Data Sheet
INFANRIX®-hexa
Combined diphtheria-tetanus-acellular pertussis, hepatitis B, enhanced inactivated polio vaccine and Haemophilus influenzae type b vaccine.
Name of the Medicinal Product
INFANRIX®-hexa
Combined diphtheria-tetanus-acellular pertussis, hepatitis B, enhanced inactivated polio vaccine and Haemophilus influenzae type b vaccine.
Qualitative and Quantitative Composition
INFANRIX®-hexa contains diphtheria toxoid, tetanus toxoid, three purified pertussis antigens [pertussis toxoid (PT), filamentous hemagglutinin (FHA) and pertactin (PRN; 69 kilo Dalton outer membrane protein)] and the purified major surface antigen (HBsAg) of the hepatitis B virus (HBV) and purified polyribosyl-ribitol-phosphate capsular polysaccharide (PRP) of Haemophilus influenzae type b (Hib), covalently bound to tetanus toxoid, adsorbed onto aluminium salts. It also contains three types of inactivated polio viruses (type 1: Mahoney strain; type 2: MEF-1 strain; type 3: Saukett strain).
The tetanus and diphtheria toxoids are obtained by formaldehyde treatment of purified Corynebacterium diphtheriae and Clostridium tetani toxins. The acellular pertussis vaccine components are obtained by extraction and purification from phase I Bordetella pertussis cultures, followed by irreversible detoxification of the pertussis toxin by glutaraldehyde and formaldehyde treatment, and formaldehyde treatment of FHA and PRN. The diphtheria toxoid, tetanus toxoid and acellular pertussis components are adsorbed onto aluminium salts. The DTPa-HBV-IPV components are formulated in saline and contain 2-phenoxyethanol.
The surface antigen of the HBV is produced by culture of genetically-engineered yeast cells (Saccharomyces cerevisiae) which carry the gene coding for the major surface antigen of the HBV. This HBsAg expressed in yeast cells is purified by several physico-chemical steps. The HBsAg assembles spontaneously, in the absence of chemical treatment, into spherical particles of 20 nm in average diameter containing non-glycosylated HBsAg polypeptide and a lipid matrix consisting mainly of phospholipids. Extensive tests have demonstrated that these particles display the characteristic properties of the natural HBsAg.
The three polioviruses are cultivated on a continuous VERO cell line, purified and inactivated with formaldehyde.
The Hib polysaccharide is prepared from Hib, strain 20,752 and after activation with cyanogen bromide and derivatisation with an adipic hydrazide spacer is coupled to tetanus toxoid via carbodiimide condensation. After purification the conjugate is adsorbed on aluminium salt, and then lyophilised in the presence of lactose as stabiliser.
INFANRIX®-hexa meets the World Health Organisation requirements for manufacture of biological substances, of diphtheria, tetanus, pertussis and combined vaccines, of hepatitis B vaccines made by recombinant DNA techniques, of inactivated poliomyelitis vaccines and of Hib conjugate vaccines.
A 0.5 ml dose of the vaccine contains not less than 30 IU of adsorbed diphtheria toxoid, not less than 40 IU of adsorbed tetanus toxoid, 25 mcg of adsorbed PT, 25 mcg of adsorbed FHA, 8 mcg of adsorbed pertactin, 10 mcg of adsorbed recombinant HBsAg protein, 40 D-antigen units of type 1 (Mahoney), 8 D-antigen units of type 2 (MEF-1) and 32 D-antigen units of type 3 (Saukett) of the polio virus. It also contains 10 mcg of adsorbed purified capsular polysaccharide of Hib (PRP) covalently bound to 20-40 mcg tetanus toxoid (T).
Excipients
Lactose, sodium chloride (NaCl), 2-phenoxyethanol, aluminium hydroxide (Al(OH)3), aluminium phosphate (AlPO4), water (H2O) for injections. Medium 199 (as stabilizer containing amino acids, mineral salts, vitamins and other substances) (M 199), potassium chloride (KCl), disodium phosphate, monopotassium phosphate, polysorbate 20 and 80, glycine, formaldehyde, neomycin sulphate, polymyxin B sulphate are present as residuals from the manufacturing process.
