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Rabavert

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Rabavert

Indications
Dosage
How Supplied

INDICATIONS

RabAvert is indicated for preexposure vaccination, in both primary series and booster dose, and for postexposure prophylaxis against rabies in all age groups.

Usually, an immunization series is initiated and completed with one vaccine product. No clinical studies have been conducted that document a change in efficacy or the frequency of adverse reactions when the series is completed with a second vaccine product. However, for booster immunization, RabAvert was shown to elicit protective antibody level responses in persons tested who received a primary series with HDCV4,11.

Preexposure Vaccination

See Table 1

(see also DOSAGE AND ADMINISTRATION section below)

Preexposure vaccination consists of three doses of RabAvert 1.0 mL, intramuscularly (deltoid region), one each on days 0, 7, and 21 or 281 (see also Table 1 for criteria for preexposure vaccination).

Preexposure vaccination does not eliminate the need for additional therapy after a known rabies exposure (see also DOSAGE AND ADMINISTRATION section, subsection C).

Preexposure vaccination should be offered to persons in high-risk groups, such as veterinarians, animal handlers, wildlife officers in areas where animal rabies is enzootic, certain laboratory workers, and persons spending time in foreign countries where rabies is endemic. Persons whose activities bring them into contact with potentially rabid dogs, cats, foxes, skunks, bats, or other species at risk of having rabies should also be considered for preexposure vaccination. International travelers might be candidates for preexposure vaccination if they are likely to come in contact with animals in areas where dog rabies is enzootic and immediate access to appropriate medical care, including biologics, might be limited27,28

Preexposure vaccination is given for several reasons. First, it may provide protection to persons with inapparent exposure to rabies. Second, it may protect persons whose postexposure therapy might be expected to be delayed. Finally, although it does not eliminate the need for prompt therapy after a rabies exposure, it simplifies therapy by eliminating the need for globulin and decreasing the number of doses of vaccine needed. This is of particular importance for persons at high risk of being exposed in countries where the available rabies immunizing products may carry a higher risk of adverse reactions.

In some instances, booster doses of vaccine should be administered to maintain a serum titer corresponding to at least complete neutralization at a 1:5 serum dilution by the RFFIT (see Table 1); each booster immunization consists of a single dose. See CLINICAL PHARMACOLOGY. Serum antibody determinations to decide upon the need for a booster dose is suggested by the ACIP and is considered cost-effective.

TABLE 1: RABIES PREEXPOSURE PROPHYLAXIS GUIDE - UNITED STATES, 1999

Risk Category and Nature of Risk Typical Populations Preexposure Recommendations
Continuous. Virus present continuously, often in high concentrations. Specific exposures likely to go unrecognized. Bite, nonbite or aerosol exposure. Rabies research lab workers,* rabies biologics production workers. Primary course. Serologic testing every 6 months; booster vaccination if antibody titer is below acceptable level.*
Frequent. Exposure usually episodic, with source recognized, but exposure might be unrecognized. Bite, nonbite or aerosol exposure. Rabies diagnostic lab workers,* spelunkers, veterinarians and staff, and animal-control and wildlife workers in rabies enzootic areas. Primary course. Serologic testing every 2 years; booster vaccination if antibody titer is below acceptable level.**
Infrequent (greater than population-at-large). Exposure nearly always episodic with source recognized. Bite or nonbite exposure. Veterinarians and animal-control and wildlife workers in areas with low rabies rates. Veterinary students. Travelers visiting areas where rabies in enzootic and immediate access to appropriate medical care including biologics is limited. Primary course. No serologic testing or booster vaccination.**
Rare (population-at-larse). Exposures always episodic. with source recognized. Bite or nonbite exposure. US population-at-large, including persons in rabies-epizootic areas. No vaccination necessary.
Adapted from the Recommendations of the Advisory Committee on Immunization Practices: Human Rabies Prevention - United States, 1999.1
* Judgment of relative risk and extra monitoring of vaccination status of laboratory workers is the responsibility of the laboratory supervisor29.
** Minimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by RFFIT. A booster dose should be administered if the titer falls below this level.

