Class: Vaccines
ATC Class: J07BG01
VA Class: IM100
Brands: Imovax, RabAvert

Introduction

Inactivated virus vaccine.^208234236 Rabies vaccine contains rabies virus antigens and is used to stimulate active immunity to rabies infection.^208234236 Commercially available in the US as human diploid-cell rabies vaccine (HDCV; Imovax) and purified chick embryo cell culture rabies vaccine (PCECV; RabAvert).²⁰⁸²³⁴ Other rabies vaccines (e.g., vero cell rabies vaccine, duck embryo rabies vaccine, nerve tissue vaccine [NTV]) may be available in other countries.^213236249

Uses for Rabies Vaccine

Prevention of Rabies

Prevention of rabies in children, adolescents, and adults exposed to or at increased risk of exposure to rabies disease or virus.^{208213234236250}

Rabies is a viral infection transmitted by saliva of infected mammals, most commonly wild, terrestrial carnivores (e.g., skunks, raccoons, foxes, coyotes) or bats.²¹³²³⁶ In the US, the greatest risk for naturally acquired rabies is from contact with and bites from insectivorous bats.^222236242 Following exposure and infection, rabies virus usually moves along a neural pathway and enters the CNS.²³⁴²³⁶ After entrance into the CNS, the virus is unlikely to be affected by antirabies antibodies and encephalomyelitis usually develops and almost always is fatal.²³⁴²³⁶ In the US, approximately 16,000–39,000 individuals receive rabies postexposure prophylaxis each year.^234236250 Although there were 27 rabies cases reported in the US during 2000–2008,²⁵⁰ these individuals evidently did not receive rabies postexposure prophylaxis.²⁵⁰ 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.²⁵⁰ However, worldwide, rabies is much more common and at least 55,000 rabies-related deaths occur each year.²⁴⁹²⁵⁰

USPHS Advisory Committee on Immunization Practices (ACIP) and AAP recommend preexposure vaccination with rabies vaccine (series of 3 doses with booster doses when indicated) in children, adolescents, and adults who are or will be at increased risk of exposure to the virus.²¹³²³⁶ (See Preexposure Vaccination Against Rabies in High-risk Groups under Uses.)

Postexposure prophylaxis with a regimen that includes local wound treatment, rabies vaccine (series of 4 or 5 doses), and a single dose of rabies immune globulin (RIG) is recommend for previously unvaccinated children, adolescents, and adults following potential rabies exposure.²¹³²³⁶Postexposure prophylaxis with a regimen that includes local wound treatment and a series of 2 booster doses of rabies vaccine (without RIG) is recommended for previously vaccinated children, adolescents, and adults following potential rabies exposure.²¹³²³⁶ (See Postexposure Prophylaxis of Rabies under Uses.)

Preexposure Vaccination Against Rabies in High-risk Groups

Preexposure vaccination in children, adolescents, and adults who are or will be at risk of exposure to rabies virus.^208213234236

Preexposure vaccination does not eliminate the need for prompt postexposure prophylaxis if an exposure to rabies occurs.^{208213234236250} (See Postexposure Prophylaxis of Rabies under Uses.)

Need for rabies preexposure vaccination depends on the nature of risk and associated level of potential exposure.²³⁶ Consider preexposure vaccination for individuals whose risk of rabies exposure is greater than that of the general population (e.g., veterinarians and their staff, animal-control and wildlife workers, field biologists, spelunkers, missionaries, rabies researchers, certain laboratory workers).²¹²²³⁶ Also consider preexposure vaccination for individuals whose activities bring them into frequent contact with rabies virus or potentially rabid bats, raccoons, skunks, cats, dogs, or other species at risk for having rabies.²³⁶ (For ACIP definitions of risk categories and recommendations regarding preexposure vaccination for each category, see Table 1.)

Travelers to areas where rabies is endemic may be at risk, especially if they are likely to come in contact with animals in areas where dog or other animal rabies is enzootic and immediate access to appropriate medical care (including rabies vaccine and RIG) is unlikely.^212236237249 Canine rabies remains highly endemic in certain areas of the world (e.g., parts of Africa, Asia, Central and South America).²¹²²³⁷ CDC recommends preexposure vaccination based on local incidence of rabies in the country to be visited, availability of appropriate agents for rabies postexposure prophylaxis in that country, and intended activity and duration of stay.²¹²

Minimum acceptable antibody titer is complete virus neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test (RFFIT). Give booster dose of rabies vaccine if titer falls below this level.

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 1. US Rabies Risk Categories and Recommendations for Preexposure Vaccination236

Category of Rabies Risk	Nature of Risk	Typical Population	Preexposure Vaccination
Continuous	Virus present continuously (often in high concentrations); specific exposure likely to go unrecognized; bite, nonbite, or aerosol exposure	Rabies research laboratory workers, rabies biologics production workers	Yes; then perform serologic testing every 6 months and give booster dose if antibody titer decreases to less than acceptable level
Frequent	Exposure usually episodic; source recognized, but exposure may go unrecognized; bite, nonbite, or aerosol exposure	Rabies diagnostic laboratory workers, cavers, veterinarians and their staff, animal-control and wildlife workers in rabies enzootic areas, individuals who frequently handle bats	Yes; then perform serologic testing every 2 years and give booster dose if antibody titer decreases to less than acceptable level
Infrequent (but greater than in general population)	Exposure is nearly always episodic with a recognized source; bite or nonbite exposure	Veterinarians and animal-control staff working with terrestrial animals in areas where rabies is uncommon to rare, veterinary students, travelers visiting areas where rabies is enzootic and immediate access to appropriate medical care is limited	Yes; serologic testing and booster doses not necessary
Rare (population at large)	Exposure always episodic with a recognized source; bite or nonbite exposure	US population at large, including those in rabies-epizootic areas	Not necessary

Postexposure Prophylaxis of Rabies

Postexposure prophylaxis of rabies in previously vaccinated and unvaccinated children, adolescents, and adults following exposure to rabies disease or virus.^{208213234236250}

History of previous vaccination against rabies simplifies the postexposure prophylaxis regimen, but does not eliminate the need for prompt postexposure prophylaxis if an exposure to rabies occurs.^208234236250

Whenever a possible human exposure to rabies occurs, the risk of infection must be accurately assessed to determine the need for postexposure prophylaxis.²³⁶²⁵⁰ Base decisions regarding the need for postexposure prophylaxis on vaccination status of exposed individual (see Table 2), type of exposure (bite, nonbite), information about the animal involved (type, vaccination status, condition at time of attack) (see Table 3), and rabies epidemiology in the specific geographic region.^213236250 Consult local or state public health officials for assistance when evaluating rabies exposures and the need for postexposure prophylaxis.^213236250

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 2. US Rabies Postexposure Prophylaxis Schedule for Adults, Adolescents, or Children250

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; Imovax] or purified chick embryo cell culture vaccine [PCECV; RabAvert]) 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 rabies immunization status, 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.^213236250 Local wound treatment is an essential initial step in rabies postexposure prophylaxis in all individuals.^213236250 (See General under Dosage and Administration.)