Pharmaceutical Form
Powder and suspension for injection.
Clinical Particulars
Therapeutic indications
INFANRIX®-hexa is indicated for primary immunisation against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis and Haemophilus influenza type b in infants from the age of 6 weeks and may be given to infants who received a first dose of hepatitis B vaccine at birth.
Posology and method of administration
Posology
The primary vaccination schedule (such as 2, 3, 4 months; 3, 4, 5 months; 2, 4, 6 months; 3, 5 and 11 or 12 months; 6, 10, 14 weeks) consists of three doses of 0.5 ml. An interval of at least 1 month should be respected between doses.
If it is intended to administer INFANRIX®-hexa according to the EPI schedule (Expanded Program on Immunisation; 6, 10, 14 weeks of age), then the vaccinee must receive a dose of hepatitis B vaccine at birth.
Available data indicate that the vaccine can be given as a fourth dose. However, the data are limited and therefore no recommendation is made for using this combination vaccine as a fourth (i.e. booster) dose during the second year of life.
Infants should receive booster vaccination with other licensed vaccines according to official local recommendations, where available.
Method of administration
INFANRIX®-hexa is for deep intramuscular injection.
Contra-indications
INFANRIX®-hexa should not be administered to subjects with known hypersensitivity to the active substances or to any of the excipients or residuals (see Excipients) or to subjects having shown signs of hypersensitivity after previous administration of diphtheria, tetanus, pertussis, hepatitis B, polio or Hib vaccines.
INFANRIX®-hexa is contra-indicated if the child 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, inactivated polio and Hib vaccines.
Special warnings and special precautions for use
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 contra-indication.
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.
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, not due to another identifiable cause.
- Collapse or shock-like state (hypotonic-hyporesponsiveness episode) within 48 hours of vaccination.
- Persistent, inconsolable crying lasting ≥ 3 hours, occurring within 48 hours of vaccination.
- Convulsions with or without fever, occurring within 3 days of vaccination.
There may be circumstances, such as a high incidence of pertussis, when the potential benefits outweigh possible risks.
In children with progressive neurological disorders, including infantile spasms, uncontrolled epilepsy or progressive encephalopathy, it is better to defer pertussis (Pa or Pw) immunization until the condition is corrected or stable. However, the decision to give pertussis vaccine must be made on an individual basis after careful consideration of the risks and benefits.
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.
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.
INFANRIX®-hexa should under no circumstances be administered INTRAVASCULARLY OR INTRADERMALLY.
INFANRIX®-hexa contains traces of neomycin and polymyxin. The vaccine should be used with caution in patients with known hypersensitivity to one of these antibiotics.
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.
A protective immune response may not be elicited in all vaccinees (see section Pharmacodynamic properties).
A history of febrile convulsions, a family history of convulsions or Sudden Infant Death Syndrome (SIDS) do not constitute contraindications 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.
Human Immunodeficiency Virus (HIV) infection is not considered as a contra-indication. The expected immunological response may not be obtained after vaccination of immunosuppressed patients.
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.
Limited data in 169 premature infants indicate that INFANRIX®-hexa can be given to premature children. However, a lower immune response may be observed and the level of clinical protection remains unknown.
The potential risk of apnoea and the need for respiratory monitoring for 48-72h should be considered when administering the primary immunization 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.
Interaction with other medicinal products and other forms of interaction
There are insufficient data with regard to the efficacy and safety of simultaneous administration of INFANRIX®-hexa and Measles-Mumps-Rubella vaccine to allow any recommendation to be made.
Data on concomitant administration of INFANRIX®-hexa with Prevenar (pneumococcal saccharide conjugated vaccine, adsorbed) have shown no clinically relevant interference in the antibody response to each of the individual antigens when given as a 3 dose primary vaccination.
However, high incidence of fever (>39.5°C) was reported in infants receiving INFANRIX®-hexa and Prevenar compared to infants receiving the hexavalent vaccine alone.
Antipyretic treatment should be initiated according to local treatment guidelines.
INFANRIX®-hexa should not be mixed in the same syringe with any other vaccine.
As with other vaccines it may be expected that in patients receiving immunosuppressive therapy or patients with immunodeficiency, an adequate response may not be achieved.
Fertility
No data available.
Pregnancy and lactation
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.
Effects on ability to drive and use machines
Not applicable.
Undesirable effects
Clinical trials:
The safety profile presented below is based on data from more than 16,000 subjects.
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.
Frequencies per dose are defined as follows:
Very common: ≥ 10%
Common: ≥ 1% and < 10%
Uncommon: ≥ 0.1% and < 1%
Rare: ≥ 0.01% and < 0.1%
Very rare: < 0.01%
Infections and infestations
Uncommon: upper respiratory tract infection
Metabolism and nutrition disorders
Very common: appetite lost
Psychiatric disorders
Very common: irritability, crying abnormal, restlessness
Common: nervousness
Nervous system disorders
Uncommon: somnolence
Very rare: convulsions (with or without fever)
Respiratory, thoracic and mediastinal disorders
Uncommon: cough**
Rare: bronchitis
Gastrointestinal disorders
Common: vomiting, diarrhoea
Skin and subcutaneous tissue disorders
Common: pruritus**
Rare: rash
Very rare: dermatitis, urticaria**
General disorders and administration site conditions
Very common: pain, redness, local swelling at the injection site (≤ 50 mm), fever ≥ 38°C, fatigue
Common: local swelling at the injection site (> 50 mm)*, fever >39.5°C, injection site reactions, including induration
Uncommon: diffuse swelling of the injected limb, sometimes involving the adjacent joint*
Post-Marketing Surveillance:
Blood and lymphatic system disorders:
Lymphadenopathy, thrombocytopenia
Immune system disorders:
Allergic reactions (including anaphylactic and anaphylactoid reactions)
Nervous system disorders:
Collapse or shock-like state (hypotonic-hyporesponsiveness episode)
Respiratory, thoracic and mediastinal disorders:
Apnoea* [see section "special Warnings and special Precautions for use" for apnoea in very premature infants (≤ 28 weeks of gestation)]
Skin and subcutaneous tissue disorders
Angioneurotic oedema
General disorders and administration site conditions:
Extensive swelling reactions, swelling of the entire injected limb*, vesicles at the injection site
* 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.
**observed with other GSK DTPa-containing vaccines
Experience with hepatitis B vaccine:
Paralysis, neuropathy, Guillain-Barré syndrome, encephalopathy, encephalitis and meningitis have been reported during post-marketing surveillance following GlaxoSmithKline Biologicals' hepatitis B vaccine in infants < 2 years old. The causal relationship to the vaccine has not been established.
Overdose
Insufficient data are available.
Pharmacological Properties
Pharmacodynamic properties
Pharmaco-therapeutic group: Bacterial and viral vaccines combined, ATC code JO7CA
Result obtained in the clinical studies for each of the components are summarised below :
- DTPa component:
One month after the 3-dose primary vaccination course, 98.5 to 100% of infants vaccinated with INFANRIX®-hexa had antibody titers of ≥ 0.1 IU/ml for both tetanus and diphtheria. The overall response rate for each of the three individual pertussis antigens (PT, FHA, pertactin) was between 97.2-99.3%, 95.2-100% and 95.9-99.3% respectively. - Hepatitis B component:
When the EPI schedule is excluded, then after the primary vaccination course with INFANRIX®-hexa, 98.5 to 100% of infants developed protective antibody titers of ≥ 10 mlU/ml. In order to ensure an adequate response to the hepatitis B component children who will be vaccinated in the EPI schedule must receive a dose of hepatitis B vaccine at birth. In a study in which the EPI schedule was applied after a dose of hepatitis B vaccine at birth, one month after the third dose, a seroprotection rate of 98.5% was obtained. - IPV component:
One month after the primary vaccination, the seroprotection rate for each of the three serotypes (type 1, 2 and 3) was 99.2 to 100%, 94.5 to 99.0% and 98.8 to 100% respectively. - Hib component:
One month after the 3-dose primary vaccination course 96.0 to 100% of infants vaccinated with INFANRIX®-hexa had antibody titers of ≥ 0.15 µg/ml and 61.9 to 84.0% of infants ≥ 1.0 µg/ml.
The protective efficacy of Infanrix™ DTPa, against WHO-defined typical pertussis (≥ 21 days of paroxysmal cough) was demonstrated in :
- a prospective blinded household contact study performed in Germany (3, 4, 5 months schedule).
Based on data collected from secondary contacts in households where there was an index case with typical pertussis, the protective efficacy of the vaccine was 88.7%, which was not statistically different from the DTPw vaccine.
- a NIH sponsored efficacy study performed in Italy (2, 4, 6 months schedule).
The vaccine efficacy was found to be 84%.
In a follow-up of the same cohort, the efficacy for GlaxoSmithKline's Infanrix™ DTPa vaccine was found to be 84% up to four years of age.
InfanrixTM DTPa is an integral part of the INFANRIX®-hexa combination vaccine.
Pharmacokinetic properties
Evaluation of pharmacokinetic properties is not required for vaccines.
Preclinical safety data
Preclinical data reveal no special hazard for humans based on conventional studies of safety, specific toxicity, repeated dose toxicity and compatibility of ingredients.
Pharmaceutical Particulars
Incompatibilities
INFANRIX®-hexa should not be mixed with other vaccines in the same syringe.
Shelf-life
The expiry date of the vaccine is indicated on the label and packaging. The date for last use corresponds to the first day of the month mentioned.
The shelf-life is 36 months.
Special precautions for storage
INFANRIX®-hexa should be stored at +2°C to +8°C. Protect from light.
During transport, recommended conditions of storage must be respected.
The DTPa-HBV-IPV suspension and the reconstituted vaccine must not be frozen. Discard if it has been frozen.
Nature and contents of container
The DTPa-HBV-IPV component is presented as a turbid white suspension in a syringe. Upon storage, a white deposit and clear supernatant can be observed.
The lyophilised Hib vaccine is presented as a white pellet in a glass vial.
The vials and syringes are made of neutral glass type I, which conforms to European Pharmacopoeia Requirements.
Vial and syringe with or without needles* in packs of 1* or 10.
*not currently marketed
Instructions for use and handling
The DTPa-HBV-IPV suspension should be well shaken in order to obtain a homogeneous turbid white suspension. The DTPa-HBV-IPV suspension and the Hib pellet should be inspected visually for any foreign particulate matter and/or variation of physical aspect. In the event of either being observed, discard the container.
The vaccine must be reconstituted by adding the entire contents of the supplied container of the DTPa-HBV-IPV to the vial containing the Hib pellet. After the addition of the DTPa-HBV-IPV vaccine to the pellet, the mixture should be well shaken until the pellet is completely dissolved.
The reconstituted vaccine presents as a slightly more cloudy suspension than the liquid component alone. This is normal and does not impair the performance of the vaccine. In the event of other variation being observed, discard the vaccine.
After reconstitution, the vaccine should be injected promptly. However the vaccine may be kept for up to 8 hours at room temperature (21°C).
After reconstitution, the vaccine should be injected promptly. However the vaccine may be kept for up to 8 hours at room temperature (21°C).
MEDICINE CLASSIFICATION
Prescription medicine.
NAME AND ADDRESS
GlaxoSmithKline NZ Ltd
AMP Centre
Cnr Albert & Customs Street
Private Bag 106600
Downtown
Auckland
NEW ZEALAND
ph (09) 367 2900
fax (09) 367 2506
DATE OF PREPARATION
12 March 2008
Ref: MDS Version 009 (Date of approval 23/11/2007)
Issue 8