Vivaxim

The dual-chamber syringe contains 0.5 millilitre of inactivated hepatitis A vaccine and 0.5 millilitre of typhoid polysaccharide vaccine which are mixed prior to administration.
After reconstitution, 1 dose (1 mL) contains: Originally contained in the suspension: Hepatitis A virus, GBM strain (inactivated)^1,2 160 U³.
¹ Produced in human diploid (MRC-5) cells.
² Adsorbed on aluminium hydroxide hydrated (0.3 milligram Al).
³ In the absence of an international standardised reference, the antigen content is expressed using an in-house reference.
Originally contained in the solution: Salmonella typhi (Ty2 strain) capsular Vi polysaccharides 25 micrograms.
The inactivated hepatitis A vaccine is a cloudy and whitish suspension; the typhoid polysaccharide vaccine is a clear and colourless solution.
Excipient(s) with known effect (see Precautions): Phenylalanine 10 micrograms.
Excipients/Inactive Ingredients: Inactivated hepatitis A vaccine components: 2-Phenoxyethanol Ethanol Formaldehyde, Medium 199 Hanks (without phenol red)* supplemented with polysorbate 80.
*Medium 199 Hanks (without phenol red) is a complex mixture of amino acids (including phenylalanine), mineral salts (including potassium), vitamins and other components (including glucose), diluted in water for injections and pH adjusted with hydrochloric acid or sodium hydroxide.
Typhoid Vi polysaccharide vaccine components: Phosphate buffer solution: Sodium chloride, Disodium phosphate dihydrate, Sodium dihydrogen phosphate dihydrate, Water for injections.
VIVAXIM may contain traces of neomycin, which is used during the manufacturing process (see Contraindications).

Pharmacotherapeutic group: Bacterial and viral vaccines combined. ATC code: J07CA10 typhoid-hepatitis A.
Pharmacology: Pharmacodynamics: Four clinical studies provided results on the immune response with VIVAXIM. In total, 1090 subjects were included, with 179, 610, 243 and 58 subjects, respectively, in each study.
After primary vaccination, the seroprotection rate against the hepatitis A virus (HAV) (% ≥ 20 mIU/mL) was between 95.6% and 99.4% after 14 days and between 98.7% and 100% after 28 days.
The seroprotection rate against the Vi antigen (% ≥1 μg/mL) was between 83% and 89% after 14 days and between 69.8% and 91% after 28 days.
In one study, which evaluated the seroprotection rate for the Vi antigen observed 1, 2 or 3 years after the first dose of VIVAXIM and after revaccination with VIVAXIM at 3 years, the results were as follows: (see Table 1).


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Serological data show continuing protection against hepatitis A for up to 36 months in subjects who responded to the first dose of VIVAXIM. Seroprotection rates against the hepatitis A virus 1, 2 or 3 years after the first dose of VIVAXIM and after revaccination with VIVAXIM at 3 years, the results were as follows: (see Table 2).


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Similar results were observed at the same dates in the control group, which received the monovalent typhoid Vi polysaccharide vaccine and the inactivated hepatitis A vaccine concomitantly.
In an open randomised study, the immunogenicity of the concomitant administration of VIVAXIM with the combined, adsorbed, tetanus, low dose diphtheria and inactivated poliomyelitis vaccine (Td-IPV) at two separate sites was compared to the separate administration at different time points in healthy adults. Seroconversion/seroprotection rates observed 28 days after vaccination in Per Protocol subjects were as follows: (see Table 3).


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Non-inferiority of the concomitant administration of VIVAXIM and Td-IPV vaccines compared to the separate administration was demonstrated for all the valences, except for the Vi valence.
For the Vi valence, the seroprotection rates (anti-Vi titres ≥ 1 μg/mL) increased from 7.5% in Group A and 7.1% in Group B at Day 0 to 86.3% and 94.8% respectively, 28 days after vaccination. In initially non-seroprotected subjects (anti-Vi titres < 1 μg/mL), seroconversion rates observed 28 days after vaccination were as follows: (see Table 4).


