TWINRIX ADULT 720 U.EI HAV+20mcg / ml AgHBs injection suspension medication leaflet

Twinrix Adult, suspension for injection in pre-filled syringe

Hepatitis A (inactivated) and hepatitis B (rDNA) (HAB) vaccine (adsorbed).

1 dose (1 ml) contains:

Hepatitis A virus (inactivated)1,2 720 ELISA Units

Hepatitis B surface antigen3,4 20 micrograms1Produced on human diploid (MRC-5) cells2Adsorbed on aluminium hydroxide, hydrated 0.05 milligrams Al3+3Produced in yeast cells (Saccharomyces cerevisiae) by recombinant DNA technology4Adsorbed on aluminium phosphate 0.4 milligrams Al3+

The vaccine may contain traces of neomycin which is used during the manufacturing process (seesection 4.3).

For the full list of excipients, see section 6.1.

Suspension for injection.

Turbid white suspension.

Twinrix Adult is indicated for use in non immune adults and adolescents 16 years of age and abovewho are at risk of both hepatitis A and hepatitis B infection.

- Dosage

A dose of 1.0 ml is recommended for adults and adolescents 16 years of age and above.

- Primary vaccination schedule

The standard primary course of vaccination with Twinrix Adult consists of three doses, the firstadministered at the elected date, the second one month later and the third six months after the firstdose.

In exceptional circumstances in adults, when travel is anticipated within one month or more afterinitiating the vaccination course, but where insufficient time is available to allow the standard 0, 1, 6month schedule to be completed, a schedule of three intramuscular injections given at 0, 7 and 21 daysmay be used. When this schedule is applied, a fourth dose is recommended 12 months after the firstdose.

The recommended schedule should be adhered to. Once initiated, the primary course of vaccinationshould be completed with the same vaccine.

- Booster dose

Long-term antibody persistence data following vaccination with Twinrix Adult are available up to 20years after vaccination (see section 5.1). The anti-HBs and anti-HAV antibody titres observedfollowing a primary vaccination course with the combined vaccine are in the range of what is seenfollowing vaccination with the monovalent vaccines. General guidelines for booster vaccination cantherefore 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 fullprimary vaccination course has not been established; however some official vaccination programmescurrently include a recommendation for a booster dose of hepatitis B vaccine and these should berespected.

For some categories of subjects or patients exposed to HBV (e.g; haemodialysis orimmunocompromised patients) a precautionary attitude should be considered to ensure a protectiveantibody level ≥ 10IU/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 beensured by immunological memory. Guidelines for boosting are based on the assumption thatantibodies are required for protection.

In situations where a booster dose of both hepatitis A and hepatitis B are desired, Twinrix Adult canbe given. Alternatively, subjects primed with Twinrix Adult may be administered a booster dose ofeither of the monovalent vaccines.

Twinrix Adult is for intramuscular injection, preferably in the deltoid region.

Exceptionally the vaccine may be administered subcutaneously in patients with thrombocytopenia orbleeding disorders. However, this route of administration may result in suboptimal immune responseto the vaccine (see section 4.4).

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or neomycin.

Hypersensitivity after previous administration of hepatitis A and/or hepatitis B vaccines.

The administration of Twinrix Adult should be postponed in subjects suffering from acute severefebrile illness.

Syncope (fainting) can occur following, or even before, any vaccination especially in adolescents as apsychogenic response to the needle injection. This can be accompanied by several neurological signssuch as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. Itis 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 atthe time of vaccination. It is not known whether Twinrix Adult will prevent hepatitis A and hepatitis Bin such cases.

The vaccine will not prevent infection caused by other agents such as hepatitis C and hepatitis E andother pathogens known to infect the liver.

Twinrix Adult 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 andpersons with an impaired immune system, adequate anti-HAV and anti-HBs antibody titres may not beobtained after the primary immunisation course and such patients may therefore require administrationof additional doses of vaccine.

Obesity (defined as BMI ≥ 30 kg/m2) has been observed to reduce the immune response to hepatitis Avaccines. A number of factors have been observed to reduce the immune response to hepatitis Bvaccines. These factors include older age, male gender, obesity, smoking, route of administration, andsome chronic underlying diseases. Consideration should be given to serological testing of thosesubjects who may be at risk of not achieving seroprotection following a complete course of Twinrix

Adult. Additional doses may need to be considered for persons who do not respond or have a sub-optimal response to a course of vaccinations.

As with all injectable vaccines, appropriate medical treatment and supervision should always bereadily 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 asuboptimal response to the vaccine, these routes should be avoided. However, exceptionally Twinrix

Adult can be administered subcutaneously to subjects with thrombocytopenia or bleeding disorderssince bleeding may occur following an intramuscular administration to these subjects (see section 4.2).

Twinrix Adult should under no circumstances be administered intravascularly.

As with any vaccine, a protective immune response may not be elicited in all vaccinees.

