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Rabies immune globulin (RIG) is a specific immune globulin (hyperimmune globulin)202, 205 that contains antibody to rabies antigen and is used to provide antirabies antibodies for temporary passive immunity to rabies virus.201, 206, 207, 216 RIG commercially available in the US is prepared from plasma of donors hyperimmunized with rabies vaccine201, 205, 206, 207 and is sometimes referred to as HRIG.216 Other types of RIG (e.g., equine rabies immune globulin; ERIG) may be available in other countries.205, 207, 210, 215
Postexposure Prophylaxis of Rabies
Rabies immune globulin (RIG) is used to provide passive immunity to rabies as part of a postexposure prophylaxis regimen in individuals exposed to the disease or virus who previously have not been vaccinated against rabies.201, 205, 206, 207, 216 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) recommend that postexposure prophylaxis following rabies exposure include immediate and thorough wound treatment (e.g., cleansing all bite wounds and scratches with soap and water and irrigation with a virucidal agent such as povidone-iodine solution) and, for previously unvaccinated individuals, passive immunization with RIG combined with active immunization with rabies vaccine (see Rabies Vaccine 80:12).205, 207, 216 RIG provides immediate, temporary rabies virus-neutralizing antibodies until the patient responds to active immunization with the vaccine and produces virus-neutralizing antibodies.205, 207, 216
Since the availability and routine use of cell culture-derived rabies vaccines began in the US in 1990, there have been no reported cases of postexposure prophylaxis failures in the US when recommended procedures, including active and passive immunization and wound management, were followed.206, 207, 216 Although prophylaxis failures have been reported rarely in other countries, in all cases there was a deviation from recommended procedures (e.g., postexposure prophylaxis not given or substantially delayed, wounds not adequately cleansed, rabies vaccine given IM into the gluteal rather than deltoid region, failure to passively immunize with RIG by infiltrating the wound site, use of less than the recommended dose of RIG, use of less than the recommended number of doses of rabies vaccine).206, 207 (See Dosage and Administration: Administration.) RIG is commercially available in the US as HyperRAB® S/D and Imogam® Rabies-HT,201, 206 and the ACIP states that both preparations of RIG are considered equally effective when used as recommended.207
Passive immunization with RIG is unnecessary and should not be administered to individuals who have been previously vaccinated against rabies.205, 207, 216 These individuals include those who have previously received a recommended preexposure or postexposure regimen of human diploid-cell vaccine (HDCV), purified chick embryo cell culture vaccine (PCECV) rabies vaccine, or rabies vaccine adsorbed (RVA; rhesus diploid-cell rabies vaccine; no longer commercially available in the US) and those who received some other rabies vaccine and have a documented adequate rabies antibody titer.205, 207, 216 Postexposure prophylaxis in these previously vaccinated individuals should include the recommended booster regimen of rabies vaccine (without RIG) since this ensures that an anamnestic response occurs following administration of the vaccine booster doses.207, 216 (See Drug Interactions: Rabies Vaccine.)
Whenever a possible human exposure to rabies occurs, the risk of infection must be accurately assessed to determine the need for postexposure prophylaxis.207 Decisions regarding the need for postexposure prophylaxis should be based on the vaccination status of the exposed individual (see Table 1), type of exposure (bite, nonbite), information about the animal involved (type, vaccination status, condition at time of attack) (see Table 2), and rabies epidemiology in the specific geographic region.205, 207, 215 Clinicians should consult local or state public health officials for assistance when evaluating rabies exposures and the need for postexposure prophylaxis.205, 207
Vaccination Status | Treatment | Regimen |
|---|---|---|
Not previously vaccinated | Wound cleansing | Immediately cleanse all wounds thoroughly with soap and water; if available, irrigate wounds with virucidal agent (e.g., povidone-iodine solution) |
RIG | Administer 20 international units/kg of RIG; if anatomically feasible, infiltrate full RIG dose around and into wound(s) and give any remaining portion of the dose IM at an anatomical site distant from site of rabies vaccine administration | |
Rabies vaccine | Administer 4-dose regimen of rabies vaccineb; give 1 mL (human diploid-cell vaccine [HDCV] or purified chick embryo cell culture vaccine [PCECV]) IMc once on days 0d, 3, 7, and 14 | |
Previously vaccinateda | Wound cleansing | Immediately cleanse all wounds thoroughly with soap and water; if available, irrigate wounds with virucidal agent (e.g., povidone-iodine solution) |
RIG | RIG should not be administered | |
Rabies vaccine | Administer 2-dose regimen of rabies vaccine; give 1 mL (HDCV or PCECV) IMc once on days 0d and 3 |
aAny person with a history of a complete preexposure or postexposure vaccination regimen with HDCV, PCECV, or rabies vaccine adsorbed (RVA; not commercially available in the US), or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination
bIndividuals with immunosuppression should receive a 5-dose regimen of rabies vaccine; give 1 mL (HDCV or PCECV) IMc once on days 0d, 3, 7, 14, and 28.
