Inactivated hepatitis A and rDNA
hepatitis B vaccine (adsorbed).
Each 1-mL dose contains Hepatitis A virus (inactivated)1,2 720 ELISA Units, Hepatitis B surface antigen3,4 20 micrograms.
1Produced on human diploid (MRC-5) cells.
2Adsorbed on aluminium hydroxide, hydrated 0.05 milligrams Al3+.
3Produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology.
4Adsorbed on aluminium phosphate 0.4 milligrams Al3+.
Excipients/Inactive Ingredients: Sodium
chloride and water for injections. Aminoacids for injection, formaldehyde,
neomycin sulphate and polysorbate 20 are present as residual from the
Pharmacotherapeutuc group: Hepatitis vaccines. ATC Code: J07BC20.
Pharmacology: Pharmacodynamics: Twinrix confers immunity against HAV and HBV infection
by inducing specific anti-HAV and anti-HBs antibodies.
Children of 1 to 15 years of age: In
clinical studies involving subjects from 1 to 15 years old, seropositivity
rates for anti-HAV antibodies were 99.1% one month after the first dose and
100% after the second dose given at month 6 (i.e. month 7). Seropositivity
rates for anti-HBs antibodies were 74.2% one month after the first dose and
100% after the second dose given at month 6 (i.e. month 7). The anti-HBs
seroprotection rates (titres ≥10 mlU/ml) at these time points were 37.4% and
In a clinical
study conducted among 12 years up to and including 15 years old subjects who
received the second dose at month 12, seropositivity rates for anti-HAV were
99.0% and seropositivity rates for anti-HBs were 99.0% at month 13 with
seroprotection rates of 97.0%.
comparative study conducted in adolescents (from 12 years up to and including
15 years of age) vs an alternative schedule of 3 doses with the combined
vaccine containing 360 ELISA Units inactivated HA virus and 10 μg HBsAg in a
dose volume of 0.5 ml, seroprotection rates for anti-HBs at intermediate time
points before the 2nd dose of Twinrix were
lower compared to those obtained with the alternative schedule comprising 3
doses, but non-inferiority was shown after completion of the schedule (month
and anti-HBs antibodies have been shown to persist for at least 10 years
following the initiation of a 0, 6 month schedule of Twinrix. After
10 years, anti-HAV seropositivity rates were 100% in both subjects aged 1-11
years and in subjects aged 12-15 years at primary vaccination. The anti-HBs seroprotection rates at this time point were 77.3% and 85.9%, respectively. In the study conducted in subjects aged 12-15 years at primary vaccination, the immune response for both antigen components was comparable to
that seen after a 3-dose regimen of the combined vaccine containing 360 ELISA
Units of inactivated hepatitis A virus and 10 µg of recombinant hepatitis B
surface antigen in a dose volume of 0.5 ml.
In a 6
year long term follow-up study involving subjects aged 12-15 years at primary
vaccination, anti-HAV seropositivity rates were 100% following a 0, 6 month or
a 0, 12 month schedule. The anti-HBs seroprotection rates were 84.8% and 92.9%,
Adults and adolescents of 16 years of age and above: In adults aged 16 years and above administered a 3-dose
schedule of Twinrix, 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 94% of the adults 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 70% of the adults after the first dose and
approximately 99% after the third dose.
For use in exceptional circumstances in adults, the 0, 7
and 21 day primary schedule plus a fourth dose at month 12 results in 82% and
85% of vaccinees having seroprotective levels of anti-HBV antibodies at 1 and 5
weeks respectively following the third dose. One month after the fourth dose,
all vaccinees demonstrated seroprotective levels of antibody. Seropositivity
rates for anti-HAV antibodies were 100% and 99.5% at 1 and 5 weeks respectively
following the third dose, and reached 100% one month after the fourth dose.
In a clinical study conducted in subjects over 40 years of
age, the seropositivity rate for anti-HAV antibodies and seroprotection rate
against hepatitis B following Twinrix on
a 0, 1, 6 month schedule were compared with the seropositivity and
seroprotection rates of monovalent hepatitis A and B vaccines when administered separately.
