Consumer medicine information

TWINRIX (720}20) and TWINRIX JUNIOR (360}10) (preservative free)

Hepatitis A child/adolescent vaccine; Hepatitis B child vaccine

BRAND INFORMATION

Brand name

Twinrix Preservative Free

Active ingredient

Hepatitis A child/adolescent vaccine; Hepatitis B child vaccine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using TWINRIX (720}20) and TWINRIX JUNIOR (360}10) (preservative free).

WHAT IS IN THIS LEAFLET

This leaflet answers some of the common questions about TWINRIX vaccine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines and vaccines have risks and benefits. Your doctor has weighed the possible risks of you or your child having TWINRIX against the expected benefits.

If you have any concerns about receiving TWINRIX talk to your doctor, nurse or pharmacist.

Keep this leaflet with this vaccine. You may need to read it again.

WHAT TWINRIX IS USED FOR

TWINRIX is a combination vaccine used to prevent hepatitis A and hepatitis B infection. The vaccine works by causing the body to produce its own protection (antibodies) against these diseases.

Hepatitis A and hepatitis B are infectious diseases, which cause the liver to become inflamed (swollen). These diseases are caused by viruses - hepatitis A and hepatitis B viruses.

Hepatitis A
Symptoms of hepatitis A usually begin 3 to 6 weeks after coming into contact with the virus. These consist of nausea (feeling sick), fever, aches and pains. After a few days the skin and/or the whites of the eyes may become yellowish (jaundice). The severity and type of symptoms can vary. Hepatitis A is often milder in young children. Most people recover completely but the illness is usually severe enough to keep adults off work for about a month.

The hepatitis A virus can be passed from person to person in food and drink, or by swimming in water contaminated by sewage. Hepatitis A is very common in many parts of the world and the risk of infection is greatest in those areas where hygiene and sanitation are poor. Vaccination is recommended for travellers to all developing countries, including people in the armed forces.

Hepatitis A occurs in Australia, but is not common. Some groups of people however are at a higher risk of exposure to the disease. Vaccination is recommended for these people:

  • nursing staff and healthcare workers in contact with patients in childrens wards, infectious diseases wards, emergency rooms and intensive care units
  • day-care centre staff particularly where children have not been toilet trained
  • staff and residents of homes for the intellectually disabled
  • sewerage workers
  • food handlers
  • homosexual men
  • people in contact with an infected person
  • people with chronic liver disease or liver transplants, or people who receive certain blood products.

Hepatitis B
The hepatitis B virus is found in body fluids such as blood, semen, vaginal secretions, or saliva of infected people. You can catch the virus if it can enter your bloodstream. Ways this can happen are through:

  • injection (eg needlestick injury, or sharing needles for IV drug use)
  • sexual intercourse
  • sores, cuts or tiny wounds coming into contact with infected fluids (eg from a human bite, sharing razors or toothbrushes, or working with human blood or body fluids)
  • an infected mother passing the virus onto her baby during or shortly after birth.

Some people infected with hepatitis B may not look or feel sick yet others will get symptoms. Symptoms may not appear for 6 weeks to 6 months after infection. Sometimes people will only have mild flu-like symptoms, but other people can become very ill. They may be extremely tired, and have dark urine, pale faeces, yellowish skin and/or eyes (jaundice), and other symptoms possibly requiring hospitalisation. There is a risk of serious liver disease, such as cirrhosis (liver scarring) and liver cancer for all chronic hepatitis B carriers.

Some groups of people are at a higher risk of exposure to hepatitis B. Vaccination is recommended for these people:

  • some healthcare workers
  • abusers of injectable drugs
  • people with many sexual partners
  • homosexual men
  • haemodialysis patients or people who receive certain blood products
  • people with chronic liver disease or hepatitis C
  • people in contact with a hepatitis B carrier or an infected person
  • staff and residents of institutions for the intellectually disabled
  • inmates and prison staff at some correctional institutions
  • some travellers to areas where the incidence of hepatitis B is high

There is no specific treatment for hepatitis A or hepatitis B. Vaccination is the best way to protect against infection.

TWINRIX will not protect against hepatitis caused by other agents or viruses (such as hepatitis C or hepatitis E). If a person is already infected with hepatitis A or hepatitis B virus at the time of vaccination, TWINRIX may not prevent the disease in these people.

BEFORE RECEIVING TWINRIX

DO NOT HAVE TWINRIX IF:

  • you have/ your child has had an allergic reaction to TWINRIX, or any ingredient contained in this vaccine (e.g. neomycin sulphate). The ingredients are listed at the end of this leaflet. Signs of an allergic reaction may include an itchy skin rash, shortness of breath and swelling of the face or tongue.
    If you have/ your child has had TWINRIX before and became unwell, tell your doctor, nurse or pharmacist before the vaccine is given.
  • you have/ your child has had an allergic reaction to any other hepatitis A or hepatitis B vaccine.
  • you have/ your child has a severe infection with a high temperature. A minor infection such as a cold should not be a problem, but talk to your doctor about this before being vaccinated.
  • the expiry date printed on the pack has passed.
  • the packaging is torn or shows signs of tampering.