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In initially non-seroprotected subjects, the anti-Vi seroconversion rate (≥ 4-fold rise) for concomitant vaccines administration was non-inferior to the separate administration.
Paediatric population: No data on the efficacy of VIVAXIM in children and adolescents below 16 years are available.
Pharmacokinetics: Not applicable.
Toxicology: Preclinical safety data: Non-clinical data obtained with the monovalent vaccines contained within this vaccine combined vaccine, reveal no special hazard for humans based on single, repeated dose and local tolerance toxicity studies.

VIVAXIM is indicated for combined active immunisation against typhoid fever and infection with Hepatitis A virus in subjects aged 16 years or more.
VIVAXIM must be administered according to official recommendations.

Posology: The recommended dose is 1 ml of mixed vaccine.
Initial protection is obtained after a single injection of VIVAXIM. Protective antibody levels are only obtained 14 days after administration of the vaccine.
In order to obtain long term protection against hepatitis A virus, a booster dose of inactivated hepatitis A virus must be given 6 to 12 months later. Anti HAV antibodies persist for several years (at least 10 Years) after the booster.
In subjects who have received one dose of VIVAXIM: Either one dose of monovalent hepatitis A vaccine should be administered within 36 months and preferably within 6 to 12 months (see Pharmacology: Pharmacodynamics under Actions).
Or, if protection against typhoid is still required, a second dose of VIVAXIM may be administered provided that approximately 36 months have elapsed since the first dose.
In subjects who have received one dose of monovalent hepatitis A vaccine: VIVAXIM may be used to provide the second dose (booster) of hepatitis A vaccine, if protection against typhoid fever is also desirable. It should then be administered within 36 months of the hepatitis A vaccine injection and preferably within 6 to 12 months.
As this vaccine has not been evaluated in subjects aged under 16 years, it is not recommended to use in this age group.
Method of administration: VIVAXIM should be administered by slow intramuscular injection in the deltoid region.
VIVAXIM must not be administered intravascularly.
VIVAXIM should not be administered into the buttock due to the varying amount of fatty tissue in this region of the body, nor by the intradermal route since these methods of administration may induce a weaker immune response.
VIVAXIM may be administered by the subcutaneous route in patients with thrombocytopenia or in patients at risk of haemorrhage.
For instructions for preparation of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage.

Cases of overdose have been reported with VIVAXIM where it was administered concomitantly with typhoid polysaccharide and/or hepatitis A vaccines. When adverse reactions were reported, they did not differ in nature from those described in Adverse Reactions.

Hypersensitivity to the active substance(s) or to any of the excipients listed in Description or to neomycin (present in trace amounts as a residual of the manufacturing process).
Vaccination should be delayed in subjects with an acute severe febrile illness.

As with all injectable vaccines, appropriate medical treatment, and in particular adrenaline, should be available for immediate management of any anaphylactic or hypersensitivity reactions occurring after vaccine administration.
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 be in place to avoid any injury from faints.
Immunogenicity of the vaccine could be impaired by immunosuppressive treatment or in immunodeficient subjects. It is recommended to delay vaccination until the completionof any immunosuppressive treatment. Subjects with chronic immunodeficiency such as HIV infection may be vaccinated if the underlying immunodeficiency allows the induction of an antibody response, even if limited.
Because of the incubation period of hepatitis A, infection may be present but not clinically apparent at the time of vaccination. It is not known whether VIVAXIM will prevent hepatitis A in this case.
VIVAXIM does not protect against infections caused by other liver pathogens such as hepatitis B, hepatitis C or hepatitis E viruses.
ViVAXIM does not protect against infection by Salmonella enterica other than serotype typhi.
As with any vaccine, a protective immune response may not be elicited in all vaccinees.
ViVAXIM contains phenylalanine, ethanol, potassium and sodium: ViVAXIM contains 10 microgram phenylalanine in each 1 mL dose which is equivalent to 0.17 microgram/kg for a 60 kg person. Phenylalanine may be harmful for people with phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.
ViVAXIM contains 2 mg of alcohol (ethanol) in each 1 mL dose. The small amount of alcohol in this medicine will not have any noticeable effects.
ViVAXIM contains less than 1 mmol potassium (39 mg) and less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'potassium-free' and 'sodium-free'.
Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Take special care with VIVAXIM: To make sure that the vaccine is not administered by the intravascular route (the needle must not penetrate a blood vessel).
Not to inject VIVAXIM in the buttock as this may induce a smaller immune response (because of the variable amount of fat tissue in this region of the body).
If the patient is receiving a treatment that lowers immune deficiency or if the patient presents deficient immune defences the immune response to the vaccine may be reduced.
If the patient suffers from blood clotting disorders; VIVAXIM must be injected subcutaneously.
If the patient may soon be exposed to hepatitis A or typhoid fever, care must be taken as protection conferred by VIVAXIM only appears 14 days after vaccination.
Fainting can occur (especially in adolescents) following, or even before, any vaccination as a psychogenic response to the needle injection. Therefore tell the doctor or nurse if the children fainted with a previous injection.
EFFECT ON ABILITY TO DRIVE AND USE MACHINES: VIVAXIM has a minor influence on the ability to drive and use machines. Dizziness have been observed as an uncommon reaction (≥1/1000, <1/100) following administration of this vaccine (see Adverse Reactions).

