Ixiaro Product Monograph

RECENT MAJOR LABEL CHANGES

Indication, Paediatrics March, 2018

Dosage and Administration March, 2018

Dosage forms, strenghts, composition and packaging March, 2018

Warnings and Precautions, Special Populations March, 2018

Special Handling Instructions March, 2018

TABLE OF CONTENTS

RECENT MAJOR LABEL CHANGES ...................................................................................... 2

TABLE OF CONTENTS ............................................................................................................... 3

PART I: HEALTH PROFESSIONAL INFORMATION .......................................................... 5

1 INDICATIONS ................................................................................................................... 5

1.1 Pediatrics .................................................................................................................... 5

2 CONTRAINDICATIONS ................................................................................................. 5

3 SERIOUS WARNINGS AND PRECAUTIONS BOX ................................................... 5

4 DOSAGE AND ADMINISTRATION .............................................................................. 6

4.1 Dosing Considerations ............................................................................................... 6

4.2 Recommended Dose and Dosage Adjustment ........................................................... 6

4.3 Administration ............................................................................................................ 7

4.4 Missed Dose ............................................................................................................... 7

5 OVERDOSAGE ................................................................................................................. 8

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ................ 8

7 WARNINGS AND PRECAUTIONS ................................................................................ 8

7.1 Special Populations .................................................................................................... 8

8 ADVERSE REACTIONS .................................................................................................. 9

8.1 Clinical Trial Adverse Reactions ............................................................................... 9

8.2 Serious Adverse Reactions reported in Clinical Trials ............................................ 12

8.3 Abnormal Hematologic and Clinical Chemistry Findings ....................................... 12

8.4 Serious Adverse Reactions reported in Clinical Trials ............................................ 13

8.5 Abnormal Hematologic and Clinical Chemistry Findings ....................................... 14

8.6 Post-Market Adverse Drug Reactions ...................................................................... 14

9 DRUG INTERACTIONS ................................................................................................ 14

9.1 Overview .................................................................................................................. 14

9.2 Drug-Drug Interactions ............................................................................................ 15

9.3 Drug-Food Interactions ............................................................................................ 15

9.4 Drug-Herb Interactions ............................................................................................ 15

9.5 Drug-Laboratory Interactions ................................................................................... 15

9.6 Drug-Lifestyle Interactions ...................................................................................... 15

10 ACTION AND CLINICAL PHARMACOLOGY ........................................................ 16

10.1 Mechanism of Action ........................................................................................... 16

10.2 Duration of effect .................................................................................................. 16

11 STORAGE, STABILITY AND DISPOSAL .................................................................. 20

12 SPECIAL HANDLING INSTRUCTIONS .................................................................... 20

PART II: SCIENTIFIC INFORMATION ................................................................................ 22

13 PHARMACEUTICAL INFORMATION ...................................................................... 22

14 CLINICAL TRIALS ........................................................................................................ 22

15 MICROBIOLOGY ........................................................................................................... 49

16 TOXICOLOGY ................................................................................................................ 51

PATIENT MEDICATION INFORMATION ........................................................................... 55

IXIARO*

Japanese encephalitis vaccine (inactivated, adsorbed)

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

IXIARO* is indicated for:

• active immunization against Japanese encephalitis for persons 2 months of age and older.

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

1.1 Pediatrics

Pediatrics (2 months of age and older): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of IXIARO* in pediatric patients has been established; therefore, Health Canada has authorized an indication for pediatric use. (see sections: Dosage and Administration as well as Special Handling Instructions)

2 CONTRAINDICATIONS

• Patients who are hypersensitive to this vaccine or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph.
• Individuals who show hypersensitivity reactions after receiving the first dose of the vaccine should not be given the second dose.
• As with other vaccines, vaccination with IXIARO* must be postponed in persons with acute severe febrile conditions.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

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.

• IXIARO* should under no circumstances be administered intravascularly.
• Like other intramuscular injections, this vaccine should not be administered intramuscularly to persons with thrombocytopenia, haemophilia or other bleeding disorders.

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Children from 2 months to < 3 years of age should receive 0.25 mL per single dose.

  See section Special Handling Instructions for instructions on preparing a 0.25 mL dose for children aged 2 months to <3 years.

• Children and adolescents from 3 years to <18 years of age should receive

0.5 mL per single dose.

• Adults (18 years and older) should receive 0.5 mL per single dose.

4.2 Recommended Dose and Dosage Adjustment

Adults (18 years of age and older)

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 vaccinees who received the first dose of IXIARO complete the primary 2-dose vaccination course with IXIARO.

