Rabies Immune Globulin

Class: Serums
ATC Class: J06BB05
VA Class: IM500
Brands: HyperRAB S/D, Imogam Rabies-HT

Introduction

Specific immune globulin (hyperimmune globulin).202 205 Rabies immune globulin (RIG) 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

Uses for Rabies Immune Globulin

Postexposure Prophylaxis of Rabies

Postexposure prophylaxis of rabies in previously unvaccinated children, adolescents, and adults following exposure to rabies disease or virus.201 205 206 207 216

Used in a postexposure prophylaxis regimen that includes active immunization with rabies vaccine and passive immunization with RIG.205 207 210 216 RIG provides immediate, temporary rabies virus-neutralizing antibodies until the patient has an immunologic response to active immunization with rabies vaccine and produces virus-neutralizing antibodies.205 207 216

RIG is not included in rabies postexposure prophylaxis regimens used in individuals who previously received preexposure or postexposure regimens that included rabies vaccine.205 207 216 Passive immunization is not necessary in such individuals and may interfere with the desired anamnestic response to booster doses of rabies vaccine used for postexposure prophylaxis in such individuals.207 216

Rabies is a viral infection transmitted by saliva of infected mammals, most commonly wild, terrestrial carnivores (e.g., skunks, raccoons, foxes, coyotes) or bats.205 207 In the US, the greatest risk for naturally-acquired rabies is from contact with and bites from insectivorous bats.207 209 212 Following exposure and infection, rabies virus usually moves along a neural pathway and enters the CNS.215 216 After entrance into the CNS, the virus is unlikely to be affected by antirabies antibodies and encephalomyelitis usually develops and almost always is fatal.207 215 In the US, approximately 16,000–39,000 individuals receive rabies postexposure prophylaxis each year.206 207 216 Although there were 27 rabies cases reported in the US during 2000–2008,205 these individuals evidently did not receive rabies postexposure prophylaxis.205 Rabies prevention and control strategies in the US 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.212 216 However, worldwide, rabies is much more common and at least 55,000 rabies-related deaths occur each year.212 216

Whenever a possible human exposure to rabies occurs, the risk of infection must be accurately assessed to determine the need for postexposure prophylaxis.207 216 Base decisions regarding the need for postexposure prophylaxis on 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.205 207 216 Consult local or state public health officials for assistance when evaluating rabies exposures and the need for postexposure prophylaxis.205 207

Any 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

Individuals with immunosuppression should receive a 5-dose regimen of rabies vaccine; give 1 mL (HDCV or PCECV) IM once on days 0, 3, 7, 14, and 28.

Deltoid 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.

Day 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.

Table 1. US Rabies Postexposure Prophylaxis Schedule for Adults, Adolescents, or Children216

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 vaccine; give 1 mL (human diploid-cell vaccine [HDCV] or purified chick embryo cell culture vaccine [PCECV]) IM once on days 0, 3, 7, and 14

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

RIG should not be administered

Rabies vaccine

Administer 2-dose regimen of rabies vaccine; give 1 mL (HDCV or PCECV) IM once on days 0 and 3

Regardless of immunization status, USPHS Advisory Committee on Immunization Practices (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 (See General under Dosage and Administration.)

In previously unvaccinated children, adolescents, and adults following potential rabies exposure, a combined regimen of active immunization with a 4- or 5-dose regimen of rabies vaccine and passive immunization with a single dose of RIG is recommended as soon as possible.205 207 216 (See Table 1.)

In previously vaccinated children, adolescents, and adults following potential rabies exposure, a 2-dose booster regimen of rabies vaccine (without RIG) is recommended as soon as possible.205 207 216 (See Table 1.)

During 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.

Initiate 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.

Euthanize 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.

Table 2. US Rabies Postexposure Prophylaxis Guide Based on Type and Status of Animal Involved207

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 rabies

Rabid or suspected rabid

Immediately begin postexposure prophylaxis

Unknown (e.g., escaped)

Consult public health officials

Skunks, raccoons, foxes, and most other carnivores; bats

Regard as rabid unless animal proven negative by laboratory tests

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

Bite exposures include any skin penetration by teeth; all bite exposures from an animal known or suspected to be rabid, regardless of bite location, pose a potential risk of rabies transmission and require postexposure prophylaxis.205 207 Risk of transmission varies in part based on the species of biting animal, anatomic site of bite, and severity of wound.207 Rabies transmission can occur from bites of some animals (e.g., bats) that inflict rather minor injury and wounds that are difficult to detect.207

