Clozapine Orally Disintegrating Tablet and Rabies Immune Globulin

• Generic Name: clozapine
• Dosage Forms: tablet, orally disintegrating
• Other Brand Names: Clozaril, Fazaclo, Versacloz, Clopine, CloZAPine Synthon, Denzapine, Zaponex

Clozapine is an antipsychotic medication. It works by changing the actions of chemicals in the brain.

Clozapine is used to treat severe schizophrenia, or to reduce the risk of suicidal behavior in people with schizophrenia or similar disorders.

Clozapine is available only from a certified pharmacy under a special program.

• Generic Name: rabies immune globulin, human
• Dosage Forms: n.a.
• Other Brand Names: Bayrab, HyperRAB, Imogam Rabies-HT, Kedrab

Prevention of Rabies

Prevention of rabies in children, adolescents, and adults exposed to or at increased risk of exposure to rabies disease or virus. 

Rabies is a viral infection transmitted by saliva of infected mammals, most commonly wild, terrestrial carnivores (e.g., skunks, raccoons, foxes, coyotes) or bats. In the US, the greatest risk for naturally acquired rabies is from contact with and bites from insectivorous bats. Following exposure and infection, rabies virus usually moves along a neural pathway and enters the CNS. After entrance into the CNS, the virus is unlikely to be affected by antirabies antibodies and encephalomyelitis usually develops and almost always is fatal. In the US, approximately 16,000-39,000 individuals receive rabies postexposure prophylaxis each year. Although there were 27 rabies cases reported in the US during 2000-2008, these individuals evidently did not receive rabies postexposure prophylaxis.  Rabies prevention and control strategies and elimination of canine rabies virus variants and enzootic transmission among dogs have lowered the number of rabies cases in the US to an average of 1-2 per year. However, worldwide, rabies is much more common and at least 55,000 rabies-related deaths occur each year. 

USPHS Advisory Committee on Immunization Practices (ACIP) and AAP recommend preexposure vaccination with rabies vaccine (series of 3 doses with booster doses when indicated) in children, adolescents, and adults who are or will be at increased risk of exposure to the virus.

Postexposure prophylaxis with a regimen that includes local wound treatment, rabies vaccine (series of 4 or 5 doses), and a single dose of rabies immune globulin (RIG) is recommend for previously unvaccinated children, adolescents, and adults following potential rabies exposure. Postexposure prophylaxis with a regimen that includes local wound treatment and a series of 2 booster doses of rabies vaccine (without RIG) is recommended for previously vaccinated children, adolescents, and adults following potential rabies exposure.

Preexposure Vaccination Against Rabies in High-risk Groups

Preexposure vaccination in children, adolescents, and adults who are or will be at risk of exposure to rabies virus. 

Preexposure vaccination does not eliminate the need for prompt postexposure prophylaxis if an exposure to rabies occurs.

Need for rabies preexposure vaccination depends on the nature of risk and associated level of potential exposure. Consider preexposure vaccination for individuals whose risk of rabies exposure is greater than that of the general population (e.g., veterinarians and their staff, animal-control and wildlife workers, field biologists, spelunkers, missionaries, rabies researchers, certain laboratory workers). Also consider preexposure vaccination for individuals whose activities bring them into frequent contact with rabies virus or potentially rabid bats, raccoons, skunks, cats, dogs, or other species at risk for having rabies.

Travelers to areas where rabies is endemic may be at risk, especially if they are likely to come in contact with animals in areas where dog or other animal rabies is enzootic and immediate access to appropriate medical care (including rabies vaccine and RIG) is unlikely. Canine rabies remains highly endemic in certain areas of the world (e.g., parts of Africa, Asia, Central and South America). CDC recommends preexposure vaccination based on local incidence of rabies in the country to be visited, availability of appropriate agents for rabies postexposure prophylaxis in that country, and intended activity and duration of stay. 

Minimum acceptable antibody titer is complete virus neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test (RFFIT). Give booster dose of rabies vaccine if titer falls below this level.

Adapted from the Recommendations of the Advisory Committee on Immunization Practices (ACIP) on Human Rabies Prevention. MMWR Recomm Rep. 2008; 57 (RR-3):1-28.

