IXIARO Japanese Encephalitis vaccine (inactivated, adsorbed)



Section 2: Potency expressed in Antigen Units. See below:

1 dose (0.5 ml) of IXIARO contains:

Japanese encephalitis virus strain SA₁₄-14-2 (inactivated)^1,2 6 micrograms³AU³

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 total protein content

³ Antigen Units

Section 4.2: Addition of subheadings and additional information for dosing: Adults (18-65 years of age), Elderly (≥ 65 years of age) and Paediatric Population. Updates to include recommendation for a booster dose in the paediatric population and recommendation for a second booster dose after 10 years. See below:

In subsection posology:

Adults (18-65 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 Adults 18-65 years of age:

Persons aged 18-65 years can be vaccinated in a rapid schedule as follows:

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 (Adults)

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). Data on the need for further booster doses are not available.

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 olderelderly persons (≥ 65 years of age) to IXIARO is lower than in younger adults. Duration of protection is uncertain in olderelderly 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.

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.

Booster dose (children and adolescents)

Data on the timing of and response to a booster dose in children and adolescents (<18 years of age) are not available.

Section 4.8: Update of the safety information based on results of clinical studies. Summary of the safety profile updated with injection site pain, injection site tenderness, and injection site redness being added as most commonly reported adverse reactions in children and adolescents. Table of Frequency of adverse reactions observed in children updated. See below:

In the section 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=771783 2 months to <3 years	0.5 ml N=540628 3 to <18 years
Blood and Lymphatic System Disorders
Lymphadenopathy	0.1	0.0
Metabolism and Nutrition Disorders
Decreased appetite	8.2	2.01.9
Nervous System Disorders
Headache	3.02.9	5.86.1
Respiratory, Thoracic and Medistinal Disorders
Cough	0.5	0.23
Gastrointestinal Disorders
Diarrhoea	11.89	1.14
Vomiting	7.43	1.9
Nausea	4.03.9	1.39
Abdominal pain	0.1	0.0
Skin and Subcutaneous Tissue Disorders
Rash	6.43	0.91.4
Musculoskeletal and Connective Tissue Disorders
Myalgia	3.10	3.27.1
General Disorders and Administration Site Conditions
Pyrexia	28.95	11.310.4
Influenza like illness	11.210.9	3.02.9
Irritability	11.010.9	1.19
Fatigue	3.5	2.23.5
Injection site redness	9.710.0	4.1
Injection site pain	6.31	12.214.1
Injection site tenderness	4.2	8.914.7
Injection site swelling	3.6	2.62
Injection site hardening	1.02	1.59
Injection site itching	0.6	1.16
Investigations
Hepatic enzymes increased	0.5	0.2

Under subsection - Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: medsafety@hpra.ie.Healthcare professionals are asked to report any suspected adverse reactions to the Pharmacovigilance Section at the Irish Medicines Board at www.imb.ie.

Section 5.1: Update for clinical trial results, the immunogenicity and safety information. See below:

Subsection Clinical efficacy and safety updated following new studies:

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 fourfive uncontrolled Phase 3 trials and in approximately 550 healthy children included in onetwo randomized, controlled and onetwo uncontrolled Phase 3 clinical trialtrials.

 

Information added for antibody persistence after booster immunisation (adults):

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.

Information updated regarding immunogenicity in elderly persons (≥65 years):

Immunogenicity in older adultselderly persons (≥65 years)

The immunogenicity of IXIARO was evaluated in an open-label, uncontrolled trial in 200 healthy older adultselderly 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). Older adultsElderly 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).

Information added for antibody persistence and booster dose in children and adolescents from a JEV-endemic country:

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.

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

Information updatd for immunogenicity and safety in children and adolescents from non-endemic countries:
 

 

Immunogenicity and Safetysafety in Childrenchildren and adolescents from non-endemic countries 

The safety and immunogenicity of IXIARO was evaluated in an interim analysis of an ongoing, 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. An interim analysis was carried out on immunogenicityImmunogenicity data for 54were evaluated in 64 subjects. The SCRs and GMTs are displayed in Table 1112.

Table 1112:     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% 46/4657/57	332.1 340.7	251.2; 439.0269.8; 430.3
		Month 7	100% 16/16 90.6% 29/32	84.0 57.1	56.3; 12538.4; 84.9

Information added for antibody persistence in children and adolescents from non-endemic countries:

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)

Section 9: Date of latest renewal entered

Date of latest renewal: 28 February 2014

Ixiaro 2015 June changes

4.2

 referal to ‘conventional’ schedule

Inclusion of rapid schedule for 18-65 years

Booster dose

‘As with many vaccines, the immune response in older persons (≥ 65 years of age) to IXIARO is lower than in younger adults. Duration of protection is uncertain in older persons, therefore a booster dose (third dose) should be considered before any further exposure to JE virus.’

Administration

‘When IXIARO is administered concomitantly with injectable vaccines, they should be given with separate syringes at opposite sites.’

4.4 Changes to include rapid schedule

‘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.’

4.5 Changes: re comcomitant use and the different schedules

‘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’ ‘The safety profiles of IXIARO and the other studied vaccines were not compromised when administered concomitantly’

4.8  Data Changes due to updated trial data

‘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 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%).’

Undesirable effects: syntax and/or reclassification additions

Syntax-Elderly to older - ‘Adult and older adults (≥65 years) population’

‘ dysgeusia’

‘Eye disorders Rare: eyelid oedema’

‘hyperhidrosis’

Arthralagia change from ‘rare’ to ’uncommon’

 ‘Fatigue’ moved from ‘common’ to ‘very common’: injection site tenderness,

Uncommon: ‘asthenia’

 

4.8 Reporting adverse reactions updated;

Reporting of suspected adverse reactions

‘Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the Pharmacovigilance Section at the Irish Medicines Board at www.imb.ie’

 

4.9       Overdose-syntax

‘No symptoms related to overdose were reported’

5.1          Trial data updates

‘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 four uncontrolled Phase 3 trials and in approximately 550 healthy children included in one randomized, controlled and one uncontrolled Phase 3 clinical trial.’

Table renumbering

New Table 5 and syntax inclusion re Rapid immunisation schedule

Inclusion of ’ Concomitant administration of IXIARO with inactivated hepatitis A virus (HAV) vaccine (HAVRIX 1440)’

Inclusion of  data re concomitant use with Rabipur ‘Concomitant administration of IXIARO with inactivated rabies vaccine (Rabipur):’

New Table 8 and 9

10 Date of Revision 15th June 2015

 

4.1     Therapeutic indications - addition of paediatric indication

 

IXIARO is indicated for active immunisation against Japanese Encephalitis in adults, adolescents, children and infants aged 2 months and older.

4.2     Posology and method of administration - paediatric dosing added

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.

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.

 

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.

 

Booster dose (children and adolescents)

Data on the timing of, and response to, a booster dose in children and adolescents (<18 years of age) are not available.

None provided