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Japanese Encephalitis Virus Vaccine (Inactivated)

Pronunciation

(jap a NEESE en sef a LYE tis VYE rus vak SEEN, in ak ti VAY ted)

Index Terms

  • IC51
  • JE-VC (Ixiaro)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Intramuscular:

Ixiaro: (0.5 mL) [latex free; contains albumin bovine, protamine sulfate, sodium metabisulfite]

Brand Names: U.S.

  • Ixiaro

Pharmacologic Category

  • Vaccine
  • Vaccine, Inactivated (Viral)

Pharmacology

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.

Onset of Action

Protective immunity was observed in ~21% of adults 10 days after the first vaccine dose and in 96% to 100% of children and adults 28 days after the second vaccine dose.

Duration of Action

Protective immunity was observed in ~80% to 85% of adults 12-36 months after the initiation of the two-dose series.

Use: Labeled Indications

Japanese encephalitis prevention: Active immunization against Japanese encephalitis (JE) for persons 2 months of age and older

The Advisory Committee on Immunization Practices (ACIP) recommends vaccination for (CDC [Fischer 2010]; CDC 2013):

- Persons spending ≥1 month in endemic areas during transmission season

- Research laboratory workers who may be exposed to the Japanese encephalitis virus

Vaccination should also be considered for the following:

• Travelers to areas with an ongoing outbreak

• Travelers spending <30 days in endemic areas during the transmission season and planning to go outside of urban areas and have an increased risk of exposure. For example, high-risk activities include extensive outdoor activity in rural areas especially at night; extensive outdoor activities such as camping, hiking, etc; staying in accommodations without air conditioning, screens or bed nets.

• Travelers to endemic areas who are unsure of specific destination, activities, or duration of travel

Japanese encephalitis vaccine is not recommended for short-term travelers whose visit will be restricted to urban areas or periods outside of the well-defined JE virus transmission season.

Contraindications

U.S. labeling: 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: Hypersensitivity to a previous dose of the vaccine or to any component of the formulation; acute severe febrile conditions

Dosing: Adult

Primary immunization: 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: Booster dose may be given prior to potential re-exposure if the primary series was completed >1 year previously.

Note: If the second dose is missed, limited data from one clinical trial in adults demonstrate a 99% seroconversion rate when the second dose was administered 11 months after the initial dose.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Primary immunization:

Infants and Children 2 months to <3 years: IM: 0.25 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.

Children ≥3 years and Adolescent: Refer to adult dosing.

Booster dose: Adolescents ≥17 years: Booster dose may be given prior to potential re-exposure if the primary series was completed >1 year previously. Note: The safety of booster doses in children and adolescents <17 years has not been established.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Administration

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]).

When administering to children 2 to 11 months of age, the preferred site for administration is the anterolateral aspect of the thigh; for children 1 to <3 years of age, the anterolateral aspect of the thigh or deltoid muscle may be used (if mass is adequate); the deltoid muscle is the preferred site in children ≥3 years, adolescents, and adults. To prevent syncope related injuries, adolescents and adults should be vaccinated while seated or lying down (ACIP [Kroger 2017]).

Ixiaro is available only in a prefilled syringe containing 0.5 mL. In order to administer a 0.25 mL dose in children 2 months to <3 years, first shake the syringe to form a homogenous suspension. Attach a sterile needle to the prefilled syringe and while holding the syringe upright, discard 0.25 mL of the suspension. Attach a new sterile needle prior to administration.

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 U.S. 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

Belimumab: May diminish the therapeutic effect of Vaccines (Inactivated). Management: Patients should receive inactivated vaccines prior to initiation of belimumab therapy whenever possible, due to the risk for an impaired response to the vaccine during belimumab therapy. Consider therapy modification

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

Venetoclax: May diminish the therapeutic effect of Vaccines (Inactivated). Monitor therapy

Adverse Reactions

Report allergic or unusual adverse reactions to the Vaccine Adverse Event Reporting System (VAERS) 1-800-822-7967 or online at https://vaers.hhs.gov/reportevent.html. In Canada, adverse reactions may be reported to local provincial/territorial health agencies or to the Vaccine Safety Section at Public Health Agency of Canada (1-866-844-0018).