The seroprotection rates against hepatitis B after the
administration of Twinrix were 92%
and 57% at 7 and 48 months following the first dose respectively, versus 80%
and 40% after the GlaxoSmithKline Biologicals monovalent 20 µg hepatitis B
vaccine, and 71% and 27% after another licensed monovalent 10 µg hepatitis B
vaccine. In all groups, anti-HBs antibody concentrations decreased as age and
body mass index increased; concentrations were also lower in males compared
The seropositivity rates for anti-HAV antibodies after Twinrix were 97% at both 7 and 48 months
following the first dose versus 99% and 94% after the GlaxoSmithKline
Biologicals monovalent hepatitis A vaccine and 99% and 96% after another
licensed monovalent hepatitis A vaccine.
Subjects received an additional
dose of Twinrix to assess the immune memory 48 months after the first dose
of the primary vaccination course with the same vaccine. One month after this
dose, 95% of subjects elicited anti-HBV antibody concentration ≥10 mIU/ml and
Geometric Mean Concentrations (GMC) increased by 179-fold (GMC of 7233.7 mIU/ml) indicative of an immune memory
long-term clinical studies conducted in adults, 15 years after the primary
vaccination with Twinrix the anti-HAV
seropositivity rates were 100% in both studies and the anti-HBs seroprotection
rates were 89.3% and 92.9%, respectively (n=56). The kinetics of decline of
anti-HAV and anti-HBs antibodies were shown to be similar to those of the
Toxicology: Pre-clinical Safety Data: Pre-clinical data reveal no special hazard for humans based
on general safety studies (see Pregnancy & Lactation).
Twinrix is indicated for use in non-immune adults,
adolescents and children aged from 1 year upwards, who are at risk of both
hepatitis A and hepatitis B infection.
Dosage: A dose
of 1.0 ml Twinrix is recommended for
adults, adolescents and children aged from 1 year upwards.
Primary vaccination schedules: Adults and adolescents of 16 years of age and above: The
standard primary course of vaccination with Twinrix consists of three doses, the first administered at the
elected date, the second one month later and the third six months after the
exceptional circumstances in adults, when travel is anticipated within one
month or more after initiating the vaccination course, but where insufficient
time is available to allow the standard 0, 1, 6 month schedule to be completed,
a schedule of three intramuscular injections given at 0, 7 and 21 days may be
used. When this schedule is applied, a fourth dose is recommended 12 months
after the first dose.
Children of 1 to 15 years of age: The standard primary
course of vaccination with Twinrix consists
of two doses, the first is administered at the elected date and the second
between six and twelve months after the first dose. As
protection against hepatitis B infection will not be obtained in all vaccinees
until after the second dose, it is important that the second dose be administered
to assure protection against hepatitis B infection.
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 in adults with a 0, 1, 6 month schedule are available for
up to 15 years after vaccination.
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. Following vaccination with Twinrix in adults, the kinetics of
antibody decline are similar to what has been observed after vaccination with
the monovalent vaccines.
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.
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 ≥10 IU/l.
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 ensured by immunological memory.
Guidelines for boosting are based on the assumption that antibodies are
required for protection; anti-HAV antibodies have been shown to persist for at
least 10 years.
situations where a booster dose of both hepatitis A and hepatitis B are
desired, Twinrix can be given.
Alternatively, subjects primed with Twinrix may
be administered a booster dose of either of the monovalent vaccines. The safety
and immunogenicity of Twinrix administered
as a booster dose following a two dose primary vaccination course have not been
Method of Administration: Twinrix should be injected intramuscularly into the
deltoid region of the upper arm in adults, adolescents and children. The
anterolateral thigh may be used in infants.
Since intradermal injection or intramuscular administration
into the gluteal muscle could lead to a suboptimal response to the vaccine,
these routes should be avoided. Exceptionally, Twinrix can be administered subcutaneously to subjects with
thrombocytopenia or bleeding disorders since bleeding may occur following an
intramuscular administration to these subjects. However, this route of
administration may result in suboptimal immune response to the vaccine.
Cases of overdose have been reported during post-marketing
surveillance after administration of Twinrix. Adverse reactions
reported following overdosage were similar to those reported with normal
Twinrix should not be administered to subjects with
known hypersensitivity to any constituent of the vaccine, or to subjects having
shown signs of hypersensitivity after previous administration of Twinrix or the monovalent hepatitis A or
hepatitis B vaccines.
As with other vaccines, the administration of Twinrix should be postponed in subjects
suffering from acute severe febrile illness.
Syncope (fainting) can occur following, or
even before, any vaccination as a psychogenic response to the needle injection.
It is important that procedures are in place to avoid injury from faints.