In the event the primary series (Day 0 and Day 28) cannot be completed due to time constraints, , a rapid immunization schedule (i.e. first dose at Day 0 and second dose at Day 7) in persons aged 18-65 years may be used. For details see Part II – Scientific Information.

With both schedules, primary immunisation should be completed at least one week prior to potential exposure to Japanese encephalitis virus (JEV).

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.

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.

Please see Part I, section Duration of Effect.

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.

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

There are no data to support a rapid immunization schedule in children and adolescents (2 months to 17 years of age).

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.

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.

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.

4.3 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. It 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* may 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. However, it should be noted that there are no clinical efficacy data to support administration by the subcutaneous route.

Each pre-filled syringe is for single use only and should not be used for more than one individual. Inject the entire contents of the syringe.

4.4 Missed Dose

If the primary vaccination series of two injections is not completed, full protection against the disease might not be achieved. The missed dose should be replaced as soon as possible. There are data that showed that a second injection given up to 11 months after the first dose results in high seroconverion rates. For details see Part II – Scientific Information.

5 OVERDOSAGE

Few cases of overdose have been reported during post-marketing surveillance. None of them was associated with any specific or serious important clinical symptoms.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Dosage form

Suspension for injection.

Composition

A single dose (0.5 mL of sterile suspension) of IXIARO* contains purified, inactivated Japanese encephalitis virus (attenuated strain SA₁₄-14-2 produced in Vero cells) having a potency ≤ 460 ng ED₅₀ per 0.5 mL adsorbed on aluminum hydroxide, hydrated (0.25 mg Al/dose).

Nonmedicinal ingredients are:

Adjuvant: Aluminium hydroxide

Phosphate Buffered Saline: Sodium chloride, Potassium dihydrogen phosphate, Disodium hydrogen phosphate, Water for injection

Packaging

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

7 WARNINGS AND PRECAUTIONS

Please see the Serious Warnings and Precautions Box at the beginning of Part I:

Health Professional Information.

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.

7.1 Special Populations

Pregnant Women:

There is limited amount of data from the use of IXIARO* in pregnant women. In animal studies findings of unclear clinical relevance have been identified.

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

Nursing Women:

IXIARO* should be given to a nursing woman only if the benefit outweighs the theoretical risks to mother and child.

It is unknown whether IXIARO* is excreted in human milk.

Pediatrics (2 months < 18 years of age):

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

Geriatrics (≥ 65 years of age):

The safety and immunogenicity of IXIARO* was evaluated in elderly persons (≥65 years).

As with many vaccines, the immune response in elderly persons (≥ 65 years of age) to IXIARO* is lower (SCR 65%, GMT 37.4 at Day 70) 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.

IXIARO* is generally well tolerated in the elderly, and the safety profile is largely comparable with younger adults.

For details see Part II – Scientific Information.

Immunosuppressed Individuals:

In patients receiving immunosuppressive therapy or patients with immunodeficiency an adequate immune response may be diminished.

8 ADVERSE REACTIONS

8.1 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adults

The safety of the vaccine was assessed in a separate Pooled Safety Analysis of 10 different controlled and uncontrolled phase 3 clinical studies in 4,043 healthy adults aged 18 to 86 years who received at least one dose of IXIARO*(Results are shown in table 1 and 3). Further studies were conducted at a later time-point, adding another 978 subjects, resulting in a total subject number of 5.021 healthy adults. No further pooled analysis was performed including these additional subjects.

Non-study population: pregnant and nursing women, persons younger than 18 years, persons with any underlying disease.

Common Adverse Reactions from Clinical Trials after primary immunisation or booster doses

Most commonly reported adverse reactions in adults included headache (20% of subjects) myalgia (13%), fatigue (12.9%), injection site pain (33%), injection site tenderness (33%).

Table 1: Adverse Reactions occurring in ≥1% of subjects who received IXIARO*: Pooled Safety Analysis

Local Tolerability

Local tolerability (pain, itching, tenderness, hardening, swelling, redness) was documented in a subject diary for seven consecutive days after each vaccination (inclusively) in studies IC51-301, IC51-302, IC51-304, IC51-309 IC51-310 and IC51-314. Tenderness was not collected in subject diaries of clinical study IC51-304.

The frequency of local symptoms of any (mild, moderate, severe or missing) severity within days 0-6 after the vaccination at day 0, vaccination at day 28 and after any vaccination are presented in Table 2.