If you are not sure whether TWINRIX should be given, talk to your doctor or nurse. Do not give this vaccine to anyone else; your doctor has prescribed it specifically for you or your child.

BEFORE RECEIVING TWINRIX TELL YOUR DOCTOR IF:

  • you have/ your child has an allergy to baker’s yeast.
  • you are or think you may be pregnant or if you intend to become pregnant. Your doctor will discuss with you the possible risks and benefits of receiving TWINRIX during pregnancy.
  • you are breast feeding. It is not known if TWINRIX passes into breast milk, however the vaccine is not expected to cause problems for breast-fed babies.
    you have/ your child has any medical conditions, such as:
    - severe heart or lung disease
    - a liver or kidney problem
    - an immune deficiency condition (eg. HIV positive)
    - a nervous system illness
    - or a bleeding disorder;
  • you have/ your child has allergies to any other medicines or substances, such as dyes, foods or preservatives.
  • you have/ your child has received another vaccine recently, or are taking any prescription or OTC (over-the-counter) medicines. In particular mention if you are taking medicines which suppress the immune system, such as steroids or cyclosporin.

Fainting can occur following, or even before, any needle injection, therefore tell the doctor or nurse if you/your child fainted with a previous injection.

Some vaccines may be affected by other vaccines or medicines. Your doctor or pharmacist will be able to tell you what to do if TWINRIX is to be given with another vaccine or medicine.

HOW TWINRIX IS GIVEN

The doctor or nurse will give TWINRIX as an injection.

If you have any concerns about how this vaccine is to be given, talk to your doctor or pharmacist.

HOW MUCH IS GIVEN

The dose using TWINRIX (720/20) is 1 mL.

The dose using TWINRIX JUNIOR (360/10) is 0.5 mL

HOW IT IS GIVEN

TWINRIX will be injected into your upper arm muscle in adults and older children, and into the thigh muscle in infants. For some people with bleeding problems, the dose may need to be given under the skin (subcutaneously). Each dose of TWINRIX is for single use only. Any residual vaccine must be discarded.

The vaccine should never be given intravenously.

WHEN IT IS GIVEN

Adults
TWINRIX (720/20) is generally given as a total of three doses over 6 months. Each dose is given on a separate visit. The first dose will be given on an elected date. The remaining two doses will be given one month, and six months after the first dose.

  • First dose: at an elected date
  • Second dose: 1 month later
  • Third dose: 6 months after the first dose

For adults, TWINRIX (720/20) can also be given as a total of three doses over 3 weeks (a 0, 7, 21 day schedule). However, the body’s immune response to this rapid schedule may be reduced compared to the above schedule. Therefore, this rapid schedule should only be used under special circumstances (e.g. adult travellers wanting to be vaccinated within one month of departure). A booster dose is recommended at 12 months.

Children (1 to 15 years inclusive)
TWINRIX (720/20) is generally given as a total of two doses 6 to 12 months apart. Each dose is given on a separate visit. The first dose will be given on an elected date. The second dose will be given 6 to 12 months after the first dose.

  • First dose: at an elected date
  • Second dose: 6 to 12 months after the first dose.

In children who are travelling to areas where there is a risk of exposure to hepatitis B, TWINRIX Junior (360/10) should be given as a total of 3 doses over 6 months ( a 0, 1, 6 month schedule).

It is important to return at the recommended times for follow up doses.

Your doctor will advise on the possible need for extra doses, and future booster dosing.

IF YOU MISS A DOSE

If you miss a scheduled dose, talk to your doctor and arrange another visit as soon as possible.

WHILE YOU ARE USING TWINRIX

THINGS YOU MUST DO:

Keep your follow up visits with the doctor or clinic. It is important that the follow-up doses of TWINRIX are given at the correct times. This will ensure the best effect of the vaccine in protecting you against hepatitis A and hepatitis B.

THINGS TO BE CAREFUL OF:

Be careful driving or operating machinery until you know how TWINRIX affects you. TWINRIX should not normally interfere with your ability to drive a car or operate machinery. But in some people vaccination can cause dizziness or lightheadedness. Make sure you know how you react to TWINRIX before you drive a car or operate machinery, or do anything that could be dangerous if you feel dizzy or lightheaded.

SIDE EFFECTS

Tell your doctor, nurse or pharmacist as soon as possible if you or your child do not feel well during or after a dose of TWINRIX.

TWINRIX helps protect most people from hepatitis A and hepatitis B, but it may have unwanted side effects in a few people. All medicines and vaccines can have side effects. Most of the time they are not serious; however, sometimes they can be. Some side effects may need medical treatment.

Ask your doctor or pharmacist to answer any questions you may have.

