Ixiaro

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 



2 

1. NAME OF THE MEDICINAL PRODUCT 
 
IXIARO suspension for injection 
Japanese encephalitis vaccine (inactivated, adsorbed) 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
1 dose (0.5 ml) of IXIARO contains: 
Japanese encephalitis virus strain SA14-14-2 (inactivated)1,2 6 AU3 
corresponding to a potency of ≤ 460 ng ED50 
 
1 produced in Vero cells 
2 adsorbed on aluminium hydroxide, hydrated (approximately 0.25 milligrams Al3+) 
3 Antigen Units 
 
Excipients with known effect: 
This medicine contains potassium, less than 1mmol (39 mg) per 0.5 ml single dosage i.e. essentially 
‘potassium-free’ and less than 1 mmol sodium (23 mg) per 0.5 ml single dosage, that is to say essentially 
‘sodium-free’. This product might contain traces of residual sodium metabisulfite which is below detection 
limit. 
 
Phosphate Buffered Saline 0.0067 M (in PO4) has the following saline composition: 
NaCl – 9mg/mL 
KH2PO4 – 0.144 mg/mL 
Na2HPO4 – 0.795 mg/mL 
 
 
For the full list of excipients, see section 6.1. 
 
3. PHARMACEUTICAL FORM 
 
Suspension for injection. 
Clear liquid with a white precipitate. 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
IXIARO is indicated for active immunisation against Japanese encephalitis in adults, adolescents, children 
and infants aged 2 months and older. 
 
IXIARO should be considered for use in individuals at risk of exposure through travel or in the course of 
their occupation. 
 
4.2 Posology and method of administration 
 
Posology 
 
Adults (18 to  ≤ 65 years of age) 
The primary vaccination series consists of two separate doses of 0.5 ml each, according to the following 
conventional schedule: 
First dose at Day 0. 
Second dose: 28 days after first dose. 
 
Rapid schedule  
Persons aged 18 to ≤ 65 years can be vaccinated in a rapid schedule as follows: 



3 

First dose at Day 0. 
Second dose: 7 days after first dose.  
 
With both schedules, primary immunisation should be completed at least one week prior to potential 
exposure to Japanese encephalitis virus (JEV) (see section 4.4). 
It is recommended that vaccinees 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 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).  
Long-term seroprotection data following a first booster dose administered 12 - 24 months after primary 
immunization suggest that a second booster should be given 10 years after the first booster dose, prior to 
potential exposure to JEV.  
 
Elderly (>65 years of age) 
The primary vaccination series consists of two separate doses of 0.5 ml each, according to the following 
conventional schedule: 
First dose at Day 0. 
Second dose: 28 days after first dose. 
 
The primary immunisation should be completed at least one week prior to potential exposure to Japanese 
encephalitis virus (JEV) (see section 4.4). 
 
It is recommended that vaccinees 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 
As with many vaccines, the immune response in elderly persons to IXIARO is lower than in younger adults. 
Duration of protection is uncertain in elderly persons, therefore a booster dose (third dose) should be 
considered before any further exposure to JE virus. Long-term seroprotection following a booster-dose is not 
known. 
 
 
Paediatric Population 
Children and adolescents from 3 years to < 18 years of age 
The primary vaccination series consists of two separate doses of 0.5 ml according to the following schedule: 
First dose at Day 0. 
Second dose: 28 days after first dose. 
 
Children from 2 months to < 3 years of age 
The primary vaccination series consists of two separate doses of 0.25 ml according to the following 
schedule: 
First dose at Day 0. 
Second dose: 28 days after first dose. 
 



4 

See section 6.6 for instructions on preparing a 0.25 ml dose for children aged 2 months to <3 years. 
 
It is recommended that vaccinees who received the first dose of IXIARO complete the primary 2-dose 
vaccination course with IXIARO. 
 

Booster dose (Children and adolescents) 

A booster dose (third dose) should be given within the second year (i.e. 12 - 24 months) after primary 
immunization, prior to potential re-exposure to JEV. 
Children and adolescents at continuous risk for acquiring Japanese encephalitis (residing in endemic areas) 
should receive a booster dose at month 12 after primary immunization (see section 5.1). 
 
Children and adolescents from 3 years to < 18 years of age should receive a single 0.5 ml booster dose. 
Children from 14 months to < 3 years of age should receive a single 0.25 ml booster dose.  
See section 6.6 for instructions on preparing a 0.25 ml dose for children aged 2 months to <3 years. 
 
No long-term seroprotection data beyond two years after a first booster administered 1 year after primary 
immunization has been generated in children.  
 
Children below 2 months of age 
The safety and efficacy of IXIARO in children younger than 2 months has not been established. No data are 
available. 
 

Method of administration  
 
The vaccine should be administered by intramuscular injection into the deltoid muscle. In infants, the 
anterolateral aspect of the thigh may be used as injection site. IXIARO should never be injected 
intravascularly. 
When IXIARO is administered concomitantly with injectable vaccines, they should be given with separate 
syringes at opposite sites. 
 
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. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 or to the residues 
protamine sulphate, formaldehyde, bovine serum albumin, host cell DNA, sodium metabisulphite (see 
section 2.), host cell protein. 
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. 
 
4.4 Special warnings and precautions for use 
 
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. 
 
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. 



5 

 
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). 
In adults a seroconversion rate of 29.4 % has been observed 10 days after the first i.m. vaccination, and 97.3 
% one week after the second i.m. vaccination in the conventional schedule. After immunisation with the 
rapid schedule a seroconversion rate of 99% has been observed 7 days after the second i.m. vaccination. 
Hence, primary immunisation 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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Concomitant administration of IXIARO with other vaccines: 
Concomitant administration of IXIARO with inactivated hepatitis A vaccine and with inactivated rabies 
vaccine in two different schedules has been evaluated in clinical studies. There was no interference with the 
immune response to Japanese encephalitis virus (JEV) or to hepatitis A or rabies virus vaccines (see section 
5.1). 
The safety profiles of IXIARO and the other studied vaccines were not compromised when administered 
concomitantly. 
 