Table 2: Local tolerability after any vaccination by symptom (mild, moderate, severe or missing severity) within Days 0-6, Pooled Safety Analysis

n=diary periods with at least one diary day with symptom, N=diary periods with at least one non-missing diary entry for symptom, %=n/N

Less Common Adverse Reactions from Clinical Trials after primary immunisation or booster doses

Table 3: Adverse Reactions occurring in <1% of subjects, condensed after medical review: Pooled Safety Analysis

8.2 Serious Adverse Reactions reported in Clinical Trials

Two serious adverse events assessed as possibly related were reported in clinical trials in adults.

Table 4: Serious Adverse Events assessed as possibly or probably related to vaccination in or as follow-up to clinical trials completed and ongoing to date

^# Syndactyly of 2^nd and 3^rd toes, in infant of vaccinated subject

^## Delivery 8.5 months after vaccination. Estimated interval between last menstrual period and last IXIARO* vaccination was 5 weeks.

8.3 Abnormal Hematologic and Clinical Chemistry Findings

There were no safety concerns with regard to haematological parameters, clinical chemistry or urinalysis across studies. Increased hepatic enzymes occurred in <1% of subjects, there was no safety concern associated.

Children and Adolescents

The safety of the vaccine was assessed in controlled and uncontrolled clinical studies in 1,559 children and adolescents (mostly from endemic countries).

Common Adverse Reactions from Clinical Trials after primary immunisation or booster doses

Most commonly reported adverse reactions in children and adolescents included pyrexia, diarrhoea, influenza like illness irritability and injections site reactions (pain, tenderness, redness). The frequency of adverse reactions observed in children and adolescents is described as follows.

Table 5: 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 to <18 years of age)

8.4 Serious Adverse Reactions reported in Clinical Trials

Two serious adverse events assessed as possibly related were reported in clinical trials in children and adolescents.

Table 6: Serious Adverse Events assessed as possibly or probably related to vaccination in clinical trials completed in children and adolescents

8.5 Abnormal Hematologic and Clinical Chemistry Findings

There were no safety concerns with regard to haematological parameters, clinical chemistry or urinalysis across studies. Increased hepatic enzymes occurred in <1% of subjects, there was no safety concern associated.

8.6 Post-Market Adverse Drug Reactions

More than 2 million persons have been vaccinated with IXIARO since licensure. The number and kind of adverse reactions reported are those which may be expected for similar inactivated vaccines and are in general in congruence with safety information gained in clinical trials. No particular safety signals have been confirmed nor important risks identified to date.

Individual review of convulsion cases received since licensure has been made. Most of the reports of possibly vaccination induced seizures – in particular where syncope is explicitly reported or where onset is temporally close to vaccination – are what may best be described as ‘convulsive syncope’. As discussed by Bergfeldt and others, causation is mostly by vasovagal mechanisms, hence it is strictly speaking not ingredient related, but rather administration related.

9 DRUG INTERACTIONS

9.1 Overview

Not applicable.

Use with other vaccines:

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 JEV and 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.

There were no statistically significant higher rates in systemic or local tolerability symptoms among subjects who received concomitant vaccination with IXIARO* and hepatitis A vaccine compared with those who received IXIARO* or hepatitis A vaccine alone.

The most frequently reported local tolerability symptom on the day of the first vaccination in all three groups was injection site pain in 59.0% of subjects receiving IXIARO* + HAVRIX, in

48.4% of subjects receiving IXIARO* + placebo vaccine and in 48.4% of subjects receiving HAVRIX + placebo vaccine. The second most frequent symptom was tenderness in 45.9%, 43.8% and 42.2% of subjects, respectively.

If co-administration with another vaccine is indicated, immunisation should be carried out on separate limbs.

In an observer-blind Phase 3 study, concomitant administration of IXIARO* and Rabipur (inactivated rabies vaccine) 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 7). There was also no interference with the immune response to Rabipur.

Table 7: 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

Vaccination schedules: IXIARO: Day 0/28, Rabipur: Day 0/7/28.

9.2 Drug-Drug Interactions

Interactions with other drugs have not been established.

9.3 Drug-Food Interactions

Interactions with food have not been established.

9.4 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.5 Drug-Laboratory Interactions

Interactions with laboratory tests have not been established.

9.6 Drug-Lifestyle Interactions

No studies on the effect of IXIARO* on the ability to drive or use machines have been performed.