Most unwanted effects with TWINRIX are mild and usually clear up within a few days. These effects, generally occur around the injection site (soreness, redness, swelling). Fatigue, headache, fever and generally feeling unwell have also been reported, as have feeling sick and vomiting.

MILD EVENTS that have been reported after hepatitis A or hepatitis B vaccination.

Tell your doctor if you notice any of the following that are troublesome or ongoing:

  • soreness, redness, swelling, bruising, hard lump or itching around the injection site
  • headache, fatigue, fever, dizziness, disturbed sleep, fainting
  • feeling sick or vomiting, gut pain, diarrhoea, loss of appetite
  • cough, sore throat, respiratory infections.
  • ringing in the ears, neck stiffness
  • sweating, chills, flushing or generally feeling unwell
  • muscle aches and pains, painful joints
  • immediate injection site pain, stinging and burning feeling

MORE SERIOUS EVENTS that have been reported rarely after hepatitis A or hepatitis B vaccination.

Tell your doctor immediately if you notice any of the following:

  • feelings of numbness, weakness and/ or fatigue in limbs, tingling in fingers or toes,
  • generalised stiffness, visual changes, difficulty passing urine
  • swollen glands, unusual bleeding, bleeding or bruising more easily than normal
  • drooping eyelids or sagging facial muscles
  • sudden headache, neck stiffness, dislike of bright lights, convulsions (fits)

As with all vaccines given by injection there is a very small risk of serious allergic reaction. This may occur days to weeks after vaccination. Contact your doctor immediately or go to the casualty department of your nearest hospital if any of the following happens:

  • swelling of limbs, face, eyes, inside of nose, mouth or throat
  • shortness of breath, breathing or swallowing difficulties
  • hives, itching (especially of the hands or feet), reddening of skin (especially around the ears), or severe skin reactions
  • unusual tiredness or weakness that is sudden and severe.

Other side effects not listed above, can also occur during or soon after a dose of TWINRIX.

Check with your doctor, nurse or pharmacist if you or your child have any other effects.

Do not be alarmed by this list of possible side effects. You or your child may not experience any.

STORAGE

TWINRIX is usually stored at the doctor’s clinic or surgery, or at the pharmacy. But if you need to store TWINRIX always:

  • Keep TWINRIX in the refrigerator stored between +2 C and +8 C. THE PACK SHOULD NEVER BE FROZEN. FREEZING DESTROYS THE VACCINE.
  • Keep the vaccine out of the reach of children.
  • Keep TWINRIX in the original pack until it is time for it to be given.

Ask your pharmacist what to do with any left over TWINRIX that has expired or has not been used.

PRODUCT DESCRIPTION

WHAT IT LOOKS LIKE:

TWINRIX comes in prefilled syringes or glass vials. It is a white, slightly milky liquid.

INGREDIENTS:

The active ingredients of TWINRIX are killed hepatitis A virus and the surface protein of the hepatitis B virus (from genetically engineered yeast cells). The vaccine is not infectious, and will not give you hepatitis A or hepatitis B.

Two different vaccine strengths are available:

  • TWINRIX (720/20): 720 ELISA units of killed hepatitis A virus and 20 micrograms of the hepatitis B surface protein.
  • TWINRIX JUNIOR (360/10): 360 ELISA units of killed hepatitis A virus and 10 micrograms of the hepatitis B surface protein.

Inactive ingredients in the vaccine are: aluminium hydroxide hydrate, aluminium phosphate, sodium chloride, amino acid supplement, formaldehyde, neomycin sulphate, polysorbate 20, -dibasic sodium phosphate heptahydrate, -monobasic sodium phosphate, trometamol and water.

TWINRIX is made without any human blood or blood products.

The manufacture of this product includes exposure to bovine derived materials. No evidence exists that any case of vCJD (considered to be the human form of bovine spongiform encephalopathy) has resulted from the administration of any vaccine product.

FURTHER INFORMATION

TWINRIX is only available if prescribed by a doctor.

TWINRIX (720/20) is available as:
Prefilled syringes in packs of 1 and 10 (AUST R 140575)

TWINRIX JUNIOR (360/10) is available as:
Prefilled syringes in packs of 1 and 10 (AUST R 140576)

MANUFACTURER

GlaxoSmithKline Biologicals S.A
rue de l'Institut 89,
1330 Rixensart,
Belgium.

SPONSOR:

GlaxoSmithKline Australia Pty Ltd
Level 4,
436 Johnston Street
Abbotsford, Victoria, 3067

Trade marks are owned or licensed to the GSK group of companies.

© 2019 GSK group of companies or its licensor.

Date of Preparation:
4 February 2020

Version 5.0

Published by MIMS July 2020

BRAND INFORMATION

Brand name

Twinrix Preservative Free

Active ingredient

Hepatitis A child/adolescent vaccine; Hepatitis B child vaccine

Schedule

S4

 

1 Name of Medicine

Combined hepatitis A and hepatitis B vaccine.

