IXIARO^®suspension for injection

Japanese encephalitis vaccine (inactivated, adsorbed)

1 dose (0.5 ml) of IXIARO^®contains:

Japanese encephalitis virus strain SA₁₄-14-2 (inactivated)^1,2 6 micrograms³

corresponding to a potency of 460 ng ED₅₀

¹ produced in Vero cells

² adsorbed on aluminium hydroxide, hydrated 0.25 milligrams Al³⁺

³ total protein content

For a full list of excipients, see section 6.1.

Suspension for injection.

Clear liquid with a white precipitate.

IXIARO^®is indicated for active immunization against Japanese encephalitis for adults.

IXIARO^®should be considered for use in individuals at risk of exposure through travel or in the course of their occupation.

Posology

Adults

The primary vaccination series consists of two doses of 0.5 ml each according to the following schedule:

First dose at Day 0.

Second dose: 28 days after first dose.

Persistence of protective immunity is unknown. Timing and effect of booster immunisation is currently under investigation.

It is recommended that vaccinees who receive the first dose of IXIARO^®complete the full vaccination course with IXIARO^®.

Paediatric

IXIARO^®is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

Method of administration

The vaccine should be administered by intramuscular injection into the deltoid muscle. It should never be injected intravascularly.

Exceptionally, IXIARO^®can also be administered subcutaneously to patients with thrombocytopenia or bleeding disorders since bleeding may occur following an intramuscular administration. Subcutaneous administration could lead to a suboptimal response to the vaccine (see section 4.4). However, it should be noted that there are no clinical efficacy data to support administration by the subcutaneous route.

Hypersensitivity to the active substance or to any of the excipients or to any residuals (e.g. protamine sulphate).

Individuals who show hypersensitivity reactions after receiving the first dose of the vaccine should not be given the second dose.

Administration must be postponed in persons with acute severe febrile conditions.

As with all injectable vaccines, appropriate medical treatment and supervision should always be available to treat rare cases of anaphylactic reactions following the administration of the vaccine.

Under no circumstances should IXIARO^®be administered intravascularly.

As with any other vaccine, vaccination with IXIARO^®may not result in protection in all cases.

IXIARO^®will not protect against encephalitis caused by other micro-organisms.

Like other intramuscular injections, this vaccine should not be administered intramuscularly to persons with thrombocytopenia, haemophilia or other bleeding disorders (see section 4.2).

A seroconversion rate of 29.4 % has been observed 10 days after the first vaccination, and 97.3 % one week after the second vaccination. Hence, primary immunization should be completed at least one week prior to potential exposure to Japanese encephalitis virus (JEV).

Concomitant administration of IXIARO^®with inactivated hepatitis A vaccine has been evaluated in one clinical study. There was no interference with the immune response to Japanese encephalitis virus (JEV) and hepatitis A virus (HAV) vaccines, respectively. Concomitant administration of IXIARO^®and hepatitis A vaccine was shown to be non inferior to single vaccinations with regard to geometric mean titres (GMT) of anti JEV neutralizing antibody and HAV antibody, and for seroconversion rates (see section 5.1). There were no statistically significant higher rates in systemic or injection site adverse reactions among subjects who received concomitant vaccination with IXIARO^®and hepatitis A vaccine compared with those who received IXIARO^®or hepatitis A vaccine alone.

In patients receiving immunosuppressive therapy or patients with immunodeficiency an adequate immune response may not be obtained.

Pregnancy

There are limited amount of data from the use of IXIARO^®in pregnant or breast-feeding women.

In animal studies findings of unclear clinical relevance have been identified (see section 5.3).

As a precautionary measure, the use of IXIARO^®during pregnancy or lactation should be avoided.

Lactation

It is unknown whether IXIARO^®is excreted in human milk.

No effects on the breastfed newborn/infant are anticipated since the systemic exposure of the breast-feeding woman to IXIARO^®is negligible.

No studies on the effects of IXIARO^®on the ability to drive and use machines have been performed.

The safety of the vaccine was assessed in different controlled clinical studies in which more than 4,715 healthy adults were included of which 3,558 healthy adults received IXIARO^®.

