Label: RABAVERT- rabies vaccine kit

Rabies in the United States: Over the last 100 years, the epidemiology of rabies in animals in the US has changed dramatically. More than 90% of all animal rabies cases reported annually to the Centers for Disease Control and Prevention (CDC) now occur in wildlife, whereas before 1960 the majority was in domestic animals. The principal rabies hosts today are wild terrestrial carnivores and bats. Annual human deaths have fallen from more than a hundred at the turn of the century to 1 to 2 per year despite major epizootics of animal rabies in several geographic areas. Within the US, only Hawaii has remained rabies free. Although rabies among humans is rare in the US, every year tens of thousands of people receive rabies vaccine for postexposure prophylaxis.

Rabies is a viral infection transmitted via the saliva of infected mammals. The virus enters the central nervous system of the host, causing an encephalomyelitis that is almost invariably fatal. The incubation period varies between 5 days and several years, but is usually between 20 and 60 days. Clinical rabies presents either in a furious or in a paralytic form. Clinical illness most often starts with prodromal complaints of malaise, anorexia, fatigue, headache, and fever followed by pain or paresthesia at the site of exposure. Anxiety, agitation, and irritability may be prominent during this period, followed by hyperactivity; disorientation; seizures; aerophobia and hydrophobia; hypersalivation; and eventually paralysis, coma, and death.

Modern day prophylaxis has proven nearly 100% successful; most human fatalities now occur in people who fail to seek medical treatment, usually because they do not recognize a risk in the animal contact leading to the infection. Inappropriate postexposure prophylaxis may also result in clinical rabies. Survival after clinical rabies is extremely rare, and is associated with severe brain damage and permanent disability.

RabAvert (in combination with passive immunization with Human Rabies Immune Globulin [HRIG] and local wound treatment) in postexposure treatment against rabies has been shown to protect patients of all age groups from rabies, when the vaccine was administered according to CDC’s Advisory Committee on Immunization Practices (ACIP) or World Health Organization (WHO) guidelines and as soon as possible after rabid animal contact. Anti-rabies antibody titers after immunization have been shown to reach levels well above the minimum antibody titer accepted as seroconversion (protective titer) within 14 days after initiating the postexposure treatment series. The minimum antibody titer accepted as seroconversion is a 1:5 titer (complete inhibition in the rapid fluorescent focus inhibition test [RFFIT] at 1:5 dilution) as specified by CDC1 or ≥0.5 IU/mL as specified by WHO.2,3

Preexposure Vaccination: See Table 1 and DOSAGE AND ADMINISTRATION.

Preexposure vaccination consists of 3 doses of RabAvert 1.0 mL given intramuscularly (deltoid region), 1 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 DOSAGE AND ADMINISTRATION: Postexposure Prophylaxis of Previously Immunized Persons).

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 limited.27,28

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 (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 ACIP and is considered cost effective.

Postexposure Treatment: See Table 2 and DOSAGE AND ADMINISTRATION.

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 prophylaxis.1

In the US, 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 non-bite 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 discontinued.1

The likelihood of rabies in a domestic animal varies from region to region; hence, the need for postexposure prophylaxis also varies.1

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 US. 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 raccoons.30 In all cases involving rodents, the state or local health department should be consulted before a decision is made to initiate antirabies postexposure prophylaxis.1

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 rabies.1

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 with lesions caused by terrestrial carnivores) should prompt consideration of postexposure prophylaxis unless the bat is available for testing and is negative for evidence of rabies.1

 Non-bite: 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 non-bite 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 2 cases of rabies in Texas could possibly have been due to airborne exposures in caves containing millions of bats.1

The only documented cases for rabies from human-to-human transmission occurred in 8 patients, including 2 in the US, who received corneas transplanted from persons who died of rabies undiagnosed at the time of death.1 Stringent guidelines for acceptance of donor corneas have been implemented to reduce this risk.

Bite and non-bite 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 prophylaxis.1

General: The healthcare provider should question the patient, parent, or guardian about (1) the current health status of the vaccinee and (2) reactions to a previous dose of RabAvert or a similar product. Preexposure vaccination should be postponed in the case of sick and convalescent persons and those considered to be in the incubation stage of an infectious disease. A separate, sterile syringe and needle should be used for each patient. Needles must not be recapped and should be properly disposed of. As with any rabies vaccine, vaccination with RabAvert may not protect 100% of susceptible individuals.

Hypersensitivity: RabAvert contains residues of egg and chicken proteins, such as ovalbumin. In instances where individuals have developed clinical symptoms of anaphylaxis such as generalized urticaria, upper airway (lip, tongue, throat, laryngeal, or epiglottal) edema, laryngeal spasm or bronchospasm, hypotension, or shock, following exposure to egg or chicken protein, the vaccine should only be administered by personnel with the capability and facilities to manage anaphylaxis post vaccination.

Since reconstituted RabAvert contains processed bovine gelatin and trace amounts of neomycin, chlortetracycline, and amphotericin B, the possibility of allergic reactions in individuals hypersensitive to these substances should be considered when administering the vaccine.

Epinephrine injection (1:1,000) must be immediately available should anaphylactic or other allergic reactions occur.