Postexposure Prophylaxis of Rabies

Postexposure prophylaxis of rabies in previously vaccinated and unvaccinated children, adolescents, and adults following exposure to rabies disease or virus. 

History of previous vaccination against rabies simplifies the postexposure prophylaxis regimen, but does not eliminate the need for prompt postexposure prophylaxis if an exposure to rabies occurs.

Whenever a possible human exposure to rabies occurs, the risk of infection must be accurately assessed to determine the need for postexposure prophylaxis.

Any person with a history of a complete preexposure or postexposure vaccination regimen with HDCV, PCECV, or rabies vaccine adsorbed (RVA; not commercially available in the US), or previous vaccination with any other type of rabies vaccine and a documented history of antibody response to the prior vaccination.

Individuals with immunosuppression should receive a 5-dose regimen of rabies vaccine; give 1 mL (HDCV or PCECV) IM once on days 0, 3, 7, 14, and 28.

Deltoid area is the only acceptable site for IM administration of rabies vaccine in adults, adolescents, and older children. For younger children, deltoid or anterolateral thigh should be used. Never administer in gluteal area.

Day 0 is the day the first dose of rabies vaccine is administered.

Adapted from Use of a Reduced (4-Dose) Vaccine Schedule for Postexposure Prophylaxis to Prevent Human Rabies. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010; 59 (RR-2):1-9.

Regardless of rabies immunization status, ACIP and AAP recommend that postexposure prophylaxis of rabies begin immediately with thorough cleansing of all bite wounds and scratches using soap and water and, if available, irrigation with a virucidal agent such as povidone-iodine solution. Local wound treatment is an essential initial step in rabies postexposure prophylaxis in all individuals.

In previously unvaccinatedchildren, adolescents, and adults following potential rabies exposure, a postexposure prophylaxis regimen of active immunization with a 4- or 5-dose regimen of rabies vaccine and passive immunization with a single dose of RIG is recommended as soon as possible. The ACIP states that a 4-dose regimen of rabies vaccine in conjunction with RIG is sufficient for postexposure prophylaxis in previously unvaccinated individuals who are immunocompetent; however, a 5-dose vaccine regimen in conjunction with RIG should be used in those with altered immunocompetence.

In previously vaccinated children, adolescents, and adults following potential rabies exposure, a 2-dose booster regimen of rabies vaccine (without RIG) is recommended as soon as possible.

During the 10-day observation period, begin postexposure prophylaxis in the exposed individual at the first sign of rabies in a dog, cat, or ferret that has bitten them. If the animal exhibits clinical signs of rabies, euthanize it immediately and perform appropriate testing.

Initiate postexposure prophylaxis as soon as possible following exposure to such wildlife, unless animal is available for testing and public health authorities are facilitating expeditious laboratory testing or it is already known that brain material from the animal has tested negative. Other factors that might influence urgency of decision-making regarding initiation of postexposure prophylaxis before diagnostic results are known include the animal species, general appearance and behavior of the animal, whether encounter was provoked by a human, and the severity and location of bites. Discontinue postexposure prophylaxis if appropriate laboratory tests (i.e., direct fluorescent antibody test) are negative.

Euthanize the animal and test as soon as possible. Holding for observation is not recommended.

Adapted from the Recommendations of the Advisory Committee on Immunization Practices (ACIP) on Human Rabies Prevention. MMWR Recomm Rep. 2008; 57 (RR-3):1-28.

Bite exposures include any skin penetration by teeth; all bite exposures from an animal known or suspected to be rabid, regardless of bite location, pose a potential risk of rabies transmission and require postexposure prophylaxis. Risk of transmission varies in part based on species of biting animal, anatomic site of bite, and severity of wound. Rabies transmission can occur from bites of some animals (e.g., bats) that inflict rather minor injury and wounds that are difficult to detect.

Any potential exposure to a bat requires thorough evaluation. If possible, the bat should be submitted for rabies diagnosis. Postexposure prophylaxis is not necessary if the individual can be reasonably certain a bite, scratch, or mucous membrane exposure did not occur or if the bat is available for testing and is negative for rabies virus. Situations that might qualify as exposures include finding a bat in the same room as a person who might be unaware that a bite or direct contact occurred (e.g., a deeply sleeping individual awakened to find a bat in the room or an adult observes a bat in the room with a previously unattended child, mentally disabled person, or intoxicated person). Other household members who did not have direct contact with the bat or were awake and aware when in the room with the bat should not be considered as having exposure to rabies.

