 1 %. Redness and/or induration > 7 cm at the injection site increased after booster immunisation but remained < 1 %. In rare instances, these cases were associated with swelling of the entire limb.

Post marketing experience

The following additional undesirable effects have been reported following the widespread use of HEXAVAC.

Common (>1/100 and <1/10)

Application site disorders (reactions at the injection site):

Oedema / Pruritus / Urticaria.

Rare (>1/10,000 and <1/1,000)

Body as a whole - General disorders: Prolonged or abnormal crying.

Very rare (<1/10,000)

Body as a whole - General disorders: Allergic reaction / Chills / Fatigue / Hypotonic-hyporesponsive episode / Malaise / Oedema / Pallor / Swelling or oedema of the entire limb(s) / Transient local lymph node swelling.

Central and peripheral nervous system disorders:

Convulsions (febrile and non febrile) / Encephalitis / Encephalopathy with acute brain oedema / Eyes rolling / Guillain Barre Syndrome / Hypotonia / Neuritis.

Gastro-intestinal system disorders:

Abdominal pain / Meteorism / Nausea.

Platelets, bleeding & clotting disorders: Petechiae / Purpura / Purpura thrombocytopenic / Thrombocytopenia.

Psychiatric disorders:

Agitation / Sleep disorder.

Respiratory system disorders

: Dyspnoea or Stridor inspiratory.

Skin and appendages disorders: Angioedema / Erythema / Pruritus / Rash / Urticaria .

Vascular (extracardiac) disorders:

Flushing.

Potential undesirable effects

In addition, other undesirable effects have been reported with the marketed use of vaccines closely related to HEXAVAC. Undesirable effects reported in clinical trials and the marketed use to date of Sanofi Pasteur MSD diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type b and inactivated poliomyelitis adsorbed vaccine are included in the list of undesirable effects for HEXAVAC. Very rare reactions following the use of Sanofi Pasteur MSD hepatitis B (recombinant) vaccine include alopecia, hypotension, optic neuritis, facial paralysis, erythema multiforme, and anaphylaxis. As with other hepatitis B vaccines, in many instances, the causal relationship to the vaccine has not been established.

Overdose

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Bacterial and viral vaccines, combined, ATC code : J07CA

The diphtheria and tetanus toxoids are prepared from the toxins of cultures of Corynebacterium diphtheriae and Clostridium tetani by formaldehyde detoxification followed by purification. The surface antigen of hepatitis B virus is produced by culture of a recombinant strain of yeast cells (Saccharomyces cerevisiae). The poliomyelitis vaccine is obtained from the propagation of poliomyelitis viruses types 1, 2 and 3 on Vero cells, purified, then inactivated by formaldehyde. The acellular pertussis components (pertussis toxin: PT and filamentous haemagglutinin: FHA) are extracted from Bordetella pertussis cultures then separately purified. The pertussis toxin (PT) is detoxified separately with glutaraldehyde to create the toxoid (PTxd). The FHA is not detoxified. It has been shown that PTxd and FHA play a major role in protection against pertussis. This vaccine contains the purified capsular polysaccharide (polyribosyl ribitol phosphate: PRP) of Haemophilus influenzae type b conjugated to tetanus toxoid. When administered alone PRP induces a serological response, but it is weakly immunogenic in infants. The covalent binding of PRP to tetanus toxoid makes it a T-cell dependent antigen which induces a specific IgG anti-PRP response in infants and which elicits immune memory. This vaccine induces specific humoral antibodies against HBsAg (anti-HBs) and against diphtheria and tetanus toxoids (anti-D and anti-T). Development of anti-HBs titre equal to or greater than 10 mIU/ml and of anti-D and anti-T equal to or greater than 0.01 IU/ml measured 1-2 months after the third injection correlates with protection against hepatitis B infection and against diphtheria and tetanus respectively.

In the pivotal clinical study, all infants (100 %) developed a seroprotective antibody level (equal to or greater than 0.01 IU/ml) to both diphtheria and tetanus antigens one month after completion of the primary series. For pertussis, 91.8 % and 90.5 % of infants achieved a four-fold rise in PT and FHA antibody titres respectively. The 4-fold increase in post immunisation titres is considered a sign of seroconversion of which the clinical significance is unknown in the absence of a serological correlate of protection. Protective levels of anti-HBs (equal to or greater than 10 mIU/ml) were achieved in 96.6 % of infants ; the geometric mean titres (GMTs) were diminished compared to the control group. Anti-poliovirus titres above the threshold of 5 (reciprocal of dilution in seroneutralisation) against poliovirus types 1, 2 and 3 were developed in 100 % of infants and these were considered protected against poliomyelitis. After primary vaccination, 93.7 % of infants had an anti-PRP titre equal to or greater than 0.15 ug/ml; the GMTs were diminished compared to the control group (2.06 ug/ml versus 3.69 ug/ml).

In the pivotal clinical study where toddlers received HEXAVAC as a booster dose after having been primed with HEXAVAC, antibody titres equal to or greater than 0.1 IU/ml were achieved by all toddlers to tetanus and by 98.8 % to diphtheria. A mean 7.4 and 4.3-fold rise in antibody titres to PT and FHA respectively was achieved and all toddlers developed protective antibody titres against poliovirus types 1, 2 and 3. Just before the booster injection anti-PRP GMTs were 0.40 ug/ml and 0.64 ug/ml for HEXAVAC and for the control group respectively. After booster, GMTs increased to 16.7 ug/ml and 23.0 ug/ml in each group respectively, indicating a strong anamnestic response. Anti- PRP titres equal to or greater than 0.15 ug/ml and equal to or greater than 1 ug/ml were achieved in 100 % and 96.6 % of toddlers respectively. Following the booster dose, 96.6 % of toddlers developed anti-HBs titres equal to or greater than 10 mIU/ml. A mean 20.5-fold rise in antibody titres to HBs was observed after the booster dose. Other trials gave similar or higher results. Surveillance and antibody long term persistence studies are ongoing and will provide additional information in regards to the duration of protection. After a 3, 5, 12 months schedule, immune responses were compatible with the sought clinical protection and of the same magnitude as those reported previously for HEXAVAC or other licensed combination vaccines during the second year of life

Pharmacokinetic properties

Preclinical safety data

Preclinical data including single-dose, repeated dose and local tolerance studies revealed no unexpected findings and no target organ toxicity.

PHARMACEUTICAL PARTICULARS

List of excipients

Formulation contains aluminium hydroxide and a buffer solution of disodium phosphate, monopotassium phosphate, sodium carbonate, sodium bicarbonate, trometamol, sucrose, medium 199 (complex blend of amino acids, mineral salts, vitamins and other ingredients) and water for injections.

Incompatibilities

The vaccine should not be mixed in the same syringe with other vaccines or parenterally administered substances.

Shelf life

Special precautions for storage

Nature and contents of container

0.5 ml of suspension in pre-filled syringe (type I glass) with a plunger stopper (chlorobromobutyl) with attached needle - pack of 1, 10, 25 and 50. 0.5 ml of suspension in pre-filled syringe (type I glass) with a plunger stopper (chlorobromobutyl) without needle - pack of 1, 10, 25 and 50. 0.5 ml of suspension in pre-filled syringe (type I glass) with a plunger stopper (chlorobromobutyl), with 1 or 2 separate needles - pack of 1 and 10. Not all pack sizes may be marketed.

Instructions for use and handling

Before use, the vaccine should be well shaken in order to obtain a homogeneous slightly opaque white suspension. For needle free syringes, the needle should be pushed firmly on to the end of the prefilled syringe and rotated through 90 degrees.

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

HEXAVAC