6.7 Physicochemical Properties

Not relevant to vaccines.

2 Qualitative and Quantitative Composition

Twinrix is a non-infectious combination vaccine containing hepatitis A virus antigen and hepatitis B surface antigen (rys).
Each 1 mL dose of Twinrix contains 720 ELISA units of hepatitis A virus antigen and 20 micrograms of hepatitis B surface antigen (rys). The viral antigens are adsorbed on 0.45 mg aluminium in the form of aluminium phosphate and aluminium hydroxide hydrate and suspended in a solution containing 9 mg of sodium chloride.
Each 0.5 mL dose of Twinrix Junior contains 360 ELISA units of hepatitis A virus antigen and 10 micrograms of hepatitis B surface antigen (rys). The viral antigens are adsorbed on 0.225 mg aluminium in the form of aluminium phosphate and aluminium hydroxide hydrate and suspended in a solution containing 4.5 mg of sodium chloride.
Twinrix is formulated using the HM 175 strain of hepatitis A grown in human cell culture (MRC5), and inactivated with formaldehyde. The hepatitis B surface antigen (rys) component is produced by culturing genetically-engineered Saccharomyces cerevisiae yeast cells (Baker's yeast), which carry the relevant gene of an adw subtype, of the surface antigen of the hepatitis B virus. Both the hepatitis A virus antigen and hepatitis B surface antigen (rys) are purified by several physico-chemical steps, and formulated as separate antigen suspensions adsorbed onto aluminium salts. Twinrix is produced by pooling bulk preparations of the purified antigens. The bulk hepatitis A virus antigen and hepatitis B surface antigen (rys) preparations are identical to those used in the manufacture of the currently licensed monovalent hepatitis A (Havrix) and hepatitis B (Engerix-B) vaccines. Standardised fermentation and purification procedures ensure batch to batch consistency. The vaccines are free of association with human blood or blood products.
The manufacture of this product includes exposure to bovine derived materials. No evidence exists that any case of vCJD (considered to be the human form of bovine spongiform encephalopathy) has resulted from the administration of any vaccine product.
Twinrix meets the World Health Organization requirements for the manufacture of biological substances.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Twinrix is a sterile suspension.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Twinrix induces the production of specific anti-HAV and anti-HBs antibodies, which confer immunity against HAV and HBV infection.

Clinical trials.

Adults - standard schedule.

The immunogenicity of Twinrix (720/20) has been investigated using a 0, 1 and 6 month vaccination schedule in randomised clinical studies involving over 700 adult volunteers.
Specific humoral antibodies (seropositivity) against HAV were elicited in:
92-96% of vaccines one month after the first dose;
97-100% of vaccines one month after the second dose;
100% of vaccines one month after the third dose.
Seropositivity was defined as anti-HAV antibody titres ≥ 33 IU/L.
Seroprotective levels of anti-HBs antibodies (titers ≥ 10 IU/L) were elicited in:
33.7% of vaccines one month after the first dose;
83.9% of vaccines one month after the second dose;
99.3% of vaccines one month after the third dose.
An anti-HBs antibody titre above 10 IU/L correlates with protection against hepatitis B infection.

Adults - rapid schedule.

The immunogenicity of Twinrix (720/20) has also been investigated using a 0, 7, 21 day primary schedule plus a fourth dose at month 12 in a randomised clinical study involving over 400 adult volunteers, of whom 239 received Twinrix (720/20).
Specific humoral antibodies (seropositivity) against HAV were elicited in:
100% of vaccines one week after the third dose;
99.5% of vaccines five weeks after the third dose;
100% of vaccines one month after the fourth dose.
Seroprotective levels of anti-HBs antibodies (titers ≥ 10 IU/L) were elicited in:
82% of vaccines one week after the third dose;
85% of vaccines five weeks after the third dose;
100% of vaccines one month after the fourth dose.

Children.

The immunogenicity of Twinrix (720/20) has been investigated using a 0 and 6 month vaccination schedule in randomised clinical studies involving 451 subjects aged 1 to 15 years old.
Specific humoral antibodies (seropositivity) against HAV were elicited in:
99.1% of vaccines one month after the first dose;
100% of vaccines one month after the second dose.
Seroprotective levels of anti-HBs antibodies (titers ≥ 10 IU/L) were elicited in:
37.4% of vaccines one month after the first dose;
70.5% of vaccines 6 months after the first dose;
98.2% of vaccines one month after the second dose.
In a clinical study involving 117 subjects who received the second dose at month 12, specific humoral antibodies (seropositivity) against HAV were elicited in 99.0% of vaccines one month after the second dose, and seroprotective levels of anti-HBs were induced in 97.0% of subjects.
The immunogenicity of Twinrix Junior (360/10) has been investigated using a 0, 1 and 6 month vaccination schedule in randomised clinical studies involving 168 children: 54 subjects aged 1 to 6 years and 114 subjects aged 6 to 15 years.
Specific humoral antibodies (seropositivity) against HAV were elicited in:
100% of vaccines one month after the second dose;
100% of vaccines one month after the third dose.
Seroprotective levels of anti-HBs antibodies (titers ≥ 10 IU/L) were elicited in:
86.2% to 94.6% of vaccines one month after the second dose;
100% of vaccines one month after the third dose.
In a comparative study in children and adolescents, Twinrix (720/20) following a 0 and 6 month schedule was proven to be noninferior for both hepatitis A and B antibody responses to Twinrix Junior (360/10) following a 0, 1 and 6 month schedule. However, seroprotection rates for hepatitis B at month 2 after two doses of Twinrix Junior (given one month apart) were higher (85.6%) than after a single dose of Twinrix (38.0%).

