2.1 Dosage and Schedule

Primary Series:
Children 2 months to <3 years of age: Primary immunization with IXIARO consists of two (2) 0.25 mL doses, administered 28 days apart.
Individuals 3 years of age and older: Primary immunization with IXIARO consists of two (2) 0.5 mL doses, administered 28 days apart.
Complete the primary immunization series at least 1 week prior to potential exposure to JEV.

Booster Dose:
Individuals 17 years of age and older: If the primary series of two doses was completed more than 1 year previously, a booster dose may be given if ongoing exposure or re-exposure to JEV is expected.
Infants, children and adolescents 2 months to <17 years of age: The safety and immunogenicity of a booster dose has not been evaluated.

2.2 Administration

IXIARO is administered intramuscularly. The preferred sites for intramuscular injection are the anterolateral aspect of the thigh in infants 2 to 11 months of age, the anterolateral aspect of the thigh (or the deltoid muscle if muscle mass is adequate) in children 1 to <3 years of age, or the deltoid muscle in individuals 3 years of age and older.
Do not administer intravenously, intradermally, or subcutaneously.

2.3 Preparation for Administration

Prior to agitation, IXIARO is a clear liquid with a white precipitate. Before administration, shake the syringe well to obtain a white, opaque, homogeneous suspension.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If either of these conditions exists, do not administer.
Preparation of a 0.25 mL Dose of IXIARO for Administration to Children 2 Months to <3 Years of Age:
1. Shake the pre-filled syringe containing 0.5 mL 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 sterile safety needle to the pre-filled syringe (needle is not provided with IXIARO).
4. Hold the syringe in an upright position and uncap the needle.
5. Push the plunger stopper up to the edge of the red line on the syringe barrel, indicated by a red arrow (see Figure1)*, and discard expelled volume into a medical waste container.
6. Lock the needle safety shield and remove the needle.
7. Attach a new sterile needle prior to injection of the remaining volume.
*If the plunger stopper is pushed beyond the red line, do not administer the vaccine. Repeat the procedure using a new pre-filled syringe.

Preparation of a 0.5 mL Dose of IXIARO for Administration to Individuals 3 Years of Age and Above:
1. Shake the pre-filled syringe containing 0.5 mL 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 sterile needle to the pre-filled syringe (needle is not provided with IXIARO).

5.1 Hypersensitivity Reactions

IXIARO contains protamine sulfate, a compound known to cause hypersensitivity reactions in some individuals [See Description (11)].

Appropriate medical care should be readily available in case of anaphylactic reaction.

5.2 Limitations of Vaccine Effectiveness

Vaccination with IXIARO may not protect all individuals.

5.3 Altered Immunocompetence

Immunocompromised individuals may have a diminished immune response to IXIARO.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice.

Clinical Studies in Children 2 Months to <18 Years of Age:

Adverse Events in a Pediatric Trial Comparing IXIARO to U.S.-Licensed Control Vaccines HAVRIX and PREVNAR:

The safety of IXIARO was evaluated in a randomized, controlled, open-label clinical trial in healthy male and female subjects 2 months to <18 years of age, conducted in the Philippines, a country where Japanese Encephalitis is endemic (Study 1)1. IXIARO was compared to two control vaccines: HAVRIX (Hepatitis A vaccine, pediatric 720 EL.U./0.5 mL formulation, GlaxoSmithKline Biologicals) and Prevnar (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM197 protein], Pfizer). A total of 1,769 subjects were randomized in an age-stratified scheme in a 3:1 ratio (2:1 ratio for ages <1 year) to receive intramuscular injections of either IXIARO (two 0.25 mL doses on Days 0 and 28 for infants and children 2 months to <3 years of age or two 0.5 mL doses on Days 0 and 28 for children 3 to <18 years of age) or HAVRIX (children 1 year of age and older, 2 doses on Day 0 and at Month 7) or Prevnar (infants 2 to <6 months of age, 3 doses on Days 0, 28, 56 and an optional 4th dose at Month 7 or later; infants 6 to <12 months of age, 3 doses on Days 0 and 56 and at Month 7). Subject numbers and dosing schemes by age group are displayed in Table 1.

