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  • CLASSES

    Disease-Specific Immunoglobulins - Antiviral
    Rabies Sera

    DEA CLASS

    Rx

    DESCRIPTION

    Parenteral gamma globulin prepared from plasma of donors hyperimmunized with rabies vaccine
    Used for postexposure prophylaxis, along with the rabies vaccine, for persons suspected of rabies exposure
    Not indicated if more than 7 days passed since rabies vaccine administration or in patients with confirmed adequate rabies antibody titer

    COMMON BRAND NAMES

    HyperRAB, HyperRAB S/D, Imogam, KEDRAB

    HOW SUPPLIED

    HyperRAB S/D/Imogam/KEDRAB/Rabies Immune Globulin (Human) Intramuscular Inj Sol: 1mL, 150IU, 300IU
    Rabies Immune Globulin (Human) Infiltration Inj Sol: 1mL, 300IU

    DOSAGE & INDICATIONS

    For early, passive postexposure rabies prophylaxis of previously unvaccinated persons.
    Infiltration and Intramuscular dosage (HyperRAB and Imogam)
    Adults

    20 International Units/kg as a single dose as soon as possible after exposure, infiltrating as much of the dose as possible into and around detectable bite wounds; inject any remaining volume IM. Administer rabies immune globulin, human RIG concurrently with a full course of rabies vaccine. Do not administer rabies immune globulin, human RIG to any person with a history of complete preexposure or postexposure vaccination regimen and confirmed adequate antirabies titer.

    Infants†, Children†, and Adolescents†

    20 International Units/kg as a single dose as soon as possible after exposure, infiltrating as much of the dose as possible into and around any detectable bite wounds; inject any remaining volume IM. Administer rabies immune globulin, human RIG concurrently with a full course of rabies vaccine. Do not administer rabies immune globulin, human RIG to any person with a history of complete preexposure or postexposure vaccination regimen and confirmed adequate antirabies titer. While some product labeling states that safety and efficacy are not established in pediatric patients, the products are considered appropriate, using the weight-based recommended dosing, for postexposure prophylaxis in all children by the ACIP.

    Neonates†

    20 International Units/kg as a single dose as soon as possible after exposure, infiltrating as much of the dose as possible into and around any detectable bite wounds; inject any remaining volume IM. Administer rabies immune globulin, human RIG concurrently with a full course of rabies vaccine. Do not administer rabies immune globulin, human RIG to any person with a history of complete preexposure or postexposure vaccination regimen and confirmed adequate antirabies titer. While some product labeling states that safety and efficacy are not established in pediatric patients, the products are considered appropriate, using the weight-based recommended dosing, for postexposure prophylaxis in all children by the ACIP.

    Infiltration and Intramuscular dosage (Kedrab)
    Adults

    20 International Units/kg as a single dose as soon as possible after exposure, infiltrating as much of the dose as possible into and around detectable bite wounds; inject any remaining volume IM. Administer rabies immune globulin, human RIG concurrently with a full course of rabies vaccine. Do not administer rabies immune globulin, human RIG to any person with a history of complete preexposure or postexposure vaccination regimen and confirmed adequate antirabies titer.

    Infants, Children, and Adolescents

    20 International Units/kg as a single dose as soon as possible after exposure, infiltrating as much of the dose as possible into and around any detectable bite wounds; inject any remaining volume IM. Administer rabies immune globulin, human RIG concurrently with a full course of rabies vaccine. Do not administer rabies immune globulin, human RIG to any person with a history of complete preexposure or postexposure vaccination regimen and confirmed adequate antirabies titer.

    Neonates

    20 International Units/kg as a single dose as soon as possible after exposure, infiltrating as much of the dose as possible into and around any detectable bite wounds; inject any remaining volume IM. Administer rabies immune globulin, human RIG concurrently with a full course of rabies vaccine. Do not administer rabies immune globulin, human RIG to any person with a history of complete preexposure or postexposure vaccination regimen and confirmed adequate antirabies titer.