cDeltoid area is the only acceptable site for IM administration of rabies vaccine in adults, adolescents, and older children. For younger children, deltoid or anterolateral thigh should be used. Never administer in gluteal area.
dDay 0 is the day the first dose of rabies vaccine is administered.
Adapted from Use of a Reduced (4-dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010; 59 (RR-2):1-9.
Regardless of immunization status, the ACIP and AAP recommend that postexposure prophylaxis of rabies begin immediately with thorough cleansing of all bite wounds and scratches using soap and water and, if available, irrigation with a virucidal agent such as povidone-iodine solution.205, 207, 216 Local wound treatment is an essential initial step in rabies postexposure prophylaxis in all individuals.205, 207, 216
When passive immunization against rabies is indicated for postexposure prophylaxis, RIG is the preferred form of rabies immune globulin since antirabies serum (equine) (no longer commercially available in the US) is associated with a high incidence of adverse reactions (e.g., anaphylaxis, serum sickness).207, 215
Animal Type | Evaluation and Disposition of Animal | Postexposure Prophylaxis Recommendations |
|---|---|---|
Dogs, cats, ferrets | Healthy and available; confine for 10 days of observation | Do not begin prophylaxis unless animal develops clinical signs of rabiesa |
Rabid or suspected rabid | Immediately begin postexposure prophylaxis | |
Unknown (e.g., escaped) | Consult public health officials | |
Skunks, raccoons, foxes, and most other carnivores; batsb | Regard as rabid unless animal proven negative by laboratory testsc | Consider immediate postexposure prophylaxis |
Livestock, small rodents, lagomorphs (rabbits, hares), large rodents (woodchucks, beavers), other mammals | Consider individually | Consult public health officials. Bites from squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, mice, other small rodents, rabbits, and hares almost never require rabies postexposure prophylaxis |
aDuring the 10-day observation period, begin postexposure prophylaxis in the exposed individual at the first sign of rabies in the dog, cat, or ferret that has bitten them. If the animal exhibits clinical signs of rabies, euthanize it immediately and perform appropriate testing.
bInitiate postexposure prophylaxis as soon as possible following exposure to such wildlife, unless animal is available for testing and public health authorities are facilitating expeditious laboratory testing or it is already known that brain material from the animal has tested negative. Other factors that might influence urgency of decision-making regarding initiation of postexposure prophylaxis before diagnostic results are known include the animal species, general appearance and behavior of the animal, whether encounter was provoked by a human, and the severity and location of bites. Discontinue postexposure prophylaxis if appropriate laboratory tests (i.e., direct fluorescent antibody test) are negative.
cEuthanize the animal and test as soon as possible. Holding for observation is not recommended.
Adapted from the Recommendations of the Advisory Committee on Immunization Practices (ACIP) on Human Rabies Prevention. MMWR Recomm Rep. 2008; 57 (RR-3):1-28.
Because the rabies incubation period in humans can range from days to years (usually 1-3 months),205, 207, 210, 215, 216 rabies postexposure prophylaxis should be initiated (regardless of the length of delay) if a documented or likely exposure has occurred and clinical signs of rabies have not appeared in the exposed individual.201, 207
For additional information on postexposure prophylaxis of rabies, see Uses: Postexposure Prophylaxis of Rabies, in Rabies Vaccine 80:12.
Individuals with Altered Immunocompetence
The ACIP states that recommendations concerning use of RIG in individuals with altered immunocompetence, including those with human immunodeficiency virus (HIV) infection and those who are severely immunocompromised because of congenital immunodeficiency, leukemia, lymphoma, aplastic anemia, generalized malignancy, or therapy with alkylating agents, antimetabolites, radiation, or corticosteroids, are the same as those for patients who are not immunocompromised.203, 216 (See Drug Interactions: Immunosuppressive Agents.)