In previously unvaccinatedchildren, adolescents, and adults following potential rabies exposure, a postexposure prophylaxis 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.^{208213234236250} The ACIP states that a 4-dose regimen of rabies vaccine in conjunction with RIG is sufficient for postexposure prophylaxis in previously unvaccinated individuals who are immunocompetent; however, a 5-dose vaccine regimen in conjunction with RIG should be used in those with altered immunocompetence.²⁵⁰

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.^213236250

During the 10-day observation period, begin postexposure prophylaxis in the exposed individual at the first sign of rabies in a 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.

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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 3. US Rabies Postexposure Prophylaxis Guide Based on Type and Status of Animal Involved236

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.²¹³²³⁶ Risk of transmission varies in part based on species of biting animal, anatomic site of bite, and severity of wound.²³⁶ Rabies transmission can occur from bites of some animals (e.g., bats) that inflict rather minor injury and wounds that are difficult to detect.²³⁶

Any potential exposure to a bat requires thorough evaluation.²³⁶ If possible, the bat should be submitted for rabies diagnosis.²³⁶Postexposure 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.²³⁶ 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 occurred (e.g., a deeply sleeping individual awakened to find a bat in the room or an adult observes a bat in the room with a previously unattended child, mentally disabled person, or intoxicated person).²³⁶ Other household members who did 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.²³⁶

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.²¹³²³⁶ Although nonbite exposures only rarely cause rabies, such exposures require assessment to determine if sufficient reasons exist to consider postexposure prophylaxis.²¹³²³⁶ 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.²³⁶

Transmission of rabies to individuals performing autopsies not reported to date;²⁵¹ no confirmed cases of rabies reported in individuals performing postmortem examinations of humans or animals.²⁵¹ CDC recommends that personnel performing autopsies on decedents with confirmed or suspected rabies use appropriate personal protective equipment, wear heavy or chain mail gloves, minimize aerosol generation by using a handsaw rather than oscillating saw, limit the number of individuals participating in the procedure and collection of specimens, and use ample amounts of 10% sodium hypochlorite solution during and after the procedure to ensure decontamination of all exposed surfaces.²⁵¹ CDC states that preexposure vaccination against rabies usually is not required for individuals performing autopsies and that rabies postexposure prophylaxis is recommended in autopsy personnel only if a wound or mucous membrane gets contaminated with the patient's saliva or other potentially infectious material (e.g., neural tissue) during the procedure.²⁵¹

Other forms of contact in the absence of a bite or nonbite exposure (e.g., petting a rabid animal or 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.²³⁶

In health-care personnel, routine delivery of health care to a patient with rabies is not an indication for postexposure rabies prophylaxis; postexposure prophylaxis in such personnel is indicated 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).²³⁶

Because the rabies incubation period in humans can range from days to years (usually 1–3 months),^{212213234236250} 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.²³⁶

Postexposure prophylaxis failures have not been reported in the US when recommended wound management and postexposure regimens were followed using commercially available rabies vaccines and RIG.²³⁶²⁵⁰ ACIP states that rabies pathogenesis data, animal data, clinical studies, and epidemiologic surveillance indicate that a 4-dose vaccine series is as effective as a 5-dose vaccine series when used in conjunction with wound management and RIG.²⁵⁰ Rare reports of postexposure prophylaxis 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 vaccine doses).^234236250

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).²¹² 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.²¹² CDC states that rabies vaccines grown in animal brains (nerve tissue vaccines; NTV) may still be used in some developing countries; 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 and RIG are available.²¹² 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.²¹²²³⁶ In such cases, consult state and local health authorities for advice regarding the need for additional postexposure prophylaxis.²³⁶ Consider serologic testing in these travelers to verify efficacy of the regimen used and to ensure an adequate immune response.²³⁶ (See Pre- and Postvaccination Serologic Testing under Cautions.)

Rabies Vaccine Dosage and Administration

General

• Rabies postexposure prophylaxis in previously unvaccinated individuals involves thorough cleansing of all bite and nonbite wounds followed by active immunization with rabies vaccine and passive immunization with RIG.^212213236250

• Rabies postexposure prophylaxis in previously vaccinated individuals involves thorough cleansing of all bite and nonbite wounds followed by booster doses of rabies vaccine (without RIG).^212213236250

• 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).^212213236250 Institute tetanus prophylaxis and measures to control secondary infection as indicated.^208213236 Consider cosmetic factors and the potential for bacterial infection before deciding to suture large wounds.²¹³²³⁶ AAP states that, if possible, the wound should not be sutured.²¹³

Administration

IM Administration

Administer by IM injection.^208213234236

Do not administer sub-Q, intravascularly, or intradermally.²⁰⁸²³⁴ (See Administration Precautions under Cautions.)

Depending on patient age, administer IM into the deltoid muscle or anterolateral thigh.^{208211212213234236250}

For adults, adolescents, and older children, the deltoid is the only acceptable IM injection site; for younger children, the deltoid or anterolateral thigh should be used.^{208211212213234236250}

Avoid use of the gluteal area as a possible IM injection site.^{208209210211212213216221234} (See Administration Precautions under Cautions.)

Avoid injection into or near blood vessels or nerves.²⁰⁸²³⁴

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, thickness of adipose tissue and muscle at the injection site, and injection technique.²¹¹

Administer immediately after reconstitution.²⁰⁸²³⁴ Use entire volume of reconstituted single-dose vaccine vial.²⁰⁸²³⁶

Use separate needles for reconstitution and administration.²⁰⁸²³⁴

Do not administer rabies vaccine in the same syringe or simultaneously at the same injection site as RIG.^213236246216 (See Specific Drugs under Interactions.)

Do not mix with any other vaccine or solution.²¹¹²¹³

Reconstitution (HDCV; Imovax)

To reconstitute, add entire contents of syringe containing diluent provided by the manufacturer to the single-dose vial of lyophilized vaccine.²⁰⁸ Use only the diluent supplied by the manufacturer.²⁰⁸

Attach reconstitution needle and plunger to the syringe and inject diluent into vaccine vial.²⁰⁸ Gently swirl until completely dissolved.²⁰⁸ The lyophilized vaccine is creamy white to orange; reconstituted suspension is pink to red.²⁰⁸

Remove reconstitution needle and discard.²⁰⁸ Use a suitable needle for IM administration.²⁰⁸ Use immediately after reconstitution.²⁰⁸

Reconstitution (PCECV; RabAvert)

To reconstitute, add entire contents of vial containing diluent (1 mL of sterile water for injection) provided by the manufacturer to the single-dose vial of lyophilized vaccine.²³⁴ Use only the diluent supplied by the manufacturer.²³⁴

Using the longer of the 2 needles provided by the manufacturer, withdraw entire contents of the diluent into the syringe.²³⁴ Insert the needle at a 45° angle into the vaccine vial; slowly inject entire contents of diluent vial into the vaccine vial.²³⁴ Mix gently to avoid foaming.²³⁴ Lyophilized vaccine is white; reconstituted suspension is clear or slightly opaque.²³⁴

Withdraw entire amount of dissolved vaccine into the syringe and replace the long needle with the smaller one for IM injection.²³⁴ Use immediately after reconstitution.²³⁴

The vaccine vial contains negative pressure that may impede withdrawal of the full dose of reconstituted vaccine.²³⁴ The manufacturer recommends that the syringe be disconnected from the needle after reconstitution to allow any remaining vacuum to exhaust; however, creating positive pressure (e.g., by injecting air into the vial) is not recommended since over-pressurization may interfere with withdrawal of the proper vaccine dose.²³⁴

Dosage

Whenever possible, the rabies vaccine (HDCV [Imovax], PCECV [RabAvert]) used for the initial dose should be used for subsequent doses in the vaccine series in the same individual.^213234236 Although only limited data available to date, most experts state that rabies vaccines currently available in the US may be considered interchangeable.^213234236 ACIP states clinical studies not available to date showing differences in efficacy or safety if the vaccine series is completed with a different preparation.²³⁶

Adhere to the recommended vaccination schedule as closely as possible.²³⁶ If a minor deviation from the schedule occurs (e.g., a dose is delayed by a few days), give the dose and resume the vaccination schedule using the same interval between doses.²³⁶ If a substantial deviation from the schedule occurs, perform serologic testing 7–14 days after the final vaccine dose to assess immune status.²³⁶ (See Pre- and Postvaccination Serologic Testing under Cautions.)