Nonbite exposures include contamination of preexisting open wounds, abrasions, mucous membranes, or scratches with saliva or other potentially infectious material (e.g., neural tissue) from an animal known or suspected to be rabid. Although nonbite exposures only rarely cause rabies, such exposures require assessment to determine if sufficient reasons exist to consider postexposure prophylaxis. Nonbite exposures of highest risk occur in 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.

Transmission of rabies to individuals performing autopsies not reported to date; no confirmed cases of rabies reported in individuals performing postmortem examinations of humans or animals. CDC recommends that personnel performing autopsies on decedents with confirmed or suspected rabies use appropriate personal protective equipment, wear heavy or chain mail gloves, minimize aerosol generation by using a handsaw rather than oscillating saw, limit the number of individuals participating in the procedure and collection of specimens, and use ample amounts of 10% sodium hypochlorite solution during and after the procedure to ensure decontamination of all exposed surfaces. CDC states that preexposure vaccination against rabies usually is not required for individuals performing autopsies and that rabies postexposure prophylaxis is recommended in autopsy personnel only if a wound or mucous membrane gets contaminated with the patient's saliva or other potentially infectious material (e.g., neural tissue) during the procedure.

Other forms of contact in the absence of a bite or nonbite exposure (e.g., petting a rabid animal or contact with blood, urine, or feces of a rabid animal, contact of saliva with intact skin) are not considered exposure and postexposure prophylaxis is not necessary.

In health-care personnel, routine delivery of health care to a patient with rabies is not an indication for postexposure rabies prophylaxis; postexposure prophylaxis in such personnel is indicated if they have been bitten by the patient or if they have mucous membranes or nonintact skin (e.g., open wounds) that were contaminated with the patient's saliva or other potentially infectious material (e.g., neural tissue).

Because the rabies incubation period in humans can range from days to years (usually 1-3 months), initiate rabies postexposure prophylaxis (regardless of the length of delay) if a documented or likely exposure has occurred and clinical signs of rabies have not appeared in the exposed individual.

Postexposure prophylaxis failures have not been reported in the US when recommended wound management and postexposure regimens were followed using commercially available rabies vaccines and RIG. ACIP states that rabies pathogenesis data, animal data, clinical studies, and epidemiologic surveillance indicate that a 4-dose vaccine series is as effective as a 5-dose vaccine series when used in conjunction with wound management and RIG. Rare reports of postexposure prophylaxis failures in other countries usually involved some deviation from recommended procedures (e.g., postexposure prophylaxis not given or substantially delayed, wounds not adequately cleansed, rabies vaccine given IM into the gluteal rather than deltoid region, failure to passively immunize with RIG by infiltrating the wound site, use of less than the recommended dose of RIG, use of less than the recommended number of vaccine doses).

Travelers to rabies-endemic countries should be warned about the risk of acquiring rabies and educated in bite prevention strategies (e.g., avoiding contact with bats, avoiding stray dogs, monkeys, or cats). Because appropriate preparations of RIG or rabies vaccine may be not available for postexposure prophylaxis in the destination country, CDC recommends that travelers to such countries have a preplanned strategy in place that may involve identifying a different country where appropriate postexposure prophylaxis can be obtained if necessary. CDC states that rabies vaccines grown in animal brains (nerve tissue vaccines; NTV) may still be used in some developing countries; if offered such a vaccine (identified by a regimen that requires 5-mL injections once daily for 14-21 days), travelers should refuse the vaccine and travel to a country where an acceptable rabies vaccine and RIG are available. If travelers in other countries receive postexposure prophylaxis with regimens and/or preparations not recommended by ACIP (or not used in the US), additional therapy may be necessary following return to the US. In such cases, consult state and local health authorities for advice regarding the need for additional postexposure prophylaxis. Consider serologic testing in these travelers to verify efficacy of the regimen used and to ensure an adequate immune response.