10 ACTION AND CLINICAL PHARMACOLOGY

Disease Burden

Japanese Encephalitis is one of the most common viral encephalitis with over 70,000 cases reported worldwide annually, although the figure could be much higher due to the lack of proper surveillance systems in many Asian countries where the virus is endemic. JEV is a mosquito-borne flavivirus; humans are an accidental host and are not considered reservoirs for virus transmission. The majority of infections in humans are asymptomatic, and overt encephalitis occurs in only one out of every 50 to 1,000 individuals infected. JE disease has an associated mortality rate of 30-40%, and 50% of affected patients are left with permanent neuropsychiatric sequelae. Hence, although the relative mortality rate in a healthy population might be very low, due to the permanent neurological sequelae, the public health burden for the society is much higher.

Visitors to areas where JE is endemic or epidemic are at higher risk of being infected with JE compared to the local population. Incidence rates for JE disease in non-immunized Western troops have been observed to reach up to 2 per 10,000 individuals per week [5]. Sporadic cases of JE disease in travellers from Europe and North America are reported every year.

10.1 Mechanism of Action

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. These studies suggest that protection is mediated by antibodies raised against the vaccine.

10.2 Duration of effect

Antibody persistence was evaluated in an uncontrolled Phase 3 follow up clinical trial, enrolling subjects who had completed two pivotal trials, 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 (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 Month 2, 6, 12, 24 and 36 are summarized in Table 8.

Table 8: SCR and GMT at Month 2, 6, 12, 24 and 36 after vaccination with IXIARO* – results from a pivotal long-term immunogenicity study

In another open-label, follow-up Phase 3 study, antibody persistence up to 24 months after primary vaccination was assessed. The primary endpoint was the SCR at 24 months after the primary vaccination. A total of 116 subjects who had received the standard schedule of IXIARO* were included in the follow-up study. SCRs and GMTs at Month 24 are summarized in Table 9 for the ITT population.

Table 9: SCR and GMT at Month 6, 12 and 24 after vaccination with IXIARO* – results from a supporting long term persistence study

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 PRNT ₅₀≥1:10 and GMT over time are summarised in Table 10:

Table 10: 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)

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 (PRNT ₅₀≥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 (PRNT ₅₀≥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.

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

n.a. = not available

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).

Immunogenicity results

Primary endpoint was seroprotection rate 12 months after primary immunisation. Subjects were followed up for 3 years after the last vaccine dose.

SPR and GMTs at Month 12 (Visit 2): The SPR of the ITT Population was 89.5% (17 of 19 subjects with available immunogenicity data) and the GMT was 47.8 (95% CI [28.7; 79.8]). SPR and GMT were similar in the Per protocol population for 12 months (SPR: 93.8% and GMT: 57.2; 95% CI [33.9; 96.5]).

SPR and GMTs at Month 24 (Visit 3): The SPR for the ITT Population was 91.3% (21 of 23 subjects with available immunogenicity data) and the GMT was 75.4 (95% CI [45.9; 123.7]). SPR and GMT were again similar in the Per protocol population for 24 months (SPR: 93.8% and GMT: 76.3; 95% CI [42.1; 138.3]).

SPR and GMTs at Month 36 (Visit 4): The SPR for the ITT Population was 89.5% (17 of 19 subjects) and the GMT was 60.8 (95% CI [34.8; 106.1]). SPR and GMT were also similar in the Per protocol Population for 36 months (SPR: 92.9% and GMT: 69.4; 95% CI [36.7; 131.3]).

11 STORAGE, STABILITY AND DISPOSAL

Store in a refrigerator (2°C - 8°C). Do not freeze.

Store in the original package to protect from light.

Do not use after the expiry date shown on the label.

12 SPECIAL HANDLING INSTRUCTIONS

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

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

Do not use if the product appears discolored (i.e. off-white) or if the syringe is damaged.

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 discolored or if the syringe appears to be physically damaged.

Any unused 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. 1. Shake the syringe to obtain a homogeneous suspension.
2. 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. 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. 1. Shake the syringe to obtain a homogeneous suspension.
2. 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. 3. Attach a needle to the pre-filled syringe.
4. 4. Hold the syringe in an upright position.
5. 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. 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

* Registered Trademark

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Japanese encephalitis purified inactivated virus (JE-PIV)

Product Characteristics

IXIARO* is a purified and inactivated Japanese encephalitis virus (JEV) vaccine. The virus is grown in Vero cells, purified, inactivated, and then adsorbed on aluminium hydroxide. The final vaccine is in the form of a suspension in a pre-filled syringe. Each unit dose of IXIARO* contains inactivated JEV, strain SA₁₄-14-2 having a potency ≤ 460 ng ED₅₀ per 0.5 mL. The vaccine does not contain any preservative or antibiotic. The vaccine does not contain any preservative or antibiotic. The vaccine is stored at 2-8°C. After thorough agitation, IXIARO* is a white, cloudy suspension.