Any potential exposure to a bat requires thorough evaluation.207 If possible, the bat should be submitted for rabies diagnosis.207 Postexposure prophylaxis is not necessary if the individual can be reasonably certain a bite, scratch, or mucous membrane exposure did not occur or if the bat is available for testing and is negative for rabies virus.207 Situations that might qualify as exposures include finding a bat in the same room as a person who might be unaware that a bite or direct contact has occurred (e.g., a deeply sleeping individual awakened to find a bat in the room; an adult observes a bat in the room with a previously unattended child, mentally disabled person, or intoxicated person).207 Other household members who do not have direct contact with the bat or were awake and aware when in the room with the bat should not be considered as having exposure to rabies.207

Nonbite exposures include contamination of preexisting open wounds, abrasions, mucous membranes, or scratches with saliva or other potentially infectious material (e.g., neural tissue) from an animal known or suspected to be rabid.205 207 Although nonbite exposures only rarely cause rabies, such exposures require assessment to determine if sufficient reasons exist to consider postexposure prophylaxis.205 207 Nonbite exposures of highest risk occur in surgical recipients of corneas, solid organs, and vascular tissue transplanted from patients who died of rabies and individuals exposed to large amounts of aerosolized rabies virus.207

Other forms of contact in the absence of a bite or nonbite exposure (e.g., petting a rabid animal; contact with blood, urine, or feces of a rabid animal; contact of saliva with intact skin) are not considered exposure, and postexposure prophylaxis is not necessary.207

In health-care personnel, routine delivery of health care to a patient with rabies is not an indication for postexposure rabies prophylaxis.207 However, 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

Because the rabies incubation period in humans can range from days to years (usually 1–3 months),205 207 210 216 initiate rabies postexposure prophylaxis (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.207

Postexposure prophylaxis failures have not been reported in the US when recommended immunization and wound management procedures were followed using commercially available rabies vaccines and RIG.206 207 216 Rare reports of failures in other countries usually involved some 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).206 207 216

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, 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 CDC states that rabies vaccines grown in animal brains (neural tissue vaccines) still may be used in some developing countries; if offered such a brain-derived vaccines (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, consult state and local health authorities for advice regarding the need for additional postexposure prophylaxis.207 Consider serologic testing 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.)

Rabies Immune Globulin Dosage and Administration

General

  • Rabies postexposure prophylaxis in previously unvaccinated individuals involves thorough cleansing of all bite and nonbite wounds followed by passive immunization with a single dose of RIG and active immunization with a series of 4 or 5 doses of rabies vaccine.201 205 206 207 216 210 216

  • RIG is not indicated for postexposure prophylaxis in individuals who previously received rabies vaccine for preexposure vaccination or postexposure prophylaxis.201 205 206 207 216 (See Specific Drugs under Interactions.)

  • Because rabies virus may remain localized at the site of inoculation for a variable time before entering neural tissue, immediately wash all bites and scratches with soap and water; if available, irrigate with a virucidal agent (e.g., povidone-iodine solution).201 205 207 210 216 Institute tetanus prophylaxis and measures to control secondary infection as indicated.205 207 Consider cosmetic factors and the potential for bacterial infection before deciding to suture large wounds.205 207 AAP states that, if possible, the wound should not be sutured.205

Administration

Administer by local infiltration with or without IM administration.201 205 206 207 216

Do not administer IV.201 206 (See Administration Precautions under Cautions.)

Local Infiltration

Infiltrate the recommended dose of RIG into the wound(s) and surrounding area if anatomically feasible.201 205 206 207 216

When the volume required to infiltrate the wound(s) exceeds the recommended dose of RIG, some clinicians recommend diluting the calculated dose in saline to yield a two- to threefold increase in solution volume to ensure that all wound areas receive adequate infiltration.205

IM Administration

After infiltrating wound(s) area, administer any remaining portion of the recommended RIG dose 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

Do not administer RIG into gluteal area (buttock muscle) because of potential for injection-associated injury to the sciatic nerve.201 202 216

Avoid injection into or near blood vessels or nerves.202 206 ACIP and 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

Do not administer RIG in the same syringe or simultaneously at the same injection site as rabies vaccine.201 205 206 207 216 (See Specific Drugs under Interactions.)