Approximately 40% of treated subjects can be expected to experience adverse reactions. They usually occur within the first three days after vaccination, are usually mild and disappear within a few days. No increase in the number of adverse reactions was noted between first and second doses.

Most commonly reported adverse reactions included headache and myalgia occurring in approximately 20% and 13% of subjects, respectively.

Adverse reactions are listed according to the following frequencies:

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 available data)

Infections and infestations

Uncommon: nasopharyngitis, rhinitis

Blood and lymphatic system disorders

Rare: lymphadenitis

Nervous system disorders

Very common: headache

Uncommon: migraine, dizziness

Ear and labyrinth disorders

Uncommon: vertigo

Respiratory, thoracic and mediastinal disorders

Uncommon: pharyngolaryngeal pain

Gastrointestinal disorders

Common: nausea

Uncommon: diarrhoea, vomiting

Skin and subcutaneous tissue disorders

Common: rash

Rare: pruritus

Musculoskeletal and connective tissue disorders

Very common: myalgia

General disorders and administration site conditions

Very common: injection site reactions (pain, tenderness)

Common: fatigue, influenza like illness, pyrexia, injection site reactions (erythema, hardening, swelling, itching)

Uncommon: chills, injection site reactions (haemorrhage, bruising)

Investigations

Uncommon: hepatic enzymes increased

No case of overdose has been reported.

Pharmacotherapeutic group: Encephalitis vaccines. ATC code: J07BA02

Mechanism of action

The mechanism of action of Japanese encephalitis (JE) vaccines is not well understood. Studies in animals have shown that the vaccine triggers the immune system to produce antibodies against Japanese encephalitis virus that are most often protective. Challenge studies were performed in mice that were treated with human IXIARO^®antisera. These studies showed that almost all mice that had a Plaque Reduction Neutralization Test titre of at least 1:10 were protected from a lethal Japanese encephalitis virus challenge.

Clinical studies

No prospective efficacy trials have been performed. Immunogenicity of IXIARO^®was studied in approximately 2,060 healthy adult subjects included in five randomized, controlled clinical studies and one non controlled trial.

Immunogenicity of the vaccine was evaluated in a randomized, active controlled, observer blinded, multicenter Phase 3 clinical trial including 867 healthy male and female subjects given IXIARO^®or the US licensed JEV vaccine JE VAX^® (on a 0 , 7 and 28 day schedule by subcutaneous injection). The co primary endpoint was seroconversion rate (anti JEV antibody titer 1:10) and geometric mean titers (GMT) at Day 56 as assessed by a Plaque Reduction Neutralization Test (PRNT) for the entire study population.

By Day 56, the proportion of subjects who had seroconverted was similar for both treatment groups (96.4% vs. 93.8% for IXIARO^®and JE VAX^®, respectively). GMT increased by Day 56 to 243.6 for IXIARO^®and to 102.0 for JE VAX^®, respectively. The immune responses elicited by IXIARO(r) were non inferior to those induced by JE VAX^® (Table 1).

Table 1: Seroconversion rates and geometric mean titers of IXIARO(r) and JE VAX(r) in the Per Protocol Population. Neutralising antibody titers against JEV was measured against the JEV strain SA₁₄-14-2.

The effect of age on the immune response to IXIARO^®and JE VAX^®was assessed as a secondary endpoint in this active controlled study, comparing subjects over 50 years of age (N=262, mean age 59.8) with those below 50 years of age (N=605, mean age 33.9).

There was no significant difference between seroconversion rates of IXIARO^®and JE VAX^®in subjects aged <50 years compared to those aged 50 years at Day 28 or Day 56 following vaccination. Geometric mean titers were significantly higher at Day 28 in subjects aged <50 years than those aged 50 years in the JE VAX^®group (80.9 vs. 45.9, p=0.0236) but there was no significant difference at Day 56 for this treatment group. There were no significant effects of age on geometric mean titer in the group receiving IXIARO^®. There was no significant difference between seroconversion rates in subjects aged <50 years compared to those aged 50 years at Day 28 or Day 56 for either treatment group.

