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.

Table 1. Rabies Preexposure Prophylaxis Guide – United States, 1999a

aAdapted from the Recommendations of the Advisory Committee on Immunization Practices: Human Rabies Prevention – United States, 1999.1

bJudgment of relative risk and extra monitoring of vaccination status of laboratory workers is the responsibility of the laboratory supervisor.29

cMinimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by rapid fluorescent focus inhibition test. A booster dose should be administered if the titer falls below this level

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

Table 2. Rabies Postexposure Prophylaxis Guide – United States, 1999a

aAdapted from the Recommendations of the Advisory Committee on Immunization Practices: Human Rabies Prevention – United States, 1999.1

bDuring 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.

cThe 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 US, the following factors should be considered before antirabies treatment is initiated.

Hypersensitivity

History of anaphylaxis to the vaccine or any of the vaccine components constitutes a contraindication to preexposure vaccination with this vaccine.

In the case of postexposure prophylaxis, if an alternative product is not available, the patient should be vaccinated with caution with the necessary medical equipment and emergency supplies available and observed carefully after vaccination. A patient's risk of acquiring rabies must be carefully considered before deciding to discontinue vaccination. Advice and assistance on the management of serious adverse reactions for persons receiving rabies vaccines may be sought from the state health department or CDC.

General

Care is to be taken by the healthcare provider for the safe and effective use of the product. The healthcare provider should also 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

At present there is no evidence that persons are at increased risk if they have egg hypersensitivities that are not anaphylactic or anaphylactoid in nature. Although there is no safety data regarding the use of RabAvert in patients with egg allergies, experience with other vaccines derived from primary cultures of chick embryo fibroblasts demonstrates that documented egg hypersensitivity does not necessarily predict an increased likelihood of adverse reactions. There is no evidence to indicate that persons with allergies to chickens or feathers are at increased risk of reaction to vaccines produced in primary cultures of chick embryo fibroblasts.

Since reconstituted RabAvert contains processed bovine gelatin and trace amounts of chicken protein, 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, pruritis, edema.

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

Cardiac: Palpitations, hot flush.

Local: Extensive limb swelling.

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 GlaxoSmithKline: phone: 1-888-825-5249.

Preexposure Dosage

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.