Antibody persistence.

Twinrix Junior (360/10).

In two long-term clinical studies, persistence of anti-HAV and anti-HBs antibodies has been demonstrated up to 10 years in children aged 12-15 years and up to 5 years in children aged 1-11 years. For 1-11 years age cohort, after the primary vaccination with 0, 1, 6 month schedule of Twinrix Junior, all subjects followed up to 5 years (N = 102) retained ≥ 15 mIU/mL anti-HAV antibody and 97% retained anti-HBs antibody ≥ 10 mIU/mL. For 12-15 years age cohort, after the primary vaccination with 0, 1, 6 month schedule of Twinrix Junior, all subjects followed up to 10 years (N = 102) retained ≥ 15 mIU/mL anti-HAV antibody and 85% retained anti-HBs antibody ≥ 10 mIU/mL. The kinetics of decline of anti-HAV and anti-HBs antibodies were shown to be similar to those of the monovalent vaccines.

Twinrix (720/20).

In two long-term clinical studies conducted in 56 healthy adults aged 17-43 years, 15 years after the primary vaccination with Twinrix (720/20) the anti-HAV seropositivity rates were 100% in both studies and the anti-HBs seroprotection rates were 89.3% and 92.9%, respectively. The kinetics of decline of anti-HAV and anti-HBs antibodies were shown to be similar to those of the monovalent vaccines.
In two clinical studies conducted in subjects over 40 years of age, the seropositivity rate for anti-HAV antibodies and seroprotection rate against hepatitis B following Twinrix (720/20) 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 (720/20) were 92% and 57% at 7 and 48 months following the first dose respectively, versus 80% and 40% after the GlaxoSmithKline Biologicals monovalent 20 microgram hepatitis B vaccine, and 71% and 27% after another licensed monovalent 10 microgram 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 with females.
The seropositivity rates for anti-HAV antibodies after Twinrix (720/20) 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 (720/20) 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 response.
Anti-HAV and anti-HBs antibodies have been shown to persist for at least 24 months following the initiation of a 0, 6 month schedule of Twinrix (720/20) in children. Specific humoral antibodies (seropositivity) against HAV were elicited in 100% of vaccines at month 24, and anti-HBs seroprotective levels were present in 93.3% of subjects. In this study, the immune response for both antigen components was comparable to that seen after a 3 dose regimen of Twinrix Junior (360/10).
The persistence of anti-HAV and anti-HBs antibodies at month 24 was shown to be similar following a 0, 6 month or a 0, 12 month schedule of Twinrix (720/20) in children.

Hepatitis D.

As hepatitis D (caused by the delta agent) does not occur in the absence of hepatitis B infection, it can be expected that hepatitis D will also be prevented by vaccination with Twinrix.

5.2 Pharmacokinetic Properties

Not relevant to vaccines.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

Twinrix (720/20) is indicated for active immunisation against hepatitis A and hepatitis B virus infection in adults and children from 1 year of age. Twinrix Junior (360/10) is indicated for use in children aged 1 to 15 years.

Immunisation against hepatitis A is recommended in the following individuals.

Travellers.

Persons travelling to areas of intermediate or high endemicity for hepatitis A. This includes all developing countries.

Armed forces.

Armed forces personnel who travel to higher endemicity areas or to areas where hygiene is poor, have an increased risk of HAV infection.
Persons for whom hepatitis A is an occupational hazard or for whom there is an increased risk of transmission. These include:
employees in day care centres, particularly in situations where children have not been toilet trained;
teachers and other close contacts of the intellectually disabled;
staff and residents of residential facilities for the intellectually disabled;
healthcare workers and teachers in remote Aboriginal and Torres Strait Islander communities;
nursing staff and other healthcare workers in contact with patients in paediatric wards, infectious diseases wards, emergency rooms and intensive care units;
sewerage workers;
food handlers, since food hygiene procedures and food processing methods are not always adequate to protect from contamination from food handlers.

Homosexual men.

Increased incidence of hepatitis A infection among homosexual males suggests that the disease may be sexually transmitted in this group.

Contacts of infected persons.

