Ixiaro

Ixiaro

vaccine, japanese encephalitis

Manufacturer:

Valneva

Distributor:

Pharmaforte
Full Prescribing Info
Contents
Japanese encephalitis vaccine (inactivated, adsorbed).
Description
Each dose (0.5 mL) of Ixiaro contains: Japanese encephalitis virus strain SA14 -14-2 (inactivated)1,2 6 micrograms3 corresponding to a potency of ≤460 ng ED50.
1 produced in Vero cells
2 adsorbed on aluminum hydroxide, hydrated 0.25 milligrams Al 3+
3 total protein content
Excipients/Inactive Ingredients: Phosphate buffered saline consisting of: Sodium chloride, Potassium dihydrogen phosphate, Disodium hydrogen phosphate, Water for injections.
From the manufacturing process, IXIARO may also contain: Formaldehyde: not more than 200 ppm; Sucrose: not more than 3% (w/v); Bovine serum albumin; not more than 32 ng/mL; Sodium metabisulphite: not more than 200 ppm; Host cell DNA: not more than 200 pg/mL, Protamine sulfate: not more than 1 mcg/mL.
No preservatives, stabilizers or antibiotics are added to the formulation.
Action
Pharmacotherapeutic group: Encephalitis vaccines. ATC code: J07BA02.
Pharmacology: Pharmacodynamics: Mechanism of action: The mechanism of action of Japanese encephalitis (JE) vaccines is not well understood. Studies in animals have shown that the vaccine triggers the immune system to produce antibodies against Japanese encephalitis virus (JEV) that are most often protective. Challenge studies were performed in mice that were treated with human IXIARO antisera. These studies showed that almost all mice that had a Plaque Reduction Neutralization Test titre of at least 1:10 were protected from a lethal Japanese encephalitis virus challenge.
Clinical efficacy and safety: No prospective efficacy trials have been performed. Immunogenicity of IXIAROwas studied in approximately 2,480 healthy adult subjects included in six randomized, controlled and three uncontrolled Phase 3 trials and in approximately 550 children included in one randomized, controlled and one uncontrolled Phase 3 clinical trial.
Pivotal Immunogenicity Trial (Adults): Immunogenicity of the vaccine was evaluated in a randomized, active controlled, observer-blinded, multicenter Phase 3 clinical trial including 867 healthy male and female subjects given IXIARO or the US licensed JEV vaccine JE VAX (on a 0, 7 and 28-day schedule by SC injection). The co-primary endpoint was seroconversion rate (anti-JEV antibody titer ≥1:10) and geometric mean titers (GMT) at Day 56 as assessed by a Plaque Reduction neutralization Test (PRNT) for the entire study population.
By Day 56, the proportion of subjects who had seroconverted was similar for both treatment groups (96.4% vs 93.8% for IXIARO and JE VAX, respectively). GMT increased by Day 56 to 243.6 for IXIARO and to 102.0 for JE VAX, respectively. The immune responses elicited by IXIARO were non-inferior to those induced by JE VAX (see Table 1).

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The effect of age on the immune response to IXIARO and JE VAX was assessed as a secondary endpoint in this active-controlled study, comparing subjects over 50 years of age (N=262, mean age 59.8) with those below 50 years of age (N=605, mean age 33.9).
There was no significant difference between seroconversion rates of IXIARO and JE VAX in subjects aged <50 years compared to those aged ≥50 years at Day 28 or Day 56 following vaccination. Geometric mean titers were significantly higher at Day 28 in subjects <50 years than those aged ≥50 years in the JE VAX group (80.9 vs 45.9, p=0.0236) but there was no significant difference at Day 56 for this treatment group. There were no significant effects of age on geometric mean titer in the group receiving IXIARO. There was no significant difference between seroconversion rates in subjects aged <50 years compared to those aged ≥50 years at Day 28 or Day 56 for either treatment group.
Antibody persistence (adults): Antibody persistence was evaluated in an uncontrolled Phase 3 follow up clinical trial, enrolling subjects who had completed two pivotal studies, and who received at least one dose of IXIARO. Long-term immunogenicity of IXIARO was assessed in a subset of 181 subjects up to month 24 [Intent-to-treat (ITT) population] and in 152 subjects up to month 36 after the first IXIARO vaccination.
Rates of subjects with PRNT50 ≥1:10 and GMTs at months 2, 6, 12, 24 and 36 are summarized in Table 2 for the ITT population. (See Table 2.)