Postexposure Treatment

See Table 2

(see also DOSAGE AND ADMINISTRATION section below)

The following recommendations are only a guide. In applying them, take into account the animal species involved, the circumstances of the bite or other exposure, the immunization status of the animal, and presence of rabies in the region (as outlined below). Local or state public health officials should be consulted if questions arise about the need for rabies prophylaxis1.

TABLE 2: RABIES POSTEXPOSURE PROPHYLAXIS GUIDE - UNITED STATES, 1999

Animal type Evaluation and disposition of animal Postexposure prophylaxis recommendations
Dogs, cats and ferrets Healthy and available for 10 days observation
Rabid or suspected rabid
Unknown (e.g., escaped)
Should not begin prophylaxis unless animal develops clinical signs of rabies*
Immediately vaccinate
Consult public health officials
Skunks, raccoons, bats, foxes, and most other carnivores Regarded as rabid unless animal proven negative by laboratory tests** Consider immediate vaccination
Livestock, small rodents, lagomorphs (rabbits and hares), large rodents (woodchucks and beavers), and other mammals Consider individually Consult public health officials. Bites of squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, mice, other small rodents, rabbits, and hares almost never require antirabies postexposure prophylaxis
Adapted from the Recommendations of the Advisory Committee on Immunization Practices: Human Rabies Prevention - United States, 1999.1
* During the 10-day observation period, begin postexposure prophylaxis at the first sign of rabies in a dog, cat or ferret that has bitten someone. If the animal exhibits clinical signs of rabies, it should be euthanized immediately and tested.
** The animal should be euthanized and tested as soon as possible. Holding for observation is not recommended. Discontinue vaccine if immunofluorescence test results of the animal are negative.

In the United States, the following factors should be considered before antirabies treatment is initiated.

Species of Biting Animal

Wild terrestrial animals (especially skunks, raccoons, foxes and coyotes) and bats are the animals most commonly infected with rabies and are the most important potential source of infection for both humans and domestic animals. Unless a wild animal is tested and shown not to be rabid, postexposure prophylaxis should be initiated upon bite or nonbite exposure to the animals (see definition in “Type of Exposure” below). If treatment has been initiated and subsequent testing in a qualified laboratory shows the exposing animal is not rabid, postexposure prophylaxis can be discontinued1.

The likelihood of rabies in a domestic animal varies from region to region; hence the need for postexposure prophylaxis also varies1.

Small rodents (such as squirrels, hamsters, guinea pigs, gerbils, chipmunks, rats, and mice) and lagomorphs (including rabbits and hares) are almost never found to be infected with rabies and have not been known to transmit rabies to humans in the United States. Bites from large rodents such as woodchucks (including groundhogs) and beavers, should be considered as possible rabies exposures, especially in regions where rabies is enzootic in raccoons30. In all cases involving rodents, the state or local health department should be consulted before a decision is made to initiate antirabies postexposure prophylaxis1.

Circumstances of Biting Incident

An UNPROVOKED attack is more likely than a provoked attack to indicate the animal is rabid. Bites inflicted on a person attempting to feed or handle an apparently healthy animal should generally be regarded as PROVOKED. A currently vaccinated dog, cat or ferret is unlikely to become infected with rabies1.

Type of Exposure

Rabies is transmitted by introducing the virus into open cuts or wounds in skin or via mucous membranes. The likelihood of rabies infection varies with the nature and extent of exposure.

Two categories of exposure should be considered:

Bite: Any penetration of the skin by teeth. Bites to highly innervated areas such as the face and hands carry the highest risk, but the site of the bite should not influence the decision to begin treatment. Recent epidemiologic data suggest that even the very limited injury inflicted by a bat bite (compared to lesions caused by terrestrial carnivores) should prompt consideration of postexposure prophylaxis unless the bat is available for testing and is negative for evidence of rabies1.