Since virus shedding from infected persons may occur for a prolonged period, active immunisation of close contacts is recommended. The use of vaccine in outbreak control has been shown to be more effective than the use of immunoglobulin.
Specific population groups known to have a higher incidence of hepatitis A: e.g. Australian Aboriginals, those in settings with recognised community wide HAV epidemics.
Individuals with chronic liver disease and recipients of liver transplants, as hepatitis A infection is likely to be more severe in these groups. Many injecting drug users will have pre-existing liver disease from hepatitis B or hepatitis C infection.
Recipients of blood products, such as factor VIII concentrates.

Immunisation against hepatitis B is recommended in the following individuals.

Persons for whom hepatitis B is an occupational hazard or for whom there is an increased risk of transmission. These include:
healthcare workers directly involved in patient care, or in the handling of human blood or tissue;
embalmers;
staff and residents of residential facilities for the intellectually disabled;
inmates of long-term correctional facilities and staff of correctional facilities.
Individuals with chronic liver disease and/or hepatitis C.
Haemodialysis patients and recipients of certain blood products such as factor VIII concentrates.
Sexually active homosexual men and persons with multiple sexual partners: e.g. clients of STD (sexually transmitted disease) clinics. Sexual risk occurs in susceptible (anti-HBs negative) partners of HBV carriers and patients with acute hepatitis B.
Abusers of injectable drugs.
Close residential contacts of deinstitutionalised intellectually disabled individuals who are HBV carriers.
Household contacts of patients with acute hepatitis B and chronic hepatitis B carriers.

Others in whom vaccination against hepatitis B might be justified.

Police and members of the armed forces.
Travellers to areas of high endemicity for hepatitis B.
Participants in contact sports.

4.3 Contraindications

Twinrix should not be administered to subjects with known hypersensitivity to any component of the vaccine (e.g. neomycin sulphate), or to subjects having shown signs of hypersensitivity after previous administration of these combined vaccines or the monovalent hepatitis A or hepatitis B vaccines.
As for any vaccine, Twinrix should not be administered to subjects suffering from acute severe febrile illness. However, the presence of minor infection does not contraindicate vaccination.

4.4 Special Warnings and Precautions for Use

Twinrix should never be administered intravenously.
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.
As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of anaphylactic reactions following the administration of the vaccine.
Twinrix should not be administered in the gluteal region. It should not be routinely administered intradermally, or subcutaneously since these routes of administration may not result in an optimum immune response.
Twinrix should be administered with caution to subjects with thrombocytopenia or a bleeding disorder since bleeding may occur following an intramuscular administration to these subjects (see Section 4.2 Dose and Method of Administration).
In elderly subjects, haemodialysis patients and persons with an impaired immune system, adequate anti-HAV and anti-HBs antibody titres may not be obtained after a primary vaccination course. The monitoring of antibody titres and if appropriate the need for additional doses of the appropriate vaccine should be considered in such patients. The rapid schedule has not been studied and is not recommended in such patients.
Caution should be exercised in administering Twinrix to patients in whom a systemic reaction due to the vaccine may pose a significant risk e.g. in patients with severely compromised cardiopulmonary function.
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. These vaccines will not induce the production of anti-HBs antibodies in hepatitis B carriers.
The vaccines will not protect against infection caused by hepatitis C or hepatitis E viruses, or other pathogens known to infect the liver.

Use in renal impairment.

See Section 4.4 Special Warnings and Precautions for Use statement regarding use in haemodialysis patients.

Use in the elderly.

See Section 4.4 Special Warnings and Precautions for Use.

Paediatric use.

See Section 4.4 Special Warnings and Precautions for Use.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Clinical studies have demonstrated that Twinrix can be administered concomitantly with diphtheria, tetanus, acellular pertussis, inactivated poliomyelitis, Haemophilus influenzae type b and measles mumps rubella vaccines. In these trials, the injectable vaccines were given at a different injection site to Twinrix.

Guidance for coadministration of Twinrix Junior and Cervarix should be drawn from those individual vaccines.

