Suspension for injection Turbid liquid suspension.

4.1 Therapeutic indications Active immunisation against HAV infection from 1 year up to and including 15 years of age. The vaccine is particularly indicated for those at increased risk of infection or transmission. It is also indicated for use during outbreaks of hepatitis A infection.4.2 Posology and method of administration **Posology** *Children/adolescents (1-15 years)* Primary immunisation consists of a single dose given intramuscularly. This provides anti-HAV antibodies for at least one year. This vaccine confers protection against hepatitis A within two to four weeks. In order to obtain more persistent immunity, for at least 10 years, a booster dose is recommended between 6 and 12 months after primary immunisation. Booster vaccination delayed up to 3 years after the primary dose induces similar antibody levels as a booster dose administered within the recommended time interval. Current recommendations do not support the need for further booster vaccination among immunocompetent subjects after a 2-dose vaccination course (see section 5.1). Havrix Junior Monodose can be used as a booster in subjects previously immunised with any inactivated hepatitis A vaccine. In the event of a subject being exposed to a high risk of contracting hepatitis A within two weeks of the primary immunisation dose, human normal immunoglobulin may be given simultaneously with this vaccine at different injection sites. **Method of administration** The vaccine should be injected intramuscularly in the deltoid region or into the antero-lateral part of the thigh in young children. The vaccine should not be administered in the gluteal region. **The vaccine should never be administered intravascularly.** The vaccine should not be administered subcutaneously/intradermally since administration by these routes may result in a less than optimal anti-HAV antibody response. In subjects with a bleeding disorder who are at risk of haemorrhage following intramuscular injection (e.g. haemophiliacs), this vaccine may be administered by deep subcutaneous injection as per local guidance. Firm pressure should be applied to the injection site (without rubbing) for at least two minutes.4.3 Contraindications Hypersensitivity to the active substance, to any of the excipients listed in section 6.1, or to neomycin (present at traces).4.4 Special warnings and precautions for use Immunisation should be postponed in subjects suffering from an acute severe febrile illness. The presence of a minor infection, such as a cold, should not result in the deferral of vaccination. As for all vaccines, appropriate medication e.g.epinephrine (adrenaline) should be readily available for immediate use in case of anaphylaxis. It is possible that subjects may be in the incubation period of a hepatitis A infection at the time of immunisation. It is not known whether Havrix Junior Monodose will prevent hepatitis A in such cases. In haemodialysis patients and in subjects with an impaired immune system, adequate anti-HAV antibody titres may not be obtained after the primary immunisation and such patients may therefore require administration of additional doses of vaccine. Syncope (fainting) can occur following, or even before, any vaccination especially in adolescents as a psychogenic response to the needle injection. This can be accompanied by several neurological signs such as transient visual disturbance, paraesthesia and tonic-clonic limb movements during recovery. It is important that procedures are in place to avoid injury from faints. **Excipients** This vaccine contains 83 micrograms of phenylalanine in each dose. Phenylalanine may be harmful to patients that have phenylketonuria (PKU). This medicine contains potassium, less than 1 mmol (39 mg) per 0.5 mL dose, i.e. essentially 'potassium- free'. This medicinal product contains less than 1 mmol sodium (23 mg) per 0.5 mL dose, that is to say essentially 'sodium- free'.4.5 Interaction with other medicinal products and other forms of interaction Simultaneous administration of Havrix with normal immunoglobulin does not influence the seroconversion rate to Havrix, however, it may result in a lower antibody titre. A similar effect could be observed with Havrix Junior Monodose. Preliminary data on the concomitant administration of Havrix, at a dose of 720 ELISA units/mL, with recombinant hepatitis B virus vaccine suggests that there is no interference in the immune response to either antigen. Havrix Junior Monodose can be given concomitantly with monovalent and combination vaccines comprised of measles, mumps, rubella and varicella. When concomitant administration is considered necessary the vaccines must be given at different injection sites. Havrix Junior Monodose must not be mixed with other vaccines in the same syringe.4.6 Fertility, pregnancy and lactation **Pregnancy** There are no or limited amount of data from the use of this vaccine in pregnant women. Animal studies are insufficient with respect to reproductive toxicity. The use of this vaccine may be considered during pregnancy, if necessary. **Breast-feeding** It is unknown whether this vaccine is excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. **Fertility** No fertility data are available.4.7 Effects on ability to drive and use machines No studies of the effects of Havrix Junior Monodose on the ability to drive and use machines have been performed. However, some of the effects mentioned under section 4.8 “Undesirable effects” may temporarily affect the ability to drive or use machines.4.8 Undesirable effects The safety profile presented below is based on data from more than 5300 subjects that participated in clinical trials, plus reactions observed through post-marketing surveillance. It should be noted that it was not possible to calculate the frequency of reactions from the post-marketing data, therefore the frequency is noted as “Not known”. The most frequently reported reactions are pain and redness at site of injection (Havrix Monodose has reports in over 50% of doses, Havrix Junior Monodose has reports in 18.2% of doses overall). Swelling at the site of injection was the next most frequently reported reactions. Frequencies per dose are defined as follows: | | | | --- | --- | | 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 | | Not Known: | Cannot be estimated from the data available | Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness \* refers to adverse reaction reported only for Havrix Monodose (1mL adult dose) \\ refers to adverse reactions reported only for Havrix Junior Monodose (0.5mL children's dose)

this adverse reaction was identified through post-marketing surveillance but was not observed in randomised controlled clinical trials. The frequency category of rare was estimated from a statistical calculation based on the total number of paediatric patients exposed to Havrix in randomised controlled clinical trials (n=4574).