Nonbite: The contamination of open wounds, abrasions, mucous membranes, or theoretically, scratches, with saliva or other potentially infectious material (such as neural tissue) from a rabid animal constitutes a nonbite exposure. In all instances of potential human exposures involving bats, and the bat is not available for testing, postexposure prophylaxis might be appropriate even if a bite, scratch or mucous membrane exposure is not apparent when there is reasonable probability that such exposure might have occurred. Postexposure prophylaxis can be considered for persons who were in the same room as the bat and who might be unaware that a bite or direct contact had occurred (e.g., a sleeping person awakens to find a bat in the room or an adult witnesses a bat in the room with a previously unattended child, mentally disabled person, or intoxicated person) and rabies cannot be ruled out by testing the bat. Other contact by itself, such as petting a rabid animal and contact with blood, urine, or feces (e.g., guano) of a rabid animal, does not constitute an exposure and is not an indication for prophylaxis. Because the rabies virus is inactivated by desiccation and ultraviolet irradiation, in general, if the material containing the virus is dry, the virus can be considered noninfectious. Two cases of rabies have been attributed to probable aerosol exposures in laboratories, and two cases of rabies in Texas could possibly have been due to airborne exposures in caves containing millions of bats1.

The only documented cases for rabies from human-to-human transmission occurred in eight patients, including two in the USA, who received corneas transplanted from persons who died of rabies undiagnosed at the time of death1. Stringent guidelines for acceptance of donor corneas have been implemented to reduce this risk.

Bite and nonbite exposure from humans with rabies theoretically could transmit rabies, but no laboratory-diagnosed cases occurring under such situations have been documented. Each potential exposure to human rabies should be carefully evaluated to minimize unnecessary rabies prophylaxis1.

Postexposure Treatment Schedule

(see also DOSAGE AND ADMINISTRATION section below)

The essential components of rabies postexposure prophylaxis are prompt local treatment of wounds and administration of both Human Rabies Immune Globulin (HRIG) and vaccine.

A complete course of postexposure treatment for previously unvaccinated adults and children consists of a total of 5 doses of vaccine, each 1.0 mL: one IM injection (deltoid) on each of days 0. 3, 7, 14 and 28. For previously immunized adults and children, a total of 2 doses of vaccine, each 1.0 mL: one IM injection (deltoid) on each of days 0 and 3. No HRIG should be administered to previously vaccinated persons as it may blunt their rapid memory response to rabies antigen.

Local Treatment of Wounds

Immediate and thorough washing of all bite wounds and scratches with soap and water is an important measure for preventing rabies. In animal studies, thorough local wound cleansing alone has been shown to reduce markedly the likelihood of rabies. Whenever possible, bite injuries should not be sutured to avoid further and/or deeper contamination. Tetanus prophylaxis and measures to control bacterial infection should be given as indicated1.

Postexposure Prophylaxis of Rabies

The regimen for postexposure prophylaxis depends on whether or not the patient has been previously immunized against rabies (see below). For persons who have not previously been immunized against rabies, the schedule consists of an initial injection IM of HRIG exactly 20 IU per kilogram body weight in total. If anatomically feasible, the FULL DOSE of HRIG should be thoroughly infiltrated in the area around and into the wounds. Any remaining volume of HRIG should be injected IM at a site distant from rabies vaccine administration. HRIG should never be administered in the same syringe or in the same anatomical site as the rabies vaccine. HRIG is administered only once (for specific instructions for HRIG use, see the product package insert). The HRIG injection is followed by a series of 5 individual injections of RabAvert (1.0 mL each) given IM on days 0, 3, 7, 14 and 28. Postexposure rabies prophylaxis should begin the same day exposure occurred or as soon after exposure as possible. The combined use of HRIG and RabAvert is recommended by the CDC for both bite and non-bite exposures, regardless of the interval between exposure and initiation of treatment.

In the event that HRIG is not readily available for the initiation of treatment, it can be given through the seventh day after administration of the first dose of vaccine. HRIG is not indicated beyond the seventh day because an antibody response to RabAvert is presumed to have begun by that time1.

The sooner treatment is begun after exposure, the better. However, there have been instances in which the decision to begin treatment was made as late as 6 months or longer after exposure due to delay in recognition that an exposure had occurred. Postexposure antirabies treatment should always include administration of both passive antibody (HRIG) and immunization, with the exception of persons who have previously received complete immunization regimens (preexposure or postexposure) with a cell culture vaccine, or persons who have been immunized with other types of vaccines and have had documented rabies antibody titers. Persons who have previously received rabies immunization should receive 2 IM doses of RabAvert: 1 on day 0 and another on day 3. They should not be given HRIG as this may blunt their rapid memory response to rabies antigen.