Table 1. Subject Numbers and Dosing Schemes by Age Group (Safety Population, Study 1§,Philippines)

§NCT01041573

*Infants and children 2 months to <3 years of age received two 0.25 mL doses administered on Days 0 and 28. Individuals 3 years of age and older received two 0.5 mL doses administered on Days 0 and 28.

Analysis of safety in children was carried out using the safety population including 1,311 subjects receiving at least one dose of IXIARO, 394 subjects receiving the first dose of HAVRIX on Day 0, and 64 subjects receiving at least one dose of Prevnar on Day 0 (all infants <1 year of age). The IXIARO and control groups were similar with regard to demographics (mean age 5.48 years, range 2 months to 17 years; 49.5% female; ethnicity: Asian: 100% for Study 1 overall). Parents or subjects recorded adverse events on a diary card for the first seven days after each vaccination.  Only those events considered to be assessable based on the subjects developmental status were recorded. Parents or subjects were queried regarding the occurrence of any unsolicited AEs following the previous vaccination at in-person visits, which included a medical exam, on Day 28, Day 56, and at Month 7.

Solicited Adverse Events

For an overview of solicited local and systemic reactions for pediatric age groups see Table 2 (infants 2 months to <1 year of age), Table 3 (toddlers 1 to <3 years of age) Table 4 (children 3 to <12 years of age), and Table 5 (adolescents 12 to <18 years of age).  As children 1 year of age and older received the second dose of HAVRIX at the final study visit at Month 7, rates of solicited AEs among these subjects after the second vaccination are only available for IXIARO.

Table 2.Rates of Solicited Adverse Reactions on Days 0-7 After Each Vaccination in Infants 2 Months to <1 Year of Age, by Dose and Treatment Group, Study 1§,Philippines

§NCT01041573

*IXIARO dose 0.25 mL.

‡N=number of subjects with available diary card data after each dose, used as the denominator to calculate percentages.

Table 3. Rates of Solicited Adverse Reactions on Days 0-7 After Each Vaccination in Children 1 Year to <3 Years of Age, by Dose and Treatment Group, Study 1§,Philippines

§NCT01041573
*IXIARO dose 0.25 mL.
‡N=number of subjects with available diary card data after each dose, used as the denominator to calculate percentages
** Where the number of subjects with available data for a particular symptom differed from the overall number of subjects with available diary card data, the rate (n/N) is provided; n is the number of subjects who reported that symptom, and N is the number of subjects with available data for that symptom.

Table 4. Rates of Solicited Adverse Reactions on Days 0-7 After Each Vaccination in Children 3 Years to <12 Years of Age, by Dose and Treatment Group, Study 1§,Philippines

§NCT01041573
*IXIARO dose 0.5 mL.
‡N=range of subjects with available diary card data after each dose, used as denominators to calculate percentages.

Table 5. Rates of Solicited Adverse Reactions on Days 0-7 After Each Vaccination in Children 12 Years to <18 Years of Age, by Dose and Treatment Group, Study 1§, Philippines

§NCT01041573
*IXIARO dose 0.5 mL.
‡N=number of subjects with available diary card data after each dose, used as the denominator to calculate percentages.

Serious Adverse Events

There was one death due to disseminated intravascular coagulation following suspected bacterial meningitis in a 12 year old male 4 months after the second dose of IXIARO. Forty serious adverse events (SAEs) were reported during the 7 month study period. Twenty-three subjects (1.6%) who received IXIARO, 1 subject (1.6%) who received Prevnar and 10 subjects (2.5%) who received HAVRIX experienced an SAE. Some subjects experienced more than one SAE.