    MAXIMUM DOSAGE

    Adults

    20 International Units/kg, via infiltration and IM, single dose.

    Geriatric

    20 International Units/kg, via infiltration and IM, single dose.

    Adolescents

    20 International Units/kg, via infiltration and IM, single dose.

    Children

    20 International Units/kg, via infiltration and IM, single dose.

    Infants

    20 International Units/kg, via infiltration and IM, single dose.

    Neonates

    20 International Units/kg, via infiltration and IM, single dose.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustments are needed.

    Renal Impairment

    No dosage adjustments are needed.

    ADMINISTRATION

     
    NOTE: Immediately and thoroughly cleanse all bites and scratches with soap and water. Additionally, irrigate the wounds with a virucidal agent, such as povidone-iodine solution. Consider tetanus prophylaxis and measures to control bacterial infection if medically indicated.
     
    NOTE: According to U.S. federal laws, the health care provider must record in the patient's permanent record the manufacturer, lot number, administration date, and the name and address of the person administering the rabies immune globulin, human RIG.
    Inform the patient, guardian, or responsible adult of the benefits and risks of the rabies immune globulin, human RIG. The action is required by the National Childhood Vaccine Injury Act of 1986.
    If the rabies immune globulin, human RIG has been previously given, question the patient or guardian about any symptoms or signs of an adverse reaction.
    Ensure epinephrine is available for treatment of acute anaphylactic symptoms.
    Complete a Vaccine Adverse Event Reporting System (VAERS) report form if adverse events have been identified. The reporting of events is required by the National Childhood Vaccine Injury Act of 1986. The toll-free number for VAERS is 1-800-822-7967. Also, report an adverse event to the manufacturer of the specific agent administered.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration. If either particulate matter or discoloration is present, discard the vial. HyperRAB is clear or slightly opalescent, and colorless to pale yellow or light brown. HyperRAB S/D is colorless to pale yellow or pink. Kedrab is a clear to opalescent liquid.
    Do not mix rabies immune globulin, human RIG with any other product in the same syringe.
    Prior to administration, clean skin over the injection site with a suitable cleansing agent.
    Using a sterile syringe and needle remove the appropriate dose, based on body weight, from the single dose vials. A separate, sterile syringe and needle MUST be used for each patient.
    Administer rabies immune globulin, human RIG at same time as first dose of rabies vaccine or up to 7 days after first dose of rabies vaccine.
    Do not administer rabies immune globulin, human RIG in the same syringe or with the same needle as the rabies vaccine.
    Never administer rabies immune globulin, human RIG at the same anatomical site as the rabies vaccine.
    Infiltrate as much of the dose as possible in and around any detectable bite wounds. If using HyperRAB solution (i.e., 300 International Units/mL) and additional volume is needed to infiltrate the entire wound, dilute the solution with an equal volume of 5% Dextrose Injection. DO NOT dilute with normal saline.
    Inject any remaining volume intramuscularly.

    Intramuscular Administration

    Administer any excess dose not able to be injected in and around the bite wounds IM, using a separate needle, at a site distant from the rabies vaccine administration site.
    When the bite site is unknown or indeterminate (undetectable), administer the full dose IM at a site distance from the rabies vaccine administration site.
    The preferred injection sites are the upper arm deltoid region, or in small children, the anterolateral aspect of the thigh. Unless the exposure site is the gluteal region, avoid administration into the gluteal region, where absorbance is unpredictable.
    If a large IM volume is required (i.e., more than 2 mL for pediatric patients or more than 5 mL for adults), inject the total volume in divided doses at different sites.

    Subcutaneous Administration

    Although there are no clinical efficacy data supporting subcutaneous administration of rabies immune globulin, human RIG, Kedrab may be administered subcutaneously in patients for whom IM injections are contraindicated (e.g., patients with uncorrectable bleeding disorders).