Children are at higher risk of rabies exposure compared with adults because of increased potential for animal contact and because they are more likely to be bitten on the head, face, and neck leading to more severe injuries.210, 215 The ACIP, Centers for Disease Control and Prevention (CDC), and AAP recommend that postexposure prophylaxis of rabies in children follow the same guidelines as those in adults.205, 207, 210, 216
Pregnancy is not considered a contraindication to postexposure prophylaxis of rabies because of the potential risks of inadequately treated rabies exposure.206, 207 (See Cautions: Pregnancy, Fertility, and Lactation.)
Rabies remains highly endemic in certain areas of the world (e.g., parts of Africa, Asia, Central and South America).210, 213 Preexposure vaccination against rabies may be indicated for certain travelers with occupational risk of exposure or for travelers (especially children) visiting endemic areas where immediate access to RIG or rabies vaccine may be limited.207, 213 Travelers to rabies-endemic countries should be warned about the risk of acquiring rabies and educated in bite prevention strategies (e.g., avoiding contact with bats, avoiding stray dogs, monkeys, or cats).210 Because appropriate preparations of RIG or rabies vaccine may be not available for postexposure prophylaxis in the destination country, the CDC recommends that travelers to such countries have a preplanned strategy in place that may involve identifying a different country where appropriate postexposure prophylaxis can be obtained if necessary.210 The CDC states that rabies vaccines grown in animal brains (neural tissue vaccines) still may be used in some developing countries and, if offered such a vaccine (identified by a regimen that requires 5-mL injections once daily for 14-21 days), travelers should refuse the vaccine and travel to a country where an acceptable rabies vaccine preparation and RIG are available.210 If travelers in other countries receive postexposure prophylaxis with regimens and/or preparations not recommended by ACIP (or not used in the US), additional therapy may be necessary following return to the US.207, 210 In such cases, state and local health authorities should be consulted for advice regarding the need for additional postexposure prophylaxis.207 Serologic testing should be considered in these travelers to verify efficacy of the regimen used and to ensure an adequate immune response.207 (See Pre- and Postvaccination Serologic Testing under Cautions.)
Routine delivery of health care to a patient with rabies is not an indication for postexposure rabies prophylaxis in health-care personnel.207 However, rabies postexposure prophylaxis is indicated in health-care personnel if they have been bitten by the patient or if they have mucous membranes or nonintact skin (e.g., open wounds) that were contaminated with the patient's saliva or other potentially infectious material (e.g., neural tissue).207
Pre- and Postvaccination Serologic Testing
Serologic testing is not indicated prior to postexposure prophylaxis in previously vaccinated individuals who are exposed to rabies.207 Such testing is inappropriate because it would delay postexposure prophylaxis and, although antirabies neutralizing antibodies are an important component of immunity, other immune effectors also play a role in disease prevention.207
Serologic confirmation of an adequate antibody response following postexposure prophylaxis with a combined regimen of passive immunization with RIG and active immunization with rabies vaccine is not necessary in most individuals because of the high rate of response among immunocompetent adults, adolescents, and children when the recommended postexposure regimen is used.205, 207, 210, 216 However, if postexposure prophylaxis is indicated in an immunocompromised individual, serologic testing is considered essential after completion of the postexposure prophylaxis regimen to confirm that an adequate antibody response was obtained.203, 205, 207, 216 (See Uses: Pre- and Postvaccination Serologic Testing, in Rabies Vaccine 80:12.)
Rabies immune globulin (RIG) is administered preferably by local wound infiltration and, when local infiltration accounts for only a portion of the dose or is not anatomically feasible, by IM injection.201, 205, 206, 207 RIG should not be administered IV .201, 206 (See Cautions: Precautions and Contraindications.)