In patients receiving immunosuppressive therapy or patients with immunodeficiency an adequate immune 
response may not be obtained. 
 
Paediatric population 
No interaction studies have been performed in children and adolescents. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There are limited amount of data from the use of IXIARO in pregnant 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 should be avoided. 
 
Breast-feeding 
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. However, in the absence of data and as a precautionary measure the use of 
IXIARO during lactation should be avoided. 
 
Fertility 
A study in rats did not indicate vaccine-related effects on female reproduction, foetal weight, survival and 
development of the off-spring. 
 
4.7 Effects on ability to drive and use machines 
 
IXIARO has no or negligible influence on the ability to drive and use machines.  
 
4.8 Undesirable effects 
 
Summary of the safety profile 
The safety of Ixiaro was assessed in controlled and uncontrolled clinical studies in 5,021 healthy adults (from 
non-endemic countries) and 1,559 children and adolescents (mostly from endemic countries). 
Approximately 40% of treated subjects experienced systemic adverse reactions and approximately 54% 
experienced injection site reactions. They usually occur within the first three days after vaccination, are 



6 

usually mild and resolve within a few days. No increase in the number of adverse reactions was noted 
between first and second doses or following a booster dose in adults.  
Most commonly reported adverse reactions in adults included headache (20% of subjects), myalgia (13%), 
injection site pain (33%), injection site tenderness (33%) and fatigue (12.9%). 
 
Most commonly reported adverse reactions in children and adolescents included pyrexia, diarrhoea,  
influenza like illness, irritability, injection site pain, injection site tenderness, and injection site redness (see 
table 1). 
 
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 
 
Adult and older adults (>65 years) population  
 
Blood and lymphatic system disorders 
Uncommon: lymphadenopathy 
Rare: thrombocytopenia  
 
Nervous system disorders 
Very common: headache 
Uncommon: migraine, dizziness  
Rare: paraesthesia, neuritis, dysgeusia, syncope*  
 
Eye disorders 
Rare: eyelid oedema 
 
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, hyperhidrosis  
Rare: urticaria, erythema 
 
Musculoskeletal and connective tissue disorders 
Very common: myalgia 
Uncommon: musculoskeletal stiffness, arthralgia 
Rare: pain in extremity  
 
General disorders and administration site conditions 
Very common: injection site pain, injection site tenderness, fatigue 
Common: influenza like illness, pyrexia, other injection site reactions e.g. redness, hardening, swelling, 
itching  
Uncommon: chills, malaise, asthenia  
Rare: oedema peripheral 



7 

 
Investigations 
Uncommon: hepatic enzymes increased 
 
*reported also from post-marketing experience 

 
Paediatric population (2 months to <18 years of age) 
 
Table 1: Frequency of adverse reactions observed in children given the 0.25 ml dose (2 months to <3 

years of age) and in children and adolescents given the 0.5 ml dose (3 years to <18 years of age) 
 
 Frequency of adverse reactions(%) by dose/age  
System Organ Class 

Preferred Term 
0.25 ml 
N=783 

2 months to <3 years  

0.5 ml 
N=628 

3 to <18 years 
Blood and Lymphatic System 
Disorders 

  

Lymphadenopathy 0.1 0.0 
Metabolism and Nutrition 
Disorders 

  

Decreased appetite 8.2 1.9 
Nervous System Disorders   

Headache 2.9 6.1 
Respiratory, Thoracic and 
Medistinal Disorders 

  

Cough 0.5 0.3 
Gastrointestinal Disorders   

Diarrhoea 11.9 1.4 
Vomiting 7.3 1.9 

Nausea 3.9 1.9 
Abdominal pain 0.1 0.0 

Skin and Subcutaneous Tissue 
Disorders 

  

Rash 6.3 1.4 
Musculoskeletal and Connective 
Tissue Disorders 

  

Myalgia 3.0 7.1 
General Disorders and 
Administration Site Conditions 

  

Pyrexia 28.5 10.4 
Influenza like illness 10.9 2.9 

Irritability 10.9 1.9 
Fatigue 3.5 3.5 

Injection site redness 10.0 4.1 
Injection site pain 6.1 14.1 

Injection site tenderness 4.2 14.7 
Injection site swelling 3.6 2.2 

Injection site hardening 1.2 1.9 
Injection site itching 0.6 1.6 

Investigations   
Hepatic enzymes increased 0.5 0.2 

 
 
Reporting of suspected adverse reactions 



8 

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 national reporting system listed in Appendix V. 
 
 
4.9 Overdose 
 
No symptoms related to overdose were reported. 
 
 
Paediatric population: 
No case of overdose has been reported in the paediatric population. Inadvertent administration of an 0.5 ml 
dose of IXIARO in children aged 1 to <3 years does not pose any safety concerns (section 5.1.). 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: Vaccines, Viral vaccines, 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 efficacy and safety  
No prospective efficacy trials have been performed. Immunogenicity of IXIARO was studied in 
approximately 3,119 healthy adult subjects included in seven randomized, controlled and five uncontrolled 
Phase 3 trials and in approximately 550 healthy children included in two randomized, controlled and two 
uncontrolled Phase 3 clinical trials. 
 
Pivotal immunogenicity trial (adults) 
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 2). 
 



9 

Table 2: 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. 