    STORAGE

    HyperRAB:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Do not use if product has been frozen
    - Store between 36 to 46 degrees F
    HyperRAB S/D:
    - Avoid use of product if it has been frozen
    - Refrigerate (between 36 and 46 degrees F)
    Imogam:
    - Protect from freezing
    - Refrigerate (between 36 and 46 degrees F)
    KEDRAB:
    - Do not freeze
    - May be stored at temperatures up to 77 degrees F if used within 1 month
    - Store between 36 to 46 degrees F
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

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

    Rabies immune globulin, human RIG is indicated for intramuscular (IM) administration and, thus, should be given cautiously to persons receiving anticoagulant therapy. Also, patients with thrombocytopenia, coagulopathy (e.g., hemophilia), other bleeding disorders, or vitamin K deficiency should be monitored closely for bleeding at the IM injection site. All steps to avoid hematoma formation are recommended. In patients for whom intramuscular administration is contraindicated, KedRAB may be administered subcutaneously; however, it should be noted that there are no clinical efficacy data supporting subcutaneous administration of rabies immune globulin, human RIG.

    Intravenous administration

    Use rabies immune globulin, human RIG with caution and monitor patients with a history of prior systemic allergic reactions for hypersensitivity after administration. Do not administer rabies immune globulin, human RIG intravenously. Intravenous administration of rabies immune globulin, human RIG increases the risk for severe allergic or hypersensitivity reactions, including anaphylactic shock. Rabies immune globulin, human RIG can precipitate a drop in blood pressure associated with an anaphylactic reaction, even in patients who tolerated previous immune globulin therapy. Immediately discontinue rabies immune globulin, human RIG if an allergic or anaphylactic reaction develops. In case of shock, implement standard medical treatment. Ensure epinephrine is available for treatment of acute anaphylactic symptoms. The patient or responsible adult should report any adverse reaction after rabies immune globulin, human RIG administration to the health care provider. The US Department of Health and Human Services has established a Vaccine Adverse Event Reporting System (VAERS) to accept all reports of suspected adverse events after the administration of any vaccine or rabies immune globulin, human RIG. This includes, but is not limited to, the reporting of events required by the National Childhood Vaccine Injury Act of 1986. The toll-free number for VAERS is 800-822-7967.

    IgA deficiency

    Weigh the benefits of rabies immune globulin, human RIG administration against the potential risks of hypersensitivity reactions in patients with IgA deficiency. Patients who are deficient in IgA have the potential to develop IgA antibodies and may have anaphylactic reactions after administration of blood products containing IgA, such as RIG.

    Viral infection

    Rabies immune globulin, human RIG is a derivative of human blood. As with other products derived from or purified with human blood components, the remote possibility of contamination with hepatitis, Creutzfeldt-Jakob disease (CJD), and other bacterial or viral infections exists in patients receiving rabies immune globulin, human RIG. Screening plasma donors for prior exposure to certain viruses, testing for the presence of viruses, and inactivating or reducing viruses has reduced the risk of transmission of infectious agents. The manufacturing processes are designed to reduce the risk of transmitting viral infection; however, none of the processes are completely effective. Some viruses, such as parvovirus B19, are particularly difficult to remove or inactivate. Parvovirus B19 most seriously affects pregnant women and immune compromised individuals and symptoms include fever, drowsiness, chills, and rhinitis followed in about 2 weeks with rash and joint pain. There is also the possibility that unknown infectious agents may be present in this product. Discuss the risks and benefits of rabies immune globulin, human RIG therapy prior to administration. Patients and caregivers should be encouraged to notify their health care provider if they develop infectious symptoms. All infections thought to have been transmitted by rabies immune globulin, human RIG should be reported to the manufacturer.

    Laboratory test interference

    After rabies immune globulin, human RIG administration, a transient increase of the concentrations of the passively transferred serum antibodies may result in misleading positive serologic tests. Passive transmission of antibodies to erythrocyte antigens may result in laboratory test interference for red cell antibodies such as the antiglobulin test (Coombs' test).