The full dose of RIG should be thoroughly infiltrated locally in the area around and into the wound(s) if anatomically feasible.201, 205, 206, 207 In cases (e.g., multiple severe wounds) where the volume required to infiltrate the wound(s) would exceed the recommended dosage of RIG, some clinicians recommend diluting the calculated dosage in saline to yield a two- to threefold increase in the volume of solution to ensure all wound areas receive RIG infiltration.205
After infiltrating the wound(s) area, any remaining portion of the recommended RIG dose should be administered by IM injection at a site distant from where rabies vaccine is being administered.201, 205, 206, 207, 216 For adults and older children, the deltoid is the only acceptable IM injection site; for younger children, the deltoid or anterolateral thigh should be used.201, 216 For children with a small muscle mass, it may be necessary to administer RIG at multiple IM sites.205
RIG should not be administered into the gluteal area (buttock muscle) because of the potential for injection-associated injury to the sciatic nerve.201, 202, 216 Injection into or near any blood vessels or nerves should be avoided.202, 206 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) state that aspiration (i.e., pulling back on the syringe plunger after needle insertion and before injection) is not required because large blood vessels are not present at recommended IM injection sites.202, 205
To ensure delivery into muscle, IM injections should be made at a 90° angle to the skin using a needle length appropriate for the individual's age and body mass, the thickness of adipose tissue and muscle at the injection site, and the injection technique.202
RIG and rabies vaccine should not be given in the same syringe and should not be injected at the same site since neutralization of the vaccine may occur.201, 205, 206, 207 In addition, RIG should not be mixed with other immune globulins, vaccines, or solutions.202, 205
Postexposure Prophylaxis of Rabies
Exposure to rabies must be individually evaluated before prophylaxis is begun and factors such as species of the biting animal, circumstances of the biting incident, vaccination status of the biting animal, presence of rabies in the geographic region, and preexposure vaccination status of the individual must be considered to determine if postexposure prophylaxis is necessary.215 (See Uses.) Local or state public health officials should be consulted if questions regarding the need for rabies prophylaxis arise. 205, 207
RIG should not be administered to those individuals who have previously received a recommended preexposure or postexposure regimen of human diploid-cell rabies vaccine (HDCV), purified chick embryo cell culture vaccine (PCECV) rabies vaccine, or rabies vaccine adsorbed (RVA; rhesus diploid-cell rabies vaccine; no longer commercially available in the US) or those who have been previously immunized with some other rabies vaccine and have a documented adequate rabies antibody titer.205, 207 (See Drug Interactions: Rabies Vaccine.)
Previously Unvaccinated Adults, Children, or Adolescents
For postexposure prophylaxis in previously unvaccinated individuals, RIG should always be administered in conjunction with rabies vaccine .205, 207
When indicated, RIG and rabies vaccine should be administered as soon as possible after bite or non-bite exposure and RIG should preferably be given at the time of the first vaccine dose.205, 207 If rabies vaccine is not immediately available, RIG should be given and immunization started as soon as possible.205 If RIG is not immediately available or not given when vaccination is initiated, RIG may be administered within 7 days after the first vaccine dose.205, 207 Beyond the seventh day, sufficient vaccine-induced rabies antibody will be present in most vaccine recipients, and RIG is not necessary.207 Some experts state that if administration of both RIG and rabies vaccine is delayed, both should be used regardless of the interval between exposure and prophylaxis.201, 205, 206
For postexposure prophylaxis in previously unvaccinated individuals, RIG is administered only once.207 The usual dose of RIG in adults, adolescents, and children is 20 international units per kg, preferably administered at the same time as the first dose of rabies vaccine.201, 202, 205, 206, 207 RIG is commercially available as HyperRAB® S/D and Imogam® Rabies-HT in 2-mL vials that contain 300 international units of RIG (sufficient dose for a 15-kg child) and 10-mL vials that contain 1500 international units of RIG (sufficient dose for a 75-kg adult).201, 206
Because RIG can suppress the active immune response to rabies vaccine, no more than the recommended dose of RIG (i.e., a single dose of 20 international units per kg) should be used and repeated doses should not be given.201, 205, 206, 207 (See Drug Interactions: Rabies Vaccine.)
Local adverse effects, including tenderness, pain, muscle soreness or stiffness, may occur at the site of injection of rabies immune globulin (RIG) and may persist for several hours.201, 206, 207 Low-grade fever may also occur.201 Mild systemic reactions to RIG administered IM are uncommon.206 In a clinical study in healthy individuals who received RIG with or without rabies vaccine, there were some reports of headache and malaise.206
Although not reported specifically for RIG, angioedema, nephrotic syndrome, rash, and anaphylaxis have been reported rarely with immune globulin; however, a causal relationship has not been established.201, 206
Precautions and Contraindications
Repeated doses of RIG are contraindicated once active immunization with rabies vaccine has been initiated since repeating the dose of RIG may partially suppress active production of antibody and interfere with the maximum immunologic response to the vaccine.206 (See Drug Interactions: Rabies Vaccine.)