 
 

Seroconversion rate  
 

Time point IXIARO 
N=365 
% (n) 

JE-VAX 
N=370 
% (n) 

Visit 0 (Screening) 0 0 
Visit 3 (Day 28) 54 (197) 86.8 (321) 
Visit 4 (Day 56) 96.4 (352) 93.8 (347) 

 
Geometric mean titer (by plaque reduction neutralization test)  

 
Time point IXIARO 

N=365 
GMT (n) 

JE-VAX 
N=370 

GMT (n) 
Visit 0 (Screening) 5.0 (365) 5.0 (370) 
Visit 3 (Day 28) 17.4 (363) 76.9 (367) 
Visit 4 (Day 56) 243.6 (361) 102.0 (364) 
 
 
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 aged ≥ 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 (adults)  
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 PRNT50≥1:10 and GMTs at Months 2, 6, 12, 24 and 36 are summarized in Table 3 for 
the ITT population.  
 
Table 3: Rates of subjects with PRNT50≥1:10 and geometric mean titers (GMT) at Month 2, 6, 12, 24 and 

36 after vaccination with IXIARO (ITT population) 
 

  Rate of subjects with PRNT50≥1:10 GMT 
Time point % (n/N) 95% Confidence 

Interval 
GMT (N) 95% Confidence 

Interval 
Month 2 98.9 (179/181) [96.1, 99.7] 310.8 (181) [268.8, 359.4] 
Month 6 95.0 (172/181) [90.8, 97.4] 83.5 (181) [70.9, 98.4] 
Month 12 83.4 (151/181) [77.3, 88.1] 41.2 (181) [34.4, 49.3] 
Month 24 81.8 (148/181) [75.5, 86.7] 44.3 (181) [36.7, 53.4] 
Month 36 84.9 (129/152) [78.3, 89.7] 43.8 (152) [36.5, 52.6] 
 



10 

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 PRNT50≥1:10 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 (adults) 
In an uncontrolled, open-label phase 3 study a single 6 mcg (0.5 ml) 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 PRNT50≥1:10 and GMT over time are summarised in table 4: 

 
Table 4:  Rates of subjects with PRNT50≥1:10 and GMT before and at months 1, 6 and 12 after a single 6 

mcg (0.5 ml) booster dose administered to subjects at 15 months after recommended primary 
immunization with IXIARO (ITT population) 

 
 Rate of subjects with PRNT50≥1:10  GMT  
  95% CI  95% CI  

Pre-booster, Day 0 
(n=198) 

69.2% [62.4%, 75.2%] 22.5 [19.0, 26.7] 

Day 28 (n=198) 100.0% [98.1%, 100.0%] 900.1 [742.4, 1091.3] 
Month 6 (n=197) 98.5% [95.6%, 99.5%] 487.4 [390.7, 608.1] 

Month 12 (n=194) 98.5% [95.6%, 99.5%] 361.4 [294.5, 443.5] 
 
Antibody persistence after booster immunisation (adults) 
In an uncontrolled, open-label extension to the booster study described above, 67 subjects were followed up 
for determination of JEV neutralizing antibody titres at approximately 6 years after a booster dose. 96% of 
subjects (64/67) still had protective antibody levels (PRNT50≥1:10), with a GMT of 148 (95%CI: 107; 207).  
Mathematical modelling was applied to project the average duration of protection. Based on this model, it is 
estimated that average duration of protection will be 14 years and 75% of vaccinees will retain protective 
antibody levels (PRNT50≥1:10) for 10 years. A second booster should therefore be given 10 years after the 
first booster dose, administered 1 year after the primary immunization, prior to potential exposure to JEV.  
 
 
Rapid immunisation schedule (adults) 
The immunogenicity of IXIARO administered in a rapid vaccination schedule was evaluated in a 
randomized, observer-blind, phase 3 study. A total of 217 subjects aged 18 to  ≤ 65 years received IXIARO 
together with inactivated rabies vaccine (Rabipur) in a rapid immunisation schedule on Day 0 and Day 7 and 
56 subjects received IXIARO alone in the conventional immunisation schedule on Day 0 and Day 28. The 
proportion of subjects that seroconverted by 7 and by 28 days after the last immunisation was similar for 
both schedules. Seroconversion rates and antibody titers also remained comparably high up to 12 months 
after the first immunisation in both schedules (Table 5). 
The rapid schedule was tested for concomitant administration of IXIARO and Rabipur but it can also be used 
for administration of IXIARO alone, as no immune interference of the two vaccines has been observed (see 
section 4.5). 
 



11 

Table 5:  Seroconversion rates and GMTs for  anti-JEV neutralizing antibodies on Day 0, 14, 21, 35, 
56 and 365 after immunisation with IXIARO and inactivated rabies vaccine in a rapid 
schedule and IXIARO alone in a conventional schedule (Per Protocol population) 

 
 Seroconversion Rate 

(Rate of subjects with PRNT50≥1:10)  
GMT  

(plaque reduction neutralization test) 
 Rapid Schedule 

% (n/N) 
Conventional 

Schedule 
% (n/N) 

Rapid Schedule 
 (N) 

Conventional 
Schedule 

 (N) 
Vaccination scheme IXIARO Day 0,7 

Rabipur Day 0,3,7 
IXIARO Day 0,28 

- 
IXIARO Day 0,7 
Rabipur Day 0,3,7 

IXIARO Day 0, 28 
- 

Day 0 6 (13/215) 9 (5/55) 5.63 (215) 5.73 (55) 
Day 14 

 
99 (206/209) NA 715 (209) NA 

Day 21 100 (207/208) NA 1255 (208) NA 
Day 35 

 
99 (203/206) 100 (47/47) 690 (206) 376 (47) 

Day 56 
 

98 (200/204) 100 (49/49) 372 (204) 337 (49) 

Day 365 94 (188/199) 88 (42/48) 117 (199) 39 (48) 
NA= not applicable 
 
 
Incomplete primary immunization (adults) 
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 (0.5 ml) 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 6. 
 