    Hemolysis

    Hemolysis may occur in patients receiving immune globulins. Patients at increased risk include those with non-O blood group types, those with underlying inflammatory conditions, and those receiving high cumulative doses of immune globulins over several days. Clinical signs and symptoms of hemolysis include fever, chills, and dark urine. If any of these occur, perform appropriate laboratory testing, and administer medical therapy as indicated.

    Geriatric, hypertriglyceridemia

    Monitor patients at increased risk for thrombosis or thrombotic complications for at least 24 hours after receiving rabies immune globulin, human RIG. Patients at increased risk for thrombosis include patients with acquired or hereditary hypercoagulable states, prolonged immobilization, in-dwelling vascular catheters, advanced age (geriatric), estrogen use, history of venous or arterial thrombosis, cardiovascular risk factors (e.g., atherosclerosis, impaired cardiac output), hyperviscosity syndromes (e.g., hypertriglyceridemia, cryoglobulinemias, fasting chylomicronemia, monoclonal gammopathies). Before administering rabies immune globulin, human RIG to patients at risk for hyperviscosity, consider measuring baseline blood viscosity.

    Pregnancy

    It is not known if rabies immune globulin, human RIG can cause fetal harm when administered during pregnancy or affect reproductive capacity. Rabies immune globulin, human RIG has not been studied in pregnant women, and animal developmental or reproduction toxicity studies with rabies immune globulin, human RIG have not been conducted. Use rabies immune globulin, human RIG during pregnancy only if clearly needed. Because of the potential consequences of inadequately treated rabies exposure, pregnancy is not considered a contraindication to use of postexposure prophylaxis regimens.

    Breast-feeding

    Immunoglobulins, such as the rabies immune globulin, are excreted in human milk. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for rabies immune globulin, human RIG and any potential adverse effects on the breast-fed child from rabies immune globulin, human RIG or from the mother's underlying condition. In general, given the potential severity of the illness, postexposure regimens using rabies immune globulin, human RIG in an exposed mother should be pursued, regardless of lactation status.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    nephrotic syndrome / Delayed / Incidence not known

    Moderate

    hematoma / Early / 1.0-7.0
    erythema / Early / 0-5.0
    edema / Delayed / 0-5.0
    pyuria / Delayed / 3.0-5.0
    hematuria / Delayed / 2.0-4.0
    sinus tachycardia / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    malaise / Early / 50.0-50.0
    headache / Early / 8.0-50.0
    fever / Early / 13.0-13.0
    infection / Delayed / 9.0-10.0
    myalgia / Early / 0-9.0
    nasal congestion / Early / 8.0-8.0
    flatulence / Early / 8.0-8.0
    diarrhea / Early / 8.0-8.0
    abdominal pain / Early / 1.0-8.0
    vomiting / Early / 7.0-7.0
    fatigue / Early / 2.0-7.0
    dizziness / Early / 4.0-6.0
    arthralgia / Delayed / 0-6.0
    insomnia / Early / 0-5.0
    nausea / Early / 4.0-4.0
    injection site reaction / Rapid / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    chills / Rapid / Incidence not known
    rash / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    photosensitivity / Delayed / Incidence not known