It is possible that subjects may be in the incubation
period of a hepatitis A or hepatitis B infection at the time of vaccination. It
is not known whether Twinrix will
prevent hepatitis A and hepatitis B 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
Twinrix 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 and persons with an impaired immune system,
adequate anti-HAV and anti-HBs antibody titres may not be obtained after the
primary immunisation course and such patients may therefore require
administration of additional doses of vaccine.
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.
Twinrix should under no circumstances be administered
Effects on ability to drive and use machines: The vaccine is unlikely to produce an effect on the ability
to drive and use machines.
Pregnancy: Twinrix should be used during pregnancy only when clearly needed and when
the possible advantages outweigh the possible risks for the foetus.
effect of Twinrix on
embryo-foetal, peri-natal and post-natal survival and development has not been
prospectively evaluated in clinical trials.
effect of Twinrix on
embryo-foetal, peri-natal and post-natal survival and development has been
assessed in rats. Such animal studies do not indicate direct or indirect
harmful effects with respect to fertility, pregnancy, embryonal/foetal development,
parturition or post-natal development.
Lactation: Adequate human data on use during lactation and adequate
animal reproduction studies are not available. Twinrix should therefore be used with caution in breastfeeding
and general adverse events reported following primary vaccination with Twinrix were categorised by frequency.
reactions reported are listed according to the following frequency:
Very common: ≥1/10; Common: ≥1/100 and <1/10; Uncommon: ≥1/1000 and <1/100
Rare: ≥1/10000 and <1/1000; Very rare: <1/10000.
Adults and adolescents of 16 years of age and above:
The safety profile presented as follows is based
on data from more than 6,000 subjects who received either the standard 0, 1, 6
month schedule or the accelerated 0, 7, 21 days schedule. (See Table 1.)
Click on icon to see table/diagram/image
comparative study it was noted that the frequency of solicited adverse events
following the administration of Twinrix is
not different from the frequency of solicited adverse events following the
administration of the monovalent vaccines.
In a clinical trial where Twinrix was administered at 0, 7, 21 days,
solicited general symptoms were reported with the same categories of frequency
as defined previously. After a fourth dose given at month 12, the incidence of
systemic adverse reactions was comparable to that seen after vaccination at 0,
7, 21 days.
Children of 1 to 15 years of age inclusive:
Clinical trials involved the
administration of 1537 doses of Twinrix as
a two dose schedule to 778 subjects from 1 year up to and including 15 years of
age. (See Table 2.)
Click on icon to see table/diagram/image
No data on concomitant administration of Twinrix 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 titres.
Clinical studies have demonstrated that Twinrix can be administered
concomitantly with diphtheria, tetanus, acellular pertussis, inactivated
poliomyelitis, Haemophilus influenzae
type b (DTPa-IPV/Hib) or Measles-Mumps-Rubella vaccines in the second year of life.
In these trials, the injectable vaccines were given at different injection
Although the concomitant administration of Twinrix and other vaccines has not
specifically been studied, it is anticipated that, if different syringes and
other injection sites are used, no interaction will be observed.
It may be expected that in patients receiving
immunosuppressive treatment or patients with immunodeficiency, an adequate
response may not be achieved.
Instructions for Use/Handling: The vaccine should be re-suspended
before use. When re-suspended, the vaccine will have a uniform hazy white
Upon storage, a fine white deposit
with a clear colourless layer above may be observed.
Re-suspension of the vaccine to obtain a uniform hazy white suspension: The vaccine can be re-suspended following the
steps as follows: Hold the syringe
upright in a closed hand.
the syringe by tipping it upside down and back again.
Repeat this action
vigorously for at least 15 seconds.
the vaccine again: If
the vaccine appears as a uniform hazy white suspension, it is ready to use – the appearance should not be clear.
the vaccine still does not appear as a uniform hazy white suspension - tip
upside down and back again for at least another 15 seconds - then inspect
The vaccine should be inspected visually for
any foreign particulate matter and/or abnormal physical appearance prior to
administration. In the event of either being observed, do not administer the
Any unused product or waste material should
be disposed of in accordance with local requirements.
Incompatibilities: Twinrix should not be mixed with other vaccines in the same syringe.
Twinrix should be stored at +2°C to +8°C.
Do not freeze; discard if the vaccine has been frozen.
J07BC02 - hepatitis A, inactivated, whole virus ; Belongs to the class of hepatitis viral vaccines.
Susp for inj (pre-filled syringe) (white, slightly milky liquid) 1 mL x 1's.