 
Table 6:  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)  

 
 (n / N) SCR   GMT  [95% CI] 

Booster following recommended 
primary immunization (2x6 mcg)  

    

Booster at Month 11 (17 / 17) 100 %  673.6 [378.7, 1198.2] 
Booster at Month 23 (27 / 27) 100 %  2536.7 [1467.7, 

4384.4] 
Second dose following incomplete 
primary immunization (1x6 mcg)  

    

Second dose at Month 11 (99 / 100) 99 %  504.3 [367.3, 692.3] 
Second dose at Month 23 (5 / 5) 100 %  571.4 [88.2, 3702.9] 

 
 



12 

Concomitant use (adults) 
Concomitant administration of IXIARO with inactivated hepatitis A virus (HAV) vaccine (HAVRIX 1440) 
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 7). 
 
Table 7: 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 

 
 

Seroconversion rates and geometric mean titer for anti-JEV neutralizing antibody at Day 56  
 

 % with SCR GMT 95% CI 
Group C: IXIARO + HAVRIX1440 100.0 202.7 [153.7, 261.2] 
Group A: IXIARO + Placebo 98.2 192.2 [147.9, 249.8] 

 
Seroconversion rates and geometric mean titer for HAV antibody at Day 28 

 
 % with SCR GMT 95% CI 
Group C: IXIARO + HAVRIX 1440 100.0 150.0 [111.7, 202.3] 
Group B: HAVRIX + Placebo 96.2 124.0 [91.4, 168.2] 
 
Concomitant administration of IXIARO with inactivated rabies vaccine (Rabipur): 
 
In an observer-blind Phase 3 study, concomitant administration of IXIARO and Rabipur has been studied in 
adults aged 18 to  ≤ 65 years of age in comparison to respective single vaccinations in conventional schedule. 
No interference was observed with regards to geometric mean titer (GMT) and seroconversion rates for anti 
JEV neutralizing antibodies (Table 8). There was also no interference with the immune response to Rabipur. 
 
Table 8:  Seroconversion rates (rate of subjects with PRNT50≥1:10) and GMTs (plaque reduction 

neutralization test) for anti-JEV neutralizing antibodies after administration of IXIARO and 
Rabipur in conventional schedule, Per Protocol population 

Seroconversion rates and geometric mean titer for JEV neutralizing antibody at Day 56 
 

 SCR [%] (n/N) GMT [95% CI] 
 (N) 

IXIARO + Rabipur  100  
(157/157) 

299 [254-352]  
(157) 

IXIARO  100  
(49/49) 

337 [252-451]  
(49) 

Vaccination schedules: IXIARO: Day 0/28, Rabipur: Day 0/7/28. 
 
 
Immunogenicity in elderly persons (>65 years) 
The immunogenicity of IXIARO was evaluated in an open-label, uncontrolled trial in 200 healthy elderly 
persons aged >65 to 83 years, including subjects with stable underlying conditions like 
hypercholesterolemia, hypertension, cardiovascular disease or non insulin-dependent diabetes mellitus. JEV 
neutralizing antibodies were determined 42 days after the second dose of the primary series (Day 70). 
Elderly persons have a lower immune response to vaccination compared to younger adults or children, in 
terms of seroconversion rates (percentage of subjects with PRNT50 titer ≥1:10) and geometric mean titers 
(Table 9).  
 
 



13 

Table 9: Seroconversion rates and geometric mean titer of JEV neutralizing antibody at Day 70 in the 
Intent-to-treat Population, for the entire study population and stratified by age 

 
Seroconversion rates and geometric mean titer for JEV neutralizing antibody at Day 70  

 
 n / N SCR GMT 95% CI 
Total Study Population 128/197 65% 37 29.2, 47.8 

Age group >65 - <75years 113/173 65.3% 37.2 28.6, 48.3 
Age group ≥75 years 15/23 65.2% 42.2 19.2, 92.7 
 
 
Paediatric population 
 
In a phase 2 study in healthy Indian toddlers aged ≥1 year to <3 years, 24 children were vaccinated with 0.25 
ml of IXIARO (the licensed dose for this age group) and 24 children received the adult 0.5 ml dose. Data are 
limited but there were no differences in the safety profile between the 0.25 ml and the 0.5 ml dose in this age 
group. 

 
Immunogenicity and safety of IXIARO in children and adolescents from a JEV-endemic country 
The safety and immunogenicity of IXIARO were evaluated in a randomized, controlled, open-label clinical 
trial conducted in the Philippines, where JEV is endemic. The safety profile of IXIARO was compared to 
control vaccines Havrix (Hepatitis A vaccine, paediatric 720 EL.U./0.5 mL formulation) and Prevenar 
(Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM197 protein]). The immunogenicity evaluation 
was performed in a subset of the study population and included the determination of the seroconversion rate 
(SCR), defined as JEV neutralizing antibody titer ≥1:10, the proportion of subjects achieving an at least four-
fold increase in antibody titers and the geometric mean titer (GMT) at Day 56 and Month 7, by dose and by 
age group. The immune responses elicited by IXIARO are presented in Table 10. 

 



14 

Table 10: Seroconversion rates, rates of subjects with at least 4-fold increase in JEV neutralizing antibody 
titers and Geometric Mean Titers at baseline, Day 56 and Month 7 stratified by age group, Intent 
To Treat Population  

Vaccine Dose 0.25 ml 0.5 ml 

Age Group 2 months –  <6 months 
6 months –  
<12 months 

1 year  –  
< 3 years 

3 years -  
< 12 years 

12 years -  
< 18 years 

Seroconversion Rates % (n/N) 

Pre-Vaccination  30% (3/10) 0% (0/20) 3.2% (4/125) 16.8% (17/101) 45.7% (64/140) 

Day 56  100% (9/9) 100% (19/19) 99.2% (119/120)  
100.0% 

(100/100) 100% (137/137)  

Month 7  
 

100% (10/10) 100% (18/18) 85.5%  
(106/124) 

91.0% (91/100) 97.1%  
(133/137)  