14 CLINICAL TRIALS

Study Demographics and Trial Design

Two pivotal and 15 supporting phase 3 clinical studies have been conducted to gather efficacy (immunogenicity) and safety data of IXIARO*.

Seroconversion

The analysis of clinical efficacy was done using a cutoff of a neutralizing antibody titre of ≥1:10, which was also used as a criterion for Seroconversion. Seroconversion or the threshold antibody level for protection is defined as a PRNT₅₀ titre ≥ 1:10, as recommended by the World Health Organization (WHO) consultation group and is widely used worldwide. Experiments done in mice also confirmed the above mentioned fact.The PRNT or Plaque neutralization assay, measures virus neutralizing antibody that correlates with protection. The virus neutralising antibody titre is expressed as the serum dilution giving a 50% plaque or virus reduction (PRNT₅₀) compared to 100% plaque formation in virus only control. All PRNT₅₀ results are expressed as reciprocal titres. GMT was defined as the geometric mean of PRNT₅₀ titres.

Pivotal Efficacy Study: IC51-301

Table 12: Trial Design and Demographics

Demographic characteristics and baseline laboratory values were similar between the groups and are presented for the safety population.

Overall, 80.8% of the subjects were Caucasian, 13.1% were African American, 5.3% were “Other” and 0.8% were Asian. Overall, 77.8% of the subjects had negative anti-flavivirus immune status at baseline; 12.4% of the subjects had received TBE vaccination within the last 10 years and 34.4% had received any vaccination within the last 3 years. Notably, a higher proportion of subjects with positive baseline anti-flavivirus status in Europe (60.7% of 201 subjects) compared with North America (7.7% of 662 subjects) were observed.

Results

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 at Day 56 were 243.6 for IXIARO* and 102.0 for JE-VAX, respectively. The immune response elicited by IXIARO* was non-inferior to those induced by JE-VAX

Table 13: SCR and GMT of IXIARO* and JE-VAX – Primary Endpoints

Risk difference estimate [95% CI]:Day 56: 1.05 [-1,33, 3.43]

Table 14: Immunogenicity Results of Study IC51-301 in Specific Indication – Secondary Endpoints

Table 15: Possibly or probably related Treatment Emergent Adverse Events:

Table 16: Subject Diary Local Tolerability One Day (Day 1) After Vaccination: Safety Population

Local tolerability symptoms were most common one day after vaccination, decreasing over time for both treatment groups.

Pivotal Safety Study: IC51-302

Table 17: Trial Design and Demographics

The two treatment groups were well matched for demographic characteristics. Brief narrative is presented for the safety population.

The most common race was Caucasian (91.7%) followed by African American (3.4%), Asian (1.8%), and Other (3.0%).

Results

Table 18: Results of Study IC51-302 in Specific Indication – Primary Endpoints

Table 19: Results of Study IC51-302 in Specific Indication – Secondary Endpoints

Table 20: Possibly or probably related Treatment Emergent Adverse Events (Total Study Period) – Safety Population

Table 21: Subject Diary Local Tolerability One Day (Day 1) After Vaccination – Safety Population

Local symptoms were most common on Day 0, decreasing over time for both treatment groups. For all symptoms the incidence on Day 1 after vaccination was slightly higher in the IXIARO* group for both vaccinations, with the exception of itching (0.8%) after vaccination 1 and 0.8% subjects after vaccination 2, hardening (2.8% after vaccination 1), swelling (1.2% after vaccination 1) and redness (3.3% after vaccination 1).

Supporting Study: IC51-303

Table 22: Trial Design and Demographics

Most of the subjects included were Caucasian (98.3% of subjects); other races were Black or African American (0.6%), Asian (0.0%) and Other (1.1%).

Results

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.

The first 298 subjects reaching Day 1 of study IC51-303 who were willing to participate in the immunogenicity part of the study were enrolled in the long-term immunogenicity study. Following the database lock for studies IC51-301 and IC51-302, subjects with negative plaque reduction neutralization assays (PRNT) or had received JE-VAX or placebo vaccine were discontinued.

Table 23: Results of Study IC51-303 in Specific Indication – Primary Endpoints

Table 24: Results of Study IC51-303 in Specific Indication – Secondary Endpoints

Supporting Study: IC51-304

Table 25: Trial Design and Demographics

The most common race was Caucasian (99.4% of subjects), followed by Asian (0.3%), and Black or African American (0.3%).