The manufacturers state that serious systemic reactions could occur following inadvertent IV administration of RIG.201, 206 Although systemic reactions to preparations containing immune globulin are rare, epinephrine should be available for treatment of acute anaphylaxis if it occurs.201, 206
Risk of Transmissible Agents in Plasma-derived Preparations
Because RIG is prepared from pooled human plasma, it is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and human immunodeficiency virus (HIV) infection, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD.201, 206, 208 Improved donor screening, viral-inactivation procedures (e.g., solvent/detergent treatment), and/or filtration procedures have reduced, but not completely eliminated, the risk of pathogen transmission with plasma-derived preparations.201, 206 In addition, the manufacturing processes for RIG include certain chemical (solvent/detergent) treatment procedures and/or heat-treatment procedures to reduce viral infectious potential.201, 206 Solvent/detergent inactivation processes apparently can inactivate lipid-enveloped (e.g., hepatitis B virus [HBV], hepatitis C virus [HCV], HIV type 1 and type 2 [HIV-1 and HIV-2]), but are less effective against viruses that do not have a lipid envelope (e.g., hepatitis A virus [HAV], parvovirus B-19).201, 206 Certain filtering procedures are effective in reducing levels of some enveloped and non-enveloped viruses.201, 206 Because no purification method has been shown to be totally effective in removing the risk of viral infectivity from plasma-derived preparations and because new blood-borne viruses or other disease agents may emerge that may not be inactivated by the manufacturing process or the chemical (solvent/detergent) treatment procedures currently used, RIG should be administered only when a benefit is expected.201, 206 Any infection believed to have been transmitted by RIG should be reported to the manufacturer.201, 206
For further information on precautions related to transmissible agents in plasma-derived preparations, see Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Precautions and Contraindications, in Albumin Human 16:00.
Anaphylaxis has been reported rarely following administration of human immune globulins.201, 206 One manufacturer states that sensitization to repeated injections has been reported in immunoglobulin-deficient patients.201
RIG should be used with caution in individuals with a history of systemic allergic reactions to immune globulins.201, 206 Epinephrine and other appropriate therapy should be readily available in case anaphylaxis occurs.201, 206
RIG (HyperRAB® S/D) may contain immunoglobulin A (IgA).201 RIG should be used with caution in individuals with IgA deficiency since such individuals may have serum antibodies to IgA and anaphylaxis could result following administration of preparations containing IgA.201, 206 The potential benefits of RIG should be weighed against the potential for hypersensitivity reactions.201
Individuals with Altered Immunocompetence
RIG may be administered to individuals immunosuppressed as the result of disease or immunosuppressive therapy.203 In addition, recommendations regarding the use of RIG in individuals with altered immunocompetence are the same as those for individuals who are not immunocompromised.203
If rabies postexposure prophylaxis is indicated in an immunocompromised individual, serologic testing is considered essential after completion of the postexposure prophylaxis regimen to confirm than an adequate antibody response is obtained.203, 205, 207 (See Uses: Pre- and Postvaccination Serologic Testing, in Rabies Vaccine 80:12.) If an acceptable antibody response is not detected after the final vaccine dose of the postexposure prophylaxis series, the patient should be managed in consultation with their clinician and appropriate public health officials.216
Individuals with Bleeding Disorders
Because bleeding may occur following IM administration in individuals with thrombocytopenia or a bleeding disorder (e.g., hemophilia) or in those receiving anticoagulant therapy, IM injection of RIG should be used with caution in such individuals.201, 202, 206
The US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that IM injections can be used in individuals who have bleeding disorders or are receiving anticoagulant therapy if a clinician familiar with the patient's bleeding risk determines that the injection can be administered with reasonable safety.202 In these cases, a fine needle (23 gauge) should be used to administer the dose and firm pressure should be applied to the injection site (without rubbing) for 2 minutes or longer.202, 205 If patient is receiving antihemophilia therapy, the IM dose should be administered shortly after a scheduled dose of such therapy.202 The individual and/or their family should be advised about the risk of hematoma from IM injections.202
RIG provides only short-term protection against rabies.207 The half-life of RIG following an IM dose is approximately 21 days.207
Rabies postexposure prophylaxis includes combined passive immunization with RIG and active immunization with rabies vaccine to provide effective and more prolonged immunity against rabies.201, 205, 206, 207 Additional (booster) doses of RIG are not recommended.201, 202, 205, 206, 207
Although the manufacturer of HyperRAB® states that safety and efficacy of RIG have not been established in children,201 the ACIP and American Academy of Pediatrics (AAP) recommend that postexposure prophylaxis of rabies (including use of RIG) in children follow the same guidelines as those in adults.205, 207
Pregnancy, Fertility, and Lactation
Because of the potential risks of inadequately treated rabies exposure, pregnancy is not a contraindication to postexposure prophylaxis.202, 206, 207 Animal reproduction studies have not been performed with RIG, and it is not known whether the drug can cause fetal harm when administered to pregnant women.201, 206 The manufacturers state that RIG should be used during pregnancy only when clearly needed.201, 206 The ACIP states that there are no known risks for the fetus from passive immunization of pregnant women with immune globulin preparations.202
It is not known if RIG affects fertility.201, 206
Information on the distribution of RIG into milk is not available; it is not known if transmission of RIG to a nursing infant presents any unusual risk.