Do not mix with other immune globulins, vaccines, or solutions.202 205

Dosage

Pediatric Patients

Postexposure Prophylaxis of Rabies
Previously Unvaccinated Children and Adolescents
Local Infiltration followed by IM

Single dose of 20 international units/kg.201 205 206 207 216 Infiltrate into and around area of wound(s); administer any remaining portion of the dose by IM injection.201 205 206 207 216 (See Administration under Dosage and Administration.)

Commercially available 2-mL vials (HyperRAB S/D, Imogam Rabies-HT) contain 300 international units of RIG (sufficient dose for a 15-kg child).201 206

Give RIG dose as soon as possible after exposure (day 0), preferably at the time of the first dose of rabies vaccine.201 205 206 207 216

If rabies vaccine is not immediately available, administer RIG and start active immunization with the vaccine as soon as possible.205 If RIG is not immediately available, it may be administered at any time through day 7 following the first vaccine dose;205 207 216 RIG is not necessary after day 7 since sufficient vaccine-induced antirabies antibody will be present in most vaccine recipients.207 Some experts suggest that if administration of both RIG and vaccine is delayed, both should be used regardless of the interval between exposure and prophylaxis.201 205 206

Do not exceed the recommended RIG dose (i.e., single dose of 20 international units/kg); do not give repeated doses of RIG.201 205 206 207 (See Specific Drugs under Interactions.)

Adults

Postexposure Prophylaxis of Rabies
Previously Unvaccinated Adults
Local Infiltration followed by IM

Single dose of 20 international units/kg.201 205 206 207 216 Infiltrate into and around area of wound(s); administer any remaining portion of the dose by IM injection.201 205 206 207 216 (See Administration under Dosage and Administration.)

Commercially available 10-mL vials (HyperRAB S/D, Imogam Rabies-HT) contain 1500 international units of RIG (sufficient dose for a 75-kg adult).201 206

Give RIG dose as soon as possible after exposure (day 0), preferably at the time of the first dose of rabies vaccine.201 205 206 207 216

If rabies vaccine is not immediately available, administer RIG and start active immunization with the vaccine as soon as possible.205 If RIG is not immediately available, it may be administered at any time through day 7 following the first vaccine dose;205 207 216 RIG is not necessary after day 7 since sufficient vaccine-induced antirabies antibody will be present in most vaccine recipients.207 If administration of both RIG and vaccine is delayed, both should be used regardless of the interval between exposure and prophylaxis.201 205 206

Do not exceed the recommended RIG dose (i.e., single dose of 20 international units/kg); do not give repeated doses of RIG.201 205 206 207 (See Specific Drugs under Interactions.)

Prescribing Limits

Pediatric Patients

Local Infiltration followed by IM

Maximum total dose of 20 international units/kg.201 205 206 207

Adults

Local Infiltration followed by IM

Maximum total dose of 20 international units/kg.201 205 206 207

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Rabies Immune Globulin

Contraindications

  • Repeated doses of RIG after active immunization with rabies vaccine is initiated.206 (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Risk of Transmissible Agents in Plasma-derived Preparations

Because RIG (HyperRAB S/D, Imogam Rabies-HT) is prepared from pooled human plasma, it is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and HIV infection, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).201 206 208

Improved donor screening, viral-inactivation procedures (e.g., solvent/detergent treatment), and/or filtration procedures have reduced, but not completely eliminated, risk of pathogen transmission with plasma-derived preparations.201 206

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, administer RIG only when a benefit is expected.201 206

Any infection believed to have been transmitted by RIG should be reported to the appropriate manufacturer.201 206

Sensitivity Reactions

Hypersensitivity Reactions

Anaphylaxis has been reported rarely following administration of human immune globulins.201 206

Use with caution in individuals with 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

Selective IgA Deficiency

HyperRAB S/D may contain IgA.201

Use 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 Weigh potential benefits against potential for hypersensitivity reactions.201

General Precautions

Administration Precautions

Do not administer RIG in the same syringe or at the same injection site as rabies vaccine.201 206 207 216 (See Specific Drugs under Interactions.)

Do not administer IV.201 206 Inadvertent IV injection may result in serious systemic reactions; epinephrine should be available if an acute anaphylactic reaction occurs.201 206

Individuals with Altered Immunocompetence

May be administered to individuals immunosuppressed as the result of disease or immunosuppressive therapy.203 216

Recommendations regarding use of RIG in individuals with altered immunocompetence are the same as those for individuals who are not immunocompromised.203 216

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.203 205 207 216 If an adequate 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 (See Pre- and Postvaccination Serologic Testing under Cautions.)