Proportion of Subjects Achieving an ≥4-fold Increase in JEV Antibody Titers % (n/N) 

Day 56  
 100 (9/9) 94.7 (18/19) 96.7 (116/120) 94.0 (94/100) 77.4 (106/137)  

Month 7  
 90.0 (9/10) 

83.3 (15/18) 
 

75.8 (94/124) 
 

71.0 (71/100)  
 

65.0 (89/137)  
 

Geometric Mean Titer (N) 

Pre-Vaccination  8.42  (10 ) 5 ◊ (20) 5.52 (124) 6.54 (101) 13.08 (140) 

Day 56  
 

687.35  (9)  
 

377.79 (19)  
 

258.90 (121) 
 

213.67 (100) 
 175.63 (137)  

Month 7  
 

159.27 (10) 
 

64.00 (18)    
 

38.91 (125) 
 

43.60 (100) 
 

86.61 (137)  
 

◊Negative Pre-Vaccination titers were imputed to 5. 

 
Safety and tolerability was evaluated in the entire study population. Parents or subjects recorded adverse 
events on a diary card for the first seven days after each vaccination. Parents or subjects were asked for any 
unsolicited AEs on the day of the second vaccination and at in-person visits including a medical exam 28 
days (Day 56) and 6 months (Month 7) after the second dose. The safety profile of IXIARO was comparable 
to that of Havrix or Prevenar.  
 
 
Antibody persistence and booster dose in children and adolescents from a JEV-endemic country 
The persistence of JEV neutralizing antibodies after primary immunisation and safety and immunogenicity 
of an IXIARO booster dose 12 months after primary immunization were evaluated in a randomized, 
controlled, open-label clinical trial conducted in the Philippines, where JEV is endemic (300 children, mean 
age 5.3 years, range 1.2 - 17.3 years). 150 children were followed-up for three years without booster, 
additional 150 children received a booster after 1 year (0.25 ml if aged <3 years at time of the booster, 0.5 ml 
if aged 3 years and above) and were followed-up for further two years. Seroprotection rate (SPR) defined as 
neutralizing antibody titer ≥1:10 and geometric mean titers (GMT) are presented in Table 11. The booster 
dose led to a pronounced increase in GMTs and seroprotection rate remained at 100% two years after the 
booster.  

 



15 

Table 11: Seroprotection Rates and Geometric Mean Titers with and without a booster of IXIARO at 
Month 12, 13, 24 and 36, Intent To Treat Population  

 Without Booster N = 150 
Booster dose 12 months after primary immunization  

N = 149 

Time point after primary 
immunization  

0.25 mL Booster Dose  
N=81 

0.5 mL Booster Dose  
N=67 

Seroprotection Rate % (n/N) 

Month 12  89.9 (134/149) 97.5 (79/81) 89.6 (60/67) 

 Month 13 n.a. 100 (81/81) 100.0 (67/67) 

Month 24 89.0 (130/146) 100 (80/80)  100.0 (67/67) 

Month 36  90.1 (128/142) 100.0 (76/76) 100.0 (67/67) 

Geometric Mean Titer  

Month 12  46 67 40 

 Month 13 n.a. 2911 1366 

Month 24 50 572 302 

Month 36  59 427 280 

n.a. = not available 

 

Immunogenicity and safety in children and adolescents from non-endemic countries   
The safety and immunogenicity of IXIARO was evaluated in an uncontrolled, open-label clinical trial 
conducted in the United States, Europe and Australia in healthy male and female subjects with planned travel 
to JEV-endemic areas. Children and adolescents aged ≥ 3 to < 18 years received two vaccine doses of 0.5ml 
and children aged  ≥ 2 months to < 3 years received two vaccine doses of 0.25ml on Day 0 and Day 28 by 
intramuscular injection. Immunogenicity data were evaluated in 64 subjects. The SCRs and GMTs are 
displayed in Table 12.  

 

Table 12: Seroconversion rates and geometric mean titer of JEV neutralizing antibody by vaccine dose 
and age group. Intent-to-treat Population 

 
 IXIARO 

Dose 
Time  
Point 

SCR 
n / N 

GMT 95% CI 

Age Group ≥2 months to <3 years 0.25 ml Day 56 
100% 

5/5 
216.2  106.0; 441.0 

  Month 7 
100% 

2/2 
48.0  0.0; 

3214485.7 

Age Group ≥3 to <18 years 0.5 ml Day 56 
100%  
57/57 

340.7 269.8; 430.3 

  Month 7 
90.6%  
29/32 

57.1  38.4; 84.9 

 
 



16 

Antibody persistence in children and adolescents from non-endemic countries   
Antibody persistence was evaluated for three years after the primary vaccination with IXIARO in an 
uncontrolled, open-label follow-up clinical trial conducted in the United States, Europe and Australia. Long-
term immunogenicity data were evaluated in 23 children, mean age 14.3 years, range 3 - 18 years). The SPRs 
and GMTs are displayed in Table 13.  

 

Table 13: Seroprotection rates and geometric mean titer of JEV neutralizing antibody by vaccine dose and 
age group. Intent-to-treat Population 

 
 Seroprotection Rate 

(Rate of subjects with PRNT50≥1:10)  
% (n/N) 

Geometric Mean Titer  
(plaque reduction neutralization test) 

GMT [95%CI] 
 After 0.25 mL Dose 

Primary 
Immunization 

After 0.5 mL Dose 
Primary 

Immunization 

After 0.25 mL Dose 
Primary 

Immunization 

After 0.5 mL Dose 
Primary 

Immunization 

Month 12 0% (0/0) 89.5% (17/19) - 48 [28; 80] 

Month 24 100% (1/1) 90.9% (20/22) 193 [n.a.]  75 [46; 124] 

Month 36 100% (1/1) 88.9% (16/18) 136 [n.a.] 61 [35; 106] 

n.a. 95% Confidence Interval could not be established (single-subject data)  
 
 
5.2 Pharmacokinetic properties 
 
Not applicable. 
 