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In another open-label, follow-up Phase 3 study, the persistence of antibodies up to 24 months after primary vaccination was assessed. A total of 116 subjects who had received the recommended primary schedule of IXIARO were included in this follow-up study. Rates of subjects with PRNT50 ≥1:10 were 82.8% (95% CI: 74.9, 88.6, N=116) at Month 6 and 58.3% at month 12 (95% CI: 49.1, 66.9, N=115). At Month 24, 48.3% (95% CI: 39.4, 57.3, N=116) of subjects who completed the recommended primary immunization still had PRNT50 titers of ≥1:10. GMT in these subjects was 16.2 (95% CI: 13.8, 19.0) at Month 24.
Booster immunization (adults): In an uncontrolled, open-label phase 3 study a single 6 mcg booster dose of IXIARO was given at month 15 after primary immunization. All of the 198 subjects treated were included in the ITT and Safety populations. Rates of subjects with PRNT50 ≥1:10 and GMT over time are summarized in Table 3. (See Table 3.)

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Incomplete primary immunization (adults): The immunogenicity of booster doses was also assessed in the study investigating persistence of immunity following different primary immunization regimens (2x6 mcg: N=116, 1x12 mcg: N=116 or 1x6 mcg: N=117). A single 6 mcg booster dose was administered at 11 or 23 months after the first dose to subjects, which were determined to be seronegative (PRNT50 titers <1:10) at month 6 and/or month 12 after the primary immunization. Results indicate that the second injection of the primary immunization series can be given up to 11 months after the first dose. The immune responses to further doses at different time points after complete or incomplete primary immunization are shown in Table 4. (See Table 4.)

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Concomitant use (adults): The concomitant use of IXIARO with inactivated hepatitis A virus (HAV) vaccine (HAVRIX 1440) has been explored in one clinical trial. There was no interference with the immune response to the JE virus and HAV, respectively. Concomitant administration of IXIARO and inactivated hepatitis A vaccine was shown to be non-inferior to single vaccinations with regard to GMT of anti-JE virus neutralizing antibody and HAV antibody and for seroconversion rates of both antibody types (see Table 5).

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Paediatric population: In a phase 2 study in healthy Indian toddlers ≥1 to <3 years, 24 children were vaccinated with 0.25 mL of IXIARO (the licensed dose for this age group) and 24 children received the adult 0.5 ml dose. Data are limited but there were no differences in the safety profile between the 0.25 ml and the 0.5 ml dose in this age group.
Immunogenicity and Safety of IXIARO in children and adolescents from a JEV-endemic country: The safety and immunogenicity of IXIARO were evaluated in a randomized, controlled, open-label clinical trial conducted in the Philippines, where JEV is endemic. The safety profile of IXIARO was compared to control vaccines Havrix (hepatitis A vaccine, paediatric 720 EL.U/0.5 mL formulation) and Prevenar [Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM197 protein)].
The immunogenicity evaluation was performed in a subset of the study population and included the determination of the seroconversion rate (SCR), defined as JEV neutralizing antibody titer ≥1:10, the proportion of subjects achieving an at least four-fold increase in antibody titers and the geometric mean titer (GMT) at Day 56 and Month 7, by dose and by age group. The immune responses elicited by IXIARO are presented in Table 6. (See Table 6.)

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Safety and tolerability was evaluated in the entire study population. Parents or subjects recorded adverse events on a diary card for the first seven days after each vaccination. Parents or subjects were asked for any unsolicited AEs on the day of the second vaccination and at in-person visits including a medical exam 28 days (Day 56) and 6 months (month 7) after the second dose. The safety profile of IXIARO was comparable to that of Havrix or Prevenar.
Immunogenicity and Safety in Children 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 ≥3 to <18 years received two vaccine doses of 0.5 ml and children ≥2 months to <3 years received two vaccine doses of 0.25 ml on Day 0 and Day 28 by IM injection. An interim analysis was carried out on immunogenicity data for 54 subjects. The SCRs and GMTs are displayed in Table 7. (See Table 7.)

