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Post Exposure Prophylaxis Treatment Guidelines for Rabies

Postexposure Prophylaxis Treatment Guidelines for Rabies

Stages & Signs of Infection

Rabies is an acute, almost invariably fatal, progressive inflammation of the brain caused by infection by viruses. The clinical spectrum of rabies manifestation is divided into 3 phases1:

  • Prodromal phase
  • Acute neurologic phase, also known as excitation
  • Coma phase, also known as terminal

The incubation period of rabies is dependent upon the virus involved, the distance of the site of bite from the central nervous system, and the size and innervations of the bite site. The incubation period may vary from 5 days to, in rare cases, years.1

Rabies is a preventable disease if proper prophylactic vaccination is provided as a part of the preexposure prophylaxis (PREP) or along with human rabies immune globulin (HRIG) as a part of the postexposure prophylaxis (PEP).1

The Centers for Disease Control and Prevention (CDC) provides recommendations for human rabies PEP, including wound care and administration of both human rabies immune globulin and vaccine.2

Chart of CDC recommendation for rabies treatment Chart of CDC recommendation for rabies treatment

Rabies Symptoms in Humans3:

  • Fever
  • Agitation, confusion
  • Painful spasms followed by excessive saliva (foaming at mouth after drinking produced by spasms in throat)

Results in death within 1 to 2 weeks after onset of symptoms*

* Only 1 patient has recovered from rabies without PEP. Patient received a controversial intensive care strategy of antiviral therapy and induced therapeutic coma. Numerous patients have subsequently failed this experimental protocol.3,4

Even in developed countries, we can't be complacent. Rabies remains the world's deadliest infectious disease,5,6 but death is preventable with education, training, and timely and appropriate treatment.

~Stephen Scholand, MD

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Postexposure Prophylaxis for Rabies

Postexposure Prophylaxis

PEP is any preventive medical treatment started immediately after exposure to a pathogen (such as rabies) in order to prevent infection by the pathogen and the development of disease.7

Left untreated, rabies has the highest fatality rate of any infectious disease, making rapid response essential.8

HyperRAB® (rabies immune globulin [human]), in conjunction with a vaccine, provides critical, comprehensive protection against rabies in previously unvaccinated persons. Rabies vaccine and HyperRAB should be given to all persons suspected of exposure to rabies, with one exception: persons who have been previously immunized with rabies vaccine and have confirmed adequate rabies antibody titer should receive only vaccine. HyperRAB should be administered as promptly as possible after exposure, but can be administered within 7 days after the first dose of rabies vaccine.9

Imminent Threat

Vaccines can take weeks to build efficacy but can protect for years. HyperRAB provides critical protection immediately, allowing the vaccine time to establish active immunity.2

Immediate Protection

HyperRAB contains high titers of rabies antibodies for PEP, providing rapid immune protection. Along with appropriate wound cleansing, a human rabies immune globulin such as HyperRAB is recommended by the CDC and World Health Organization (WHO) to be administered at the same time as the rabies vaccine in previously unvaccinated persons immediately following a transdermal bite or scratch by an animal suspected of being rabid.2,10

For unvaccinated individuals, the combination of human rabies immune globulin and vaccine is recommended for both bite and nonbite exposures, regardless of the time interval between exposure and initiation of PEP. If PEP has been initiated and appropriate laboratory diagnostic testing (ie, the direct fluorescent antibody test) indicates that the animal that caused the exposure was not rabid, PEP may be discontinued.2

Chart of HyperRAB (R) S/D vs Vaccine for Rabies Chart of HyperRAB (R) S/D vs Vaccine for Rabies

The most common adverse reactions in >5% of subjects during clinical trials were injection-site pain, headache, injection-site nodule, abdominal pain, diarrhea, flatulence, nasal congestion, and oropharyngeal pain.

Rabies PEP schedule – United States2

Vaccination status
 Intervention Regimen*
Not previously vaccinated
 Wound cleansing All PEP should begin with immediate thorough cleansing of all wounds with soap and water. If available, a virucidal agent (eg, povidine-iodine solution) should be used to irrigate the wounds.
Human rabies immune globulin (HRIG) Administer 20 IU/kg body weight. If anatomically feasible, the full dose should be infiltrated around and into the wound(s), and any remaining volume should be administered at an anatomical site (intramuscular [IM]) distant from vaccine administration. Also, HRIG should not be administered in the same syringe as vaccine. Because rabies immune globulin (RIG) might partially suppress active production of rabies virus antibody, no more than the recommended dose should be administered.
Vaccine Human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) 1.0 mL IM (deltoid area†), 1 each on days 0,§ 3, 7, and 14.‡
Previously vaccinated**
 Wound cleansing All PEP should begin with immediate thorough cleansing of all wounds with soap and water. If available, a virucidal agent such as povidone-iodine solution should be used to irrigate the wounds.
HRIG HRIG should not be administered.
Vaccine HDCV or PCECV 1.0 mL IM (deltoid area†), 1 each on days 0‡ and 3.