Results

Table 26: Results of Study IC51-304 in Specific Indication – Primary Endpoints

Table 27: Results of Study IC51-304 in Specific Indication – Secondary Endpoints

Supporting Study: IC51-305

Table 28: Trial Design and Demographics

The most common race was Caucasian (99.4% of subjects), followed by Asian (0.9%), and Black or African American (0.9%).

Results

Table 29: Results of Study IC51-305 in Specific Indication – Primary Endpoints

Table 30: Results of Study IC51-305 in Specific Indication – Secondary Endpoints

Supporting Study: IC51-311

Table 31: Trial Design and Demographics

The most common race was Caucasian (98% of subjects), followed by Other (1%), Asian (0.5%), and Black or African American (0.5%).

Results

Table 32: Results of Study IC51-311 in Specific Indication – Primary Endpoints

Table 33: Results of Study IC51-311 in Specific Indication – Secondary Endpoints

Supporting study IC51-311_FU2013

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 (PRNT ₅₀≥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 (PRNT ₅₀≥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.

Supporting Study: IC51-308

Table 34: Trial Design and Demographics

At least 95% of subjects in each group were Caucasian; other races were Oriental, Asian, Caucasian/Black/African American, and Hispanic, all occurring in 2 subjects or less in any treatment group.

Results

Table 35: Results of Study IC51-308 in Specific Indication – Primary Endpoints

Table 36: Results of Study IC51-308 in Specific Indication – Secondary Endpoints

Pooled Safety Analysis

Ten clinical trials (IC51-301, -302, -303, -304, -305, -308, -309, -310, -311 and -314) have been pooled for analysis of the safety and tolerability of IC51 during six months after the first vaccination.

Table 37: Overview of Treatment-Emergent Adverse Events

^# Data taken from two different pooled analyses

Supporting study V49_23 Rapid immunization

Results

Table 38: Trial Design and Demographics

The most common race was White (98%) followed by Asian Black and other (<1%).

Table 39: Immunogenicity Results of Study V49_23, Per Protocol Population – Secondary Endpoints

SCR=Seroconversion Rate (Rate of subjects with PRNT50≥1:10)

GMT=plaque reduction neutralization test

Supporting study IC51-315

Study IC51-315 was an open-label, uncontrolled, multicenter, Phase 4 study that investigated the safety and immunogenicity of IXIARO in elderly (≥ 65 years). Overall 200 subjects have been enrolled to receive 0.5 mL (6mcg) IXIARO at Day 0 and Day 28. Primary analysis (safety and immunogenicity) was done at day 70 post first dose. Only safety was assessed at month 7 post first dose.

Results:

The rate of subjects with serious or medically attended AEs up to Day 70 (primary endpoint) was 19.0% (38 subjects, 95% CI: 14.2 to 25.0) and none of which were assessed as related to IXIARO vaccination.

Immunogenicity results showed seroconversion (defined as reaching a PRNT50 titer of 1:10 or above) at day 70 in 65.0% of subjects (N=197) compared to 4.0% of subjects at Visit 1 (Day 0, N=200). The corresponding GMT at day 70 was 37.4, with a 95% CI of 29.2 to 47.8 and a range of 5.0 to 10856.0. GMT and SCR at Day 70 were comparable between subjects aged 65 to <75 years (N=173) and subjects aged ≥75 years (N=23), with GMTs of 32.7 and 42.2 and SCRs of 65.3% and 65.2%, respectively (p=n.s.).

Pediatric Studies

Pediatric Study IC51-322:

Results

Table 40: Trial Design and Demographics

¹ 0.25 mL vaccine containing 3 mcg per dose. The most common race were White (83%) followed by Asian (13%) and Black or African heritage (3%).

Table 41: Results of Study IC51-322 -Primary Endpoints

¹ To counteract recruitment challenges, the primary endpoint was changed during the study. After reduction of the number of immunogenicity samples, the primary objective was changed to focus on the assessment of safety.

Table 42: Immunogenicity Results of Study IC51-322, Intent-to-treat Population – Secondary Endpoints

Pediatric Study IC51-323:

Results

Table 43: Trial Design and Demographics

¹ 0.25 mL vaccine containing 3 mcg per dose

The subjects included in this trial were Asian (100%.

Table 44: Results of Study IC51-323 - Primary Endpoints

Table 45: Immunogenicity Results of Study IC51-323, Intent-to-treat Population – Secondary Endpoints

n.a. not applicable

◊Negative Pre-vaccination titers were imputed to 5

Pediatric Study IC51-325:

Results

Table 46: Trial Design and Demographics

The subjects included in this study were Asian (100%).

Table 47: Results of Study IC51-325 - Primary Endpoints

Table 48: Immunogenicity Results of Study IC51-325, Intent-to-treat Population– Secondary Endpoints

n.a.= not available

Comparative Bioavailability Studies

Not applicable.