Postexposure Prophylaxis Outside the United States

If postexposure treatment is begun outside the United States with regimens or biologics that are not used in the United States, it may be prudent to provide additional treatment when the patient reaches the USA. State or local health departments should be contacted for specific advice in such cases1.

DOSAGE AND ADMINISTRATION

The individual dose for adults, children, and infants is 1 mL, given intramuscularly. In adults, administer vaccine by IM injection into the deltoid muscle. In small children and infants, administer vaccine into the anterolateral zone of the thigh. The gluteal area should be avoided for vaccine injections, since administration in this area may result in lower neutralizing antibody titers. Care should be taken to avoid injection into or near blood vessels and nerves. After aspiration, if blood or any suspicious discoloration appears in the syringe, do not inject but discard contents and repeat procedure using a new dose of vaccine, at a different site.

Preexposure Dosage

Primary Immunization

In the United States, the Advisory Committee on Immunization Practices (ACIP) recommends three injections of 1.0 mL each: one injection on day 0 and one on day 7, and one either on day 21 or 28 (for criteria for preexposure vaccination, see Table 1).

Booster Immunization

The individual booster dose is 1 mL, given intramuscularly.

Booster immunization is given to persons who have received previous rabies immunization and remain at increased risk of rabies exposure by reasons of occupation or avocation.

Persons who work with live rabies virus in research laboratories or vaccine production facilities (continuous-risk category: see Table 1) should have a serum sample tested for rabies antibodies every 6 months. The minimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test (RFFIT). A booster dose should be administered if the titer falls below this level.

The frequent-risk category includes other laboratory workers such as those doing rabies diagnostic testing, spelunkers, veterinarians and staff, animal-control and wildlife officers in areas where rabies is epizootic. Persons in the frequent-risk category should have a serum sample tested for rabies antibodies every 2 years and, if the titer is less than complete neutralization at a 1:5 serum dilution by RFFIT, should have a booster dose of vaccine.

Alternatively, a booster can be administered in the absence of a titer determination.

The infrequent-risk category, including veterinarians, animal-control and wildlife officers working in areas of low rabies enzooticity (infrequent-exposure group) and international travelers to rabies enzootic areas do not require routine preexposure booster doses of RabAvert after completion of a full primary preexposure vaccination scheme (Table 1).

Postexposure Dosage

Immunization should begin as soon as possible after exposure. A complete course of immunization consists of a total of 5 injections of 1 mL each: one injection on each of days 0, 3, 7, 14 and 28 in conjunction with the administration of HRIG on day 0. For children, see Pediatric Use section under PRECAUTIONS.

Begin with the administration of HRIG. Give 20 IU/kg body weight.

This formula is applicable to all age groups, including infants and children. The recommended dosage of HRIG should not exceed 20 IU/kg body weight because it may otherwise interfere with active antibody production. Since vaccine-induced antibody appears within 1 week, HRIG is not indicated more than 7 days after initiating postexposure prophylaxis with RabAvert. If anatomically feasible, the FULL DOSE of HRIG should be thoroughly infiltrated in the area around and into the wounds. Any remaining volume of HRIG should be injected IM at a site distant from rabies vaccine administration. HRIG should never be administered in the same syringe or in the same anatomical site as the rabies vaccine.

Because the antibody response following the recommended immunization regimen with RabAvert has been satisfactory, routine post-immunization serologic testing is not recommended. Serologic testing is indicated in unusual circumstances, as when the patient is known to be immunosuppressed. Contact the appropriate state health department or the CDC for recommendations.

Postexposure Prophylaxis Of Previously Immunized Persons

When rabies exposure occurs in a previously vaccinated person, then that person should receive two IM (deltoid) doses (1.0 mL each) of RabAvert: one immediately and one 3 days later. HRIG should not be given in these cases. Persons considered to have been immunized previously are those who received a complete preexposure vaccination or postexposure prophylaxis with RabAvert or other tissue culture vaccines or have been documented to have had a protective antibody response to another rabies vaccine. If the immune status of a previously vaccinated person is not known, full postexposure antirabies treatment (HRIG plus 5 doses of vaccine) is recommended. In such cases, if a protective titer can be demonstrated in a serum sample collected before vaccine is given, treatment can be discontinued after at least two doses of vaccine.