 
5.3 Preclinical safety data 
 
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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Phosphate buffered saline consisting of: 
 
Sodium chloride 
Potassium dihydrogen phosphate 
Disodium hydrogen phosphate 
Water for injections 
 
For adjuvant, see section 2. 
 
6.2 Incompatibilities 
 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products. 
 



17 

 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C - 8°C). 
Do not freeze. 
Store in the original package in order to protect from light. 
 
6.5 Nature and contents of container 
 
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. 
 
6.6 Special precautions for disposal and other handling  
 
The pre-filled syringe is for single use only and should not be used for more than one person. The pre-filled 
syringe is ready to use. If a needle is not provided, use a sterile 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.  
Before administration, shake the syringe well to obtain a white, opaque, homogeneous suspension. Do not 
administer if particulate matter remains following shaking or if discoloration is observed or if the syringe 
appears to be physically damaged.. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Information on the administration of a 0.5 ml dose of IXIARO for persons 3 years of age and above 
 
For administration of the full 0.5 ml dose follow the steps below:  
 

1. Shake the syringe to obtain a homogeneous suspension.  
2. 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. 
3. Attach a needle to the pre-filled syringe.  

 
 
Information on the preparation of a 0.25 ml dose of IXIARO for use in children below 3 years of age 
 
For administration of a 0.25 ml dose in children aged 2 months to < 3 years, follow the steps below:  
 

1. Shake the syringe to obtain a homogeneous suspension.  
2. 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. 
3. Attach a needle to the pre-filled syringe.  
4. Hold the syringe in an upright position. 
5. Push the plunger stopper up to the edge of the red line on the syringe barrel, indicated by a red 
arrow (see Figure 1)*, to discard excess volume. 
6. Attach a new sterile needle prior to injection of the remaining volume. 

 
* If you pushed the plunger stopper beyond the red line, a 0.25 ml dose is not guaranteed and a new syringe 
should be used. 
 



18 

 
 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Valneva Austria GmbH 
Campus Vienna Biocenter 3 
A-1030 Vienna 
Austria 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/501/001 
EU/1/08/501/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 31 March 2009 
Date of latest renewal: 22 November 2018 
 
10. DATE OF REVISION OF THE TEXT 
 
<{MM/YYYY}> 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 

Figure 1:  
Preparation for 
Administration of 
0.25 ml Dose 



19 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 
OF THE MEDICINAL PRODUCT 
 



20 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer(s) of the biological active substance(s) 
 
Valneva Scotland Ltd. 
Oakbank Park Road 
Livingston EH53 0TG 
United Kingdom 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Valneva Scotland Ltd. 
Oakbank Park Road 
Livingston EH53 0TG 
United Kingdom 
 
Valneva Austria GmbH 
Campus Vienna Biocenter 3 
1030 Wien 
Austria 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to medical prescription. 
 
• Official batch release 
 
In accordance with Article 114 Directive 2001/83/EC as amended, the official batch 
release will be undertaken by a state laboratory or a laboratory designated for that purpose. 
 
 
C. OTHER CONDITIONS OR REQUIREMENTS OF THE MARKETING AUTHORISATION 
 
• Periodic Safety Update Reports 
 
 
The requirements for submission of periodic safety update reports for this medicinal product are set out in 
the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC 
and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE 

OF THE MEDICINAL PRODUCT   
 
Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 



21 

• Whenever the risk management system is modified, especially as the result of new information being 
received that may lead to a significant change to the benefit/risk profile or as the result of an important 
(pharmacovigilance or risk minimisation) milestone being reached. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



22 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 



23 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Outer carton 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IXIARO suspension for injection 
Japanese encephalitis vaccine (inactivated, adsorbed) 
Presentation for adults, adolescents and children 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
1 dose (0.5 ml) of IXIARO contains: 
6 AU (Antigen Units, corresponding to a potency of ≤ 460 ng ED50) of inactivated Japanese encephalitis 
virus strain SA14-14-2 (produced in Vero cells) adsorbed on aluminium hydroxide, hydrated (approximately 
0.25 milligrams Al3+). 
 
3. LIST OF EXCIPIENTS 
Excipients: 
Phosphate buffered solution consisting of sodium chloride, potassium dihydrogen phosphate, disodium 
hydrogen phosphate and water for injections. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Suspension for injection. 
0.5 ml single dose in a pre-filled syringe. 
0.5 ml single dose in a pre-filled syringe + 1 needle. 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intramuscular (IM) use. 
Shake to form a uniform suspension. 
Read the package leaflet before use. 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
  
Do not inject intravascularly. 
 
8. EXPIRY DATE 
 
EXP: 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator (2°C - 8°C). 
Do not freeze. 
Store in the original package in order to protect from light. 



24 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 
 
Dispose of in accordance with local requirements. 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Valneva Austria GmbH 
Campus Vienna Biocenter 3 
A-1030 Vienna 
Austria 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/08/501/001  
EU/1/08/501/002  
 
13. BATCH NUMBER AND PRODUCT CODES 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 



25 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Blister foil 
 
Blank white foil without any printed information. 
 



26 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Pre-filled syringe label 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
IXIARO suspension for injection 
Japanese encephalitis vaccine  
Intramuscular (IM) use 
 
2. METHOD OF ADMINISTRATION 
 
 
3. EXPIRY DATE 
 
EXP: 
 
4. BATCH NUMBER 
 
 
Lot: 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 dose, 0.5 ml 
 
6. OTHER 
 
Store in a refrigerator 
Do not freeze. 
 
 



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



28 

 
PACKAGE LEAFLET: INFORMATION FOR THE USER 

 
IXIARO suspension for injection 

Japanese encephalitis vaccine (inactivated, adsorbed) 
 
 

Read all of this leaflet carefully before you or your child receive this vaccine because it contains 
important information for you. 
 