Twinrix Junior (360/10) can be given concomitantly with human papillomavirus (HPV) vaccine (Cervarix). Administration of Twinrix Junior (360/10) at the same time as Cervarix (HPV vaccine) has shown no clinically relevant interference in the antibody response to the HPV and hepatitis A antigens. Anti-HBs geometric mean antibody concentrations were lower on coadministration, but the clinical significance of this observation is not known since the seroprotection rates remain unaffected. The proportion of subjects reaching anti-HBs ≥ 10 mIU/mL was 98.3% for concomitant vaccination and 100% for Twinrix Junior (360/10) alone. The Product Information documents for Twinrix Junior and Cervarix should be consulted for guidance with respect to appropriate usage, population and dosing guidelines for these vaccines.
The concomitant administration of Twinrix with other vaccines (e.g. pneumococcal, influenza) given at separate sites using separate syringes has not been specifically studied.
Twinrix must not be mixed with other vaccines in the same syringe.
As with other vaccines, it may be expected that patients receiving immunosuppressive therapy or patients with an immunodeficiency, may not achieve an adequate immune response. (See Section 4.4 Special Warnings and Precautions for Use).
Concomitant administration of normal human immunoglobulin with the first dose of hepatitis A vaccine does not influence the seroconversion rate, but may result in a relatively lower anti-HAV antibody titre than when the primary course of vaccine is given alone. Twinrix and normal human immunoglobulin should be administered at separate injection sites.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy.
(Category B2)
Twinrix should be used during pregnancy only when clearly needed, and when the possible advantages outweigh the possible risks for the foetus.
The effect of Twinrix on embryofoetal, perinatal and postnatal survival and development has not been prospectively evaluated in clinical trials.
The effect of Twinrix on embryofoetal, perinatal and postnatal survival and development has been assessed in a study in rats. There were no direct or indirect harmful effects with respect to fertility, pregnancy, embryonal/foetal development, parturition or postnatal development, at 1/5 the adult human dose (9 times greater than the clinical adult exposure based on mg/m2).
Adequate human data on use during lactation and adequate animal reproduction studies are not available.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety profile presented below 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 of Twinrix (720/20).
Events are listed within body systems and categorised by frequency according to the following definitions: very common: ≥ 1/10; common: ≥ 1/100 and < 1/10; uncommon: ≥ 1/1000 and < 1/100; rare: ≥ 1/10,000 and < 1/1000; very rare: < 1/10,000.

Gastrointestinal disorders.

Common: gastrointestinal symptoms (such as diarrhoea, nausea, vomiting).

General disorders and administration site conditions.

Very common: pain and redness at the injection site, fatigue.
Common: injection site reaction, malaise, swelling at the injection site.
Uncommon: fever (≥ 37.5°C).
Rare: influenza-like illness, chills.

Infections and infestations.

Common: viral infection.
Uncommon: upper respiratory tract infection.

Blood and lymphatic system disorders.

Rare: lymphadenopathy.

Metabolism and nutrition disorders.

Rare: decreased appetite.

Nervous system disorders.

Very common: headache.
Uncommon: dizziness.
Rare: hypoaesthesia, paraesthesia.

Vascular disorders.

Rare: hypotension.

Skin and subcutaneous tissue disorders.

Rare: rash, pruritus.
Very rare: urticaria.

Musculoskeletal and connective tissue disorders.

Uncommon: myalgia.
Rare: arthralgia.
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 above. 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.
During clinical studies with Twinrix Junior (360/10) (n = 538 doses of vaccines administered) the frequency of local reactions in children, although still considered common, were almost half that reported with Twinrix (720/20) in adults. Of the general reactions reported in these children, most were reported at a similar frequency to Twinrix (720/20) in adults except upper respiratory tract infection, fever and vomiting which were commonly reported at frequencies of 9.3%, 3.7% and 1.9% respectively.
Other adverse events observed in clinical trials performed with Twinrix Junior include:

Blood and lymphatic system disorders.

Rare: lymphadenopathy.

Metabolism and nutrition disorders.

Common: appetite lost.

General disorders and administration site conditions.

Very common: pain and redness at the injection site.
Common: irritability, swelling at the injection site, injection site reaction, fatigue, malaise, fever (≥ 37.5°C).

Nervous system disorders.

Common: drowsiness, headache.
Rare: dizziness.

Gastrointestinal disorders.

Common: gastrointestinal symptoms (such as nausea, vomiting).

Skin and subcutaneous tissue disorders.

Uncommon: rash.
Rare: urticaria.
In a comparative trial in children and adolescents, (n = 745 doses) the percentage of subjects reporting solicited adverse events after a primary course of Twinrix (720/20) used in a two dose schedule was similar to that seen with Twinrix Junior (360/10) given in a 3 dose schedule. Pain was reported in 50.7% of the Twinrix (720/20) group and in 39.1% of the Twinrix Junior (360/10) group. Incidence of redness was 16.1% and 11.9% and swelling was reported in 4.4% and 4.9% in the Twinrix and Twinrix Junior groups respectively.
General reactions solicited in controlled clinical trials that may occur in temporal association with Twinrix used in a two dose schedule in children and adolescents include:

General disorders and administration site conditions.

Very rare: influenza-like illness, chills.

Nervous system disorders.

Very rare: hypoaesthesia, paraesthesia.

Gastrointestinal disorders.

Common: gastrointestinal symptoms (such as diarrhoea).

Musculoskeletal and connective tissue disorders.

Very rare: myalgia, arthralgia.

Skin and subcutaneous tissue disorders.

Very rare: pruritus.

Vascular disorders.

Very rare: hypotension.

Postmarketing data.

The following adverse reactions have been reported with either Twinrix or with monovalent hepatitis A or B vaccines.

Infections and infestations.

Meningitis.

Blood and lymphatic system disorders.

Thrombocytopenia, thrombocytopenic purpura.

Immune system disorders.

Anaphylaxis, allergic reactions including anaphylactoid reactions and mimicking serum sickness.