The SAEs occurring most frequently in all study groups were febrile convulsions. A total of 12 febrile convulsions were reported (9 of them as SAEs), in 8 subjects (1.0% of children below the age of 3 years) receiving IXIARO, 3 subjects (1.4% of children below the age of 3 years) receiving HAVRIX and 1 subject (1.6%) receiving Prevnar. All febrile convulsions occurred in children below the age of 3 years. Onset of febrile convulsions ranged from 2 days to >5 months after doses of IXIARO with no apparent temporal clustering, 4 weeks after Prevnar and 9 days to >16 weeks after HAVRIX.

Adverse Events in a Pediatric Trial2 of IXIARO in Children Traveling from Western Countries:

The safety of IXIARO was evaluated in an ongoing, uncontrolled, open-label clinical trial conducted in the United States, Europe and Australiain healthy children with planned travel to JEV-endemic areas (Study 2)2. IXIARO (0.25 mL dose for children 2 months to <3 years of age, 0.5 mL dose for children and adolescents 3 to <18 years of age) was administered by intramuscular injection on Day 0 and Day 28. An analysis of safety was carried out after enrolment of 60 subjects (mean age: 12.50 years, range 10 months to 17 years; 56.7% female; ethnicity: White: 83.3%, Asian: 13.3%, Black: 3.3%). Parents or subjects recorded adverse events on a diary card for the first seven days after each vaccination. Only those events considered to be assessable based on the subjects developmental status were recorded. Parents or subjects were queried about the occurrence of unsolicited AEs through 6 months after the last vaccination (Month 7).

At the time of the analysis, 40% (2/5) subjects 2 months to <3 years of age experienced injection site hardening, injection site redness, and diarrhea following the first or second dose of IXIARO. Solicited adverse reactions among subjects 3 to <18 years of age are summarized in Table 6.

Table 6. Rates of Solicited Adverse Reactions on Days 0-7 After Each IXIARO 0.5 mL Vaccination in Children 3 Years to <18 Years of Age Traveling From Western Countries, Study 2§

§NCT01047839
‡N=number of subjects with available diary card data after each dose, used as the denominator to calculate percentages.

Clinical Studies in Adults 18 Years of Age and Older:

In five randomized, controlled clinical studies4, 5, 6, 7, 8 conducted in North America, Europe, Australia and New Zealand, a total of 3,558 healthy adults 18 to 86 years of age received at least one dose of IXIARO and were followed-up for safety for 6 months after the first dose. In this pooled dataset of subjects who received IXIARO, one death occurred in a subject with metastatic lung adenocarcinoma four months after completing the two-dose regimen. About 1% of subjects who received IXIARO experienced a serious adverse event, including one case of multiple sclerosis. Approximately 1% of subjects who received IXIARO discontinued due to adverse events.

Adverse Events in a Clinical Trial Comparing IXIARO to a Control in Adults:

The safety of IXIARO was evaluated in a randomized, controlled, double‑blind clinical trial in healthy male and female subjects 18 years of age (Study 4)4. IXIARO was compared to a control: Phosphate Buffered Saline containing 0.1% aluminum hydroxide [PBS + Al(OH)3]. A total of 2,675 subjects were randomized in a 3:1 ratio to receive either an intramuscular injection of IXIARO (0.5 mL) each on Day 0 and Day 28, or an intramuscular injection of PBS + Al(OH)3 (0.5 mL) each on Day 0 and Day 28. Analysis of safety was carried out using the safety population including 1,993 subjects receiving at least one dose of IXIARO and 657 subjects receiving at least one dose of PBS + Al(OH)3 (mean age: 33.8 years, range 18 to 86 years; 55.3% female; ethnicity: White: 91.7%, Asian: 1.8%, Black: 3.4%, Other: 3.0%). The IXIARO and control groups were similar with regard to demographics. Subjects recorded adverse events on a diary card for the first seven days after each vaccination. In addition, the study investigator took a medical history and performed a physical exam to evaluate for adverse events on the day of each vaccination and at a visit 4 weeks after the second vaccination.