• Keep this leaflet. You and your child may need to read it again.  
• If you have any further questions, ask your doctor. 
• This vaccine has been prescribed for you and/or your child only. Do not pass it on to others.   
• If you and/or your child get any side effects, talk to your doctor. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 

 
What is in this leaflet 
 
1. What IXIARO is and what it is used for 
2. What you need to know before you and/or your child receive IXIARO 
3. How IXIARO is given 
4. Possible side effects 
5. How to store IXIARO 
6. Contents of the pack and other information 
 
 
1. What IXIARO is and what it is used for 
 
IXIARO is a vaccine against the Japanese encephalitis virus. 
The vaccine causes the body to produce its own protection (antibodies) against this disease. 
 
IXIARO is used to prevent infection with the Japanese encephalitis virus (JEV). This virus is mainly found 
in Asia and is transmitted to humans by mosquitoes that have bitten an infected animal (like pigs). Many 
infected people develop mild symptoms or no symptoms at all. In people who develop severe disease, JE 
usually starts as a flu-like illness, with fever, chills, tiredness, headache, nausea, and vomiting. Confusion 
and agitation also occur in the early stage of disease. 
 
IXIARO should be given only to adults, adolescents, children and infants aged 2 months and older travelling 
to countries, where JE is endemic or who are at risk through work. 
 
 
2. What you need to know before you and/or your child receive IXIARO  
 
Do not use IXIARO: 
• If you and/or your child are allergic (hypersensitive) to the active substance or any of the other 

ingredients of this medicine (listed in section 6). 
• If you and/or your child have developed an allergic reaction after receiving a former dose of 

IXIARO. Signs of an allergic reaction may include an itchy rash, shortness of breath and swelling of 
the face and tongue. 

• If you and/or your child are ill with a high fever. In this case, your doctor will postpone the 
vaccination. 

 
Warnings and precautions  
IXIARO must not be injected into a blood vessel. 
Primary immunization should be completed at least one week prior to potential exposure to JEV. 
 



29 

Tell your doctor: 
• If you and/or your child have experienced any health problems after previous administration of any 

vaccine. 
• If you and/or your child have any other known allergies. 
• If you and/or your child have a bleeding disorder (a disease that makes you bleed more than normal) 

or a reduction in blood platelets, which increases risk of bleeding or bruising (thrombocytopenia). 
• If your child is younger than 2 months of age, since IXIARO has not been tested in infants younger 

than 2 months of age. 
• If your or your child’s immune system does not work properly (immunodeficiency) or you and/or 

your child are taking medicines affecting your immune system (such as a medicine called cortisone 
or cancer medicine). 

 
Your doctor will discuss with you the possible risks and benefits of receiving IXIARO. 
 
Please note that: 
• IXIARO cannot cause the disease it protects against. 
• IXIARO will not prevent infections caused by other viruses than the Japanese encephalitis virus. 
• As with any other vaccine, vaccination with IXIARO may not result in protection in all cases. 
• You should take appropriate precautions for you and your child to reduce mosquito bites (adequate 

clothing, use of repellents, mosquito nets) even after receiving IXIARO. 
 
Other medicines and IXIARO 
Studies in humans to evaluate the effectiveness and safety of medicines (clinical trials) have shown that 
IXIARO can be given at the same time with hepatitis A vaccine and rabies vaccine. 
Tell your doctor if you and/or your child are taking or have recently taken, or might take any other 
medicines, including medicines obtained without a prescription or have recently received any other vaccine. 
 
Pregnancy and breast-feeding and fertility 
There are limited amount of data from the use of IXIARO in pregnant or breast-feeding women. 
As a precautionary measure, the use of IXIARO during pregnancy or breast-feeding should be avoided. 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor for advice before receiving this vaccine. 
 
Driving and using machines 
IXIARO has no or negligible influence on the ability to drive and use machines.  
 
IXIARO contains potassium and sodium  
This medicine contains potassium, less than 1mmol (39 mg) per 0.5 ml single dosage i.e. essentially 
‘potassium-free’ and less than 1 mmol sodium (23 mg) per 0.5 ml single dosage, that is to say essentially 
‘sodium-free’. This product might contain traces of residual sodium metabisulfite which is below detection 
limit.  
 

 
3. How to use IXIARO 
 
The recommended dosage for adults, adolescents and children aged 3 years of age and older is a total of 2 
injections of 0.5 ml each: 
 
• The first injection on Day 0 
• The second injection 28 days after the first injection (Day 28). 

 
Adults aged 18 to  ≤ 65 years can also be vaccinated as follows: 
• The first injection on Day 0 
• The second injection 7 days after the first injection (Day 7). 
 
Babies and children aged 2 months to < 3 years of age  



30 

The recommended dosage for babies and children aged 2 months to < 3 years is a total of 2 injections of 0.25 
ml each: 
• The first injection on Day 0 
• The second injection 28 days after the first injection (Day 28). 

 
For instruction on the preparation of the 0.25 ml dose, please refer to the end of this package leaflet. 
 
Make sure you and/or your child finish the complete vaccination course of 2 injections. The second injection 
should be given at least 1 week before you and/or your child will be at risk of exposure to JE virus. If not, 
you and/or your child may not be fully protected against the disease. 
 
For adults, adolescents, children and infants aged 1 year and older a booster dose can be given within the 
second year (i.e. 12 - 24 months) after the first dose of the recommended primary immunization. In adults, a 
second booster can be given 10 years after the first booster. For elderly persons (>65 years) the first booster 
dose may be given earlier. Your doctor will decide on the requirement and timing for booster doses. 
 