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, use caution in such individuals.201 202 206

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, use a fine needle (23 gauge) to administer the dose and apply firm pressure to the injection site (without rubbing) for ≥2 minutes.202 205 If patient is receiving antihemophilia therapy, administer the IM dose shortly after a scheduled dose of such therapy.202

Advise the individual and/or their family about the risk of hematoma from IM injections.202

Duration of Immunity

RIG provides only short-term protection against rabies.207 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.201 205 206 207 216 Additional (booster) doses of RIG not recommended.201 205 206 207

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 rabies immunity following postexposure prophylaxis is not necessary in most individuals because of the high rate of response among immunocompetent adults, adolescents, and children when the recommended rabies postexposure regimen is used (i.e., proper wound care followed by a single dose of RIG and a 4- or 5-dose regimen of a cell culture-derived rabies vaccine).205 207 210 216

When postexposure prophylaxis against rabies 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 This includes individuals receiving immunosuppressive agents (e.g., those receiving corticosteroids for the treatment of life-threatening neuroparalytic reactions to rabies vaccine).207 (See Individuals with Altered Immunocompetence under Cautions.)

Consider serologic testing to confirm that an adequate antibody response was obtained in travelers who received rabies postexposure prophylaxis with regimens and/or preparations not currently recommended by ACIP.207 (See Postexposure Prophylaxis of Rabies under Uses.)

If serologic testing for serum antirabies antibody is performed 1–2 weeks after postexposure prophylaxis is completed, 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 WHO states that an enterobius antibody titer of ≥0.5 international units/mL can be considered protective.215

Specific Populations

Pregnancy

Category C.201 206

Pregnancy is not considered a contraindication for postexposure prophylaxis with RIG because of the potential risks of inadequately treated rabies exposure.206 207

ACIP states there are no known risks for the fetus associated with use of immune globulin preparations for passive immunization of pregnant women.202

Lactation

Not known whether RIG is distributed into milk or if transmission of RIG to a nursing infant would present any unusual risk.a

Pediatric Use

HyperRAB S/D: Safety and efficacy not established in children.201

ACIP and AAP recommend that postexposure prophylaxis (including use of RIG) in children follow the same guidelines as those in adults.205 207

Geriatric Use

Information not available regarding differences in efficacy and safety between geriatric and younger individuals.

Common Adverse Effects

Injection site reactions (e.g., tenderness, pain, muscle soreness, stiffness),201 206 207 low-grade fever,201 headache.206 207

Interactions for Rabies Immune Globulin

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; 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

Live Vaccines

Antibodies present in immune globulins, including RIG, may interfere with the immune response to certain live virus vaccines (e.g., measles, mumps, and rubella virus vaccine live (MMR), rotavirus vaccine live oral, varicella virus vaccine live); these vaccines should not be administered simultaneously with or for specified intervals before or after administration of RIG.201 202 204 205 206 (See Specific Drugs under Interactions.) There is no evidence that immune globulin preparations interfere with the immune response to yellow fever virus vaccine live, typhoid vaccine live oral, influenza virus vaccine live intranasal, or poliovirus vaccine live oral (OPV; no longer commercially available in the US).202 205

Specific Drugs

Drug

Interaction

Comments

Immunosuppressive agents (e.g., alkylating agents, antimetabolites, corticosteroids, radiation)

Potential for decreased antibody response to postexposure prophylaxis using combined active immunization with rabies vaccine and passive immunization with RIG; increased risk of rabies infection despite use of postexposure prophylaxis203 205 207 210 216

Avoid immunosuppressive therapy in patients receiving rabies postexposure prophylaxis unless such therapy is considered essential for treatment of other serious conditions203 207 216

If rabies postexposure prophylaxis is used in an individual receiving immunosuppressive agents, perform serologic testing for rabies antibody after completion of the postexposure regimen to confirm adequate immune response203 207 (See Pre- and Postvaccination Serologic Testing under Cautions.)

