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    Japanese Encephalitis Vaccines

    DEA CLASS

    Rx

    DESCRIPTION

    Inactivated viral vaccine that induces antibodies that neutralize live virus
    Used for prevention of Japanese encephalitis
    Ixiaro is only vaccine available in the US to help prevent Japanese encephalitis

    COMMON BRAND NAMES

    Ixiaro

    HOW SUPPLIED

    Ixiaro Intramuscular Inj Susp: 1dose, 6mcg

    DOSAGE & INDICATIONS

    For Japanese encephalitis prophylaxis.
    Intramuscular dosage (Ixiaro)

    NOTE: Receipt of only 1 dose may lead to a suboptimal response. Also, receipt of both doses may not protect 100% of patients and will not protect against encephalitis caused by viruses or pathogens other than the Japanese encephalitis virus.

    Geriatric

    0.5 mL IM, followed by a second 0.5 mL IM injection administered 28 days later. Administer the second dose at least 1 week before potential exposure to the Japanese encephalitis virus. Individuals with ongoing or repeated exposure may receive a 0.5 mL IM booster injection (3rd dose) if more than 11 months have elapsed since completion of the primary 2 dose series.[48500] Data is not available on the response to a booster dose administered more than 2 years after the primary series. Clinical trial data show high rates of seroprotection for at least 6 years after a booster dose; no longer-term study data are available.[64479]

    Adults 18 to 65 years of age

    0.5 mL IM, followed by a second 0.5 mL IM injection administered either 7 or 28 days later. Administer the second dose at least 1 week before potential exposure to the Japanese encephalitis virus. Individuals with ongoing or repeated exposure may receive a 0.5 mL IM booster injection (3rd dose) if more than 11 months have elapsed since completion of the primary 2 dose series.[48500] Data is not available on the response to a booster dose administered more than 2 years after the primary series. Clinical trial data show high rates of seroprotection for at least 6 years after a booster dose; no longer-term study data are available.[64479]

    Children and Adolescents 3 to 17 years

    0.5 mL IM, followed by a second 0.5 mL IM injection administered 28 days later. Administer the second dose at least 1 week before potential exposure to the Japanese encephalitis virus. Individuals with ongoing or repeated exposure may receive a 0.5 mL IM booster injection (3rd dose) if more than 11 months have elapsed since completion of the primary 2 dose series.[48500] Data is not available on the response to a booster dose administered more than 2 years after the primary series. Clinical trial data show high rates of seroprotection for at least 6 years after a booster dose; no longer-term study data are available.[64479]

    Children 14 months to 2 years

    0.25 mL IM, followed by a second 0.25 mL IM injection administered 28 days later. Administer the second dose at least 1 week before potential exposure to the Japanese encephalitis virus. Individuals with ongoing or repeated exposure may receive a 0.25 mL IM booster injection (3rd dose) if more than 11 months have elapsed since completion of the primary 2 dose series.[48500] Data is not available on the response to a booster dose administered more than 2 years after the primary series. Clinical trial data show high rates of seroprotection for at least 6 years after a booster dose; no longer-term study data are available.[64479]

    Infants and Children 2 to 13 months

    0.25 mL IM, followed by a second 0.25 mL IM injection administered 28 days later. Administer the second dose at least 1 week before potential exposure to the Japanese encephalitis virus. Safety and immunogenicity of a booster dose have not been established.

    MAXIMUM DOSAGE

    Adults

    0.5 mL/dose IM.

    Geriatric

    0.5 mL/dose IM.

    Adolescents

    0.5 mL/dose IM.

    Children

    >= 3 years: 0.5 mL/dose IM.
    1—2 years: 0.25 mL/dose IM.

    Infants

    2—11 months: 0.25 mL/dose IM.
    < 2 months: Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: Epinephrine 1:1000 must be immediately available in the event of an anaphylactic reaction. Interview the potential vaccine recipient before administration. A severe allergic reaction after a previous Japanese encephalitis virus vaccine dose is a contraindication to Ixiaro administration.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intramuscular Administration

    Shake the syringe well to obtain a white, opaque, homogeneous suspension. Do not administer if particulate matter is present after shaking or if discoloration is observed.
    With a careful twist, remove the syringe tip cap; do not attempt to snap or pull off the tip cap as this may damage the syringe.
    Attach a safety needle to the syringe.
    For adults and pediatric patients >= 3 years:
    Administer the full 0.5 mL by intramuscular injection into the deltoid muscle.
    For pediatric patients 2 months to < 3 years:
    Hold the syringe upright, uncap the needle, and slowly push the plunger up to the edge of the red line on the syringe barrel. Discard the expelled volume in a medical waste container. If the plunger stopper is pushed beyond the line, the entire syringe must be wasted and the process repeated with a new pre-filled syringe.
    Once the plunger stopper is at the edge of the red line, lock the needle safety shield and remove the needle.
    Attach a new sterile needle and inject the remaining 0.25 mL volume by intramuscular injection into the anterolateral aspect of the thigh. Alternatively, the deltoid muscle may be used for children ages 1 to < 3 years if muscle mass is adequate.
    Do not mix with any other vaccine in the same syringe or vial.