15 MICROBIOLOGY

Detailed pharmacology

Non-clinical pharmacology data

Pharmacodynamic Summary

Primary pharmacodynamic studies performed with IXIARO* included immunogenicity studies in mice, rats and rabbits. Active protection following immunization, passive protection following injection of immune sera from Phase 2 and Phase 3 clinical studies, and cross protection to different strains of JEV (namely JEV Beijing and JEV KE-093) was demonstrated for IXIARO* in lethal challenge studies in mice. The efficacy was based on the number of mice surviving 21 days after the JEV challenge. A dose-dependent increase in neutralizing antibody titre (PRNT₅₀ assay) which correlated with protection was demonstrated for IXIARO* in each of these studies.

In several non-clinical studies, JE-VAX was used as a comparator. JE-VAX is a Japanese encephalitis (JE) vaccine produced by a Japanese company, BIKEN (Research Foundation for

Microbial Disease of Osaka University). The vaccine is manufactured using the virulent Nakayama-NIH virus strain, propagated in suckling mouse brains, purified and inactivated with formaldehyde. In addition to in vivo studies, cross-protection of IXIARO* and JE-VAX immune sera was evaluated in vitro using different JEV viruses in the PRNT (Plaque Reduction Neutralization Test) assay.

IXIARO* was immunogenic when administered by various routes in mice (s.c. and i.p. routes), rats (i.m.) and rabbits (i.m.). A dose-related increase in immunogenicity with IXIARO* could be clearly demonstrated.

The efficacy of IXIARO* was ascertained by challenge studies in mice, immunized twice, 2 weeks apart, with different concentrations of IXIARO* vaccine. This was followed by a challenge with a lethal dose of the wild-type JEV strain SA14.

The results demonstrated a dose-related increase in protection, i.e. immunization with higher doses of IXIARO* resulted in greater protection against lethal challenge.

In a second study, IXIARO* and JE-VAX were tested at various doses for protection in mice against challenge with a lethal dose of JEV strains SA14 and Beijing following a similar protocol as described above. IXIARO* was shown to protect mice in a dose dependent manner against both JEV strains. In addition, a. dose dependent relationship between vaccine dose and neutralizing antibody titre (PRNT₅₀) in both IXIARO* and JE-VAX treatment groups was observed.

Furthermore, comparison of GMT titres and survival demonstrates a direct relationship between the antibody titre and survival of mice. The overall conclusion of the described studies is that IXIARO* provided equal or better protection to mice against two JEV strains (SA14 and Beijing) than the currently licensed JEV vaccine, JE-VAX. IXIARO* doses of 0.6 to 36.4 mcg/kg bw provided 90% to 100% protection in mice against lethal challenge with JEV SA14. IXIARO* doses of 2.1 to 35.2 mcg/kg bw provided 90% to 100% protection in mice against lethal challenge with JEV Beijing.

The proposed dose for IXIARO* in humans is two injections of 6mcg each, and for an average adult of 60 kg body weight the comparative dose is 0.1mcg/kg body weight.

A passive immunization study was performed to test JEV antiserum obtained from human subjects vaccinated with IXIARO* or JE-VAX for the ability to confer protection against challenge with two wild-type JEV strains (SA14 or KE-093) in a JEV mouse model. Human sera were obtained from subjects who had taken part in clinical study IC51-301, a Phase 3 randomized, blinded non-inferiority study to compare the immunogenicity of IXIARO* against JE-VAX (see Clinical Trials section). IXIARO* immune sera were collected from study subjects vaccinated with two doses of 6 mcg/0.5 mL IXIARO*. Serum was pooled into four batches based on antibody titre: high (measured pooled titre: 214), medium (43), low (21) and negative (non-responders, imputed to titre of 5).

Intermediate titre from subjects vaccinated with the recommended schedule of 3 doses of JE-VAX served as a positive control (55) and negative titre serum from subjects never vaccinated with a JEV vaccine served as a negative control.

Mice were given 0.5 mL of test serum, pre-diluted to either 1:2 or 1:10, via i.p. injection, followed 17-18 hours later by a challenge with a lethal dose of either JEV strain SA14 or KE-093.

Serum from human subjects vaccinated with IXIARO* successfully protected mice against lethal challenge with two different JEV strains in the highest titre groups. The protection offered in the intermediate titre groups was somewhat lower with the heterologous KE-093 challenge as compared to the homologous SA14 challenge. In addition survival range and median survival data indicated that pre-treatment with serum from individuals vaccinated with IXIARO* also delayed the onset of disease in affected animals.