Pediatric Patients

Preexposure Vaccination Against Rabies in High-risk Groups

Primary Immunization in Children and Adolescents

IM

Interpol our love to admire deluxe torrent. Primary immunization consists of a series of 3 doses.^208213234236 Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.^208234236

Give first dose on a selected date; give second and third doses 7 and 21 (or 28) days, respectively, after first dose.^208213234236

Completion of the recommended 3-dose primary series before an expected exposure to rabies virus ensures the highest level of protection.^208213234236

Serologic confirmation of rabies immunity following the 3-dose primary series is not necessary in most individuals.^{208212213234236} (See Pre- and Postvaccination Serologic Testing under Cautions.)

Duration of immunity following the recommended 3-dose primary series is ≥2 years.^213234236 (See Duration of Immunity under Cautions.) Need for additional (booster) doses depends on the category of risk for rabies infection and levels of antirabies antibody.²³⁶ (See Booster Doses in Children and Adolescents under Dosage and Administration.)

Booster Doses in Children and Adolescents

IM

Each booster dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.^208213234236

Give a booster dose if indicated to maintain adequate levels of antirabies antibody.^208213234236 Booster doses may be indicated in those at continuous or frequent risk of rabies, but not in those at infrequent or rare risk.^208213234236 (For ACIP definitions of risk categories and recommendations regarding preexposure vaccination for each category, see Table 1 under Uses.)

In those at continuous risk of rabies, perform serologic testing every 6 months and administer booster dose if necessary.^208212213236 (See Pre- and Postvaccination Serologic Testing under Cautions.)

In those at frequent risk, perform serologic testing every 2 years and administer booster dose if necessary.^208212213236 (See Pre- and Postvaccination Serologic Testing under Cautions.)

Postexposure Prophylaxis of Rabies

Previously Unvaccinated Children and Adolescents

IM

Postexposure prophylaxis in previously unvaccinated individuals consists of active immunization with a series of 4 or 5 doses of rabies vaccine in conjunction with passive immunization with a single dose of RIG.^{208213234236250}

Although the manufacturers recommend a 5-dose regimen of rabies vaccine in conjunction with RIG for postexposure prophylaxis in all previously unvaccinated individuals,²⁰⁸²³⁴ the ACIP states that a 4-dose regimen of rabies vaccine in conjunction with RIG is sufficient for previously unvaccinated individuals who are immunocompetent and that a 5-dose vaccine regimen in conjunction with RIG should be used in those with altered immunocompetence.²⁵⁰

Immunocompetent children and adolescents: ACIP recommends first vaccine dose as soon as possible after exposure (day 0); give 3 remaining doses on days 3, 7, and 14, respectively, after first dose.²⁵⁰ Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.^208234236250

Immunocompromised children and adolescents: ACIP recommends first vaccine dose as soon as possible after exposure (day 0); give 4 remaining doses on days 3, 7, 14, and 28, respectively, after first dose.²⁵⁰ Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.^208234236250

Administer RIG dose preferably at the time of the first dose of rabies vaccine.^{208213234236250} If rabies vaccine is not immediately available, administer RIG dose and start the vaccine series as soon as possible.²¹³²⁵⁰ If RIG is not immediately available, it may be administered at any time through day 7 following the first vaccine dose.²¹³²³⁶ RIG is not necessary after day 7 since sufficient vaccine-induced rabies antibody will be present in most vaccine recipients.²³⁶ (See Specific Drugs under Interactions.)

Previously Vaccinated Children and Adolescents

IM

Postexposure prophylaxis in previously vaccinated individuals consists of a series of 2 booster doses of rabies vaccine (without RIG).^{208213234236250}

Each booster dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.^208234236250

Give first dose as soon as possible after exposure (day 0); give second dose 3 days later.^{208213234236250}

This 2-dose regimen can be used in those who previously received a preexposure or postexposure vaccination regimen with HDCV (Imovax), PCECV (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 those who previously received preexposure vaccination with some other vaccine and had documented levels of antirabies antibody considered adequate.^{208213234236250} (See Pre- and Postvaccination Serologic Testing under Cautions.)

Adults

Preexposure Vaccination Against Rabies in High-risk Groups

Primary Immunization in Adults

IM

Primary immunization consists of a series of 3 doses.^208213234236 Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.^208234236

Give first dose on a selected date; give second and third doses 7 and 21 (or 28) days, respectively, after first dose.^208213234236

Completion of the 3-dose primary series before an expected exposure to rabies virus ensures the highest level of protection.^208213234236

Serologic confirmation of rabies immunity following the 3-dose primary series is not necessary in most individuals.^{208212213234236} (See Pre- and Postvaccination Serologic Testing under Cautions.)

Duration of immunity following the recommended 3-dose primary series is ≥2 years.^213234236 (See Duration of Immunity under Cautions.) Need for additional (booster) doses depends on the category of risk for rabies infection and levels of antirabies antibody.²³⁶ (See Booster Doses in Adults under Dosage and Administration.)

Booster Doses in Adults

IM

Each booster dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.^208213234236

Give a booster dose if indicated to maintain adequate levels of antirabies antibody.^208213234236 Booster doses may be indicated in those at continuous or frequent risk of rabies, but not in those at infrequent or rare risk.^208213234236 (For ACIP definitions of risk categories and recommendations regarding preexposure vaccination for each category, see Table 1 under Uses.)

In those at continuous risk of rabies, perform serologic testing every 6 months and administer booster dose if necessary.^208212213236 (See Pre- and Postvaccination Serologic Testing under Cautions.)

In those at frequent risk, perform serologic testing every 2 years and administer booster dose if necessary.^208212213236 (See Pre- and Postvaccination Serologic Testing under Cautions.)

Postexposure Prophylaxis of Rabies

Previously Unvaccinated Adults

IM

Postexposure prophylaxis in previously unvaccinated individuals consists of active immunization with a series of 4 or 5 doses of rabies vaccine in conjunction with passive immunization with a single dose of RIG.^{208213234236250}

Although the manufacturers recommend a 5-dose regimen of rabies vaccine in conjunction with RIG for postexposure prophylaxis in all previously unvaccinated individuals,²⁰⁸²³⁴ the ACIP states that a 4-dose regimen of rabies vaccine in conjunction with RIG is sufficient for previously unvaccinated individuals who are immunocompetent and that a 5-dose vaccine regimen in conjunction with RIG should be used in those with altered immunocompetence.²⁵⁰

Immunocompetent adults: ACIP recommends first vaccine dose as soon as possible after exposure (day 0); give 3 remaining doses on days 3, 7, and 14, respectively, after first dose.²⁵⁰ Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.^208234236250

Immunocompromised adults: ACIP recommends first vaccine dose as soon as possible after exposure (day 0); give 4 remaining doses on days 3, 7, 14, and 28, respectively, after first dose.²⁵⁰ Each dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.^208234236250

Administer RIG dose preferably at the time of the first dose of rabies vaccine.^{208213234236250} If rabies vaccine is not immediately available, administer RIG dose and start the vaccine series as soon as possible.²¹³²⁵⁰ If RIG is not immediately available, it may be administered at any time through day 7 following the first vaccine dose.^213236250 RIG is not necessary after day 7 since sufficient vaccine-induced rabies antibody will be present in most vaccine recipients.²³⁶ (See Specific Drugs under Interactions.)