Serious Adverse Events

No deaths occurred during this trial. Sixteen serious adverse events (SAE) were reported during the study period. Ten subjects (0.5%) who received IXIARO and 6 subjects (0.9%) who received PBS + Al(OH)3 experienced a SAE. The serious adverse events occurring in the IXIARO group were as follows: Dermatomyositis, appendicitis, rectal hemorrhage, limb abscess (contralateral to the injected arm), chest pain, ovarian torsion, ruptured corpus luteal cyst, and three orthopedic injuries.

Systemic Adverse Events

Overall, the percentage of subjects who experienced at least one adverse event during the study period was 58.9% in the IXIARO group compared to 56.6% in the PBS + Al(OH)3 group. Adverse events of any severity grade occurring with an incidence of 1% of subjects are shown in Table 7. Most adverse events (>90%) were mild to moderate.

Table 7. Rates of Common Solicited and Unsolicited Systemic Adverse Events* in Adults Residing in Non-Endemic Areas After IXIARO or Control [PBS + Al(OH)3], Safety Population, Study 4§

§NCT00605085
*The adverse events in this table are those observed at an incidence of ≥1% in the IXIARO or PBS + Al(OH)3 groups.
† These symptoms were solicited in a subject diary card. Percentages also include unsolicited events that occurred after the 7 day period covered by the diary card.
‡N=number of subjects in the safety population (subjects treated with at least one dose) who received the respective dose

Injection Site Reactions

Injection site reactions after IXIARO were compared to reactions after PBS + Al(OH)3. Symptoms were recorded into a subject diary for the first seven days after each injection, and the injection site was assessed by the investigator at each visit. The rates of injection site reactions are shown in Table 8. Most injection site reactions (>90%) were mild to moderate. 

Table 8. Rates of Injection Site Solicited Adverse Reactions* After IXIARO or Control [PBS + Al(OH)3], Adults Residing in Non-Endemic Areas, Safety Population With Evaluable Diary Cards, Study 4§

§NCT00605085
* Injection site reactions were assessed for 7 days after each dose.
† Denominators used to calculate percentages are based on the number of evaluable diary card entries (defined as documented presence on any day [i.e., entry of “yes”] or absence on all days [i.e., entry of “no”]) for each individual symptom and observation period.
‡N=number of subjects who returned diary cards after each dose

Adverse Events in a Clinical Trial Comparing IXIARO to JE-VAX in Adults:

The safety of IXIARO compared to another U.S.-licensed inactivated JE vaccine (JE-VAX) was evaluated in a randomized, double-blind clinical trial in subjects 18 years of age (Study 5)5.

No deaths occurred during this trial. One serious adverse event occurred in this trial in a subject with a history of myocardial infarction (MI) who experienced a MI three weeks after receiving the 2nd dose of IXIARO. The most common adverse events after immunization occurring in 1% of subjects were headache, myalgia, fatigue, influenza-like illness, nausea, nasopharyngitis, fever, pharyngolaryngeal pain, cough, rash, diarrhea, sinusitis, upper respiratory tract infection, back pain, migraine, vomiting and influenza, which occurred with similar frequency in both treatment groups. Local injection site reactions solicited in diary cards for 7 days after each vaccination were observed at a rate of 54% in the IXIARO group (N=428) compared to a rate of 69.1% in the JE-VAX group (N=435).

Adverse Events in a Clinical Trial Investigating a Booster Dose of IXIARO in Adults:

The safety of a booster dose of IXIARO administered 14 months after completion of the primary series was evaluated in an open-label, uncontrolled study in subjects 18 years of age (Study 9)9.

Within 28 days of booster vaccination, adverse events were reported by 35.4% of subjects (N=198). Within 12 months of booster vaccination, subjects who experienced at least one adverse event were 56.1%. Injection site reactions were reported in the subject diary for 30.8% of subjects within 7 days of booster vaccination. Adverse events considered by the investigators to be treatment-related were recorded for 11.6% of subjects (these related events were all observed within one month after the booster dose administration).