    DRUG INTERACTIONS

    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Defer immunization with measles virus vaccine, live attenuated for 4 months after rabies immune globulin, human RIG administration. Antibodies in RIG may interfere with the immune response to the live virus vaccine. According to the Advisory Committee on Immunization Practices, if the measles virus vaccine, live attenuated is administered less than 4 months after receipt of RIG, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. The repeat dose and serologic tests must be performed 4 months or more after RIG administration. (Major) Defer immunization with mumps virus vaccine, live for 4 months after rabies immune globulin, human RIG administration. Antibodies in RIG may interfere with the immune response to the live virus vaccine. According to the Advisory Committee on Immunization Practices, if the mumps virus vaccine, live is administered less than 4 months after receipt of RIG, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. The repeat dose and serologic tests must be performed 4 months or more after RIG administration. (Major) Defer immunization with rubella virus vaccine, live for 4 months after rabies immune globulin, human RIG administration. Antibodies in RIG may interfere with the immune response to the live virus vaccine. According to the Advisory Committee on Immunization Practices, if the rubella virus vaccine, live is administered less than 4 months after receipt of RIG, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. The repeat dose and serologic tests must be performed 4 months or more after RIG administration. (Major) Defer immunization with varicella-zoster virus vaccine, live for at least 5 months after rabies immune globulin, human RIG administration. Do not give immune globulins for 2 months after varicella-zoster virus vaccine, live administration unless immune globulin use outweighs the benefits of vaccination. Antibodies in RIG may interfere with the immune response to the live virus vaccine. According to the Advisory Committee on Immunization Practices, if the varicella virus vaccine live is administered less than 4 months after receipt of RIG, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. The repeat dose and serologic tests must be performed 4 months or more after RIG administration.
    Measles/Mumps/Rubella Vaccines, MMR: (Major) Defer immunization with measles virus vaccine, live attenuated for 4 months after rabies immune globulin, human RIG administration. Antibodies in RIG may interfere with the immune response to the live virus vaccine. According to the Advisory Committee on Immunization Practices, if the measles virus vaccine, live attenuated is administered less than 4 months after receipt of RIG, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. The repeat dose and serologic tests must be performed 4 months or more after RIG administration. (Major) Defer immunization with mumps virus vaccine, live for 4 months after rabies immune globulin, human RIG administration. Antibodies in RIG may interfere with the immune response to the live virus vaccine. According to the Advisory Committee on Immunization Practices, if the mumps virus vaccine, live is administered less than 4 months after receipt of RIG, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. The repeat dose and serologic tests must be performed 4 months or more after RIG administration. (Major) Defer immunization with rubella virus vaccine, live for 4 months after rabies immune globulin, human RIG administration. Antibodies in RIG may interfere with the immune response to the live virus vaccine. According to the Advisory Committee on Immunization Practices, if the rubella virus vaccine, live is administered less than 4 months after receipt of RIG, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. The repeat dose and serologic tests must be performed 4 months or more after RIG administration.
    Rabies Vaccine: (Minor) The rabies immune globulin, human RIG may be administered concurrently with, and up to 8 days after the rabies vaccine. The RIG and the rabies vaccine must be administered via separate syringes and at different anatomical site. Avoid administering RIG if more than 7 days have elapsed since administration of the rabies vaccine as this may impair rabies vaccine-induced active immunity. Additionally, RIG doses greater than the recommended 20 International Units/kg and repeat RIG doses should also be avoided as these too may partially suppress active production of antibodies by the rabies vaccine.
    Rotavirus Vaccine: (Major) Defer immunization with rotavirus pentavalent live vaccine for 4 months after rabies immune globulin, human RIG administration. Antibodies in RIG may interfere with the immune response to the live virus vaccine. According to the Advisory Committee on Immunization Practices, if the rotavirus pentavalent live vaccine is administered less than 4 months after receipt of RIG, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. The repeat dose and serologic tests must be performed 4 months or more after RIG administration.
    Rubella Virus Vaccine Live: (Major) Defer immunization with rubella virus vaccine, live for 4 months after rabies immune globulin, human RIG administration. Antibodies in RIG may interfere with the immune response to the live virus vaccine. According to the Advisory Committee on Immunization Practices, if the rubella virus vaccine, live is administered less than 4 months after receipt of RIG, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. The repeat dose and serologic tests must be performed 4 months or more after RIG administration.
    Varicella-Zoster Virus Vaccine, Live: (Major) Defer immunization with varicella-zoster virus vaccine, live for at least 5 months after rabies immune globulin, human RIG administration. Do not give immune globulins for 2 months after varicella-zoster virus vaccine, live administration unless immune globulin use outweighs the benefits of vaccination. Antibodies in RIG may interfere with the immune response to the live virus vaccine. According to the Advisory Committee on Immunization Practices, if the varicella virus vaccine live is administered less than 4 months after receipt of RIG, the vaccine dose should be repeated unless serologic testing is feasible and indicates a response to the vaccine. The repeat dose and serologic tests must be performed 4 months or more after RIG administration.