Nervous system disorders.

Encephalitis, encephalopathy, neuritis, neuropathy, paralysis, convulsions.

Vascular disorders.

Vasculitis.

Skin and subcutaneous tissue disorders.

Angioneurotic oedema, lichen planus, erythema multiforme.

Musculoskeletal and connective tissue disorders.

Arthritis, muscular weakness.

General disorders and administration site conditions.

Immediate injection site pain, stinging and burning sensation.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

The vaccine should be resuspended before use. When resuspended, the vaccine will have a uniform hazy white appearance.
Upon storage, a fine white deposit with a clear colourless layer above may be observed.

Resuspension of the vaccine to obtain a uniform hazy white suspension.

The vaccine can be resuspended following the steps below.
1. Hold the syringe upright in a closed hand.
2. Shake the syringe by tipping it upside down and back again.
3. Repeat this action vigorously for at least 15 seconds.
4. Inspect the vaccine again:
a. If the vaccine appears as a uniform hazy white suspension, it is ready to use - the appearance should not be clear.
b. If 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 again.
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 vaccine.
Each dose of Twinrix is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.
Twinrix should be injected intramuscularly into the deltoid region of the upper arm in adults and older children. The anterolateral aspect of the thigh may be used in infants.
Exceptionally, the vaccine may be administered subcutaneously in patients with thrombocytopenia or bleeding disorders (e.g. haemophiliacs) since bleeding may occur following an intramuscular administration to these subjects. (See Section 4.4 Special Warnings and Precautions for Use).
Twinrix must not be given intravenously.

Immunisation schedule.

Twinrix (720/20).

In children and adults not previously exposed to hepatitis A or hepatitis B viruses or vaccines the primary course of Twinrix is as follows in Table 1.

Rapid schedule.

The rapid schedule is used in exceptional circumstances in adults when more rapid protection is required, e.g. in travellers commencing vaccination within one month or more of departure. When this rapid schedule is used, a fourth dose is recommended 12 months after the first dose to ensure adequate protection, as lower seroprotection rates against hepatitis B were observed after the third dose as compared to the standard 0, 1, 6 month schedule (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

Twinrix Junior (360/10).

In circumstances where a child is at immediate risk of exposure to hepatitis B (e.g. travellers), and did not receive a primary course of hepatitis B vaccine as an infant, Twinrix Junior should be used as follows in Table 2.

Booster dose.

Long-term clinical studies have demonstrated persistence of anti-HAV and anti-HBs antibodies 15 years after immunisation with Twinrix (720/20) and 10 years after immunisation with Twinrix Junior (360/10). As persistence of antibodies and kinetics of antibody decline were similar to those following the monovalent vaccines, general guidelines for booster vaccination can therefore be drawn from those for the monovalent vaccines.

Hepatitis B.

The National Health and Medical Research Council recommends that booster doses against hepatitis B are not required in immunocompetent individuals, since there is good evidence that a completed primary course of hepatitis B vaccination provides long lasting protection in these individuals. This applies to adults, children and all subgroups (such as healthcare workers). However, booster doses are recommended for immunosuppressed individuals, for people living with HIV infection or with renal failure. The timing for boosting in these individuals should be decided by regular monitoring of hepatitis B antibody levels at six to twelve monthly intervals. (Source: The Australian Immunisation Handbook, 7th edition, NHMRC).

Hepatitis A.

Data available from clinical studies using hepatitis A vaccine (Havrix) show persistence of antibodies after 8 years which is consistent with a projected 20 years persistence (based on mathematical calculations). Further long-term follow-up of immunised cohorts will be required to determine the duration of protection following hepatitis A immunisation and whether and when booster doses may be required.
In situations where a booster dose of both hepatitis A and hepatitis B are desired, the combined vaccine can be given. Alternatively, subjects primed with Twinrix may be administered a booster dose of either of the monovalent vaccines.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

Cases of overdose have been reported during postmarketing surveillance. Adverse events reported following overdosage were similar to those reported with normal vaccine administration.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

6 Pharmaceutical Particulars

6.1 List of Excipients

The vaccine preparation also contains 1 mg/mL of amino acid supplement, < 20 nanogram/mL of neomycin sulphate, 50 microgram/mL of polysorbate 20, < 7 microgram/mL of dibasic sodium phosphate heptahydrate, < 5 microgram/mL of monobasic sodium phosphate, < 250 microgram/mL of trometamol and < 100 microgram/mL of formaldehyde.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Twinrix must be stored between +2°C to +8°C. Do not freeze; freezing destroys the potency of the product. Discard the vaccine if it has been frozen.

6.5 Nature and Contents of Container

Twinrix and Twinrix Junior are available as a monodose vial in packs of one or ten and as a pre-filled syringe in packs of one or ten.
The vials and prefilled syringes are made of neutral glass type 1, which conforms to European Pharmacopoeia requirements.
Not all presentations and pack sizes may be marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes