Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Suspension, Intramuscular [preservative free]:
Ixiaro: (0.5 mL) [latex free; contains albumin bovine, protamine sulfate, sodium metabisulfite]
Pharmacology
Mechanism of Action
This vaccine induces antibodies to neutralize the Japanese encephalitis virus. Antibody response is measured using a 50% plaque-reduction neutralization antibody test (PRNT50); a threshold of ≥1:10 is considered protective immunity.
Pharmacokinetics/Pharmacodynamics
Onset of Action
Protective immunity was observed in ≥95% of children and adults (<65 years of age) 28 days after the second vaccine dose.
Duration of Action
Protective immunity was observed in ~80% to 85% of adults 12 to 36 months after the initiation of the two-dose series. In 96% of adults, seroprotection was shown to last ≥6 years after a booster dose administered 15 months after the first dose of a two-dose primary series. In children, 100% were reported to be seroprotective up to 24 months after the booster dose; pharmacodynamic modeling suggest median duration of seroprotection of 9 years in children (CDC/ACIP [Hills 2019]).
Use: Labeled Indications
Japanese encephalitis prevention: Active immunization against Japanese encephalitis (JE) for persons ≥2 months of age.
The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for (CDC/ACIP [Hills 2019]):
- Persons moving to or frequently traveling to JE-endemic areas
- Persons spending ≥1 month in endemic areas
- Laboratory workers who may be exposed to the JE virus other than SA14-14-2 JE vaccine virus. For those working with SA14-14-2 JE virus, vaccination should be considered for those working with high concentrations or volumes or passaging virus. Note: Vaccination not required for workers handling routine clinical samples.
- Persons traveling for shorter periods of time (eg, <1 month) who are at increased risk for JE based on travel duration, season, location, activities, accommodations or those with uncertain travel itineraries should consider vaccination. Note: Not recommended for very low-risk travelers (eg, those traveling for shorter terms and only to urban areas or periods outside of the well-defined JE virus transmission season).
Contraindications
Severe allergic reaction to a previous dose of the vaccine, any other Japanese encephalitis virus vaccine, or any component of the vaccine, including protamine sulfate.
Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to a previous dose of the vaccine or to any component of the formulation; acute severe febrile conditions
Dosage and Administration
Dosing: Adult
Primary immunization: Adults ≤65 years: IM: 0.5 mL/dose; a total of 2 doses given on days 0 and 7 to 28. Series should be completed at least 1 week prior to potential exposure (CDC/ACIP [Hills 2019]).
Booster dose: IM: 0.5 mL/dose; given ≥1 year after completion of the primary immunization series if exposure to Japanese encephalitis is ongoing or expected (CDC/ACIP [Hills 2019]).
Note: If the second dose is missed, limited data from one clinical trial in adults demonstrated a 99% seroconversion rate when the second dose was administered 11 months after the initial dose (CDC/ACIP [Hills 2019]).
Dosing: Geriatric
Primary immunization: Adults >65 years: IM: 0.5 mL/dose; a total of 2 doses given on days 0 and 28. Series should be completed at least 1 week prior to potential exposure.
Booster dose: Refer to adult dosing.
Dosing: Pediatric
Primary immunization: Note: Series should be completed at least 1 week prior to potential exposure.
ACIP/CDC Recommendations (CDC/ACIP [Hills 2019]):
Infants 2 months to Children ≤35 months: IM: 0.25 mL/dose on days 0 and 28 for a total of 2 doses.
Children ≥3 years (36 months) and Adolescents ≤17 years: IM: 0.5 mL/dose on days 0 and 28 for a total of 2 doses.
Adolescents ≥18 years: IM: 0.5 mL/dose with dose 1 administered on day 0 and dose 2 administered any time between days 7 to 28 for a total of 2 doses; second doses can be administered as early as 7 days after the first dose.
Booster dose, for patients with ongoing or expected reexposure (CDC/ACIP [Hills 2019]):
Children <3 years: IM: 0.25 mL/dose administered ≥1 year after primary immunization series completed; there is no efficacy data on booster doses administered >2 years after series completion.
Children ≥3 years and Adolescents: IM: 0.5 mL/dose administered ≥1 year after primary immunization series completed; there is no efficacy data on booster doses administered >2 years after series completion.
Administration
IM: For IM injection. Do not inject IV, SubQ, or intradermally. Shake well prior to use to form a homogeneous suspension. Do not use if discolored or if particulate matter remains. Do not mix with other vaccines or injections; separate needles and syringes should be used for each injection (ACIP [Kroger 2017]).
The preferred site for administration is the deltoid muscle. To prevent syncope related injuries, patients should be vaccinated while seated or lying down (ACIP [Kroger 2017]).
Canadian labeling recommends avoiding IM administration in patients with bleeding disorders (eg, thrombocytopenia, hemophilia) and suggests that SubQ administration may be considered in these patients. Clinical efficacy data regarding this route is lacking and the US labeling does not recommend SubQ administration. For patients at risk of hemorrhage following intramuscular injection, the vaccine should be administered intramuscularly if, in the opinion of the physician familiar with the patient's bleeding risk, the vaccine can be administered by this route with reasonable safety. If the patient receives antihemophilia or other similar therapy, intramuscular vaccination can be scheduled shortly after such therapy is administered. A fine needle (23 gauge or smaller) can be used for the vaccination and firm pressure applied to the site (without rubbing) for at least 2 minutes. The patient should be instructed concerning the risk of hematoma from the injection. Patients on anticoagulant therapy should be considered to have the same bleeding risks and treated as those with clotting factor disorders (ACIP [Kroger 2017]).
Storage
Store in original packaging under refrigeration at 2°C to 8°C (35°F to 46°F); do not freeze. Protect from light. A clear liquid with a white precipitate can be observed during storage.
Drug Interactions
Fingolimod: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting fingolimod. If vaccinated during fingolimod therapy, revaccinate 2 to 3 months after fingolimod discontinuation. Consider therapy modification
Immunosuppressants: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Exceptions: Cytarabine (Liposomal). Consider therapy modification
Siponimod: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Avoid administration of vaccines (inactivated) during treatment with siponimod and for 1 month after discontinuation due to potential decreased vaccine efficacy. Consider therapy modification
Venetoclax: May diminish the therapeutic effect of Vaccines (Inactivated). Monitor therapy
Adverse Reactions
Percentage of adverse reactions reported over days 0 to 56 in adults and 0 to 7 in pediatric patients. In general, incidence decreased with subsequent dosing.
>10%:
Central nervous system: Headache (adults: 13% to 28%; children & adolescents: 1% to 5%), irritability (infants & children: ≤15%; adolescents: 2%), fatigue (≤11%)
Gastrointestinal: Diarrhea (infants, children, & adolescents: ≤17%; adults: ≤2%)
Local: Injection site reaction (adults: 33% to 55%), tenderness at injection site (infants, children, & adolescents: ≤50%; adults: 23% to 29%), pain at injection site (2% to 28%), erythema at injection site (infants, children, & adolescents: ≤25%; adults: 5% to 7%)
Neuromuscular & skeletal: Myalgia (infants, children, & adolescents: ≤31%; adults: 6% to 16%)
Miscellaneous: Fever (infants & children: ≤24%; adolescents & adults: ≤5%)
1% to 10%:
Central nervous system: Migraine (adults: ≥1%)
Dermatologic: Skin rash (infants & children: 1% to 8%; adolescents & adults: ≤1%)
Gastrointestinal: Vomiting (infants & children: ≤8%; adolescents & adults: ≤1%), anorexia (infants & children: 1% to 6%; adolescents: ≤2%), nausea (≤7%)
Infection: Influenza (adults: ≥1%)
Local: Induration at injection site (adults: 4% to 5%; children & adolescents: ≤1%), itching at injection site (adults: 2% to 3%; infants, children, & adolescents: ≤1%), swelling at injection site (≤2%)
Neuromuscular & skeletal: Back pain (adults: ≤1%)
Respiratory: Flu-like symptoms (≤12%), nasopharyngitis (adults: 2% to ≤5%), cough (adults: ≤1%), pharyngolaryngeal pain (adults: ≤2%), sinusitis (adults: ≥1%), upper respiratory tract infection (adults: ≤2%), rhinitis (adults: ≤1%)
Miscellaneous: Febrile seizures (children: 1%)
<1%, postmarketing, and/or case reports: Bacterial meningitis, myocardial infarction, neuritis, paresthesia, syncope
Warnings/Precautions
Concerns related to adverse effects:
- Anaphylactoid/hypersensitivity reactions: Immediate treatment (including epinephrine 1 mg/mL) for anaphylactoid and/or hypersensitivity reactions should be available during vaccine use (ACIP [Kroger 2017]).
- Syncope: Syncope has been reported with use of injectable vaccines and may result in serious secondary injury (eg, skull fracture, cerebral hemorrhage); typically reported in adolescents and young adults and within 15 minutes after vaccination. Procedures should be in place to avoid injuries from falling and to restore cerebral perfusion if syncope occurs (ACIP [Kroger 2017]).
Disease-related concerns:
- Acute illness: The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and the etiology of the disease. Defer administration in patients with moderate or severe acute illness (with or without fever); vaccination should not be delayed for patients with mild acute illness (with or without fever) (ACIP [Kroger 2017]).
- Bleeding disorders: Use with caution in patients with bleeding disorders (including thrombocytopenia); bleeding/hematoma may occur from IM administration; if the patient receives antihemophilia or other similar therapy, IM injection can be scheduled shortly after such therapy is administered (ACIP [Kroger 2017]). Canadian labeling recommends avoiding IM administration in patients with bleeding disorders (eg, thrombocytopenia, hemophilia) and suggests that SubQ administration may be considered in these patients. Clinical efficacy data regarding this route is lacking and the US labeling does not recommend SubQ administration.
Concurrent drug therapy issues:
- Anticoagulant therapy: Use with caution in patients receiving anticoagulant therapy; bleeding/hematoma may occur from IM administration (ACIP [Kroger 2017]).
- Vaccines: In order to maximize vaccination rates, the Advisory Committee on Immunization Practices recommends simultaneous administration (ie, >1 vaccine on the same day at different anatomic sites) of all age-appropriate vaccines (live or inactivated) for which a person is eligible at a single clinic visit, unless contraindications exist (ACIP [Kroger 2017]).
Special populations:
- Altered immunocompetence: Consider deferring immunization during periods of severe immunosuppression (eg, patients receiving chemo/radiation therapy or other immunosuppressive therapy [including high dose corticosteroids]); may have a reduced response to vaccination. In general, household and close contacts of persons with altered immunocompetence may receive all age appropriate vaccines. Inactivated vaccines should be administered ≥2 weeks prior to planned immunosuppression when feasible; inactivated vaccines administered during chemotherapy should be readministered after immune competence is regained (ACIP [Kroger 2017]; Rubin 2014).
- Adults ≥65 years of age: May have a reduced response to the vaccine (CDC/ACIP [Hills 2019])
- Pediatric: Apnea has occurred following IM vaccine administration in premature infants; consider clinical status implications. In general, preterm infants should be vaccinated at the same chronological age as full-term infants (ACIP [Kroger 2017]).
Dosage form specific issues:
- Protamine sulfate: May contain protamine sulfate, which may cause hypersensitivity reactions in certain individuals.
Other warnings/precautions:
- Antipyretics: Antipyretics have not been shown to prevent febrile seizures; antipyretics may be used to treat fever or discomfort following vaccination (ACIP [Kroger 2017]). One study reported that routine prophylactic administration of acetaminophen prior to vaccination to prevent fever decreased the immune response of some vaccines; the clinical significance of this reduction in immune response has not been established (Prymula 2009).
- Appropriate use: Because of the potential for severe adverse reactions, not recommended for all persons traveling to or residing in Asia. Use is not recommended for short-term travelers (<1 month) who will not be outside of an urban area or when the visit is outside of a well-defined Japanese encephalitis (JE) virus transmission season. Risk of exposure to the JE virus may vary from year to year for a particular area. Immunization should be completed ≥1 week prior to potential exposure (CDC/ACIP [Hills 2019]).
- Effective immunity: Vaccination may not result in effective immunity in all patients. Response depends upon multiple factors (eg, type of vaccine, age of patient) and may be improved by administering the vaccine at the recommended dose, route, and interval. Vaccines may not be effective if administered during periods of altered immune competence (ACIP [Kroger 2011]).
- Other methods to reduce mosquito exposure: Use of vaccine should also include other means to reduce the risk of mosquito exposure (bed nets, insect repellents, permethrin-impregnated clothing, avoidance of travel in endemic areas, and avoidance of outdoor activity during twilight and evening periods) (CDC/ACIP [Hills 2019]).
Monitoring Parameters
Observe for anaphylaxis and syncope for 15 minutes following administration (ACIP [Kroger 2017]). If seizure-like activity associated with syncope occurs, maintain patient in supine or Trendelenburg position to reestablish adequate cerebral perfusion.
Pregnancy
Pregnancy Considerations
Outcome information following inadvertent use of the Japanese encephalitis (JE) virus vaccine during pregnancy is limited (WHO 2015).
In general, vaccination should be deferred during pregnancy. However, use may be considered in pregnant women at high risk for infection. Intrauterine transmission of the JE virus has been reported; miscarriages have occurred in women infected during the first or second trimester of pregnancy (CDC/ACIP [Hills 2019]).
To report inadvertent use of Ixiaro during pregnancy, contact Valneva USA, Inc (1-844-349-4276).
Patient Education
- Discuss specific use of vaccine and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience headache, muscle pain, joint pain, flu-like symptoms, stuffy nose, sore throat, injection site pain or irritation, nausea, lack of appetite, irritability (children), diarrhea (children), or vomiting (children). Have patient report immediately to prescriber severe dizziness, passing out, severe loss of strength and energy, or fast heartbeat (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