Rabies PEP schedule – United States2

Not previously vaccinated
Wound cleansing regimen*
All PEP should begin with immediate thorough cleansing of all wounds with soap and water. If available, a virucidal agent (eg, povidine-iodine solution) should be used to irrigate the wounds.
Human rabies immune globulin (HRIG) regimen*
Administer 20 IU/kg body weight. If anatomically feasible, the full dose should be infiltrated around and into the wound(s), and any remaining volume should be administered at an anatomical site (intramuscular [IM]) distant from vaccine administration. Also, HRIG should not be administered in the same syringe as vaccine. Because rabies immune globulin (RIG) might partially suppress active production of rabies virus antibody, no more than the recommended dose should be administered.
Vaccine regimen*
Human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) 1.0 mL IM (deltoid area†), 1 each on days 0,§ 3, 7, and 14.‡
Previously vaccinated||
Wound cleansing regimen*
All PEP should begin with immediate thorough cleansing of all wounds with soap and water. If available, a virucidal agent such as povidone-iodine solution should be used to irrigate the wounds.
HRIG regimen*
HyperRAB® S/D should not be administered.
Vaccine regimen*
HDCV or PCECV 1.0 mL IM (deltoid area†), 1 each on days 0‡ and 3.

* These regimens are applicable for persons in all age groups, including children.

† The deltoid area is the only acceptable site of vaccination for adults and older children. For younger children, the outer aspect of the thigh may be used. Vaccine should never be administered in the gluteal area.

§ Day 0 is the day dose 1 of vaccine is administered.

‡ For persons with immunosuppression, rabies PEP should be administered using all 5 doses of vaccine on days 0, 3, 7, 14, and 28.

|| Any person with a history of pre-exposure vaccination with HDCV, PCECV, or rabies vaccine absorbed (RVA); prior PEP with HDCV, PCECV or RVA; or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination.

Administration of the full HRIG dose typically requires multiple intramuscular injections beyond the initial injection directly into and around the wound site. This is especially true with small wound sites in children and adults.

~Ken Stephens, RN

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RIG Icon

Effective RIG Administration

When administering rabies immunoglobulin (RIG), focus on neutralizing the virus:

Infiltration matters

  • The highest viral load occurs at the wound site(s)
  • The CDC recommends that if anatomically feasible, the full dose of RIG should be thoroughly infiltrated in the area around and into the wound(s)11
  • The most commonly encountered causes of PEP management failures are when RIG is not used at all, it is injected only IM and not into wound(s), or not all bite wound(s) are injected12,13

Administration of the total dose matters

  • The CDC recommends that a total dose (20 IU/kg) always be administered11
  • Any remaining volume following infiltration of the wound should be injected IM at a site distan from vaccine administration11

RIG volume matters

Weight-based dosing can create challenges with the volume required to be administered in a total dose:

  • Anatomical constraints of some wounds (eg, ear, nose, or finger) can limit the portion of the dose that can be injected14,15
  • Risk of compartment syndrome should be minimized when possible15
  • Locating sufficient distant sites on the body to complete administration of the total dose can be challenging14

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Dosing and Administration Recommendations for Rabies icon

Dosing and Administration Recommendations9

Keep enough HyperRAB® (rabies immune globulin [human]) in stock to treat a family of 5.

General Guidelines
(previously unvaccinated adults and children)

  • HyperRAB (300 IU/mL), supplied in 1-mL and 5-mL vials, for twice the potency of currently available HRIG options
  • The recommended dose for HyperRAB is 20 IU/kg (0.0665 mL/kg) of body weight, given preferably at the time of first vaccine. If vaccine is not available, treat with HyperRAB immediately
  • HyperRAB should be administered as promptly as possible after exposure, but can be administered within
    7 days after the first dose of rabies vaccine.
  • HyperRAB and vaccine should never be administered in the gluteal area

Ensure the correct strength is used for the calculation. HyperRAB is formulated with a strength of 300 IU/mL. The predecessor product, HyperRAB S/D, was formulated at 150 IU/mL. The volume required of HyperRAB (300 IU/mL) to achieve the recommended dose of 20 IU/kg is approximately one-half of that required for the previous HyperRAB S/D (150 IU/mL).