Rabies immune globulin (RIG) has been reported to partially suppress the active antibody response to rabies vaccine.201, 206, 207 There is evidence that a single RIG dose of 20 international units/kg given at the same time as the first dose of rabies vaccine provides maximum circulating antirabies antibody with minimal interference with the active immune response to the vaccine.201, 206 To minimize potential suppression of the active immune response to the vaccine, single doses of more than 20 international units/kg of RIG or repeated RIG doses should not be given.201, 206, 207 When anatomically feasible, the full dose of RIG should be thoroughly infiltrated in the area around and into the wound(s) and any remaining volume should be administered IM at a site distant from where rabies vaccine is being administered.201, 205, 206, 207 (See Dosage and Administration.)
Neutralization of rabies vaccine may occur if RIG and rabies vaccine are mixed in the same syringe or administered into the same injection site.201, 205, 206, 207
Antibodies present in immune globulins, including RIG, may interfere with the immune response to certain live virus vaccines, including measles, mumps, and rubella virus vaccine live (MMR), rotavirus vaccine live oral, and varicella virus vaccine live, and these vaccines should not be administered simultaneously with or for a specified interval before or after administration of RIG.201, 202, 204, 205, 206
There is no evidence that immune globulin preparations interfere with the immune response to yellow fever virus vaccine, typhoid vaccine live oral (Vivotif®), influenza virus vaccine live intranasal, or poliovirus vaccine live oral (OPV; no longer commercially available in the US), and these vaccines may be administered simultaneously with or at any time before or after administration of RIG.202, 205
Measles, Mumps, and Rubella Vaccine
RIG may interfere with the immune response to measles and rubella antigens contained in MMR;201, 202, 205, 206 however, the effect of RIG on the immune response to the mumps antigen is unknown.202
Manufacturers of RIG (HyperRAB® S/D and Imogam® Rabies-HT) state that MMR should not be administered within 3 months after RIG.201, 206 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics (AAP) state that MMR should not be administered simultaneously with or within 4 months after RIG.202, 205
The fact that revaccination may be necessary in individuals who receive RIG shortly after MMR also should be considered.202 In general, vaccine virus replication and stimulation of active immunity occur within 7-14 days after administration of a live virus vaccine.202 Therefore, if RIG must be administered within 14 days after receipt of MMR, revaccination is necessary at least 4 months after administration of RIG, unless serologic testing indicates that there was an adequate antibody response to all 3 antigens contained in MMR.202, 205
RIG may interfere with the immune response to rotavirus vaccine live oral.202 If possible, the dose of rotavirus vaccine live oral should be deferred until 42 days (6 weeks) after RIG; however, a shorter interval should be used if the 42-day deferral would result in the first dose of rotavirus vaccine being scheduled when the child is 13 weeks of age or older.202 Safety and efficacy data are not available regarding use of rotavirus vaccine live oral in infants who have received an immune globulin within 42 days.211
RIG may interfere with the immune response to varicella virus vaccine live.202, 204, 205 The manufacturers of RIG (HyperRAB® S/D and Imogam® Rabies-HT) state that live vaccines should not be administered simultaneously with or within 3 months after RIG.201, 206 However, ACIP and AAP recommend an interval of at least 4 months between administration of varicella virus vaccine live and RIG.202, 205
Inactivated Vaccines and Toxoids
Immune globulins, including RIG, are not expected to have a clinically important effect on the immune response to inactivated vaccines or toxoids; therefore, inactivated vaccines, recombinant vaccines, polysaccharide vaccines, and toxoids may be administered simultaneously with (using different syringes and different injection sites) or at any interval before or after administration of RIG.202, 205
Specific studies evaluating the concomitant use of parenteral inactivated typhoid vaccine (Typhim Vi®) with immune globulins are not available;214 however, an interaction is not expected since Typhim Vi® is an inactivated vaccine.202, 205 Therefore, parenteral inactivated typhoid vaccine may be given simultaneously with RIG (using different syringes and injection sites) or at any time before or after RIG.202, 205
Immunosuppressive agents (e.g., alkylating agents, antimetabolites, corticosteroids, radiation) may decrease the antibody response to postexposure prophylaxis using combined active immunization with rabies vaccine and passive immunization with RIG, and there is a potential for an increased risk of rabies infection despite use of postexposure prophylaxis.203, 205, 207, 210 Therefore, immunosuppressive therapy should be avoided in patients receiving rabies postexposure prophylaxis, unless such therapy is considered essential for treatment of other serious conditions.203
If rabies postexposure prophylaxis is used in an individual receiving immunosuppressive agents, serologic testing for rabies antibody should be performed after completion of the postexposure prophylaxis regimen to confirm adequate immune response.207 (See Uses: Pre- and Postvaccination Serologic Testing, in Rabies Vaccine 80:12.)