Percentage of adverse reactions reported over days 0-56 in adults and 0-7 in pediatric patients. In general, incidence decreased with subsequent dosing.

>10%:

Central nervous system: Headache (adults 28%; infants, children, and adolescents 2% to 5%), irritability (infants and children <3 years 8% to 15%; children ≥3 years and adolescents ≤2%), fatigue (adults 11%; infants, children, and adolescents 2% to 3%)

Gastrointestinal: Diarrhea (infants and children <3 years 7% to 12%; children ≥3 years, adolescents, and adults <1% to 2%)

Local: Tenderness at injection site (adults 36%; children ≥3 years and adolescents 4% to 10%; infants and children <3 years 3%), pain at injection site (adults 33%; children ≥3 years and adolescents 6% to 15%; infants and children <3 years 4%), erythema at injection site (infants and children <3 years 6% to 18%; adults 10%; children ≥3 years and adolescents ≤3%)

Neuromuscular & skeletal: Myalgia (adults 16%; infants, children, and adolescents 2% to 3%)

Respiratory: Flu-like symptoms (adults 12%; infants, children, and adolescents 1% to 8%)

Miscellaneous: Fever (infants and children <3 years 20% to 24%; children ≥3 years and adolescents 4% to 11%; adults 3%)

1% to 10%:

Dermatologic: Skin rash (infants and children <3 years 4% to 8%; children ≥3 years, adolescents, and adults ≤1%)

Gastrointestinal: Nausea (adults 7%, infants, children, and adolescents ≤2%), vomiting (infants and children <3 years 4% to 8%; children ≥3 years, adolescents, and adults 1% to 2%), decreased appetite (infants, children, and adolescents 1% to 6%)

Infection: Influenza (adults ≥1%)

Local: Induration at injection site (adults 8%; infants, children, and adolescents ≤1%), swelling at injection site (≤2% to 4%), itching at injection site (adults 4%; infants, children, and adolescents ≤1%)

Neuromuscular & skeletal: Back pain (adults 1%)

Respiratory: Nasopharyngitis (adults 5%), pharyngolaryngeal pain (adults 2%), upper respiratory tract infection (adults 2%), sinusitis (adults ≥1%), cough (adults 1%), rhinitis (adults 1%)

Miscellaneous: Febrile seizures (children <3 years 1%)

<1%, postmarketing, and/or case reports (Limited to important or life-threatening): Appendicitis, cerebral infarction, chest pain, dermatomyositis, disseminated intravascular coagulation, encephalitis, epilepsy, herpes zoster, iritis, labyrinthitis, limb abscess, limb pain, musculoskeletal injury, neuritis, oropharyngeal spasm, ovarian torsion, paresthesia, rectal hemorrhage, rupture of ovarian cyst, seizure, 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 U.S. 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 ACIP 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).

• Pediatric: Apnea has occurred following intramuscular 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 (<30 days) who will not be outside of an urban area or when the visit is outside of a well-defined Japanese encephalitis virus transmission season. Risk of exposure to the Japanese encephalitis virus may vary from year to year for a particular area. Immunization should be completed ≥7 days prior to potential exposure (CDC [Fischer 2010]).

• 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, protective clothing, avoidance of travel in endemic areas, and avoidance of outdoor activity during twilight and evening periods) (CDC [Fischer 2010]).

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 Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Risks of vaccine administration should be carefully considered and in general, pregnant women should only be vaccinated if they are at high risk for exposure. Infection from Japanese encephalitis during the first or second trimesters of pregnancy may increase risk of miscarriage. Intrauterine transmission of the Japanese encephalitis virus has been reported (CDC [Fischer 2010]). To report inadvertent use of Ixiaro during pregnancy, contact Intercell USA (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, or injection site pain or irritation. Have patient report immediately to prescriber severe dizziness, passing out, loss of strength and energy, or tachycardia (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 healthcare 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.

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