    PREGNANCY AND LACTATION

    Pregnancy

    It is not known if rabies immune globulin, human RIG can cause fetal harm when administered during pregnancy or affect reproductive capacity. Rabies immune globulin, human RIG has not been studied in pregnant women, and animal developmental or reproduction toxicity studies with rabies immune globulin, human RIG have not been conducted. Use rabies immune globulin, human RIG during pregnancy only if clearly needed. Because of the potential consequences of inadequately treated rabies exposure, pregnancy is not considered a contraindication to use of postexposure prophylaxis regimens.

    Immunoglobulins, such as the rabies immune globulin, are excreted in human milk. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for rabies immune globulin, human RIG and any potential adverse effects on the breast-fed child from rabies immune globulin, human RIG or from the mother's underlying condition. In general, given the potential severity of the illness, postexposure regimens using rabies immune globulin, human RIG in an exposed mother should be pursued, regardless of lactation status.

    MECHANISM OF ACTION

    Rabies immune globulin, human RIG is administered in conjunction with the rabies vaccine to previously unvaccinated persons who have been exposed to the rabies virus. The purpose of RIG is to provide immediate, passive immunity until vaccine-induced active immunity is developed (i.e., approximately 1 week). In previously unimmunized persons, the role of rabies immune globulin, human RIG in establishing early, passive protection against the virus is key to protecting patients against the disease.
     
    When a rabies immune globulin, human RIG dose of 20 International Units/kg is given simultaneously (but at a separate site) with the first dose of rabies vaccine, concentrations of passive rabies antibody are detected 24 hours after injection in all individuals. There is minimal interference with the immune response to the initial and subsequent doses of vaccine, including booster doses. However, the vaccine-induced immune response may be suppressed if patients receive repeated or excessive rabies immune globulin, human RIG doses, or if rabies immune globulin, human RIG is administered more than 1 week after the vaccine.

    PHARMACOKINETICS

    Rabies immune globulin, human RIG is administered intramuscularly and infiltrated into the inoculation site. KedRAB is not bioequivalent to comparator rabies immune globulin, human RIG when coadministered with a 5-dose rabies vaccine regimen; however, pharmacokinetic differences are not expected to affect clinical outcomes.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none

    Intramuscular Route

    For Imogam, HyperRAB, and HyperRAB S/D, 20 International Units/kg produced measurable passive rabies antibody concentrations within 24 hours in all subjects. Detection of these antibodies in the serum continued throughout the 21-day study period. In another study evaluating the pharmacokinetic parameters of KedRAB and a comparator RIG product, the median time for KedRAB to achieve maximum serum concentration (Tmax) was 7 days (range 3 to 14 days) and elimination half-life was about 17.9 days after a single dose of 20 International Units/kg; maximum plasma rabies virus neutralizing antibody (RVNA) concentration after the single KedRAB dose was 0.25 IU/mL. A plot of plasma RVNA titer concentration vs. time found that in both groups, plasma RVNA declined in a biphasic manner after the absorption phase was complete. When coadministered with a 5-dose rabies vaccine regimen, the peak plasma RVNA concentrations were 71.9 IU/mL and 53.9 IU/mL, respectively; median Tmax for both groups was 14 days (range, 14 to 49 days). Half-lives for KedRAB and the comparator RIG were 48.6 hours and 52.7 hours, respectively. Administration of a single 20 International Unit/kg rabies immune globulin, human RIG dose produces minimal interference with the endogenous immune response to the rabies vaccine series.