Previously Vaccinated Adults

IM

Postexposure prophylaxis in previously vaccinated individuals consists of a series of 2 booster doses of rabies vaccine (without RIG).^{208213234236250}

Each booster dose consists of the entire contents (1 mL) of a reconstituted single-dose vial.^208234236250

Give first dose as soon as possible after exposure (day 0); give second dose 3 days later.^{208213234236250}

This 2-dose regimen can be used in those who previously received a preexposure or postexposure vaccination regimen with HDCV (Imovax), PCECV (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 those who previously received preexposure vaccination with some other vaccine and had documented titers of antirabies antibody considered adequate.^{208213234236250} (See Pre- and Postvaccination Serologic Testing under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Rabies Vaccine

Contraindications

• HDCV (Imovax) for preexposure vaccination: Manufacturer states none known other than situations such as developing febrile illness, etc.²⁰⁸ (See Concomitant Illness under Cautions.)

• PCECV (RabAvert) for preexposure vaccination: History of anaphylactic reactions to the vaccine or any component.²³⁴ (See Sensitivity Reactions under Cautions.)

• HDCV (Imovax) and PCECV (RabAvert) for postexposure prophylaxis: No known contraindications, including pregnancy, because of the almost invariably fatal outcome of rabies infection.²⁰⁸²³⁴ (See Pregnancy under Cautions.)

Warnings/Precautions

Warnings

Nervous System Effects

Neurologic effects, sometimes serious (e.g., Guillain-Barré syndrome, transient neuroparalysis, myelitis, retrobulbar neuritis, multiple sclerosis, subacute peripheral and focal CNS disorders) temporally associated with HDCV (Imovax) and PCECV (RabAvert).²⁰⁸²³⁴

If neurologic effects occur, carefully consider the individual's risk of acquiring rabies when deciding whether to discontinue the vaccination series.²⁰⁸²³⁴ Contact state health departments or CDC for advice and assistance regarding management of these individuals.²⁰⁸²³⁶

Use of corticosteroids to treat life-threatening neuroparalytic reactions may interfere with the immune response to rabies vaccine.²⁰⁸²³⁴ (See Specific Drugs under Interactions.) Perform serologic testing in individuals receiving corticosteroids to verify seroconversion following vaccination.²⁰⁸ (See Pre- and Postvaccination Serologic Testing under Cautions.)

Immediately report all serious vaccine-associated neuroparalytic reactions to the manufacturer and to the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or [Web].²⁰⁸²³⁴

Administration Precautions

Administer IM into the deltoid or anterolateral thigh in infants and young children and into the deltoid in adults, adolescents, and older children.^211213236250 (See Administration under Dosage and Administration.)

Do not administer into gluteal muscle; suboptimal immunologic response may occur.^{208209210211212213216221234250} Reason for suboptimal response unclear; may occur because of inadvertent sub-Q injection or administration into fatty tissue instead of muscle.^209210211221 Fatal rabies paralysis and encephalitis reported in several individuals who received HDCV (Imovax) by IM injection into the gluteal area.^210216221

Inadvertent intravascular injection of PCECV (RabAvert) may result in systemic reactions (e.g., shock); immediate countermeasures include use of catecholamines, volume replacement, high doses of corticosteroids, and oxygen.²³⁴

Do not administer RIG in the same syringe or simultaneously at the same injection site as rabies vaccine.^213236246250 (See Specific Drugs under Interactions.)

Individuals with Altered Immunocompetence

May be administered to individuals immunosuppressed as the result of disease or immunosuppressive therapy.^211233236250 Consider possibility that the immune response to rabies vaccine and efficacy may be reduced in these individuals.^{208213234236250}

ACIP states that recommendations concerning use of rabies vaccine in individuals with altered immunocompetence (e.g., patients with HIV infection, congenital immunodeficiency, leukemia, lymphoma, aplastic anemia, generalized malignancy, solid organ transplant, asplenia, renal failure, diabetes, alcoholism, or alcoholic cirrhosis, or in those receiving therapy with alkylating agents, antimetabolites, radiation, corticosteroids, or other chronic immunosuppressive therapy) generally are the same as those for patients who are not immunocompromised.^233236250 However, the ACIP states that a 5-dose vaccine series (not a 4-dose series) of HDCV (Imovax) or PCECV (RabAvert) should be used when rabies postexposure prophylaxis is indicated in previously unvaccinated individuals with altered immunocompetence.²⁵⁰ (See Previously Unvaccinated Children and Adolescents and also see Previously Unvaccinated Adults under Dosage and Administration.)

Postpone preexposure vaccination (3-dose primary series) in immunocompromised individuals and advise them to avoid activities for which rabies preexposure vaccination is indicated.²¹²²³⁶ If this is not possible, administer preexposure vaccination and perform serologic testing to document seroconversion.²¹²²³⁶ (See Pre- and Postvaccination Serologic Testing under Cautions.) Individuals who fail to seroconvert after the third vaccine dose should be managed in consultation with their clinician and appropriate public health officials.²³⁶

Avoid use of immunosuppressive agents during rabies postexposure prophylaxis, unless considered essential for the treatment of other conditions.^233234236250 (See Specific Drugs under Interactions.)

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.^234236250 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.²¹⁶²⁵⁰ (See Pre- and Postvaccination Serologic Testing under Cautions.)

Risk of Transmissible Agents in Preparations Containing Albumin

HDCV (Imovax) and PCECV (RabAvert) contain albumin human.²⁰⁸²³⁴

Since albumin 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).²³⁴²⁴⁵

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.²³⁴

Sensitivity Reactions

Hypersensitivity Reactions

Allergic reactions, including anaphylaxis and immune complex-like reactions, reported in association with HDCV (Imovax) or PCECV (RabAvert).^208219234236 Bronchospasm, edema, pruritus, and urticaria also reported during postmarketing surveillance.²³⁴

Serious anaphylactic reactions during rabies vaccination pose a serious therapeutic dilemma.^208234236 Carefully consider the individual's risk of acquiring rabies when deciding whether to discontinue the vaccination series.²⁰⁸²³⁶ Contact state health departments or CDC for advice and assistance regarding management of these individuals.²⁰⁸²³⁶

When rabies vaccine is indicated in an individual with a history of hypersensitivity to the vaccine or any ingredient, observe patient closely following each dose and ensure that appropriate therapy (e.g., epinephrine, corticosteroids, oxygen) is readily available to treat a reaction if it occurs.^208234236 Use of prophylactic antihistamines is acceptable.²³⁴²³⁶