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Pharmacokinetics: Evaluation of pharmacokinetic properties is not required for vaccines.
Toxicology: Preclinical safety data: Nonclinical toxicity data are limited.
In a reproductive and pre-/post-natal toxicity study, no vaccine-related effects were detected on reproduction, foetal weight, survival and development of the offspring. However, incomplete ossification of parts of the skeleton was observed in the group receiving 2 doses, but not in the group receiving 3 doses. It is currently difficult to explain if this phenomenon is treatment related or not.
Indications/Uses
IXIARO is indicated for active immunization against Japanese encephalitis in adults, adolescents, children and infants aged 2 months and older.
IXIARO should be considered for use in individuals at risk of exposure through travel or in the course of their occupation.
Dosage/Direction for Use
Adults: The primary vaccination series consists of two separate doses of 0.5 ml each, according to the following schedule: First dose at Day 0.
Second Dose: 28 days after the first dose.
It is recommended that vacinees who received the first dose of IXIARO complete the primary 2-dose vaccination course with IXIARO.
If the primary immunization of two injections is not completed, full protection against the disease might not be achieved. There is data that a second injection given up to 11 months after the first dose results in high seroconversion rates (see Pharmacology: Pharmacodynamics under Actions).
Booster Dose (Adults): A booster dose (third dose) should be given within the second year (ie, 12-24 months) after the recommended primary immunization, prior to potential re-exposure to JEV. Persons at continuous risk for acquiring Japanese encephalitis (laboratory personnel or persons residing in endemic areas) should receive a booster dose at month 12 after primary immunization (see Pharmacology: Pharmacodynamics under Actions). Data on the need for further booster doses are not available.
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 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 Cautions for Usage.
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 children and adolescents (<18 years of age) are not available.
Method of Administration: The vaccine should be administered by intamuscular injection into the deltoid muscle. In infants, the anterolateral aspect of the thigh may be used as injection site. IXIARO should never be injected intravascularly.
Exceptionally, IXIARO can also be administered subcutaneously to patients with thrombocytopenia or bleeding disorders since bleeding may occur following an intramuscular administration. Subcutaneous administration could lead to a suboptimal response to the vaccine (see Precautions). However, it should be noted that there are no clinical efficacy data to support administration by the subcutaneous route.
Overdosage
No case of overdose has been reported.
Paediatric Population: No case of overdose has been reported in the paediatric population. Inadvertent administration of an 0.5 ml dose of IXIARO in children aged 1 to <3 years does not pose any safety concerns (see Pharmacology: Pharmacodynamics under Actions).
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description or to the residues protamine sulphate, formaldehyde, bovine serum albumin, host cell DNA, sodium metabisulphite, host cell protein.
Individuals who show hypersensitivity reactions after receiving the first dose of the vaccine should not be given the second dose.
Administration must be postponed in persons with acute severe febrile conditions.
Special 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.
Under no circumstances should IXIARO be administered intravascularly.
As with any other vaccine, vaccination with IXIARO may not result in protection in all cases. IXIARO will not protect against encephalitis caused by other microorganisms.
Like other intramuscular injections, this vaccine should not be administered intramuscularly to persons with thrombocytopenia, haemophilia or other bleeding disorders (see Dosage & Administration).
In adults, a seroconversion rate of 29.4% has been observed 10 days after the first vaccination, and 97.3% one week after the second vaccination. Hence, primary immunization should be completed at least one week prior to potential exposure to Japanese encephalitis virus.
Protection against Japanese encephalitis is not ensured until the second dose has been received.
Effects on the ability to drive or use machines: Ixiaro has no or negligible influence on the ability to drive and use machines.
Pregnancy: There are limited amount of data from the use of IXIARO in pregnant women.
In animal studies findings of unclear clinical relevance have been identified (see Pharmacology: Toxicology under Actions).
As a precautionary measure, the use of IXIARO during pregnancy should be avoided.
Breast-feeding: It is unknown whether IXIARO is excreted in human milk.
No effects on the breastfed newborn/infant are anticipated since the systemic exposure of the breast-feeding woman to IXIARO is negligible. However, in the absence of data and as a precautionary measure the use of IXIARO during lactation should be avoided.
Fertility: A study in rats did not indicate vaccine-related effects on female reproduction, foetal weight, survival and development of the off-spring.
Adverse Reactions
The safety of Ixiaro was assessed in controlled and uncontrolled clinical studies in 4,248 healthy adults (from non-endemic countries) and 1371 children and adolescents (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.
Most commonly reported adverse reactions included headache and myalgia occurring in approximately 20% and 13% of subjects, respectively.
Adverse reactions are listed according to the following frequencies: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1000 to <1/100); Rare (≥1/10,000 to <1/1000).
Adult and Elderly Subjects: Blood and lymphatic system disorders: Uncommon: lymphadenopathy. Rare: Thrombocytopenia.
Nervous system disorders: Very Common: headache. Uncommon: migraine, dizziness. Rare: paraesthesia, neuritis.
Ear and labyrinth disorders: Uncommon: Vertigo.
Cardiac disorders: Rare: palpitations, tachycardia.
Respiratory, thoracic and mediastinal disorders: Rare: dyspnoea.
Gastrointestinal disorders: Common: nausea. Uncommon: vomiting, diarrhoea, abdominal pain.
Skin and subcutaneous tissue disorders: Uncommon: rash, pruritus. Rare: urticaria, erythema.
Musculoskeletal and connective tissue disorders: Very Common: myalgia. Uncommon: musculoskeletal stiffness. Rare: pain in extremity, arthralgia.
General disorders and administration site conditions: Very Common: injection site pain, tenderness. Common: fatigue, influenza-like illness, pyrexia; injection site reactions eg, redness, hardening, swelling, itching. Uncommon: chills, malaise, injection site haematoma. Rare: oedema peripheral.
Investigations: Uncommon: hepatic enzymes increased.
Children and adolescents: See table 8.