The 12 months immune response to IXIARO^®was assessed in an uncontrolled Phase 3 follow up clinical trial, enrolling subjects who had completed two pivotal studies, and who received at least one dose of IXIARO^®. The primary objective was the evaluation of the immune response to IXIARO^®24 months after the first vaccination. Secondary objectives were the evaluation of the immune response to IXIARO^®6 and 12 months after the first vaccination and to evaluate the safety of IXIARO^®during the respective study period. A total of 3,258 healthy male and female subjects were enrolled of which 2,283 subjects had received IXIARO^®, 338 subjects had received JE VAX^®, and 637 subjects had received placebo in the respective previous study. Long term immunogenicity to IXIARO^®was assessed in a subset of 181 subjects (Intent-to-treat (ITT) population). Immunogenicity data covering a period of 12 months after the first vaccination were as follows:

Seroconversion rates for anti JEV antibodies and GMT at Months 2, 6 and 12 are summarized in Table 2 for the ITT population. At Month 2, 98.9% of subjects had seroconverted (95% CI: 96.06, 99.70). By Month 12, the percentage of subjects who had seroconverted was 83.4% (95% CI: 77.33, 88.14). GMT at Months 2, 6, and 12 after vaccination with IXIARO^®are summarized in Table 2. At Month 2, the GMT was 310.8 (95% CI: 268.76, 359.44) which decreased to 83.5 (95% CI: 70.89, 98.38) at Month 6 and to 41.2 (95% CI: 34.39, 49.33) at Month 12 after vaccination with IXIARO^® (Table 2).

Table 2: Seroconversion rates (SCR) and geometric mean titers (GMT) at Month 2, 6 and 12 after vaccination with IXIARO^® (ITT population)

The observed decline in GMT is as expected and compares well with data from other inactivated JE vaccines.

The concomitant use of IXIARO^®with inactivated hepatitis A virus (HAV) vaccine (HAVRIX^®1440) has been explored in one clinical trial. There was no interference with the immune response to the JE virus and HAV, respectively. Concomitant administration of IXIARO^®and inactivated hepatitis A vaccine was shown to be non-inferior to single vaccinations with regard to GMT of anti-JE virus neutralizing antibody and HAV antibody, and for seroconversion rates of both antibody types (Table 3).

Table 3: Seroconversion rates and geometric mean titer of anti JEV neutralizing antibody at Day 56 and seroconversion rates and geometric mean titer for HAV antibody at Day 28 in the Per Protocol Population

Evaluation of pharmacokinetic properties is not required for vaccines.

Non-clinical toxicity data are limited.

In a reproductive and pre-/post-natal toxicity study, no vaccine-related effects were detected on reproduction, foetal weight, survival and development of the off-spring. However, incomplete ossification of parts of the skeleton was observed in the group receiving 2 doses, but not in the group receiving 3 doses. It is currently difficult to explain if this phenomenon is treatment related or not.

Phosphate buffered saline consisting of:

Sodium chloride

Potassium dihydrogen phosphate

Disodium hydrogen phosphate

Water for injections

For adjuvant, see section 2.

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

1 year

Store in a refrigerator (2°C - 8°C). Do not freeze. Store in the original package in order to protect from light.

0.5 ml of suspension in a pre-filled syringe (Type I glass) with a plunger stopper (chlorobutyl elastomer). Pack size of 1 syringe with or without a separate needle.

Do not use if the blister foil is not intact or packaging is damaged.

Upon storage, a fine white deposit with a clear colourless supernatant can be observed.

The pre-filled syringe is ready to use. If a needle is not provided, use a sterile needle. Shake before use. Thorough agitation immediately before administration is necessary to maintain suspension of the vaccine. The full recommended dose of the vaccine should be used.

Prior to agitation, IXIARO^®may appear as a clear liquid with a white precipitate. After thorough agitation, it forms a white, cloudy liquid/suspension. The vaccine should be visually inspected for particulate matter and discoloration prior to administration. Discard the product if particulates are present or if it appears discoloured or if the syringe appears to be physically damaged.

Any unused product or waste material should be disposed of in accordance with local requirements.

Intercell AG

Campus Vienna Biocenter 3

A-1030 Vienna

Austria

EU/1/08/501/001 and EU/1/08/501/002

02 April 2009

April 2009

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

JE09ARR037 July 2009