As overall conclusion, these pharmacodynamic studies demonstrate that:

1. 1. Antibodies are able to protect against JE infection i.e. protection is antibody based.
2. 2. Antibodies generated against IXIARO* vaccination protect mice equally against lethal challenge with JEV SA14 and KE-093 (genotype III and genotype I respectively).
3. 3. Protection against JEV correlates with the anti-JEV neutralizing antibody titre as measured by PRNT₅₀ assay.
4. 4. A protective threshold for neutralizing antibodies of 1:10 is confirmed for the validated PRNT assay done at Intercell.
5. 5. A PRNT titre of 1:10 is a reasonable cut-off for seroconversion.

16 TOXICOLOGY

Single dose and repeat dose toxicity studies, and local tolerance studies were not performed.

An extensive pre- and postnatal development study was performed with IXIARO* in rats which covered all stages of female reproduction.

Dosing was initiated with 6 mcg/0.5 mL IXIARO* either one or three weeks prior to mating, and continued every two weeks up to day 6 of gestation (i.e. either 2 or 3 intramuscular injections were administered in total). The rats were allowed to litter and followed together with the F1 generation for 21 days after birth for assessment of postnatal development and maternal behaviour.

Preliminary immunogenicity studies predicted that antibody levels would remain high up 42 days after the first injection. Therefore the animals were exposed both to the vaccine itself, as well as to antibodies generated against the vaccine, during the critical time periods likely to affect fertility, organogenesis, early to late embryo-foetal development, birth, maternal function, and also postnatal development. Furthermore, different levels of anti-JE virus antibodies were induced in the rats by two different IXIARO* treatment schedules prior to mating.

Table 49: Toxicology Studies Overview

There were no significant effects of treatment on the adult females (as measured by clinical signs, bodyweight or food consumption), or on the reproductive performance in terms of fertility, pregnancy outcome or post-natal care. There were no effects on F1 neonatal pup weight, survival or development as assessed by the physical and functional tests applied.

The only statistically significant finding in this study was an increased incidence of incomplete ossification on skeletal examination of fetuses in the Vaccine II group at day 20 of gestation. The mean incidences per litter per group attained statistical significance (p>0.05) for incomplete ossification of 4 or more skull bones and ischia in the Vaccine II fetuses (where the adult females received 2 injections). Paradoxically, incomplete ossification in the Vaccine I group (where the animals received 3 injections) was essentially similar to the Controls.

The relevance of these findings for the use of the IXIARO* vaccine in humans was investigated further by considering historical control data on the strain of rats used in this study. The results from the control group used in this study were comparable to historical control data obtained in this strain of rats.

In the Vaccine II group, the only parameter that was statistically different from the control group was the incomplete in utero ossification in some regions (particularly pelvis and skull) noted in some gestation day 20 fetuses. There were no other indications of in utero growth delays and no indication of any postnatal growth retardation. If this truly represented a delay in in utero growth, it would be expected that other parameters measured would also reflect this. Since this observed delay in ossification occurred in isolation and was not corroborated by other evidence of delayed development (such as lower foetal weights corrected for litter size) and was without consequence (based on the extensive postnatal evaluations conducted in this study up to day 21 after birth), it was not considered to be an adverse effect. Furthermore, since it occurred in the group given just two injections and not in the group given three injections and in the group with the lower antibody titre at the beginning of gestation and a similar titre at the end of gestation (when ossification occurs), it seems unlikely that it can be attributed to treatment with the vaccine. Therefore, this isolated instance of more fetuses with incomplete ossification of some regions of the skeleton in the Vaccine II group (2 injections) was considered to be a spurious event and without relevance to the use of the vaccine in humans.

In the pre- and postnatal development toxicity study performed in rats either two or three doses of 6 mcg/0.5 mL IXIARO* were administered by intramuscular injection at two-week intervals. The dose, route of administration and the immunization schedule used in these studies is comparable to the intended clinical use in humans of two intramuscular injections of 6 mcg / 0.5 mL given four weeks apart, which was used in the Phase 1, Phase 2 and Phase 3 clinical studies. This represents a very wide safety margin (i.e. a much higher dose in animals with respect to the human dose) in terms of dose per body weight and injection schedule.

In conclusion, the overall toxicology data demonstrate that IXIARO* is a safe and well tolerated vaccine. The findings concerning incomplete ossification in the pre- and postnatal development toxicity study could not be attributed to treatment with IXIARO* and were considered to be a spurious event although of unknown significance to the use of the vaccine in humans.

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