Immediately report all serious anaphylactic reactions associated with rabies vaccine to the manufacturer and the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or [Web].^213234236

Immune Complex-like Reactions

Immune complex (serum sickness)-like (type III hypersensitivity) reactions reported in up to 6% of individuals 2–21 days following booster doses of HDCV (Imovax).^208219236 Similar reactions also reported following primary immunization with HDCV (Imovax), but much less frequently.^208219236

These reactions involved generalized urticaria with or without arthralgia, arthritis, angioedema, nausea, vomiting, fever, and malaise and were not life-threatening.^208219236

May be caused by β-propiolactone-altered albumin human formed as a result of the manufacturing process for HDCV (Imovax); β-propiolactone is thought to render the albumin allergenic resulting in development of IgE antibodies to the allergen.²³⁶

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Do not administer additional doses of HDCV (Imovax) in individuals who experienced immune complex-like reactions to a previous dose, unless postexposure prophylaxis with the vaccine is considered necessary.²⁰⁸

Allergy to Neomycin or Other Anti-infectives

Each dose of HDCV (Imovax) contains <150 mcg of neomycin sulfate.²⁰⁸ Each dose of PCECV (RabAvert) contains <1 mcg of neomycin and trace amounts of chlortetracycline (<20 ng) and amphotericin B (<2 ng).²³⁴

Use caution in individuals sensitive to these antibiotics.²³⁴ Weigh possibility of an allergic reaction against the potential risk of contracting rabies if the vaccine is not given.²⁰⁸²³⁴

Neomycin allergy usually results in delayed-type (cell-mediated) hypersensitivity reactions manifested as contact dermatitis.²¹¹ ACIP and AAP state that vaccines containing trace amounts of neomycin should not be used in individuals with a history of anaphylactic reaction to neomycin, but use of such vaccines may be considered in those with a history of delayed-type neomycin hypersensitivity if benefits of vaccination outweigh the risks.²¹¹²¹³

Gelatin Allergy

PCECV (RabAvert) contains <12 mg of polygeline (bovine gelatin).²³⁴ Consider possibility of allergic reactions in individuals sensitive to bovine gelatin.²¹¹²³⁴ Bovine components of the vaccine originate only in the US, Australia, and New Zealand.²³⁴

Allergy to Egg-related Antigens

PCECV (RabAvert) is produced in chick embryo cell culture and may contain minimal amounts of chicken protein.²³⁴ HDCV (Imovax) is produced in human diploid cells and does not contain chicken protein.²⁰⁸

Consider possibility that an allergic reaction may occur if PCECV (RabAvert) is used in individuals allergic to chicken protein.²³⁴

Safety data regarding use of PCECV (RabAvert) in individuals with egg allergy not available.²³⁴ Experience with other vaccines produced using primary cultures of chick embryo fibroblasts indicate that documented egg hypersensitivity does not necessarily predict an increased likelihood of adverse reactions.²³⁴

No evidence to date that individuals with allergies to chickens or feathers are at increased risk of reaction to vaccines produced in chick embryo fibroblasts.²³⁴

General Precautions

Local or Systemic Adverse Effects

Once initiated, postexposure prophylaxis for rabies should not be interrupted or discontinued because of local or mild systemic adverse reactions to rabies vaccine.^208234236 These reactions generally can be managed with NSAIAs or antipyretic agents (e.g., ibuprofen, acetaminophen).^208234236

Serious systemic, anaphylactic, or neuroparalytic reactions pose a therapeutic dilemma.²⁰⁸²³⁶ Contact state health departments or CDC for advice and assistance regarding management of these individuals.²⁰⁸²³⁶

Limitations of Vaccine Effectiveness

May not protect all vaccine recipients against rabies.²³⁴

May not prevent rabies in individuals who do not achieve adequate antibody titers.²³⁴²³⁶ (For information on adequate antibody titers, see Pre- and Postvaccination Serologic Testing under Cautions.)

Duration of Immunity

Duration of immunity following the recommended 3-dose preexposure vaccine series (primary immunization) of HDCV (Imovax) or PCECV (RabAvert) is ≥2 years.^213234236

Need for additional (booster) doses after primary immunization depends on the nature and category of risk associated with the potential exposure.²³⁶ (See Booster Doses in Children and Adolescents and also see Booster Doses in Adults under Dosage and Administration)

Concomitant Illness

A decision to administer or delay vaccination in an individual with current or recent febrile illness depends on the severity of symptoms and etiology of the illness.²¹¹

ACIP states that minor acute illness, such as mild diarrhea or mild upper respiratory tract infection (with or without fever) generally does not preclude vaccination.^211212213

The manufacturers and ACIP state that preexposure rabies vaccination (but not postexposure prophylaxis) with HDCV (Imovax) or PCECV (RabAvert) generally should be deferred in individuals with moderate or severe acute illness until improvement of the condition is noted.^208211234

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.²¹¹

ACIP states that vaccines may be given IM to individuals who have bleeding disorders or are receiving anticoagulant therapy if a clinician familiar with the patient's bleeding risk determines that the vaccine can be administered with reasonable safety.²¹¹ In these cases, use a fine needle (23 gauge) to administer the vaccine and apply firm pressure to the injection site (without rubbing) for ≥2 minutes.²¹¹ If patient is receiving antihemophilia therapy, administer the IM vaccine shortly after a scheduled dose of such therapy.²¹¹

Advise the individual and/or their family about the risk of hematoma from IM injections.²¹¹

Pre- and Postvaccination Serologic Testing

If serologic testing for serum antirabies antibody is performed 1–2 weeks after preexposure vaccination or postexposure prophylaxis, 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).²³⁶²⁵⁰ WHO states that an antirabies antibody titer of ≥0.5 international units/mL can be considered protective.²⁴⁹

Serologic confirmation of rabies immunity following preexposure vaccination (3-dose primary series) is not necessary in most individuals because of the high rate of response in immunocompetent adults, adolescents, and children when the recommended vaccine regimen is used.^{208212213234236}

Postvaccination serologic testing may be particularly important in immunocompromised individuals who receive preexposure vaccination since these individuals may have impaired immune response to vaccination.^208213234236 Manage individuals who fail to seroconvert after the third vaccine dose in the primary series in consultation with appropriate public health officials.²³⁶ (See Individuals with Altered Immunocompetence under Cautions.)

To determine the need for preexposure booster doses of rabies vaccine in individuals who received preexposure vaccination with a primary vaccine series, serum antirabies antibody titers should be measured every 6 months in those at continuous risk of rabies exposure and every 2 years for those at frequent risk of rabies exposure.^208212213236 (For ACIP definitions of risk categories and recommendations regarding preexposure vaccination for each category, see Table 1 under Uses.)

Serologic testing is not indicated prior to postexposure prophylaxis in previously vaccinated individuals who are exposed to rabies.²³⁶ 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.²³⁶

Serologic confirmation of rabies immunity following postexposure prophylaxis is not necessary in most individuals because of the high rate of vaccine response among immunocompetent adults, adolescents, and children when the recommended rabies postexposure prophylaxis 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).^208212213236

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.^208213234236 This includes individuals receiving immunosuppressive agents (e.g., those receiving corticosteroids for the treatment of life-threatening neuroparalytic reactions to rabies vaccine).²³⁶ (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.²³⁶ (See Postexposure Prophylaxis of Rabies under Uses.)