    STORAGE

    Ixiaro:
    - Do not freeze
    - Protect from light
    - Store in original carton in refrigerator (35 to 46 degrees F) until time of use
    JE-VAX:
    - Protect from freezing
    - Reconstituted unused product should be stored at 36-46 degrees F and used within 8 hours
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Ixiaro is contraindicated for use by patients with a previous severe allergic reaction, such as anaphylaxis, to the vaccine. Because of differing vaccine components, individuals with a history of severe allergic reactions to another Japanese encephalitis vaccine should be referred to an allergist for evaluation. Ixiaro contains protamine sulfate, which may cause a hypersensitivity reaction. It also contains sodium metabisulfite and bovine serum albumin and may be inappropriate for use by patients with either sulfite hypersensitivity or albumin hypersensitivity. Review the patient's immunization history for possible vaccine sensitivity and previous vaccination-related adverse reactions. As with any biologic product, precautions should be taken to prevent allergic reactions. The health care professional should have immediate availability of epinephrine (1:1000) injection and other agents used in the treatment of severe anaphylaxis in the event of a serious allergic reaction to the vaccine.

    Anticoagulant therapy, coagulopathy, hemophilia, thrombocytopenia, vitamin K deficiency

    Ixiaro is only given intramuscularly and may be inappropriate for patients with thrombocytopenia, vitamin K deficiency, or coagulopathy such as hemophilia. Patients taking anticoagulant therapy also may not be appropriate candidates for Ixiaro receipt.

    Immunosuppression

    Patients with immunosuppression may not have an adequate antibody response to vaccination with the Japanese encephalitis virus vaccine. No safety or efficacy data exist regarding use in immunocompromised individuals. Consider the patient's degree of altered immunocompetence. Inactivated vaccines administered during the period of altered immunocompetence might need to be repeated after immune function has improved.

    Pregnancy

    No adequate and well-controlled studies have been conducted in pregnant women and the ability of the vaccine to cause fetal harm or affect reproductive capacity is unknown. During a developmental toxicity study preformed in rats, there was no evidence of fetal harm. According to the Advisory Committee on Immunization Practices (ACIP), administration of inactivated virus vaccines to pregnant women have not resulted in adverse effects in the fetus. The ACIP recommends vaccination during pregnancy when the likelihood of disease exposure is high, potential infection would cause harm to mother or fetus, and when the vaccine is unlikely to cause harm. Infection with the Japanese encephalitis virus during pregnancy may cause intrauterine infection and fetal death. Health professionals caring for patients who receive the Japanese encephalitis virus vaccine during pregnancy are encouraged to contact Valneva USA, Inc by telephone at 844-349-4276.

    Infants, neonates

    Safety and efficacy of Ixiaro have not been established in neonates and infants less than 2 months of age.

    Breast-feeding

    Data are limited regarding use of the Japanese encephalitis virus vaccine during breast feeding and its' excretion in human milk is unknown. The manufacturer recommends caution when administering to nursing mothers; however according to the Advisory Committee on Immunization Practices (ACIP), inactivated vaccines pose no risk to breast-feeding mothers or their infants. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    Geriatric

    Limited data indicate that geriatric patients have a similar response to Ixiaro. Among 24 patients at least 65 years of age, 95.8% seroconverted. Vaccination may be desirable, as advanced age may be a risk factor for developing symptomatic illness after infection.

    ADVERSE REACTIONS

    Severe

    anaphylactic shock / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known

    Moderate

    erythema / Early / 9.6-19.6
    edema / Delayed / 4.2-4.2
    wheezing / Rapid / Incidence not known
    dyspnea / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    neuritis / Delayed / Incidence not known

    Mild

    injection site reaction / Rapid / 32.6-48.5
    fatigue / Early / 11.3-33.9
    headache / Early / 11.1-30.4
    anorexia / Delayed / 16.1-16.1
    myalgia / Early / 15.6-16.1
    pharyngitis / Delayed / 4.7-15.2
    nausea / Early / 6.6-14.3
    arthralgia / Delayed / 5.4-5.4
    pruritus / Rapid / 3.8-3.8
    fever / Early / 3.2-3.2
    infection / Delayed / 1.7-1.7
    diarrhea / Early / 1.5-1.5
    rhinitis / Early / 1.4-1.4
    vomiting / Early / 1.4-1.4
    rash / Early / 1.3-1.3
    back pain / Delayed / 1.3-1.3
    cough / Delayed / 1.2-1.2
    weakness / Early / Incidence not known
    dizziness / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    paresthesias / Delayed / Incidence not known
    syncope / Early / Incidence not known