Pregnancy: Data on a limited number (more than 150 cases for the monovalent typhoid Vi polysaccharide vaccine, more than 40 cases with monovalent inactivated hepatitis A vaccine and more than 10 cases for VIVAXIM or the two components given simultaneously) of exposed pregnancies indicate no adverse effects of VIVAXIM on pregnancy or on the foetus/newborn.
To date, no other relevant epidemiological data are available.
Animal studies did not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition, and post-natal development.
VIVAXIM should only be administered after careful consideration in pregnant women (see Pharmacology: Pharmacokinetics under Actions).
When the patient is considered to be at risk only for hepatitis A or typhoid fever, the monovalent vaccine should be used.
Breastfeeding: It is unknown whether VIVAXIM is excreted in human milk. The excretion of VIVAXIM in milk has not been studied in animals. The decision of whether to discontinue breast-feeding or to discontinue/abstain from VIVAXIM 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.

Summary of the safety profile: During clinical studies, the most commonly reported reactions were those occurring at the injection site.
Pain at the VIVAXIM injection site was reported in 89.9% of subjects (severe in 4.5%). For subjects who received the two monovalent vaccines concomitantly at separate injection sites, pain was reported in 83.2% of subjects (severe in 5.0%) for both vaccine sites combined. Pain was reported by 79.3% of subjects (severe in 5.0%) at the Vi vaccine site and by 50.3% of subjects (severe in 0.6%) at the hepatitis A vaccine site.
Pain at the injection site lasting more than 3 days was reported by 17.4% of subjects after VIVAXIM, by 2.8% of subjects for the monovalent Vi vaccine site and by 0.6% of subjects for the monovalent hepatitis A vaccine site.
Severe oedema/induration (> 5 cm) was reported in 7.9% of subjects at the VIVAXIM injection site. For subjects who received the two monovalent vaccines concomitantly at separate injection sites, severe oedema/induration was reported in 1.7% of subjects for both vaccine sites combined (in 1.1% of subjects at the Vi vaccine site and in 0.6% of subjects at the hepatitis A vaccine site).
The overall incidence of systemic reactions was similar between subjects who were vaccinated with VIVAXIM and subjects who received the two monovalent vaccines concomitantly at separate injection sites.
All reactions resolved without any sequelae.
Tabulated list of adverse reactions: Adverse reaction data are derived from clinical trials and worldwide post-marketing experience.
Within each system organ class, the adverse reactions are ranked under headings of frequency, most frequent reactions first, using the following convention: Very common (≥1/10), Common (≥1/100, <1/10), Uncommon (≥1/1000, <1/100), Rare (≥1/10,000, <1/1000), Very rare (<1/10,000), Not known: cannot be estimated from the available data. Based on spontaneous reporting, these adverse events have been very rarely reported during commercial use of VIVAXIM. Because events are reported spontaneously from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to vaccine exposure.
Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness.
Immune system disorders: Not known: anaphylactic/anaphylactoid reactions, including shock; serum sickness.
Nervous system disorders: Very common: headache.
Uncommon: dizziness.
Not known: vasovagal syncope in response to injection, paraesthesia.
Gastrointestinal disorders: Common: nausea, diarrhoea.
Not known: vomiting, abdominal pain.
Skin and subcutaneous tissue disorders: Uncommon: pruritus, rash.
Not known: urticaria.
Musculoskeletal and connective tissue disorders: Very common: myalgia.
Common: arthralgia.
General disorders and administration site conditions: Very common: malaise, asthenia, injection site disorders (pain, induration, oedema, erythema).
Common: fever.
Investigations: Not known: transaminases increased (mild and reversible).
The following adverse reactions were not reported during the commercial use of VIVAXIM but were reported respectively following the use of the monovalent typhoid Vi polysaccharide vaccine and the monovalent inactivated hepatitis A vaccine.
Respiratory, thoracic and mediastinal disorders: Not known: aggravation of asthma.
General disorders and administration site conditions: Very rare: injection site nodule.
Paediatric Population: No data on the safety of VIVAXIM in children and adolescents below 16 years are available.