Measles, mumps, and rubella vaccine (MMR)

RIG may interfere with the immune response to measles and rubella antigens contained in MMR; the effect of RIG on the immune response to mumps antigens contained in the vaccine is unknown201 202 205 206

Manufacturers of HyperRAB S/D and Imogam Rabies-HT state that MMR should not be administered within 3 months after RIG201 206

ACIP and AAP state that MMR and RIG should not be administered simultaneously and that MMR should not be administered within 4 months after RIG202 205

ACIP and AAP also state that if RIG must be administered within 14 days after a dose of MMR, revaccination is necessary at least 4 months after RIG, unless serologic testing indicates an adequate antibody response to all 3 vaccine antigens202 205

Rabies vaccine

RIG, may partially suppress the active immune 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 vaccine201 206

Neutralization of rabies vaccine may occur if RIG and rabies vaccine are mixed in the same syringe or administered into the same injection site201 202 205 206 207

Repeating the dose of RIG may interfere with the active immune response to rabies vaccine 206

If rabies postexposure prophylaxis requires active immunization with rabies vaccine and passive immunization with RIG, a single dose of RIG should be administered simultaneously with the first vaccine dose;201 206 207 216 infiltrate the full RIG dose into and around the wound(s) if anatomically feasible and administer any remaining portion of the RIG dose IM (using a different syringe and injection site than rabies vaccine)201 202 205 206 207 216

To minimize potential suppression of the active immune response to the vaccine, do not exceed the recommended dosage of RIG (20 international units/kg) and do not give repeated RIG doses201 206 207

RIG may be administered simultaneously with or through day 7 after the first dose of rabies vaccine without impairing the active immune response to the vaccine201 205 206 207 216

RIG is not indicated for postexposure prophylaxis in individuals who previously received recommended preexposure or postexposure regimens of human diploid-cell rabies vaccine (Imovax), purified chick embryo cell culture (RabAvert), Imovax Rabies I.D. (no longer commercially available in the US]), or rabies vaccine adsorbed (RVA) (no longer commercially available in the US) or in those who previously received other rabies vaccines and have documented adequate antirabies antibody titers205 206 207 216

Rotavirus vaccine

RIG may interfere with the immune response to rotavirus vaccine202

Safety and efficacy data not available regarding use of rotavirus vaccine in infants who have received an immune globulin within 42 days211

If possible, defer dose of rotavirus vaccine until 42 days (6 weeks) after the immune globulin; use a shorter interval if the 42-day deferral would result in the first dose of rotavirus vaccine being scheduled at ≥13 weeks of age202

Typhoid vaccine

Oral live typhoid vaccine (Vivotif): No evidence that immune globulin preparations, including RIG, interfere with the immune response to the vaccine202 205

Parenteral inactivated typhoid vaccine (Typhim Vi): Specific studies evaluating concomitant use with immune globulins not available;214 interaction not expected since this is an inactivated vaccine202 205

Oral live typhoid vaccine (Vivotif): May be given simultaneously with or at any time before or after RIG202 205

Parenteral inactivated typhoid vaccine (Typhim Vi): May be given simultaneously with RIG (using different syringes and injection sites) or at any time before or after RIG202 205

Varicella vaccine

RIG may interfere with the immune response to varicella virus vaccine live202 204 205

Manufacturers of HyperRAB S/D and Imogam Rabies-HT state that live vaccines should not be administered within 3 months after RIG201 206

ACIP and AAP state that varicella vaccine and RIG should not be administered simultaneously and that the vaccine should not be administered within 4 months after RIG202 205

ACIP and AAP also state that if RIG must be administered within 14 days after a dose of varicella, revaccination is necessary at least 4 months after RIG, unless serologic testing indicates an adequate antibody response to the vaccine202 205

Yellow fever vaccine

No evidence that immune globulin preparations, including RIG, interfere with the immune response to yellow fever virus vaccine live202 205

Yellow fever vaccine may be given simultaneously with RIG (using different syringes and injection sites) or at any time before or after RIG202 205

Rabies Immune Globulin Pharmacokinetics

Absorption

Bioavailability

Absorbed slowly following IM administration.a

Following a single IM dose of 20 international units/kg, antirabies antibodies appear in serum within 24 hours201 206 and are still detectable on day 21.201

Distribution

Extent

Although specific information not available, it is likely that RIG crosses the placenta since other immunoglobulins cross the placenta.a

Information on distribution of RIG into milk not available; RIG may be distributed into milk since immunoglobulins (e.g., IgA, IgM, IgG) are present in colostrum.a