Rabies immune globulin (RIG) is used to provide temporary passive immunity to rabies infection as part of a postexposure prophylaxis regimen in unvaccinated individuals exposed to the disease or virus.201, 206, 207 Specific rabies antibodies present in RIG neutralizes rabies virus so that spread of the virus is retarded and its infective or pathogenic properties are inhibited.201, 206
Rabies virus is an RNA virus classified in the Rhabdovirus family.205, 207, 210, 215 Rabies is a viral infection transmitted by the saliva of infected mammals.207, 215, 216 Following exposure and infection, rabies virus appears to remain close to the wound for an indeterminate time and can be partially neutralized with rabies immune globulin (RIG) while at this site.205 Unimpeded, the virus usually moves along a neural pathway via the peripheral nerves toward the CNS.206, 215, 216 Once the virus enters the CNS of the host, it replicates and disseminates rapidly via the nervous system to many different tissues, including the salivary glands.215 At this stage the virus is unlikely to be affected by antibodies, and a fatal encephalomyelitis almost invariably ensues.207, 215 The incubation period in humans can range from days to years (usually 1-3 months);205, 210, 215, 216 after severe bites to the face, neck, or arms, the incubation period may be as short as 10 days.206 The length of the incubation period depends on factors such as the amount of viral inoculum, the degree of innervation at the site of viral entry, and the proximity of the bite to the CNS.215
Common prodromal symptoms of rabies include malaise, anorexia, fatigue, headache, and fever followed by pain or paresthesia at the site of exposure.215 Anxiety, agitation, and irritability may occur during the prodromal stage, followed by hyperactivity, disorientation, seizures, aerophobia, hydrophobia, hypersalivation, and eventually paralysis, coma and death.205, 210, 215 Following the appearance of clinical symptoms of rabies, use of RIG or rabies vaccine will not improve the prognosis and may be detrimental; there is no specific proven effective treatment for rabies once symptoms develop.205, 210, 215
In the US, approximately 16,000-39,000 individuals receive rabies postexposure prophylaxis each year.207, 216 Although there were 27 rabies cases reported in the US during 2000-2008,216 these individuals evidently did not receive rabies postexposure prophylaxis.216 Rabies prevention and control strategies and elimination of canine rabies virus variants and enzootic transmission among dogs have lowered the number of rabies cases in the US to an average of 1-2 per year.216 However, worldwide, rabies is much more common and more than 55,000 rabies-related deaths occur each year.215, 216
Response to Rabies Postexposure Prophylaxis
Development of immunity and protection from rabies infection are evaluated by the appearance of antirabies antibody in serum.207 However, the actual serum titer of antirabies antibody indicating immunity and protection against rabies has not been definitely established to date and reported values for antibody titers vary among laboratories and are influenced by the type of test performed.207
If serologic testing for serum antirabies antibody is performed 1-2 weeks after postexposure prophylaxis, the ACIP defines an adequate antibody response as complete virus neutralization at a 1:5 serum dilution when determined by rapid fluorescent-focus inhibition test (RFFIT).207, 216 The World Health Organization (WHO) states that a titer of 0.5 international units/mL or greater can be considered protective.215
Passively acquired antirabies antibodies present in RIG may partially suppress the active immune response to rabies vaccine;201, 206, 207 however, there is evidence that a single RIG dose of 20 international units/kg given at the same time as the first dose of rabies vaccine provides maximum circulating antirabies antibody with minimal interference with the active immune response to the vaccine.201, 206 Once vaccination with rabies vaccine has been initiated, administration of larger than usual doses of RIG (i.e., greater than 20 international units/kg) or repeated doses of RIG may interfere with the immune response to the vaccine.201, 206, 207 (See Drug Interactions: Rabies Vaccine.)