This vaccine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

No data on concomitant administration of Twinrix Adult with specific hepatitis A immunoglobulin orhepatitis B immunoglobulin have been generated. However, when the monovalent hepatitis A andhepatitis B vaccines were administered concomitantly with specific immunoglobulins, no influence onseroconversion was observed although it may result in lower antibody titres.

Although the concomitant administration of Twinrix Adult and other vaccines has not specificallybeen studied, it is anticipated that, if different syringes and other injection sites are used, no interactionwill be observed.

It may be expected that in patients receiving immunosuppressive treatment or patients withimmunodeficiency, an adequate response may not be achieved.

The effect of Twinrix Adult on embryo-fetal, peri-natal and post-natal survival and development hasbeen assessed in rats. This study did not indicate direct or indirect harmful effects with respect tofertility, pregnancy, embryonal/fetal development, parturition or post-natal development.

The effect of Twinrix Adult on embryo-fetal, peri-natal and post-natal survival and development hasnot been prospectively evaluated in clinical trials.

Data on outcomes of a limited number of pregnancies in vaccinated women do not indicate anyadverse effects of Twinrix Adult on pregnancy or on the health of the fetus/newborn child. While it isnot expected that recombinant hepatitis B virus surface antigen would have adverse effects onpregnancies or the fetus it is recommended that vaccination should be delayed until after deliveryunless there is an urgent need to protect the mother against hepatitis B infection.

It is unknown whether Twinrix Adult is excreted in human breast milk. The excretion of Twinrix

Adult in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Twinrix Adult should be made taking into account thebenefit of breast-feeding to the child and the benefit of Twinrix Adult therapy to the woman.

Twinrix Adult has no or negligible influence on the ability to drive and use machines.

The safety profile presented below is based on a pooled analysis of events per dose from more than6,000 subjects who received either the standard 0, 1, 6 month schedule (n=5,683) or the accelerated 0,7, 21 days schedule (n=320). The most commonly reported adverse reactions following Twinrix Adultadministration with the standard 0, 1, 6 month schedule are pain and redness occurring in a per dosefrequency of 37.6% and 17.0% respectively.

In the two clinical trials in which Twinrix Adult was administered at 0, 7, 21 days, overall solicitedgeneral and local symptoms were reported with the same categories of frequency as defined below.

After a fourth dose given at month 12, the incidence of systemic and local adverse reactions wascomparable to that seen after vaccination at 0, 7, 21 days.

In comparative studies, it was noted that the frequency of solicited adverse events following theadministration of Twinrix Adult is not different from the frequency of solicited adverse eventsfollowing the administration of the monovalent vaccines.

Frequencies are reported as:

Very common: ≥ 1/10

Common: ≥ 1/100 to < 1/10

Uncommon: ≥ 1/1,000 to < 1/100

Rare: ≥ 1/10,000 to < 1/1,000

Very rare: < 1/10,000

System Organ Class Frequency Adverse reactions

Infections and infestations 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

Gastrointestinal disorders Common Gastrointestinal symptoms, diarrhoea,nausea

Uncommon Vomiting, abdominal pain*

Skin and subcutaneous tissue disorders Rare Rash, pruritus

Very rare Urticaria

Musculoskeletal and connective tissue Uncommon Myalgiadisorders Rare Arthralgia

General disorders and administration Very common Pain and redness at the injection site,site conditions fatigue

Common Swelling at the injection site, injectionsite reactions (such as haematoma,pruritus and bruising), malaise

Uncommon Fever (≥ 37.5°C)

Rare Influenza like illness, chills

Post-marketing surveillance

The following adverse reactions have been reported with either Twinrix or with GlaxoSmithKlinemonovalent hepatitis A or B vaccines:

Infections and infestations Meningitis

Blood and lymphatic system disorders Thrombocytopenia, thrombocytopenic purpura

Immune system disorders Anaphylaxis, allergic reactions including anaphylactoidreactions 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, erythemamultiforme

Musculoskeletal and connective tissue Arthritis, muscular weaknessdisorders

General disorders and administration Immediate injection site painsite conditions

Following widespread use of the monovalent hepatitis A and/or hepatitis B vaccines, the followingundesirable events have additionally been reported in temporal association with vaccination:

Nervous system disorders Multiple sclerosis, myelitis, facial palsy, polyneuritissuch as Guillain-Barré syndrome (with ascendingparalysis), optic neuritis

General disorders and administration Stinging and burning sensationsite conditions

Investigations Abnormal liver function tests

* refers to adverse reactions observed in clinical trials performed with the paediatric formulation

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Cases of overdose have been reported during post-marketing surveillance. Adverse events reportedfollowing overdosage were similar to those reported with normal vaccine administration.

Pharmaco therapeutic group: Hepatitis vaccines, ATC code: J07BC20.