Instructions For Reconstituting RabAvert

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. If either of these conditions exists, the vaccine should not be administered.

The package contains a vial of freeze-dried vaccine, a syringe containing 1 mL of sterile diluent, a sterile needle for reconstitution and a sterile needle suitable for intramuscular injection. The longer of the 2 needles supplied is the reconstitution needle. Affix the reconstitution needle to the syringe containing the Sterile Diluent for RabAvert. Insert the needle at a 45° angle and slowly inject the entire contents of the diluent (1 mL) into the vaccine vial. Mix gently to avoid foaming. The white, freeze-dried vaccine dissolves to give a clear or slightly opaque suspension. Withdraw the total amount of dissolved vaccine into the syringe and replace the long needle with the smaller needle for IM injection. The reconstituted vaccine should be used immediately.

A separate, sterile syringe and needle should be used for each patient. Needles must not be recapped and should be properly disposed of.

The lyophilization of the vaccine is performed under reduced pressure and the subsequent closure of the vials is done under vacuum. If there is no negative pressure in the vial, injection of Sterile Diluent for RabAvert would lead to an excess positive pressure in the vial. After reconstitution of the vaccine, it is recommended to unscrew the syringe from the needle to eliminate the negative pressure. After that, the vaccine can be easily withdrawn from the vial. It is not recommended to induce excess pressure, since over-pressurization may prevent withdrawing the proper amount of the vaccine.

HOW SUPPLIED

RabAvert product presentation is listed in Table 3 below:

TABLE 3: RABAVERT PRODUCT PRESENTATION

Presentation Carton NDC Number Components
Single dose kit 63851-501-02
  • 1 vial of freeze-dried vaccine containing a single dose [NDC 63851-511-11]
  • 1 disposable pre-filled syringe of Sterile Diluent for reconstitution (1 mL) [NDC 63851-512-12]
  • 1 small needle for injection (25 gauge, 1 inch) and 1 long needle for reconstitution (21 gauge, 1 % inch)

CAUTION: Federal law prohibits dispensing without a prescription.

Storage

RabAvert should be stored protected from light at 2°C to 8°C (36°F to 46°F). After reconstitution the vaccine is to be used immediately. The vaccine may not be used after the expiration date given on package and container.

REFERENCES

1. CDC. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Human Rabies Prevention - United States, 1999. Morbidity and Mortality Weekly Report Recommendations and Report, January 8, 1999, Vol.48, RR-1, pg 1.1-21.

4. Dreesen DW, et al. Two-year comparative trial on the immunogenicity and adverse effects of purified chick embryo cell rabies vaccine for preexposure immunization. Vaccine. 1989; 7: 397-400.

11. Bijok U, et al. Clinical trials in healthy volunteers with the new purified chick embryo cell rabies vaccine for man. J Commun Dis. 1984; 16: 61-69.

27. Centers for Disease Control and Prevention. Health Information for International Travel, 2003-2004 (The Yellow Book). Atlanta: US Department of Health and Human Services, Public Health Service, 2003. Internet version at: http://www.cdc.gov/travel/yb

28. World Health Organization. International Travel and Health, 2002. Geneva, Switzerland. Internet version at: http://www.who.int/ith

29. CDC and NIH. Biosafety in microbiological and biomedical laboratories. 3rd. ed. Washington, D.C. HHS Publication no. (CDC) 93-8395, Washington, DC: US Department of Health and Human Services, 1993.

30. Krebs JW, et al. Rabies surveillance in the United States in 2001. J Am Vet Med Assoc. 2002; 221:1690-1701.

Manufactured by: Novartis Vaccines and Diagnostics GmbH, D-35006 Marburg, Germany. Distributed by: Novartis Vaccines and Diagnostics, Inc. 350 Massachusetts Ave. Cambridge, MA. Revised: Nov 2013

Last reviewed on RxList: 9/22/2014
This monograph has been modified to include the generic and brand name in many instances.

Indications
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