The most common injection site reactions (>10% of subjects) were pain (12.8%) and tenderness (19.2%); the most common systemic adverse events (>10%) were nasopharyngitis (15.2%) and headache (11.1%).

Safety in Concomitant Use with the Hepatitis A Vaccine, HAVRIX in Adults (Study 7)7

The safety of IXIARO when administered concomitantly with inactivated Hepatitis A Virus vaccine (HAVRIX) was evaluated in a controlled trial in which subjects 18 years of age were assigned randomly to one of three treatment groups: Group A (N=62) received IXIARO + HAVRIX; Group B (N=65) received IXIARO + control [PBS + Al(OH)3]; Group C (N=65) received HAVRIX + control [PBS + Al(OH)3]. One serious adverse event occurred in this trial in a subject with a history of alcoholism and seizure disorder who experienced a seizure three weeks after receiving the 2nd dose of IXIARO + control.

The percentage of subjects who experienced at least one adverse event was as follows: Group A: 38.7%; Group B: 41.5%; Group C: 47.7%. The most frequently reported injection site reaction on the day of the first vaccination in all three groups was injection site pain in 59.0% of subjects in Group A, in 48.4% of subjects in Group B and in 48.4% of subjects in Group C.

6.2 Post-Marketing Experience

The following additional adverse reactions have been identified during post approval use of IXIARO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to the vaccine.
Nervous system disorders: Paraesthesia, Neuritis.

7.1 Use with HAVRIX

In one clinical trial7 in adults, IXIARO was administered concomitantly with HAVRIX (Hepatitis A Vaccine) [SeeAdverse Reactions (6) and Clinical Studies (14)]. In this trial, there was no evidence for interference with the immune response to IXIARO or to HAVRIX when HAVRIX was administered concomitantly with dose 1 of IXIARO [See Clinical Studies (14)]. Data are not available on concomitant administration of IXIARO with other US-licensed vaccines.

When IXIARO is administered concomitantly with injectable vaccines, they should be given with separate syringes at different injection sites. IXIARO should not be mixed with any other vaccine in the same syringe or vial. 

7.2 Use with Immunosuppressive Therapies

Immunosuppressive therapies may decrease the immune response to IXIARO [See Warnings and Precautions (5)].

8.1 Pregnancy

Pregnancy category B. Reproduction studies have been performed in female rats at doses approximately 300-fold excess relative to the projected human dose (on a mg/kg basis) and have revealed no evidence of impaired fertility or harm to the fetus due to IXIARO. There are, however, no adequate and well‑controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, IXIARO should be used during pregnancy only if clearly needed.

The effect of IXIARO vaccine on embryo-fetal and pre-weaning development was evaluated in a developmental toxicity study using pregnant rats. One group of rats was administered IXIARO twice prior to gestation and once during the period of organogenesis (gestation Day 6). A second group of pregnant rats was administered IXIARO once prior to gestation and once during the period of organogenesis (gestation Day 6). IXIARO was administered at 0.5 mL/rat/occasion (approximately 300-fold excess relative to the projected human dose on a mg/kg basis), by intramuscular injection. No adverse effects on mating, fertility, pregnancy, parturition, lactation, embryo-fetal or pre-weaning development were observed. There was a statistically significant finding of incomplete ossification in a few fetuses derived from the second group of pregnant rats. However, there are no data to suggest that this finding is vaccine related. There were no vaccine-related fetal malformations or other evidence of teratogenesis noted in this study.

Healthcare practitioners are encouraged to report inadvertent use in pregnant women to the distributor, Novartis Vaccines, at 1-877-683-4732.

8.3 Nursing Mothers

It is not known whether this vaccine is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised if IXIARO is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness of IXIARO have not been established in infants younger than 2 months of age [See Adverse Reactions (6)and Clinical Studies (14)].

8.5 Geriatric Use

Clinical studies of IXIARO did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects. In a study that included 24 subjects ≥65 years of age who received IXIARO per protocol (Study 5)5, the proportion of these subjects achieving a JEV neutralizing antibody titer ≥1:10 at 28 days after the second dose of IXIARO was 95.8% (geometric mean titer: 255.2).