Improper Storage and Handling

Improper storage or handling of vaccines may result in loss of vaccine potency and reduced immune response in vaccinees.²¹¹

Do not administer HDCV (Imovax) or PCECV (RabAvert) that has been mishandled or has not been stored at the recommended temperature.²¹¹ (See Storage under Stability.)

Inspect all vaccines upon delivery and monitor during storage to ensure that the appropriate temperature is maintained.²¹¹ If there are concerns about mishandling, contact the manufacturer or state or local health departments for guidance on whether the vaccine is usable.²¹¹

Specific Populations

Pregnancy

Category C.²⁰⁸²³⁴

Manufacturers state that HDCV (Imovax) and PCECV (RabAvert) should be given to pregnant women only if clearly needed.²⁰⁸²³⁴

However, ACIP, CDC, AAP, American College of Obstetricians and Gynecologists (ACOG), and the manufacturers state that pregnancy is not considered a contraindication for postexposure prophylaxis with rabies vaccine because of the potential risks of inadequately treated rabies exposure and because there is no evidence of an association between fetal abnormalities and rabies vaccine.^{204208212213234236} ACOG recommends that each pregnant woman be considered individually and that public health authorities be consulted.²⁰⁴

Preexposure vaccination may also be indicated during pregnancy when a substantial risk of rabies exposure is present.²⁰⁸²³⁶

Lactation

Not known whether antigens contained in rabies vaccine are distributed into milk.²³⁴ CDC states that use of rabies vaccine in nursing women should follow the same guidelines as other adults.²¹²

Because inactivated vaccines do not multiply within the body, the ACIP states that they should not pose any unusual problems for nursing women or their infants.²¹¹

PCECV (RabAvert): Manufacturer states nursing is not considered a contraindication when the vaccine is indicated for postexposure prophylaxis because of the possible risks of inadequately treated rabies exposure.²³⁴ In addition, use of the vaccine for preexposure vaccination may be indicated in nursing women when a substantial risk of rabies exposure is present.²³⁴

Pediatric Use

HDCV (Imovax): Safety and efficacy in children established.²⁰⁸

PCECV (RabAvert): Limited data available regarding safety and efficacy in children.²³⁴ Used effectively for preexposure vaccination in children ≥2 years of age and for postexposure prophylaxis in children ≥1 year of age.²³⁴

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.^212213237249

ACIP, CDC, AAP, and the manufacturers recommend that postexposure prophylaxis in children follow the same guidelines as in adults.^{208212213234236}

Geriatric Use

PCECV (RabAvert): Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently to the vaccine than younger adults.²³⁴ Clinical experience with PCECV (RabAvert) reveals that there are no overall differences in safety between geriatric and younger individuals.²³⁴

Common Adverse Effects

HDCV (Imovax): Local effects at injection site (pain, swelling, erythema, itching), mild systemic reactions (headache, nausea, abdominal pain, muscle aches, dizziness).²⁰⁸

PCECV (RabAvert): Local effects at injection site (pain, swelling, erythema, itching), influenza-like symptoms (mild to moderate asthenia, fatigue, fever, myalgia, malaise, headache).²³⁴

Interactions for Rabies Vaccine

Other Vaccines

HDCV (Imovax) and PCECV (RabAvert) rabies vaccines are inactivated viral vaccines; interactions with other inactivated vaccines, live virus vaccines, recombinant vaccines, or toxoids are unlikely.²¹¹²¹³ Inactivated vaccines can be administered either simultaneously with or at any time before or after inactivated or live vaccines.²¹¹²¹³ However, each vaccine should be administered using a different syringe and a different injection site.²¹¹²¹³

Specific Drugs

Drug	Interaction	Comments
Immunosuppressive agents (e.g., alkylating agents, antimetabolites, corticosteroids, radiation)	Potential for decreased antibody response to rabies vaccine; concomitant administration may predispose patient to rabies infection208212213233234236	Postpone preexposure vaccination and consider avoiding activities for which vaccination is indicated;212236250 if not possible, serologic testing should be performed after preexposure vaccination to document seroconversion236250 (see Pre- and Postvaccination Serologic Testing under Cautions) Avoid immunosuppressive therapy during rabies postexposure prophylaxis unless considered essential for treatment of other serious conditions208233234236250 If rabies postexposure prophylaxis is indicated in a previously unvaccinated individual receiving immunosuppressive therapy that cannot be discontinued, ACIP states that a 5-dose series (not a 4-dose series) of HDCV (Imovax) or PCECV (RabAvert) should be used250 (see Postexposure Prophylaxis or Rabies under Uses) If rabies postexposureprophylaxis is used in individuals receiving immunosuppressive agents or when corticosteroids are used to treat life-threatening neuroparalytic reactions to rabies vaccine, perform serologic testing for rabies antibody after completion of the regimen to ensure adequate immune response208233234236250 (see Pre- and Postvaccination Serologic Testing under Cautions)
Rabies immune globulin (RIG)	Passively acquired antibody to rabies antigen, which is present in RIG, may partially suppress the active immune response to rabies vaccine;213234236250 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 vaccine246 Neutralization of rabies vaccine may occur if RIG and the vaccine are mixed in the same syringe or administered into the same injection site211213236	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;208213234236250 infiltrate the full RIG dose around the wound(s) if anatomically feasible and administer any remaining portion of the RIG dose IM (using a different syringe and different injection site than rabies vaccine)213234236250 To minimize potential suppression of the active immune response to the vaccine, do not give single doses of RIG >20 international units/kg or repeated RIG doses213234236250 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 vaccine213234236250 RIG is not indicated for postexposure prophylaxis in individuals who previously received recommended preexposure or postexposure regimens of HDCV (Imovax), PCECV (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 titers213236250

Stability

Storage

Parenteral

Suspension for IM Injection

HDCV (Imovax): Prior to reconstitution, 2–8°C; avoid freezing.²⁰⁸

PCECV (RabAvert): Prior to reconstitution, 2–8°C; protect from light.²³⁴

Must be used immediately after reconstitution; discard if not used immediately.²⁰⁸²³⁴

HDCV (Imovax) and PCECV (RabAvert) do not contain thimerosal or any other preservatives.²⁰⁸²³⁴

Actions

• Rabies vaccine is a sterile, freeze-dried vaccine containing inactivated rabies virus antigen (≥2.5 international units/mL).²⁰⁸²³⁴

• Commercially available as human diploid-cell rabies vaccine (HDCV; Imovax) or purified chick embryo cell culture rabies vaccine (PCECV; RabAvert).²⁰⁸²³⁴

• HDCV (Imovax) contains antigen prepared from the Wistar Institute Pitman-Moore strain (PM-1503-3M) of rabies virus propagated in MRC-5 strain of human diploid-cell tissue culture.²⁰⁸ PCECV (RabAvert) contains antigens prepared from the fixed-virus strain Flury low egg passage (LEP) of rabies virus propagated in primary cultures of chicken fibroblasts.²³⁴

• Stimulates active immunity to rabies by inducing production of antirabies neutralizing antibodies.^208213234236 Antirabies antibodies neutralize rabies virus and are believed to have a primary role in preventing rabies infection.²³⁶

• HDCV (Imovax) and PCECV (RabAvert) are highly immunogenic in immunocompetent children, adolescents, and adults.^208234236 When administered according to the recommended preexposure immunization schedule in clinical studies, 100% of vaccinees achieved protective levels of antirabies antibody.²⁰⁸²³⁴

