CLINICAL PHARMACOLOGY
Rabies is a viral infection transmitted in the saliva of infected mammals.
Both dog and bat saliva exposures appear to be major contributors (see below)
with or without apparent bites. The virus enters the central nervous system
of the host, causing an encephalomyelitis that is fatal. After the marked decrease
of rabies cases among domestic animals in the US in the 1940s and 1950s, indigenously
acquired rabies among humans decreased substantially. 1, 2 In 1950,
for example, 4, 979 cases of rabies were reported among dogs, and 18 cases were
reported among humans. Between 1980 and 1997, 95 to 247 cases were reported
each year among dogs, and on average only two human cases were reported each
year in which rabies was attributable to variants of the virus associated with
indigenous dogs. 1, 3 Thus, the likelihood of human exposure to a rabid
domestic animal in the US has decreased greatly. However, during the same period,
12 cases of human rabies were attributed to variants of the rabies virus associated
with dogs from outside the US. 1, 4, 5 Therefore, international travelers
to areas where canine rabies is still endemic have an increased risk of exposure
to rabies. 1
Rabies among wildlife – especially raccoons, skunks, and bats – has become
more prevalent since the 1950s, accounting for > 85% of all reported cases
of animal rabies every year since 1976. 1, 2 Rabies among wildlife
occurs throughout the continental US; only Hawaii remains consistently rabies-free.
Wildlife is the most important potential source of infection for both humans
and domestic animals in the US. Since 1980, a total of 21 (58%) of the 36 human
cases of rabies diagnosed in the US have been associated with bat variants. 1, 3, 6, 7
In most other countries – including most of Asia, Africa, and Latin America –
dogs remain the major species with rabies and the most common source of rabies
among humans. Twelve (33%) of the 36 human rabies deaths reported to Centers
of Disease Control and Prevention (CDC) from 1980 through 1997 appear to have
been related to rabid animals outside the US. 1, 3, 7
Although rabies among humans is rare in the US, every year approximately 16, 000
to 39, 000 persons receive postexposure prophylaxis. 1, 8 In order to
manage potential human exposures to rabies appropriately, the risk of infection
must be accurately assessed. Administration of rabies postexposure prophylaxis
is a medical urgency, not a medical emergency, but decisions must not be delayed.
Systemic prophylactic treatments occasionally are complicated by adverse reactions, but
these reactions are rarely severe. 1, 9-13
Data on the safety, immunogenicity, and efficacy of active and passive rabies
immunization have come from both human and animal studies. Although controlled
human trials have not been performed, extensive field experience from many areas
of the world indicates that postexposure prophylaxis combining local wound treatment,
passive immunization, and vaccination is uniformly effective when appropriately
applied. 1, 14-19
Although no postexposure vaccine failures have occurred in the US since cell
culture vaccines have been routinely used, failures have occurred abroad when
some deviation was made from the recommended postexposure treatment protocol
or when less than the currently recommended amount of antirabies sera was administered. 1, 20-23
Specifically, patients who contracted rabies after postexposure prophylaxis
did not have their wounds cleansed with soap and water, did not receive their
rabies vaccine injections in the deltoid area (i. e. , vaccine was administered
in the gluteal area), or did not receive Rabies Immune Globulin (RIG) around
the wound site. 1
Rabies antibody provides passive protection when given immediately to individuals
exposed to rabies virus. 24 In a clinical study, Rabies Immune Globulin
(Human) [RIG(H)] of adequate potency25 was used in conjunction with
Rabies Vaccine of duck embryo origin. 25, 26 When a Rabies Immune Globulin
(Human) dose of 20 IU/kg of rabies antibody was given simultaneously with the
first dose of vaccine, levels of passive rabies antibody were detected 24 hours
after injection in all individuals. There was minimal or no interference with
the immune response to the initial and subsequent doses of vaccine, including
booster doses.
Studies of Rabies Immune Globulin (Human), 27 Imogam® Rabies,
given with the first of five doses of Aventis Pasteur SA HDCV1 confirmed that
passive immunization with 20 IU/kg of Rabies Immune Globulin (Human) provides
maximum circulating antibody with minimum interference of active immunization
by HDCV.
A double-blind randomized trial28 was conducted to compare the safety
and antibody levels achieved following intramuscular injection of Imogam®
Rabies – HT (heat treated) and Rabies Immune Globulin (Human), Imogam® Rabies
(non-heat treated). Each Rabies Immune Globulin (Human) was administered on
day 0, either alone or in combination with the human diploid cell Rabies Vaccine
(Imovax® Rabies) using the standard postexposure prophylactic schedule of
day 0, 3, 7, 14, and 28.
Sixty-four healthy veterinary student volunteers were randomized into four
parallel groups of 16 each to receive the following Rabies Immune Globulin (Human)
and vaccine regimens:
Imogam® Rabies – HT + Imovax®
Imogam® Rabies + Imovax®
Imogam® Rabies – HT + placebo
Imogam® Rabies + placebo
The treatment of both Rabies Immune Globulin (Human) and vaccine corresponded
to the postexposure recommended dose of 20 IU/kg of Rabies Immune Globulin (Human)
and was administered in three, equally divided IM injections of under 5 mL in
either gluteus. Serum rabies antibody levels were assessed before treatment
and on days 3, 7, 14, 28, 35, and 42 by the Rabies Fluorescent Focus Inhibition
Test (RFFIT).
Serum antibody levels were similar in the Imogam® Rabies – HT (rabies immune globulin (human)) and Imogam®
Rabies groups. By day three, 60% of each group had detectable antibody titers
of ≥ 0. 05 IU/mL. By day 14, the geometric mean titers (with 95%
confidence interval) were 19 IU/mL (11-38) in the Imogam® Rabies – HT (rabies immune globulin (human)) +
vaccine group and 31 IU/mL (20 to 48) in the Imogam® Rabies + vaccine group. These
differences were not statistically different.
Two subjects reported severe headaches, one in the Imogam® Rabies – HT (rabies immune globulin (human)) + placebo group and one in the Imogam® Rabies + Imovax® Rabies group. One third of the volunteers had moderate systemic (headache and malaise) reactions. These were equally distributed among the 4 treatment groups with no significant differences between the groups.
Both Imogam® Rabies – HT (rabies immune globulin (human)) and Imogam® Rabies were safe and without serious
adverse events or allergic reactions. The safety profile did not differ between
groups, although Imogam® Rabies – HT (rabies immune globulin (human)) produced fewer and milder local reactions
such as pain or tenderness at the injection site.
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