In subjects 65 years of age and older who had been vaccinated in any of five trials4 ,5 ,6 ,7 ,8 included in a pooled dataset (N=161), adverse events were reported in 61.9% (73/118) of subjects in the IXIARO group, 57.7% (15/26) in the JE-VAX group, and 70.6% (12/17) in the control [PBS + Al(OH)3] group. Serious adverse events (SAE) were experienced by four subjects (3.4%) who received IXIARO, no subjects who received JE-VAX, and one subject (5.9%) who received the control [PBS + Al(OH)3]. The SAEs occurring in the IXIARO group were as follows: one case each of rectal hemorrhage, pancreatic adenocarcinoma, breast cancer, and one death in a subject with metastatic lung adenocarcinoma, which occurred four months after the subject completed the two-dose regimen.

12.1 Mechanism of Action

Japanese encephalitis is a disease caused by the mosquito-borne Japanese encephalitis virus (JEV). IXIARO acts by inducing antibodies that neutralize live JEV. Accumulated data from animal studies, clinical trials of other JE vaccines, and human epidemiological studies, suggest that a virus neutralizing antibody response, as measured in vitro in a 50% plaque-reduction neutralization antibody test (PRNT50) with a threshold titer of ≥1:10, provides evidence of protective immunity11, 12. The evaluation of vaccine effectiveness of IXIARO was therefore based on neutralizing antibody response using a threshold PRNT50 titer of ≥1:10. 

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

IXIARO has not been evaluated for carcinogenic or mutagenic potential. IXIARO was found to have no effect on fertility of female rats at intramuscular doses of up to 300‑fold excess relative to the projected human dose (on a mg/kg basis) administered prior to and after mating [See Use in Specific Populations (8.1)]. The effect of IXIARO on male fertility has not been evaluated.

16.1 How Supplied

IXIARO is supplied as a sterile 0.5 mL suspension in a pre filled syringe (Type I glass) with a plunger stopper (chlorobutyl elastomer) in a pack size of 1 single-dose syringe with or without a separate needle. See Section 2.3 for information on preparing a 0.25 mL dose for children 2 months to <3 years of age and a 0.5 mL dose for individuals 3 years of age and older. NDC 42515-001-01.

Neither the syringe nor the packaging materials are made with natural rubber latex.

16.2 Storage and Handling

Store in a refrigerator at 2° to 8° C (35° to 46° F).  Do not freeze.

Do not use the vaccine after the expiration date shown on the label. Store in the original package in order to protect from light. During storage, a clear liquid with a white precipitate can be observed.

Question the vaccine recipient about reactions to previous vaccines, and inform the vaccine recipient of the benefits and risks of IXIARO.
Consult current U.S. and international advisories regarding prevalence of Japanese encephalitis in specific locations. Advise the parent, guardian, or recipient that IXIARO may not fully protect everyone who gets the vaccine and that personal precautions should be taken to reduce exposure to mosquito bites (adequate clothing, use of repellents, mosquito nets).
Give the parent, guardian, or recipient the Vaccine Information Statements, which are required by the National Childhood Vaccine Injury Act of 1986 to be given prior to immunization, and inquire about previous reactions to vaccines.

Inform the parent, guardian, or recipient of the importance of completing the immunization series.

Instruct the parent, guardian, or recipient to immediately report any signs and/or symptoms of a severe adverse reaction, including anaphylaxis (difficulty breathing, wheezing, weakness or fast heart beat, hives).

Manufactured by:
Valneva Scotland Ltd.
Oakbank Park Road, EH53 0TG, Livingston, UK
T: +44.1506.446.600
F: +44.1506.446.601
www.valneva.com

Distributed by:
Novartis Vaccines and Diagnostics, Inc.
350 Massachusetts Avenue
Cambridge, Massachusetts 02139
USA
T: 1-877-683-4732

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-CARTON

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-SYRINGE LABEL