Rabies immune globulin (RIG) is absorbed slowly following IM administration. Following IM administration of RIG, rabies antibodies appear in serum within 24 hours201, 206 and are still detectable on day 21.201
Although information on the distribution of RIG across the placenta is not available, it is likely that RIG crosses the placenta since other immunoglobulins cross the placenta. Virtually all transplacental passage of immunoglobulins occurs during the last 4 weeks of pregnancy. Information on the distribution of RIG into milk is not available; RIG may be distributed into milk since immunoglobulins (e.g., IgA, IgM, IgG) are present in the colostrum.
The serum half-life for RIG is approximately 21 days following IM administration.207
Rabies immune globulin (RIG) is a sterile, concentrated, nonpyrogenic solution containing 10-18% protein.201, 206 The concentrated solution is prepared from plasma of healthy adults hyperimmunized with rabies vaccine.201, 206 Commercially available RIG is standardized against the US Standard for RIG and contains at least 150 international units (IU, units) of rabies neutralizing antibody per mL.201, 206
RIG occurs as a practically colorless to slightly opalescent solution and is adjusted to a pH of 6.4-7.2201, 206 with sodium hydroxide or hydrochloric acid.206 RIG is commercially available in the US as HyperRAB® S/D and Imogam® Rabies-HT.201, 206 HyperRAB® S/D undergoes a chemical (solvent/detergent) procedure and Imogam® Rabies-HT undergoes a heat-treatment procedure during manufacture to decrease the risk of transmission of viral infection.201, 206 However, no method has been shown to be totally effective in removing the risk of viral infectivity from plasma-derived products.201, 206 HyperRAB® S/D and Imogam® Rabies-HT are stabilized with glycine, but do not contain thimerosal or any other preservative.201, 206
RIG should be refrigerated at 2-8°C; freezing should be avoided.201, 206 RIG that has been frozen should be discarded.201 Because HyperRAB® S/D and Imogam® Rabies-HT contain no preservatives,201, 206 any unused solution remaining in the vial should be discarded.206
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2025, Selected Revisions September 1, 2010. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
Only references cited for selected revisions after 1984 are available electronically.
201. Talecris Biotherapeutics, Inc. HyperRAB® S/D (rabies immune globulin [human] solvent/detergent treated) prescribing information. Research Triangle Park, NC; 2008 Mar.
202. Centers for Disease Control and Prevention. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep . 2006; 55(RR-15):1-47. [Fulltext MMWR]
203. Centers for Disease Control and Prevention. Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence. MMWR Recomm Rep . 1993; 42(No. RR-4):1-18. [Fulltext MMWR]
204. Centers for Disease Control and Prevention. Prevention of varicella: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep . 2007; 56( RR-04):1-40. [Fulltext MMWR]
205. American Academy of Pediatrics. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
206. Sanofi Pasteur. Imogam® Rabies-HT (rabies immune globulin [human] USP, heat treated) prescribing information. Swiftwater, PA; 2005 Dec.
207. Centers for Disease Control and Prevention. Human rabies prevention—United States, 2008. Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep . 2008; 57(RR-3):1-27. [Fulltext MMWR]
208. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). Guidance for industry. Revised preventive measures to reduce the possible risk of transmission of Creutzfeldt-Jacob disease (CJD) and variant Creutzfeldt-Jacob disease (vCJD) by blood and blood products. January 2002. From FDA website. [Web]
209. Centers for Disease Control and Prevention. Human rabies-Florida, 2004. MMWR Morb Mortal Wkly Rep . 2005; 54:767-9. [PubMed 16094285]
210. US Centers for Disease Control and Prevention. Health information for international travel, 2010. Atlanta, GA: US Department of Health and Human Services; 2010. Updates available from CDC website. [Web]
211. Merck & Co. RotaTeq® (Rotavirus Vaccine, Live, Oral, Pentavalent) prescribing information. Whitehouse Station, NJ; 2008 Jul.
212. Rupprecht CE, Smith JS, Fekadu M et al. The ascension of wildlife rabies: a cause for public health concern or intervention? Emerg Infect Dis. 1995 (Oct-Dec); 1:107-14.
213. Anon. Advice for travelers. Med Lett Treat Guidel . 2009; 7:83-94.
214. Sanofi-Pasteur. Typhim Vi® (typhoid Vi polysaccharide vaccine) prescribing information. Swiftwater, PA; 2005 Dec.
215. World Health Organization. Rabies vaccines WHO position paper. Weekly epidemiological record. 2007; 82: 425-35. From WHO website. [Web]
216. Centers for Disease Control and Prevention. Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies. Recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep . 2010; 59(RR-2):1-9. [Fulltext MMWR]