Elimination

Half-life

Approximately 21 days following IM administration.207

Stability

Storage

Parenteral

Injection

HyperRAB S/D and Imogam Rabies-HT: 2–8°C.201 206 Do not freeze; if freezing occurs, discard RIG.201 206

HyperRAB S/D and Imogam Rabies-HT do not contain thimerosal or any other preservatives.201 206 Discard any unused portion.206

Actions

  • RIG commercially available in the US is a sterile, nonpyrogenic solution prepared from plasma of healthy individuals with high titers of antibody to rabies antigen (average or minimum potency 150 international units/mL).201 206 207

  • RIG is used to provide temporary passive immunity to rabies infection as part of a postexposure prophylaxis regimen in unvaccinated individuals exposed to rabies virus.201 206 207 216 Specific antirabies antibodies present in RIG neutralize rabies virus and inhibit the spread of the virus and its infective properties.201 206 216

  • Following rabies exposure and inoculation, the virus remains close to the wound for an indeterminate time205 and can be partially neutralized by direct contact with RIG at this site.206 a In susceptible individuals, the virus may move along a neural pathway via the peripheral nerves toward the CNS.206 215 a 216 Following entrance into the CNS, the virus is unlikely to be affected by antibodies, and a fatal encephalomyelitis almost always develops.206 After clinical symptoms of rabies develop, use of RIG or rabies vaccine will not improve the prognosis; there is no specific treatment for rabies.205 210 215

  • Incubation period for rabies infection in humans can range from days to years (usually 1–3 months).205 206 210 216 After severe bites to the face, neck, or arms, the incubation period may be as short as 10 days.206

  • Development of immunity and protection from rabies infection are evaluated by appearance of antirabies antibody in serum.207 Minimum titers of antirabies antibodies indicating protection not definitely established to date (varies among laboratories and by type of test performed).207 215 ACIP considers antirabies antibody titers ≥1:5 as determined by RFFIT to be indicative of an adequate response to rabies immunization.207 216 WHO states that an anterobius antibody titer of ≥0.5 international units/mL can be considered protective.215

  • There have been no cases of rabies in the US in previously unvaccinated individuals who received the recommended postexposure prophylaxis regimen (i.e., proper wound care followed by a single dose of RIG and a 4- or 5-dose regimen of a cell culture-derived rabies vaccine).206 207 216

Advice to Patients

  • Advise patient and/or patient's parent or guardian of the risks and benefits of RIG.201 206

  • Advise patient and/or patient's guardian that RIG is only one component of a regimen used to prevent rabies in individuals who have been bitten, scratched, or licked on an open wound by an animal known or suspected of having rabies.201 206

  • When rabies postexposure prophylaxis is indicated in previously unvaccinated individuals, importance of receiving a single dose of RIG and completing a 4- or 5-dose series of rabies vaccine as soon as possible following rabies exposure.201 206 207

  • Importance of informing clinicians if the patient has altered immunocompetence because of disease (e.g., cancer, HIV/AIDS) or immunosuppressive therapy (e.g., corticosteroids, cancer treatment).203

  • Importance of informing clinicians if any adverse reactions (e.g., hypersensitivity reactions) occur.201 206

  • Advise patient and/or patient's parent or guardian that HyperRAB S/D and Imogam Rabies-HT are prepared from pooled human plasma.201 206 Although improved donor screening and viral-inactivating and purification procedures used in manufacture of plasma-derived preparations have reduced the risk of pathogen transmission, RIG is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and HIV infection, and theoretically may carry a risk of transmitting the causative agent of CJD or vCJD.201 206 208

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.201 206

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.201 206

  • Importance of informing patients of other important precautionary information.201 206 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Rabies Immune Globulin (Human)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection

150 units/mL

HyperRAB S/D (solvent/detergent treated)

Talecris

Imogam Rabies-HT (heat treated)

Aventis Pasteur

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 1, 2010. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

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.

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(RR-4):1-18.

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.

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.

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-Jakob disease (CJD) and variant Creutzfeldt-Jakob disease (vCJD) by blood and blood products. January 2002. From FDA website.

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.

211. Merck & Co. RotaTeq (rotavirus vaccine, live, oral, pentavalent) prescribing information. Whitehouse Station, NJ; 2009 Dec.

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.

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.

a. AHFS drug information 2010. McEvoy GK, ed. Rabies immune globulin. Bethesda, MD: American Society of Health-System Pharmacists; 2010.

Hide
(web4)