Sample Patient Weight Dosing Recommendation
Adult 80 kg (176.4 lbs) 80 kg x 20 IU/kg = 1600 IU
Recommend one 5 mL vial and one 1 mL vial
Adult 75 kg (165.4 lbs) 75 kg x 20 IU/kg = 1500 IU
Recommend one 5 mL vial
Adult/Adolescent 60 kg (132 lbs) 60 kg x 20 IU/kg = 1200 IU
Recommend four 1 mL vials
Child 40 kg (88 lbs) 40 kg x 20 IU/kg = 800 IU
Recommend three 1 mL vials
Child 30 kg (66 lbs) 30 kg x 20 IU/kg = 600 IU
Recommend two 1 mL vials
Dosing Recommendation
Adult - 80 kg (176.4 lbs)
80 kg x 20 IU/kg = 1600 IU
Recommend one 5 mL vial and one 1 mL vial
Adult - 75 kg (165.4 lbs)
75 kg x 20 IU/kg = 1500 IU
Recommend one 5 mL vial
Adult/Adolescent - 60 kg (132 lbs)
60 kg x 20 IU/kg = 1200 IU
Recommend four 1 mL vials
Child - 40 kg (88 lbs)
40 kg x 20 IU/kg = 800 IU
Recommend three 1 mL vials
Child - 30 kg (66 lbs)
30 kg x 20 IU/kg = 600 IU
Recommend two 1 mL vials

Severe hypersensitivity reactions may occur with HyperRAB. Patients with a history of prior systemic allergic reactions to human immunoglobulin preparations are at a greater risk of developing severe hypersensitivity and anaphylactic reactions. Have epinephrine available for treatment of acute allergic symptoms, should they occur.

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Post-Bite Wound Care for Rabies icon

Post-bite Wound Care8

Regardless of the risk for rabies, the optimal medical treatment of animal bite wounds includes the recognition and treatment of serious injury (eg, nerve or tendon laceration), avoidance or management of infection (both local and systemic), and approaches that will yield the best possible cosmetic results. For many types of bite wounds, immediate gentle irrigation with water or a water-diluted povidone-iodine solution will reduce the risk for bacterial infection. Care should be taken not to damage skin or tissues. Wound cleansing is especially important in rabies prevention because thorough wound cleansing, even without other PEP, has been shown to reduce the likelihood of rabies in animal studies. Consideration should be given to the need for a booster dose of tetanus vaccine. Decisions regarding the use of antibiotic prophylaxis and primary wound closure should be individualized based on the animal species, size and location of the wound(s), and time interval since the bite. When possible, avoid suturing. 

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Animal Scratches and Nonbite Explosure Icon

Animal Scratches and Nonbite Exposures

Nonbite exposures from animals very rarely cause rabies; however, occasional reports of nonbite transmission suggest that such exposures require assessment to determine if sufficient reasons exist to consider PEP. Nonbite exposures can include 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.16

The contamination of open wounds or abrasions, including scratches, or mucous membranes with saliva or other potentially infectious material, such as neural tissue, from a rabid animal can constitute a nonbite exposure. Rabies virus is inactivated by desiccation, ultraviolet irradiation, or other factors and does not persist in the environment. Generally, if the material in question is dry, the virus can be considered noninfectious. Nonbite exposures other than organ or tissue transplants have almost never been shown to cause rabies, and PEP is not indicated unless the nonbite exposure meets the definition of saliva or other potentially infectious material being introduced into fresh, open cuts in the skin or onto mucous membranes.8

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Myth or Fact?

Rabies, left untreated, is fatal.

Myth Fact

isi

Important Safety Information for HyperRAB® (rabies immune globulin [human])

Indication and Usage

HYPERRAB® (rabies immune globulin [human]) is indicated for postexposure prophylaxis, along with rabies vaccine, for all persons suspected of exposure to rabies.

Limitations of Use 

Persons who have been previously immunized with rabies vaccine and have a confirmed adequate rabies antibody titer should receive only vaccine.

For unvaccinated persons, the combination of HYPERRAB and vaccine is recommended for both bite and nonbite exposures regardless of the time interval between exposure and initiation of postexposure prophylaxis.

Beyond 7 days (after the first vaccine dose), HYPERRAB is not indicated since an antibody response to vaccine is presumed to have occurred.

Important Safety Information

For infiltration and intramuscular use only.

Severe hypersensitivity reactions may occur with HYPERRAB. Patients with a history of prior systemic allergic reactions to human immunoglobulin preparations are at a greater risk of developing severe hypersensitivity and anaphylactic reactions. Have epinephrine available for treatment of acute allergic symptoms, should they occur.

HYPERRAB is made from human blood and may carry a risk of transmitting infectious agents, eg, viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

The most common adverse reactions in >5% of subjects during clinical trials were injection-site pain, headache, injection-site nodule, abdominal pain, diarrhea, flatulence, nasal congestion, and oropharyngeal pain.

Do not administer repeated doses of HYPERRAB once vaccine treatment has been initiated as this could prevent the full expression of active immunity expected from the rabies vaccine.