| | | | | --- | --- | --- | | **System Organ Classes** | **Frequency** | **Adverse reaction** | | Infections and infestations | Uncommon | Upper respiratory tract infection\* Rhinitis\* | | Immune system disorders | Not known | Anaphylaxis Allergic reactions including anaphylactoid reactions and mimicking serum sickness | | Metabolism and nutrition disorders | Common | Appetite lost | | Psychiatric disorders | Very common | Irritability\\ | | Nervous system disorders | Very common | Headache (common with Havrix Junior Monodose formulation) | | Common | Drowsiness\\ | | Uncommon | Dizziness\* | | Rare | Hypoaesthesia Paraesthesia | | Not known | Convulsions Guillain Barre Syndrome Transverse myelitis Neuralgic amyotrophy | | Vascular disorders | Not known | Vasculitis | | Gastrointestinal disorders | Common | Gastrointestinal symptoms\(rare with Havrix Junior Monodose formulation#) Nausea Diarrhoea (uncommon with Havrix Junior Monodose formulation) | | Uncommon | Vomiting | | Hepatobiliary disorders | Not known | Transient increase in liver function tests | | Skin and subcutaneous tissue disorders | Uncommon | Rash\\* | | Rare | Pruritus | | Not known | Angioneurotic oedema Erythema multiforme Urticaria | | Musculoskeletal and connective tissue disorders | Uncommon | Myalgia\* Musculoskeletal stiffness\* | | Not known | Arthralgia | | General disorders and administration site conditions | Very common | Pain and redness at the injection site Fatigue\* (rare with Havrix Junior Monodose formulation#) | | Common | Fever (≥ 37.5 °C) Injection site reaction, such as swelling or induration (uncommon with Havrix Junior Monodose formulation) Malaise | | Uncommon | Influenza like illness\* | | Rare | Chills | **Reporting of suspected adverse reactions** Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.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.

5.1 Pharmacodynamic properties Pharmaco-therapeutic group: Hepatitis A vaccine, ATC code J07BC02. Havrix confers immunisation against HAV by stimulating specific immune responses evidenced by the induction of antibodies against HAV. *Immune response* In clinical studies involving subjects of 1 – 18 years of age, specific humoral antibodies against HAV were detected in 93% of vaccines at day 15 and 99% of vaccines one month following administration of Havrix Junior Monodose. *Persistence of the immune response* In order to ensure long term protection, a booster dose should be given between 6 and 12 months after the primary dose. In clinical trials, virtually all vaccinees were seropositive one month after the booster dose. Long term persistence of hepatitis A antibody titres has been evaluated following 2 doses of Havrix given 6 to 12 months apart to healthy immunocompetent subjects aged 17 to 40 years . Data available after 17 years allow prediction that at least 95% and 90% of subjects will remain seropositive (> 15 mIU/mL) 30 and 40 years after vaccination, respectively. Current data do not support the need for further booster vaccination among immunocompetent subjects after a 2 dose vaccination course. ***Efficacy of Havrix for outbreak control*** The efficacy of Havrix was evaluated in different community outbreaks. These studies indicated that administration of a single dose of Havrix contributed to termination of the outbreaks. In one study, vaccine coverage in excess of 80% was followed by termination of the outbreak within 4 to 8 weeks. ***Impact of mass vaccination on disease incidence*** A reduction in the incidence of hepatitis A was observed in countries where a two-dose Havrix immunization programme was implemented for children in their second year of life: • In Israel, a retrospective database study showed up to 95 % reduction in hepatitis A incidence in the general population 8 years after the implementation of the vaccination program. Data from the National Surveillance also showed a 95% reduction in hepatitis A incidence as compared to the pre-vaccination era. • In Panama, a retrospective database study showed a 90% reduction in reported hepatitis A incidence in the vaccinated population, and 87% in the general population, 3 years after implementation of the vaccination programme. The observed reduction in hepatitis A incidence in the general population (vaccinated and non-vaccinated) in both countries are consistent with herd immunity.5.2 Pharmacokinetic properties Not applicable to vaccine products.5.3 Preclinical safety data Not applicable to vaccine products.

6.1 List of excipients Polysorbate 20 Amino acids for injection (containing phenylalanine) Disodium phosphate Monopotassium phosphate Sodium chloride Potassium Chloride Water for injections For adsorbent, see section 26.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.6.3 Shelf life 36 months.6.4 Special precautions for storage Store at 2 – 8 °C in a refrigerator. Store in the original package in order to protect from light. Do not freeze. Stability data indicate that Havrix is stable at temperatures up to 25 °C for 3 days. These data are intended to guide healthcare professionals in case of temporary temperature excursion only.6.5 Nature and contents of container 0.5 mL of suspension in a pre-filled syringe (type I glass) with a plunger stopper (butyl rubber) and with a rubber tip cap or 0.5 mL of suspension in a vial (type I glass) with a stopper (butyl rubber) with or without needles - pack size of 1 or 10. The tip cap and rubber plunger stopper of the pre-filled syringe and the stopper of the vial are made with synthetic rubber. Not all pack sizes may be marketed.6.6 Special precautions for disposal and other handling The vaccine should be inspected visually for any foreign particulate matter and/or variation of physical aspect prior to administration. Before use, the vaccine should be well shaken to obtain a slightly opaque white suspension. Discard the vaccine if the content appears otherwise. **Instructions for the pre-filled syringe** | | | | --- | --- | | SMPC_2040_image1_24.png | Hold the syringe by the barrel, not by the plunger. Unscrew the syringe cap by twisting it anticlockwise. | | SMPC_2040_image2_24.png | To attach the needle, connect the hub to the Luer Lock Adaptor and rotate a quarter turn clockwise until you feel it lock. Do not pull the syringe plunger out of the barrel. If it happens, do not administer the vaccine. | **Disposal** Any unused medicinal product or waste material should be disposed of in accordance with local requirements.