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Drug Interactions
Concomitant administration of IXIARO with inactivated hepatitis A vaccine has been evaluated in one clinical study. There was no interference with the immune response to Japanese encephalitis virus (JEV) and hepatitis A virus (HAV) vaccines, respectively. Concomitant administration of IXIARO and hepatitis A vaccine was shown to be non-inferior to single vaccinations with regard to geometric mean titres (GMT) of anti-JEV neutralizing antibody and HAV antibody, and for seroconversion rates (see Pharmacology: Pharmacodynamics under Actions).
There were no statistically significant higher rates in systemic or injection site adverse reactions among subjects who received concomitant vaccination with Ixiaro and HAV compared with those who received Ixiaro or HAV alone.
It is recommended to use the contralateral site if IXIARO is co-administered with another vaccine.
In patients receiving immunosuppressive therapy or patients with immunodeficiency an adequate immune response may not be obtained.
Paediatric population: No interaction studies have been performed in children and adolescents.
Caution For Usage
Special precautions for disposal and other handling: The pre-filled syringe is for single use only and should not be used for more than 1 person. The pre-filled syringe is ready to use. If a needle is not provided, use a sterile needle.
Do not use if the blister foil is not intact or packaging is damaged.
Upon storage, a fine white deposit with a clear colourless supernatant can be observed.
Before administration, shake the syringe well to obtain a white, opaque, homogeneous suspension. Do not administer if particulate matter remains following shaking or if discoloration is observed or if the syringe appears to be physically damaged.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Information on the administration of a 0.5 ml dose of IXIARO for persons 3 years of age and above: For administration of the full 0.5 ml dose follow the steps as follows: 1. Shake the syringe to obtain a homogeneous suspension.
2. Remove the syringe tip cap by gently twisting it. Do not attempt to snap or pull the tip off as this may damage the syringe.
3. Attach a needle to the pre-filled syringe.
Information on the preparation of a 0.25 ml dose of IXIARO for use in children below 3 years of age: For administration of a 0.25 ml dose in children 2 months to <3 years, follow the steps as follows: 1. Shake the syringe to obtain a homogeneous suspension.
2. Remove the syringe tip cap by gently twisting it. Do not attempt to snap or pull the tip off as this may damage the syringe.
3. Attach a needle to the pre-filled syringe.
4. Hold the syringe in an upright position.
5. Push the plunger stopper up to the edge of the red line on the syringe barrel, to discard excess volume.
6. Attach a new sterile needle prior to injection of the remaining volume.
*If you pushed the plunger stopper beyond the red line, a 0.25 ml dose is not guaranteed and a new syringe should be used.
Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Storage
Store in a refrigerator (2°C-8°C).
Do not freeze.
Store in original package in order to protect from light.
Shelf-Life: 2 years.
ATC Classification
J07BA02 - encephalitis, Japanese, inactivated, whole virus ; Belongs to the class of encephalitis viral vaccines.
Presentation/Packing
Susp for inj 6 mcg/0.5 mL (pre-filled syringe; clear liquid with a white precipitate) x 1's.
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