When a person with a history of hypersensitivity must be given RabAvert, antihistamines may be given; epinephrine (1:1,000), volume replacement, corticosteroids, and oxygen should be readily available to counteract anaphylactic reactions.

Drug Interactions: Radiation therapy, antimalarials, corticosteroids, other immunosuppressive agents, and immunosuppressive illnesses can interfere with the development of active immunity after vaccination and may diminish the protective efficacy of the vaccine. Preexposure vaccination should be administered to such persons with the awareness that the immune response may be inadequate. Immunosuppressive agents should not be administered during postexposure therapy unless essential for the treatment of other conditions. When rabies postexposure prophylaxis is administered to persons receiving corticosteroids or other immunosuppressive therapy, or who are immunosuppressed, it is important that a serum sample on Day 14 (the day of the fourth vaccination) be tested for rabies antibody to ensure that an acceptable antibody response has been induced.1

HRIG must not be administered at more than the recommended dose, since active immunization to the vaccine may be impaired.

No data are available regarding the concurrent administration of RabAvert with other vaccines.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term studies with RabAvert have not been conducted to assess the potential for carcinogenesis, mutagenesis, or impairment of fertility.

Use in Pregnancy: Animal reproductive studies have not been conducted with RabAvert. It is also not known whether RabAvert can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RabAvert should be given to a pregnant woman only if clearly needed. The ACIP has issued recommendations for use of rabies vaccine in pregnant women.1

Use in Nursing Mothers: It is not known whether RabAvert is excreted in animal or human milk, but many drugs are excreted in human milk. Although there are no data, because of the potential consequences of inadequately treated rabies exposure, nursing is not considered a contraindication to postexposure prophylaxis. If the risk of exposure to rabies is substantial, preexposure vaccination might also be indicated during nursing.

Pediatric Use: Children and infants receive the same dose of 1 mL, given intramuscularly, as do adults.

Only limited data on the safety and efficacy of RabAvert in the pediatric age group are available. However, in 3 studies some preexposure and postexposure experience has been gained12,19,26 (see CLINICAL PHARMACOLOGY: Clinical Studies).

Geriatric Use: Clinical studies of RabAvert did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Observed During Clinical Practice (See WARNINGS and PRECAUTIONS): The following adverse reactions have been identified during post approval use of RabAvert. Because these reactions are reported voluntarily from a population of uncertain size, estimates of frequency cannot be made. These events have been chosen for inclusion due to their seriousness, frequency of reporting, causal connection to RabAvert, or a combination of these factors:

Allergic: Anaphylaxis, Type III hypersensitivity-like reactions, bronchospasm, urticaria, pruritus, edema.

Central Nervous System: Neuroparalysis, encephalitis, meningitis, transient paralysis, Guillain-Barré Syndrome, myelitis, retrobulbar neuritis, multiple sclerosis, presyncope, syncope, vertigo, visual disturbance.

Cardiac: Palpitations, hot flush.

Local: Extensive limb swelling.

Skin and Subcutaneous Tissue Disorders: Angioedema.

The use of corticosteroids to treat life-threatening neuroparalytic reactions may inhibit the development of immunity to rabies (see PRECAUTIONS, Drug Interactions).

Once initiated, rabies prophylaxis should not be interrupted or discontinued because of local or mild systemic adverse reactions to rabies vaccine. Usually such reactions can be successfully managed with anti-inflammatory and antipyretic agents.

Reporting of Adverse Events: Adverse events should be reported by the healthcare provider or patient to the US Department of Health and Human Services (DHHS) Vaccine Adverse Event Reporting System (VAERS). Report forms and information about reporting requirements or completion of the form can be obtained from VAERS by calling the toll-free number 1-800-822-7967.1 In the US, such events can be reported to Bavarian Nordic: phone: 1-800-675-9596.

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: 1 injection on each of Days 0, 3, 7, 14, and 28 in conjunction with the administration of HRIG on Day 0. For children, see PRECAUTIONS: Pediatric Use.

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 intramuscularly 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 CDC for recommendations.

Postexposure Prophylaxis of Previously Immunized Persons: When rabies exposure occurs in a previously vaccinated person, that person should receive 2 IM (deltoid) doses (1 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 2 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.

Step 1: With one hand, hold the syringe (E) with the cap pointing upward. Be sure to hold the syringe by the white textured holding ring (D).
Step 2: With the other hand, grasp the cap (A) and firmly rock it back and forth to break its connection to the white textured holding ring (D). Do not twist or turn the cap.
Step 3: Lift up to remove the cap (A) and the attached gray tip cap (B). Be careful not to touch the sterile syringe tip (C).

Needle application (these instructions apply to both the green and the orange needles):

Step 1: Twist to remove the cap from the green reconstitution needle. Do not remove the plastic cover (G). This needle is the longer of the two needles.
Step 2: With one hand, firmly hold syringe (E) by white textured holding ring (D). With your other hand, insert needle (F) and twist clockwise until it locks into place. Once needle is locked, remove its plastic cover (G). The syringe (E) is now ready for use.

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 IM 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 to slightly opalescent, colorless to slightly pink 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 disposed of properly.

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.