Other antibodies in the HYPERRAB preparation may interfere with the response to live vaccines such as measles, mumps, polio, or rubella. Defer immunization with live vaccines for 4 months after HYPERRAB administration.  

Please see full Prescribing Information for HyperRAB.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

Important Safety Information for HyperTET® S/D (tetanus immune globulin [human])

HyperTET® S/D (tetanus immune globulin [human]) is indicated for prophylaxis against tetanus following injury in patients whose immunization is incomplete or uncertain.

HyperTET S/D should be given with caution to patients with a history of prior systemic allergic reactions following the administration of human immunoglobulin preparations.

In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, HyperTET S/D should be given only if the expected benefits outweigh the risks.

Slight soreness at the site of injection and slight temperature elevation may be noted at times. Sensitization to repeated injections of human immunoglobulin is extremely rare. In the course of routine injections of large numbers of persons with immunoglobulin, there have been a few isolated occurrences of angioneurotic edema, nephrotic syndrome, and anaphylactic shock after injection. Administration of live virus vaccines (eg, MMR) should be deferred for approximately 3 months after tetanus immune globulin (human) administration.

HyperTET S/D is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent that can cause disease. There is also the possibility that unknown infectious agents may be present in such products.

Please see HyperTET S/D full Prescribing Information for complete prescribing details.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.


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References:

  1. Kaur M, Garg R, Singh S, Bhatnagar R. Rabies vaccines: where do we stand, where are we heading? Expert Rev Vaccines. 2015;14(3):369-381.
  2. 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 Morb Mortal Wkly Rep. 2010;59(RR02);1-9.
  3. Crowcroft NS, Thampi N. The prevention and management of rabies. BMJ. 2015;350:g7827.
  4. Nigg AJ, Walker PL. Overview, prevention, and treatment of rabies. Pharmacotherapy. 2009;29(10):1182-1195.
  5. Rupprecht CE, Turmelle A, Kuzmin IV. A perspective on lyssavirus emergence and perpetuation. Curr Opin Virol. 2011;1(6):662-670.
  6. Feder HM Jr, Petersen BW, Robertson KL, Rupprecht CE. Rabies: still a uniformly fatal disease? Historical occurence, epidemiological trends, and paradigm shifts. Curr Infect Dis Rep. 2012;14(4):408-422.
  7. Centers for Disease Control and Prevention. What care will I receive? Centers for Disease Control and Prevention website. http://www.cdc.gov/rabies/medical_care/index.html. Updated March 23, 2016. Accessed April 11, 2016.
  8. Centers for Disease Control. Human rabies prevention — United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2008;57(RR03);1-26,28.
  9. HyperRAB® (rabies immune globulin [human]) Prescribing Information. Grifols.
  10. World Health Organization. Guide for post-exposure prophylaxis. World Health Organization website. http://www.who.int/rabies/human/postexp/en/#. Updated 2016. Accessed April 11, 2016.
  11. Manning SE, Rupprecht CE, Fishbein D, et al; Advisory Committee on Immunization Practices Centers for Disease Control and Prevention (CDC). Human rabies prevention—United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2008;57(RR-3):1-28.
  12. Wilde H. Failures of post-exposure rabies prophylaxis. Vaccine. 2007;25(44):7605-7609.
  13. Wilde H, Sirikawin S, Sabcharon A, et al. Failure of postexposure treatment of rabies in children. Clin Infect Dis. 1996;22(2):228-232.
  14. Madhusudana SN, Ashwin BY, Sudarshan S. Feasibility of reducing rabies immunoglobulin dosage for passive immunization against rabies: results of in vitro and in vivo studies. Hum Vaccin Immunother. 2013;9(9):1914-1917.
  15. SAGE Working Group on Rabies vaccines and immunoglobulins and the World Health Organization (WHO) Secretariat. Background paper: proposed revision of the policy on rabies vaccines and rabies immunoglobulins. September 22, 2017. http://www.who.int/immunization/sage/meetings/2017/october/1_Background_paper_WG_RABIES_ nal.pdf. Accessed March 8, 2018.
  16. Centers for Disease Control and Prevention. How is rabies transmitted? Centers for Disease Control and Prevention website. http://www.cdc.gov/rabies/transmission/index.html. Updated April 22, 2011. Accessed April 11, 2016.
  17. Dyer JL, Yager P, Orciari L, et al. Rabies surveillance in the United States during 2013. J Am Vet Med Assoc. 2014;245(10):1111-1123.
  18. Centers for Disease Control and Prevention. What are the signs and symptoms of rabies? Centers for Disease Control and Prevention website. http://www.cdc.gov/rabies/symptoms/index.html. Updated February 15, 2012. Accessed April 11, 2016.