• Following IM administration of rabies vaccine, antirabies antibody levels are detectable in serum within 7–10 days and persist for several years.²³⁶

• Development of immunity and protection from rabies infection are evaluated by appearance of antirabies antibody in serum.²³⁶ Minimum titers of antirabies antibodies indicating protection against rabies have not been definitely established to date (varies among laboratories and by type of test performed).²³⁶ ACIP considers antirabies antibody titers ≥1:5 as determined by RFFIT to be indicative of an adequate response to rabies immunization.²³⁶²⁵⁰ WHO states that an antirabies antibody titer of ≥0.5 international units/mL can be considered protective.²⁴⁹

• Following rabies exposure and inoculation, the virus remains close to the wound for an indeterminate time and can be partially neutralized with RIG while at this site.²¹³ In susceptible individuals, the virus is transported to the CNS via the peripheral nerves.²⁴⁹ Following entrance into the CNS, the virus is unlikely to be affected by antirabies antibodies and a fatal encephalomyelitis almost always develops.²³⁴²⁴⁹

• Incubation period for rabies infection in humans can range from days to years (usually 1–3 months).^{212213234236250} After severe bites to the face, neck, or arms, the incubation period may be as short as 10 days.²⁴⁶

• Common prodromal symptoms of rabies infection include malaise, anorexia, fatigue, headache, and fever followed by pain or paresthesia at the site of exposure.²³⁴²⁴⁹ Anxiety, agitation, and irritability may also occur during the prodromal stage followed by hyperactivity, disorientation, seizures, aerophobia, hydrophobia, hypersalivation, and eventually paralysis, coma, and death.^212213234249 Following appearance of clinical symptoms of rabies, use of rabies vaccine or RIG will not improve the prognosis and may be detrimental; there is no specific proven effective treatment for rabies once symptoms develop.^212213236249

• 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 HDCV [Imovax] or PCECV [RabAvert] rabies vaccine).^236246250

Advice to Patients

• Prior to administration of each vaccine dose, provide a copy of the appropriate CDC Vaccine Information Statement (VIS) to the patient or patient's legal representative as required by the National Childhood Vaccine Injury Act (VISs are available at [Web]).²⁴⁴

• Advise the patient and/or patient's parent or guardian of the risks and benefits of vaccination with rabies vaccine.²⁰⁸²³⁴

• Advise the patient and/or patient's parent or guardian that rabies vaccine is used to prevent rabies and is given to persons at high risk of exposure to rabies as a result of employment, travel, or hobbies (e.g., certain laboratory workers, veterinarians, animal control and wildlife workers, spelunkers, hunters).²⁰⁸²³⁴

• Advise the patient and/or patient's parent or guardian that rabies vaccine is also 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.²⁰⁸²³⁴

• When rabies preexposure vaccination is indicated, importance of completing the 3-dose primary vaccination series.²¹³²³⁶

• When rabies postexposure prophylaxis is indicated in previously unvaccinated individuals, importance of completing a 4- or 5-dose series of rabies vaccine and receiving a single dose of RIG as soon as possible following rabies exposure.^208213234236

• When rabies postexposure prophylaxis is indicated in previously vaccinated individuals, importance of receiving a 2-dose regimen of rabies vaccine as soon as possible following rabies exposure.^208213234236

• Importance of informing clinicians if the patient has a weakened immune system (e.g., cancer, HIV/AIDS) or receives treatment that may weaken the immune system (e.g., corticosteroids, cancer treatment).²⁰⁸²³⁴

• Importance of informing clinicians if a patient has a fever or serious illness.²⁰⁸²³⁴ Advise patient that preexposure vaccination may be deferred if they are moderately or severely ill, but that rabies postexposure prophylaxis will still be administered, regardless of any other illness they may have.²⁴⁴

• Importance of informing clinicians if any serious adverse reactions (e.g., hypersensitivity, neurologic reactions) occur.²⁰⁸²³⁴ Clinicians or individuals can report any adverse reactions that occur following vaccination to the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967 or [Web].^208213234

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.²⁰⁸²³⁴

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.²⁰⁸²³⁴

• Importance of informing patients of other important precautionary information.²⁰⁸²³⁴ (See Cautions.)

Preparations

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.

Rabies Vaccine (Human Diploid-cell)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injectable suspension, for IM use only	≥2.5 units (of rabies antigen)	ImovaxRabies	Sanofi Pasteur

Rabies Vaccine (Purified Chick Embryo Cell Culture)

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	For injectable suspension, for IM use only	≥2.5 units (of rabies antigen)	RabAvert	Novartis

AHFS DI Essentials™. © Copyright 2019, Selected Revisions September 1, 2010. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

200. Connaught. Imovax rabies I.D. (rabies vaccine human diploid cell) prescribing information. Swiftwater, PA; 1991 Jul.

204. American College of Obstetricians and Gynecologists. Immunization during pregnancy. Committee opinion No. 282. Obstet Gynecol. 2003; 101:207-12. http://www.ncbi.nlm.nih.gov/pubmed/12517674?dopt=AbstractPlus

208. Sanofi Pasteur. Imovax rabies (rabies vaccine human diploid cell) prescribing information. Swiftwater, PA; 2005 Dec.

209. Fishbein DB, Sawyer LA, Reid-Sanden FL et al. Administration of human diploid-cell rabies vaccine in the gluteal area. N Engl J Med. 1988; 318:124-5. http://www.ncbi.nlm.nih.gov/pubmed/3336395?dopt=AbstractPlus

210. Shill M, Baynes RD, Miller SD. Fatal rabies encephalitis despite appropriate post-exposure prophylaxis: a case report. N Engl J Med. 1987; 316:1257-8. http://www.ncbi.nlm.nih.gov/pubmed/3574385?dopt=AbstractPlus

211. 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. http://www.cdc.gov/mmwr/PDF/rr/rr5515.pdf

212. 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 (http://wwwnc.cdc.gov/travel/contentYellowBook.aspx).

213. 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.

214. Bernard KW, Mallonee J, Wright JC et al. Preexposure immunization with intradermal human diploid cell rabies vaccine: risks and benefits of primary and booster vaccination. JAMA. 1987; 257:1059-63. http://www.ncbi.nlm.nih.gov/pubmed/3806894?dopt=AbstractPlus

215. Fishbein DB, Pacer RE, Holmes DF et al. Rabies preexposure prophylaxis with human diploid cell rabies vaccine: a dose-response study. J Infect Dis. 1987; 156:50-55. http://www.ncbi.nlm.nih.gov/pubmed/3598225?dopt=AbstractPlus

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As opposed to other US states, Hawaii has somewhat strict import rules due to its more delicate island ecosystem and rabies free status. This doesn’t mean bringing pets to Hawaii is impossible, but you’ll need to prepare carefully and carry out each step correctly.

First, familiarize yourself with Hawaii’s 5-Day-or-Less program and the requirements for Direct Release. If all rules are followed, pets will not have to undergo a quarantine upon arrival.

Read on to find out more about pet transport to Hawaii, and if you find yourself in need of further assistance, don’t hesitate to reach out to our team of PetRelocation Specialists.

Moving Your Pet to Hawaii

Attention: This information is to be used as general guidelines and may not be updated to meet the current requirements. Before you travel, be sure to contact the appropriate authorities or your PetRelocation Specialist.