VIVAXIM must not be mixed with other vaccines in the same syringe.
Concomitant administration of VIVAXIM with the combined, adsorbed, tetanus, low dose diphtheria and inactivated poliomyelitis vaccine (Td-IPV) at two separate sites demonstrated non-inferiority compared to the separate administration of the two vaccines at different time points for all valences, except for the Vi valence, in terms of immune response obtained one month after vaccination. Nevertheless, anti-Vi seroconversion rate (≥ 4-fold rise) for concomitant administration was non-inferior to the separate administration in subjects who were not seroprotected before vaccination (see Pharmacology: Pharmacodynamics under Actions). Since the seroprotection rate (the percentage of subjects reaching the threshold of protection for anti-Vi antibodies ≥1 μg/mL) was consistent with the expected rate of responses when VIVAXIM is given alone, it is unlikely that concomitant administration of VIVAXIM with the Td-IPV at different sites will have clinical consequences. Therefore, concomitant administration of VIVAXIM with the Td-IPV at two separate sites can be performed.
No interaction studies have been performed with VIVAXIM and other inactivated vaccines. However, based on data obtained from the concomitant administration of the monovalent typhoid Vi polysaccharide vaccine with diphtheria-tetanus (DT), tetanus-inactivated poliomyelitis (T-IPV), rabies, meningococcal polysaccharide A/C vaccines, no interferences with the immune responses to any of these antigens are expected.
Concomitant administration of yellow fever vaccine and VIVAXIM has not been specifically studied. However, based on data obtained from the concomitant administration of the monovalent vaccines (purified Vi polysaccharide typhoid vaccine and inactivated Hepatitis A vaccine) with yellow fever vaccine show that no interference between the immune response to these three antigens is expected.
The effect of the concomitant administration of immunoglobulins on the immunogenicity of VIVAXIM has not been assessed. Therefore, interference with the immune response to VIVAXIM cannot be ruled out.
Data obtained during concomitant administration of immunoglobulins with the monovalent inactivated hepatitis A vaccine showed that anti-HAV seroconversion rates were not modified whereas anti-HAV antibody titres could be lower than after vaccination with a monovalent vaccine alone.

INCOMPATIBILITIES: In the absence of compatibility studies, this vaccine must not be mixed with other vaccines or medicinal products.
SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING: The two monovalent vaccines must be mixed immediately before injection.
Shake before mixing and again before the injection to obtain a homogeneous suspension. The content of the two chambers is mixed by gently pushing the plunger. The final volume to be injected is 1 millilitre.
The vaccine should be visually inspected before administration to check the absence of foreign particles. The mixed vaccine is a whitish opalescent suspension. The vaccine should not be used in case of foreign particles in it.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

SHELF LIFE: 3 years.
Store in a refrigerator (2°C - 8°C). Do not freeze. Keep the vaccine in the outer carton in order to protect from light.
Do not use VIVAXIM if there is the presence of foreign particles.

Vaccines, Antisera & Immunologicals

J07CA10 - typhoid-hepatitis A ; Belongs to the class of combined bacterial and viral vaccines.

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