Twinrix Adult is a combined vaccine formulated by pooling bulk preparations of the purified,inactivated hepatitis A (HA) virus and purified hepatitis B surface antigen (HBsAg), separatelyadsorbed onto aluminium hydroxide and aluminium phosphate. The HA virus is propagated in MRC5human diploid cells. HBsAg is produced by culture, in a selective medium, of genetically engineeredyeast cells.

Twinrix Adult confers immunity against HAV and HBV infection by inducing specific anti-HAV andanti-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 94% of the adults onemonth after the first dose and in 100% one month after the third dose (i.e. month 7). Specific humoralantibodies against hepatitis B were observed in 70% of the adults after the first dose andapproximately 99% after the third dose.

The 0, 7 and 21 day primary schedule plus a fourth dose at month 12 is for use in exceptionalcircumstances in adults. In a clinical trial where Twinrix Adult was administered according to thisschedule, 82% and 85% of vaccinees had seroprotective levels of anti-HBV antibodies at 1 and 5weeks respectively following the third dose (i.e. at months 1 and 2 after the initial dose). Theseroprotection rate against hepatitis B increased to 95.1% by three months after the first dose.

Seropositivity rates for anti-HAV antibodies were 100%, 99.5% and 100% at months 1, 2 and 3 afterthe initial dose. One month after the fourth dose, all vaccinees demonstrated seroprotective levels ofanti-HBs antibodies and were seropositive for anti-HAV antibodies.

In a clinical study conducted in subjects over 40 years of age, the seropositivity rate for anti-HAVantibodies and seroprotection rate against hepatitis B of Twinrix Adult following a 0, 1, 6 monthsschedule were compared with the seropositivity and seroprotection rates of monovalent hepatitis Aand B vaccines when administered in opposite arms.

The seroprotection rate against hepatitis B after the administration of Twinrix Adult was 92% and56% at 7 and 48 months respectively, versus 80% and 43% after the GlaxoSmithKline Biologicalsmonovalent 20µg hepatitis B vaccine, and 71% and 31% after another licensed monovalent 10µghepatitis B vaccine. Anti-HBs antibody concentrations decreased as age and body mass indexincreased; they were also lower in male than in female subjects.

The seropositivity rate for anti-HAV antibodies after Twinrix Adult was 97% at both 7 and 48 monthsversus 99% and 93% after the GlaxoSmithKline Biologicals monovalent hepatitis A vaccine and 99%and 97% after another licensed monovalent hepatitis A vaccine.

Subjects received an additional dose of the same vaccine(s) 48 months after the first dose of theprimary vaccination course. One month after this dose, 95% of the subjects vaccinated with Twinrix

Adult achieved seroprotective levels of anti-HBV antibodies (≥ 10 mIU/ml).

In two long-term clinical studies conducted in adults aged 17 years to 43 years, respectively 18 and 25subjects had evaluable tests 20 years after the primary vaccination with Twinrix Adult; the anti-HAVseropositivity rates were 100% and 96% respectively and the anti-HBs seroprotection rates were 94%and 92%, respectively.

Evaluation of pharmacokinetic properties is not required for vaccines.

Non-clinical data reveal no special hazard for humans based on general safety studies.

Sodium chloride

Water for injections

For adjuvants, see section 2.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store in the original package, in order to protect from light.

1 ml of suspension in a pre-filled syringe (type I glass) with a plunger stopper (butyl rubber) and witha rubber tip cap.

The tip cap and rubber plunger stopper of the pre-filled syringe are made with synthetic rubber.

Pack sizes of 1, 10 and 25, with or without needles.

Not all pack sizes may be marketed.

Upon storage, a fine white deposit with a clear colourless layer above may be observed.

The vaccine should be re-suspended before use. When re-suspended, the vaccine will have a uniformhazy white appearance.

Re-suspension of the vaccine to obtain a uniform hazy white suspension

The vaccine should be re-suspended 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 - theappearance should not be clear.

b. If the vaccine still does not appear as a uniform hazy white suspension - tip upsidedown 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 physicalappearance prior to administration. In the event of either being observed, do not administer thevaccine.

Instructions for the pre-filled syringe after re-suspension

Luer Lock Adaptor

Hold the syringe by the barrel, not by theplunger.

Plunger Unscrew the syringe cap by twisting it

Barrel anticlockwise.

Cap

Needle hub

To attach the needle, connect the hub to the Luer

Lock Adaptor and rotate a quarter turnclockwise until you feel it lock.

Do not pull the syringe plunger out of the barrel.

If it happens, do not administer the vaccine.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

GlaxoSmithKline Biologicals s.a.rue de l'Institut 89

B-1330 Rixensart, Belgium

EU/1/96/020/001

EU/1/96/020/002

EU/1/96/020/003

EU/1/96/020/007

EU/1/96/020/008

EU/1/96/020/009

Date of first authorisation: 20 September 1996

Date of latest renewal: 28 August 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.