1. Name Of The Medicinal Product
Twinrix Paediatric, suspension for injection in prefilled syringe
Hepatitis A (inactivated) and hepatitis B(rDNA) (HAB) vaccine ((adsorbed).
2. Qualitative And Quantitative Composition
1 dose (0.5 ml) contains:
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For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Suspension for injection in prefilled syringe
Turbid white suspension.
4. Clinical Particulars
4.1 Therapeutic Indications
Twinrix Paediatric is indicated for use in non immune infants, children and adolescents from 1 year up to and including 15 years who are at risk of both hepatitis A and hepatitis B infection.
4.2 Posology And Method Of Administration
Posology
- Dosage
The dose of 0.5 ml (360 ELISA Units HA/10 µg HBsAg) is recommended for infants, children and adolescents from 1 year up to and including 15 years of age.
- Primary vaccination schedule
The standard primary course of vaccination with Twinrix Paediatric consists of three doses, the first administered at the elected date, the second one month later and the third six months after the first dose. The recommended schedule should be adhered to. Once initiated, the primary course of vaccination should be completed with the same vaccine.
- Booster dose.
Long-term antibody persistence data following vaccination with Twinrix Paediatric are available up to 48 months after vaccination. The anti-HBs and anti-HAV antibody titres observed following a primary vaccination course with the combined vaccine are in the range of what is seen following vaccination with the monovalent vaccines. The kinetics of antibody decline are also similar. General guidelines for booster vaccination can therefore be drawn from experience with the monovalent vaccines.
Hepatitis B
The need for a booster dose of hepatitis B vaccine in healthy individuals who have received a full primary vaccination course has not been established; however some official vaccination programmes currently include a recommendation for a booster dose of hepatitis B vaccine and these should be respected.
For some categories of subjects or patients exposed to HBV (e.g. haemodialysis or immunocompromised patients) a precautionary attitude should be considered to ensure a protective antibody level
Hepatitis A
It is not yet fully established whether immunocompetent individuals who have responded to hepatitis A vaccination will require booster doses as protection in the absence of detectable antibodies may be insured by immunological memory. Guidelines for boosting are based on the assumption that antibodies are required for protection; anti-HAV antibodies have been predicted to persist for at least 10 years.
In situations where a booster dose of both hepatitis A and hepatitis B are desired, Twinrix Paediatric can be given. Alternatively, subjects primed with Twinrix Paediatric may be administered a booster dose of either of the monovalent vaccines.
Method of administration
Twinrix Paediatric is for intramuscular injection, preferably in the deltoid region in adolescents and children or in the anterolateral thigh in infants.
Exceptionally, the vaccine may be administered subcutaneously in patients with thrombocytopenia or bleeding disorders. However, this route of administration may result in suboptimal immune response to the vaccine. (see section 4.4)
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients or neomycin.
Hypersensitivity after previous administration of hepatitis A and/or hepatitis B vaccines.
The administration of Twinrix Paediatric should be postponed in subjects suffering from acute severe febrile illness.
4.4 Special Warnings And Precautions For Use
It is possible that subjects may be in the incubation period of a HA or HB infection at the time of vaccination. It is not known whether Twinrix Paediatric will prevent HA and HB in such cases.
The vaccine will not prevent infection caused by other agents such as hepatitis C and hepatitis E and other pathogens known to infect the liver.
Twinrix Paediatric is not recommended for postexposure prophylaxis (e.g. needle stick injury).
The vaccine has not been tested in patients with impaired immunity. In haemodialysis patients, patients receiving immunosuppressive treatment or patients with an impaired immune system, the anticipated immune response may not be achieved after the primary immunisation course. Such patients may require additional doses of vaccine; nevertheless immunocompromised patients may fail to demonstrate an adequate response.
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.
Since intradermal injection or intramuscular administration into the gluteal muscle could lead to a suboptimal response to the vaccine, these routes should be avoided. However, exceptionally Twinrix Paediatric can be administered subcutaneously to subjects with thrombocytopenia or bleeding disorders since bleeding may occur following an intramuscular administration to these subjects. (see section 4.2)
TWINRIX PAEDIATRIC SHOULD UNDER NO CIRCUMSTANCES BE ADMINISTERED INTRAVASCULARLY.
As with any injection procedure, vasovagal syncope can infrequently occur following administration of Twinrix Paediatric to adolescents.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No data on concomitant administration of Twinrix Paediatric with specific hepatitis A immunoglobulin or hepatitis B immunoglobulin have been generated. However, when the monovalent hepatitis A and hepatitis B vaccines were administered concomitantly with specific immunoglobulins, no influence on seroconversion was observed although it may result in lower antibody titers.
As the concomitant administration of Twinrix Paediatric and other vaccines has not specifically been studied it is advised that the vaccine should not be administered at the same time as other vaccines.
4.6 Pregnancy And Lactation
Pregnancy
The effect of Twinrix Paediatrict on embryo-fetal, peri-natal and post-natal survival and development has been assessed in rats. This study did not indicate direct or indirect harmful effects with respect to fertility, pregnancy, embryonal/fetal development, parturition or post-natal development.
The effect of Twinrix Paediatric on embryo-fetal, peri-natal and post-natal survival and development has not been prospectively evaluated in clinical trials.
Data on outcomes of a limited number of pregnancies in vaccinated women do not indicate any adverse effects of Twinrix Paediatric on pregnancy or on the health of the fetus/newborn child. While it is not expected that recombinant hepatitis B virus surface antigen would have adverse effects on pregnancies or the fetus it is recommended that vaccination should be delayed until after delivery unless there is an urgent need to protect the mother against hepatitis B infection.
Lactation
It is unknown whether Twinrix Paediatric is excreted in human breast milk. The excretion of Twinrix Paediatric in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Twinrix Paediatric should be made taking into account the benefit of breast-feeding to the child and the benefit of Twinrix Paediatric therapy to the woman.
4.7 Effects On Ability To Drive And Use Machines
Twinrix Paediatric has no or negligible influence on the ability to drive and use machines.
4.8 Undesirable Effects
• Clinical trials
The current formulation of Twinrix does not contain thiomersal (an organomercuric compound) or any preservative. In a clinical study conducted with the current formulation, the incidence of pain, redness, swelling, fatigue, gastro-enteritis, headache and fever was comparable to the incidence observed with the former thiomersal and preservative containing vaccine formulation. The following undesirable events have been reported following the widespread use of the former formulation.
The safety profile presented below is based on data from approximately 800 subjects.
Frequencies are reported as:
Very common:
Common:
Uncommon:
Rare:
Very rare: < 1/10,000
* refers to adverse reactions observed in clinical trials performed with the adult formulation
Blood and lymphatic system disorders
Rare: lymphadenopathy
Nervous system disorders
Common: drowsiness, headache
Rare: hypoaesthesia*, paraesthesia*, dizziness
Gastrointestinal disorders
Common: gastrointestinal symptoms, nausea
Uncommon: diarrhoea, vomiting, abdominal pain
Skin and subcutaneous tissue disorders
Uncommon: rash
Rare: urticaria, pruritus*
Musculoskeletal and connective tissue disorders
Uncommon: myalgia*
Rare: arthralgia*
Metabolism and nutrition disorders
Common: appetite lost
Infections and infestations
Uncommon: upper respiratory tract infection*
Vascular disorders
Rare: hypotension*
General disorders and administration site conditions
Very common: pain and redness at the injection site
Common: swelling at the injection site, injection site reaction (such as bruising), fatigue, malaise, fever (
Rare: influenza like illness*, chills*
Psychiatric disorders
Common: irritability
• Post-marketing surveillance
The following adverse reactions have been reported with either Twinrix or with GlaxoSmithKline monovalent hepatitis A or B vaccines:
Blood and lymphatic system disorders
Thrombocytopenia, thrombocytopenic purpura
Nervous system disorders
Encephalitis, encephalopathy, neuritis, neuropathy, paralysis, convulsions
Skin and subcutaneous tissue disorders
Angioneurotic oedema, lichen planus, erythema multiforme
Musculoskeletal and connective tissue disorders
Arthritis, muscular weakness
Infections and infestations
Meningitis
Vascular disorders
Vasculitis
Immune system disorders
Anaphylaxis, allergic reactions including anaphylactoid reactions and mimicking serum sickness
Following widespread use of the monovalent hepatitis A and/or hepatitis B vaccines, the following undesirable events have additionally been reported in temporal association with vaccination.
Investigations
Abnormal liver function tests
Nervous system disorders
Multiple sclerosis, myelitis, facial palsy, polyneuritis such as Guillain-Barré syndrome (with ascending paralysis), optic neuritis
4.9 Overdose
Cases of overdose have been reported during post-marketing surveillance. Adverse events reported following overdosage were similar to those reported with normal vaccine administration.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmaco-therapeutic group: Hepatitis vaccines, ATC code J07BC20.
Twinrix Paediatric is a combined vaccine formulated by pooling bulk preparations of the purified, inactivated hepatitis A (HA) virus and purified hepatitis B surface antigen (HBsAg), separately adsorbed onto aluminium hydroxide and aluminium phosphate.
The HA virus is propagated in MRC5 human diploid cells. HBsAg is produced by culture, in a selective medium, of genetically engineered yeast cells.
Twinrix Paediatric confers immunity against HAV and HBV infection by inducing specific anti-HA and anti-HBs antibodies.
Protection against hepatitis A and hepatitis B develops within 2-4 weeks. In the clinical studies, specific humoral antibodies against hepatitis A were observed in approximately 89% of the subjects one month after the first dose and in 100% one month after the third dose (i.e. month 7). Specific humoral antibodies against hepatitis B were observed in approximately 67% of the subjects after the first dose and 100% after the third dose.
In a long term clinical trial, persistence of anti-HAV and anti-HBs antibodies has been demonstrated up to 48 months following the initiation of a primary vaccination course of Twinrix Paediatric in the majority of vaccinees (see section 4.2). The kinetics of decline of anti-HAV and anti-HBs antibodies were shown to be similar to those of the monovalent vaccines.
These data were generated with the former Twinrix formulation containing thiomersal and a preservative. A clinical study conducted with the current formulation of Twinrix in adults showed that the current formulation elicited similar seroprotection and seroconversion rates as compared to the former formulation.
5.2 Pharmacokinetic Properties
Evaluation of pharmacokinetic properties is not required for vaccines.
5.3 Preclinical Safety Data
Non-clinical data reveal no special hazard for humans based on general safety studies (see section 4.6).
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium chloride
Water for injections
For adjuvants, see section 2.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
Store in a refrigerator (2°C - 8°C).
Do not freeze.
Store in the original package, in order to protect from light.
6.5 Nature And Contents Of Container
0.5 ml of suspension in a prefilled syringe (type I glass) with a plunger stopper (rubber butyl).
Pack sizes of 1, 10 and 50 with or without needles.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
Upon storage, a fine white deposit with a clear colourless supernatant can be observed.
The vaccine should be well shaken to obtain a slightly opaque, white suspension and visually inspected for any foreign particulate matter and/or variation of physical aspect prior to administration. In the event of either being observed, discard the vaccine.
Any unused product of waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
GlaxoSmithKline Biologicals s.a.
rue de l'Institut 89
B-1330 Rixensart, Belgium
8. Marketing Authorisation Number(S)
EU/1/97/029/001
EU/1/97/029/002
EU/1/97/029/006
EU/1/97/029/007
EU/1/97/029/008
EU/1/97/029/009
EU/1/97/029/010
9. Date Of First Authorisation/Renewal Of The Authorisation
Renewal of the Authorisation
Date of first authorisation: 10 February 1997
Date of latest renewal: 10 February 2007
10. Date Of Revision Of The Text
19/06/2008
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