Requirements for 5-Day-or-Less Program (and Direct Release)

All of the following steps must be completed in order for your pet to qualify for the 5-Day-or-Less program. If your pet does not meet any of these requirements, then they will have to undergo quarantine for up to 120 days.

Due to the minimum amount of time needed to prepare a puppy or kitten to meet the requirements of the 5-Day-or-Less program, a puppy or kitten will be about 10 months of age by the time all preparations are completed. Puppies and kittens not able to meet all of the requirements for the 5-Day-or-Less program will be quarantined for 120 days.

Rabies Vaccinations

Pets should be vaccinated at least twice for rabies in their lifetime.

These rabies vaccines should be administered more than 30 days apart.

The most recent rabies vaccination should be done no more than 12 months prior to the date of arrival in Hawaii for a 1-year rabies vaccine, or no more than 36 months prior to the date of arrival for a 3-year rabies vaccine.

The most recent rabies vaccination should be done no less than 90 days before pet’s date of arrival in Hawaii.

The most recent rabies vaccination must not be expired when pet arrives in Hawaii.

The date and type of vaccine must be indicated on the pet’s vaccination and health certificate.

Microchip

Pets must have an electronic microchip implanted (required before an OIE-FAVN rabies blood test is performed).

The microchip must be scanned by your veterinarian to verify that it is working and that the microchip number is correct on all documentation.

If the pet cannot be identified by scanning the microchip, they will not qualify for either direct airport release or the 5-Day-or-Less program and will undergo the 120 day quarantine.

OIE-FAVN Rabies Blood Test

A blood sample must be sent to Kansas State University (KSU) or the DOD Food Analysis and Diagnostic Laboratory in Texas.

This should take place no more than 36 months and no less than 120 days before the date of arrival in Hawaii.

Blood test results must be greater than or equal to 0.5 IU/ml.

You must have a copy of the successful blood test results showing the pet’s microchip number.

Make sure your veterinarian lists “Hawaii” as the destination on the blood test submission form. KSU and DOD will then automatically send your pet’s results to Hawaii.

Documents

Original signature or carbon copy of rabies vaccination certificates for the two most recent rabies vaccinations (photocopies are not acceptable). Certificates must contain:

• Vaccine name
• Lot or serial number
• Booster interval
• Vaccination date
• Expiration date

Original health certificate in English, which was done within 10 days of arrival in Hawaii including rabies vaccine name, lot or serial number, booster interval, vaccination date and expiration date.

Pets must be treated for ticks with a product containing Fipronil or an equivalent, long-acting product (Revolution is not acceptable) within 14 days of arrival and the product name and date of treatment should be recorded on the health certificate.

Submission of Documents

Ensure your documents are received by the Rabies Quarantine Branch more than 10 days before your pet arrives in Hawaii for a direct release.

Required Documentation:

Completed Dog & Cat Import Form AQS-278 (must be notarized)

Two original rabies vaccination certificates with actual veterinarian signature.

Fee payments accepted by cashier’s check or money order only (pet’s microchip number must be included with payment), payable to: Department of Agriculture

$165/pet in advance for direct airport release

$224/pet in advance for 5-Day-or-Less program

Documents must be sent to:

Animal Quarantine Station 99-951 Halawa Valley St., Aiea, Hawaii 96701

Do not send each document separately. Send all documents in as a set.

Send documents by mail with return receipt to verify delivery, or by another overnight carrier that provides tracking.

If you do not send the original health certificate to the Rabies Quarantine Branch in advance of your pet’s arrival when you submit your other documents, you must provide the health certificate upon arrival at the Airport Animal Quarantine Holding Facility. Failure to bring the original health certificate (photocopy not acceptable), will prevent your pet from being released.

Keep copies of the necessary documents (health certificate, rabies vaccination records, and blood test results) to accompany your pet as backup.

Direct Release at Airport

Direct Airport Release is only done at the Honolulu International Airport.

Pets must arrive at the Airport Animal Quarantine Holding Facility (808-837-8092) at the Honolulu International Airport during normal inspection hours of 8:00 a.m. to 4:30 p.m. Keep in mind that it may take up to one hour for the airlines to transport your pet to the Airport Animal Quarantine Holding Facility.

Pets not arriving at the facility during normal inspection hours will not be released at the airport, so it is important to note that your pet’s flight will need to arrive no later than 3:30 p.m. in Honolulu if you would like to have your pet released the same day.

Pets on international flights will also need to clear US Customs before they may be released from the Airport Animal Quarantine Holding Facility. You may check with your airline regarding US Customs hours of operation.

If the pet is not picked up on the day of arrival, they will be transferred to the Animal Quarantine Station, 99-951 Halawa Valley Street, Aiea, Hawaii 96701 at 8:30 a.m. the following morning and will be entered into the 5-Day-or-Less program at a cost of $224 per pet.

Pets will not qualify for direct airport release if ticks or other parasites are found at the time of arrival.

Pets may only be released to the consignee identified on the shipmaster’s declaration. If you are not traveling with your pet, make arrangements with the airlines to consign your pet to the individual who will pick them up.

5-Day-or-Less Program Release

Pets arriving between 5:00 p.m. and 8:00 a.m. will be transferred to the Animal Quarantine Station and entered under the 5-Day-or-Less program. The first day of quarantine shall be the day following the date of animal arrival into Hawaii. In this situation, after all necessary documents are received and verified, pets may be picked up at the Animal Quarantine Station, 99-951 Halawa Valley Street, Aiea, Hawaii 96701 (808-483-7151), during normal office hours:

Monday through Friday: 9:00 a.m. to 11:00 a.m. and 1:00 p.m. to 4:30 p.m.

Saturday, Sunday, State Holidays: 8:00 a.m. to 10:00 a.m. and 12:00 p.m. to 3:30 p.m.

An additional fee of $17.80 will be added each day your pet remains at the Animal Quarantine Station beyond the scheduled release date.

Hawaii Rabies Quarantine Information

Department of Agriculture

Rabies Quarantine Branch

99-951 Halawa Valley Street

Aiea, Hawaii 96701-5602

Telephone (808) 483-7151

Airport Animal Quarantine Holding Facility

Contact: (808) 837-8092 (24-hours)

Quarantine Website - Find information and details on Hawaii pet quarantine requirements.

RabiesFree@hawaii.gov

Business Counter

Monday, Tuesday, Thursday, Friday: 8:00 a.m. to 11:00 a.m.; 1:00 p.m. to 4:30 p.m.

Wednesday: 8:00 a.m. to 11:00 a.m.; 1:00 p.m. to 5:30 p.m.

Saturday, Sunday, and State Holidays: 7:00 a.m. to 10:00 a.m.; 12:00 p.m. to 3:30 p.m.

Pet Release

Monday through Friday: 9:00 a.m. to 11:00 a.m.; 1:00 p.m. to 4:30 p.m.

Saturday, Sunday, and State Holidays: 8:00 a.m. to 10:00 a.m.; 12:00 p.m. to 3:30 p.m.

Pet Visitation Hours

Tuesday, Thursday: 1:00 p.m. to 4:30 p.m.

Wednesday: 1:00 p.m. to 5:30 p.m.

Saturday, Sunday: 12:00 p.m. to 3:30 p.m.

No visiting on Mondays, Fridays, and State Holidays