Administration 
IXIARO is injected into your or your child's upper arm muscle (deltoid muscle) by your doctor or a nurse. It 
must not be injected into a blood vessel. In case you and/or your child suffer from a bleeding disorder, your 
doctor may decide to administer the vaccine under the skin (subcutaneously). 
If you have any further questions on the use of this product, ask your doctor or pharmacist. 
 
If you forget to get IXIARO 
If you and/or your child miss a scheduled injection, talk to your doctor and arrange another visit for the 
second injection. 
Without the second injection you and/or your child will not be fully protected against the disease. There is 
data showing that the second injection can be given up to 11 months after the first one. 
 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
The majority of the side effects listed below have been observed during clinical trials. They usually occur 
within the first 3 days after vaccination, are usually mild and disappear within a few days. 
 
Very common (affects more than 1 user in 10): 
headache, muscle pain, injection site pain, injection site tenderness, tiredness 
 
Common (affects 1 to 10 users in 100):  
Nausea, influenza like illness, fever, other injection site reactions (e.g. redness, hardening, swelling, itching) 
 
Uncommon (affects 1 to 10 users in 1,000): 
vomiting, skin rash, changes in the lymph-nodes, migraine (throbbing headache, often accompanied by 
nausea and vomiting and sensitivity to light), dizziness, vertigo (spinning sensation), diarrhoea, belly pain, 
excessive sweating, itching, chills, general condition of feeling unwell, musculoskeletal stiffness, joint pain, 
weakness, abnormal laboratory liver test results (hepatic enzymes increased) 
 
 
Rare (affects 1 to 10 users in 10,000): 
palpitations, rapid heartbeat, difficulty to breathe, abnormal sensation of skin (for example pins and needles), 
hives, skin redness, pain in leg or arm, platelet deficiency, nerve inflammation, limb swelling and ankle 
swelling, taste disturbance, swelling of eyelid, fainting 
 
 
Additional side effects in children aged 2 months to <3 years 



31 

 
In children aged 2 months to <3 years, the following side effects have been observed more frequently 
compared to children aged 3 years to <12 years, adolescents and adults: 
Very common: fever (28.9%), diarrhoea (11.8%), influenza like illness (11.2%), irritability (11.0%) 
Common: loss of appetite, vomiting, skin rash 
Uncommon: cough 
 
 
 
Reporting of side effects 
If you and/or your child get any side effects, talk to your doctor. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store IXIARO 
 
• Keep this medicine out of the sight and reach of children. 
• Do not use this medicine after the expiry date which is stated on the carton and label after “EXP”. 

The expiry date refers to the last day of that month. 
• Store in a refrigerator (2°C - 8°C). 
• Do not freeze. If the vaccine has been frozen it should not be used. 
• Store in the original package in order to protect from light. 
• Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you and/or your child no longer use. These measures will help protect the 
environment. 

 
6. Contents of the pack and other information 
 
What IXIARO contains 
 
1 dose (0.5 ml) of IXIARO contains:  
Japanese encephalitis virus strain SA14-14-2 (inactivated)1,2 6 AU3 
corresponding to a potency of ≤ 460 ng ED50  
 
1 produced in Vero cells 
2 adsorbed on aluminium hydroxide, hydrated (approximately 0.25 milligrams Al3+) 
3 Antigen Units 
 
Aluminium hydroxide is included in this vaccine as an adjuvant. 
 
The other ingredients are: Sodium chloride, potassium dihydrogen phosphate, disodium hydrogen phosphate, 
water for injections 
 
What IXIARO looks like and contents of the pack 
 
IXIARO is a suspension for injection (0.5 ml in a glass syringe with or without a separate needle, pack size 
of 1). 
 
IXIARO is a white and slightly milky sterile suspension, which becomes homogenous on shaking. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Valneva Austria GmbH 
Campus Vienna Biocenter 3 



32 

A-1030 Vienna 
Austria 
Email: infoixiaro@valneva.com 
 
Manufacturer:  
Valneva Scotland Ltd. 
Oakbank Park Road,  
Livingston EH53 0TG, Scotland,  
United Kingdom 
 
Valneva Austria GmbH 
Campus Vienna Biocenter 3 
A-1030 Vienna 
Austria 
 
 
For any information about this medicine, please contact the  Marketing Authorization Holder by the 
following email-address: 
infoixiaro@valneva.com 
 
 
This leaflet was last revised in         . 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu/. 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 
---------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for healthcare professionals only: 
 
The pre-filled syringe is for single use only and should not be used for more than one person. The pre-filled 
syringe is ready to use. If a needle is not provided, use a sterile 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.  
Before administration, shake the syringe well to obtain a white, opaque, homogeneous suspension. Do not 
administer if particulate matter remains following shaking or if discoloration is observed or if the syringe 
appears to be physically damaged. 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
Information on the administration of a 0.5 ml dose of IXIARO for persons 3 years of age and above 
 
For administration of the full 0.5 ml dose follow the steps below:  
 

1. Shake the syringe to obtain a homogeneous suspension.  
2. 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. 
3. Attach a needle to the pre-filled syringe.  

 
 



33 

Information on the preparation of a 0.25 ml dose of IXIARO for use in children below 3 years of age 
 
For administration of a 0.25 ml dose in children aged 2 months to < 3 years, follow the steps below:  
 

1. Shake the syringe to obtain a homogeneous suspension.  
2. 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. 
3. Attach a needle to the pre-filled syringe.  
4. Hold the syringe in an upright position. 
5. Push the plunger stopper up to the edge of the red line on the syringe barrel, indicated by a red 
arrow (see Figure 1)*, to discard excess volume. 
6. Attach a new sterile needle prior to injection of the remaining volume. 

 
*If you pushed the plunger stopper beyond the red line, a 0.25 ml dose is not guaranteed and a new syringe 
should be used. 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 

Figure 1:  
Preparation for 
Administration of 
0.25 ml Dose 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
	C. OTHER CONDITIONS OR REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  
	A. LABELLING
	B. PACKAGE LEAFLET