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 in 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 separate doses of 0.5 ml each according to the following schedule:

First dose at Day 0.

Second dose: 28 days after first dose.

It is recommended that vacinees who received the first dose of IXIARO complete the primary 2-dose vaccination course with IXIARO.

If the primary immunization of two injections is not completed, full protection against the disease might not be achieved. There is data that a second injection given up to 11 months after the first dose results in high seroconversion rates (see section 5.1).

Booster Dose

A booster dose (third dose) should be given within the second year (i.e. 12 - 24 months) after the recommended primary immunization, prior to potential re-exposure to JEV. Persons at continuous risk for acquiring Japanese encephalitis (laboratory personnel or persons residing in endemic areas) should receive a booster dose at month 12 after primary immunization (see section 5.1). Data on the need for further booster doses are not available.

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. protamin 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).

Protection against Japanese Encephalitis is not ensured until the second dose has been received.

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 and uncontrolled clinical studies in which 4,043 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 or following a booster dose.

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

Uncommon: lymphadenopathy

Rare: thrombocytopenia

Nervous system disorders

Very common: headache

Uncommon: migraine, dizziness

Rare: paraesthesia, neuritis

Ear and labyrinth disorders

Uncommon: vertigo

Cardiac disorders

Rare: palpitations, tachycardia

Respiratory, thoracic and mediastinal disorders

Rare: dyspnoea

Gastrointestinal disorders

Common: nausea

Uncommon: vomiting, diarrhoea, abdominal pain

Skin and subcutaneous tissue disorders

Uncommon: rash, pruritus

Rare: urticaria, erythema

Musculoskeletal and connective tissue disorders

Very common: myalgia

Uncommon: musculoskeletal stiffness

Rare: pain in extremity, arthralgia

General disorders and administration site conditions

Very common: injection site: pain, tenderness

Common: fatigue , influenza like illness, pyrexia, injection site: redness, hardening, swelling, itching

Uncommon: chills, malaise. injection site: haematoma

Rare: oedema peripheral

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 2,228 healthy adult subjects included in seven randomized, controlled clinical studies and three uncontrolled trials.

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 were non inferior to those induced by JE VAX (Table 1).

Table 1: Seroconversion rates and geometric mean titers of IXIARO and JE VAX in the Per Protocol Population. Neutralising antibody titers against JEV were 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.

Antibody persistence

Antibody persistence was evaluated 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. Long term immunogenicity of IXIARO was assessed in a subset of 181 subjects up to month 24 (Intent-to-treat (ITT) population) and in 152 subjects up to month 36 after the first IXIARO vaccination.

Rates of subjects with PRNT₅₀1:10 and GMTs at Months 2, 6, 12, 24 and 36 are summarized in Table 2 for the ITT population.

Table 2 Rates of subjects with PRNT₅₀1:10 and geometric mean titers (GMT) at Month 2, 6, 12 , 24 and 36 after vaccination with IXIARO (ITT population)

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

In another open-label, follow-up Phase 3 study, the persistence of antibodies up to 24 months after primary vaccination was assessed. A total of 116 subjects who had received the recommended primary schedule of IXIARO were included in this follow-up study. Rates of subjects with PRNT₅₀1:10 were 82.8% (95% CI: 74.9, 88.6, N=116) at Month 6 and 58.3% at Month 12 (95% CI: 49.1, 66.9, N=115). At Month 24, 48.3% (95% CI: 39.4, 57.3, N=116) of subjects who completed the recommended primary immunization still had PRNT₅₀ titers of 1:10. GMT in these subjects was 16.2 (95% CI: 13.8, 19.0) at Month 24.

Booster immunisation

In an uncontrolled, open-label phase 3 study a single 6 mcg booster dose of IXIARO was given at month 15 after primary immunization. All of the 198 subjects treated were included in the ITT and Safety Populations.

Rates of subjects with PRNT₅₀1:10 and GMT over time are summarised below in table 3:

Table 3: Rates of subjects with PRNT₅₀1:10 and GMT before and at months 1, 6 and 12 after a single 6 mcg booster dose administered to subjects at 15 months after recommended primary immunization with IXIARO (ITT population)

Incomplete primary immunization

The immunogenicity of booster doses was also assessed in the study investigating persistence of immunity following different primary immunization regimens (2x6 mcg: N=116, 1x12mcg: N=116 or 1x6 mcg: N=117). A single 6 mcg booster dose was administered at 11 or 23 months after the first dose to subjects, which were determined to be seronegative (PRNT₅₀ titers < 1:10) at month 6 and/or month 12 after the primary immunization. Results indicate that the second injection of the primary immunization series can be given up to 11 months after the first dose. The immune responses to further doses at different time points after complete or incomplete primary immunization are shown in table 4.

Table 4: SCR and GMT at four weeks after a single 6 mcg booster dose administered to subjects with a PRNT₅₀ <1:10 (PRNT₅₀<1:10 means a subject is no longer seroprotected) at month 11 or month 23 after recommended primary immunization (2x 6 mcg) or incomplete (1x6 mcg) primary immunization with IXIARO (ITT population)

Concommitant use

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 5).

Table 5: 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.

24 months

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. To attach Luer needle, remove the syringe tip cap by gently twisting it. Do not attempt to snap or pull the tip off as this may damage the syringe.

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

EU/1/08/501/002

31/03/ 2009

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