    DRUG INTERACTIONS

    Ocrelizumab: (Moderate) Administer all non-live vaccines at least 2 weeks before ocrelizumab initiation, whenever possible. Ocrelizumab may interfere with the effectiveness of non-live virus vaccines. Attenuated antibody responses to tetanus toxoid-containing vaccine, pneumococcal polysaccharide and pneumococcal conjugate vaccines, and seasonal influenza vaccine were observed in patients exposed to ocrelizumab at the time of vaccination during an open-label study. Infants born to mothers exposed to ocrelizumab during pregnancy may receive non-live vaccines as indicated before B-cell recovery; however, consider assessing the immune response to the vaccine. ACIP recommends that patients receiving any vaccination during immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated a minimum of 3 months after discontinuation of therapy. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination.
    Ofatumumab: (Major) Administer all needed non-live vaccines according to immunization guidelines at least 2 weeks before initiation of ofatumumab. Ofatumumab may interfere with the effectiveness of inactivated vaccines due to its actions, which cause B-cell depletion.
    Satralizumab: (Major) Administer all non-live vaccines according to immunization guidelines at least 2 weeks before initiation of satralizumab.
    Siponimod: (Moderate) Administer all non-live vaccines at least 2 weeks before siponimod initiation, whenever possible. Vaccines may be less effective if given during siponimod treatment. Patients should be considered unimmunized if vaccinated within a 14-day period before starting immunosuppresive therapy or during immunosuppressive therapy, and should they be revaccinated at least 3 months after therapy is discontinued if immune competence is restored.

    PREGNANCY AND LACTATION

    Pregnancy

    No adequate and well-controlled studies have been conducted in pregnant women and the ability of the vaccine to cause fetal harm or affect reproductive capacity is unknown. During a developmental toxicity study preformed in rats, there was no evidence of fetal harm. According to the Advisory Committee on Immunization Practices (ACIP), administration of inactivated virus vaccines to pregnant women have not resulted in adverse effects in the fetus. The ACIP recommends vaccination during pregnancy when the likelihood of disease exposure is high, potential infection would cause harm to mother or fetus, and when the vaccine is unlikely to cause harm. Infection with the Japanese encephalitis virus during pregnancy may cause intrauterine infection and fetal death. Health professionals caring for patients who receive the Japanese encephalitis virus vaccine during pregnancy are encouraged to contact Valneva USA, Inc by telephone at 844-349-4276.

    Data are limited regarding use of the Japanese encephalitis virus vaccine during breast feeding and its' excretion in human milk is unknown. The manufacturer recommends caution when administering to nursing mothers; however according to the Advisory Committee on Immunization Practices (ACIP), inactivated vaccines pose no risk to breast-feeding mothers or their infants. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Receipt of the Japanese encephalitis virus vaccine induces antibody production. The antibodies neutralize live Japanese encephalitis virus. Neutralizing antibodies are measured by a 50% plaque reduction neutralization test (PRNT50), with a PRNT50 titer of at least 1:10 being a reasonable correlate for protection. As determined 28 days after the last dose, a titer of at least 1:10 (seroconversion) was obtained by 96.4% of adult Ixiaro recipients and 99.2—100% of pediatric recipients (depending on age). Two doses are required for most patients; 28 days after the first dose, only 39.8% of adults had seroconverted whereas 97.3% seroconverted 7 days and 28 days after dose 2.
     
    In most patients, neutralizing antibodies persist for at least 6 months after completion of the 2-dose Ixiaro series. In one study, the percentage of adults who maintained the titer threshold was 95% at 6 months, 83.4% at 12 months, 81.8% at 24 months, and 84.9% at 36 months. In another study the results were not as favorable, with only 58.3% and 48.3% of adults maintaining a titer of at least 1:10 at 11 and 23 months, respectively, after completion of the primary series. Based on this data, a booster dose is recommended for patients ages 17 years and older who have completed the primary series more than 1 year prior and who continue to be at risk of exposure; immunogenicity of the booster has not been established in patients less than 17 years of age.

    PHARMACOKINETICS

    The Japanese encephalitis virus vaccine (Ixiaro) is administered intramuscularly.

    Intramuscular Route

    Twenty-eight days after the last dose of Ixiaro, 96.4% of recipients (352/365) achieved protective immunity as evident by a 50% plaque-reduction neutralization titer (PRNT50) >/= 1:10. The geometric mean titer at the same time point was 243.6 (95% CI, 216.4—274.1). Ixiaro was administered IM on days 0 and 28. Another study evaluated the efficacy of a single booster dose administered 14 months after completion of the primary series in 198 adults. The proportion of subjects achieving PRNT50 >/= 1:10 at time points day 0, day 28, month 6, and month 12 were 69.2%, 100%, 98.5%, and 98.5%, respectively.