Rabies Vaccine Inactivated (Diploid Cell Origin), Dried
Action And Clinical Pharmacology: The administration of Rabies Vaccine Inactivated (Diploid Cell Origin), Dried stimulates the rapid development of specific antibodies.

Pre-exposure Immunization: Pre-exposure clinical trials have been carried out since 1979 with the present vaccine or its less purified predecessors in over 600 volunteers. Following 3 injections of 1 mL each of vaccine, all developed antibodies at a level of 1 IU/mL or greater.

In a clinical trial done in Canada in 1989 and 1990, 119 individuals who had rabies vaccine antibody titers of less than 0.16 IU received pre-exposure immunization by either the i.m. or s.c. route. Following administration of 3 doses of vaccine on days 0, 7 and 21, 100% of recipients had protective rabies antibody titers with postimmunization levels ranging from 2.8 IU/mL to 82.2 IU/mL. The i.m. route produced significantly higher levels of rabies antibodies.

In clinical trials in 1983 and 1984 in which 187 individuals received 3 injections of vaccine at 0, 7 and 21 days, and were tested 4 weeks following the third injection, all had antibody levels equal to or greater than 3 IU/mL by the Rapid Fluorescent Focus Inhibition Test (RFFIT).

The National Advisory Committee on Immunization considers a protective antibody level to be 1:32 by the RFFIT test. The WHO currently considers a minimal acceptable antibody titer to be 0.5 IU/mL. The CDC currently considers a minimal acceptable antibody titer to be 1:5 by the RFFIT test.

Persistence of antibody following three 1 mL injections of the primary immunization series with Rabies Vaccine Inactivated (Diploid Cell Origin), Dried in 197 adults showed a 10-fold drop in geometric mean levels in one year from 30 IU/mL to 3 IU/mL. However, the mean antibody response of 3 IU/mL is still considerably above the minimal acceptable antibody level of 0.5 IU/mL.

Reinforcement Immunization: Since 1979 single dose reinforcement immunization has been administered to more than 400 individuals. A single reinforcement dose of 1 mL of vaccine administered between 1983 and 1984 to 84 individuals immunized at different times previously with various rabies vaccines induced an antibody response in all and at least a 4-fold increase in all but 7 of those tested.

Post-Exposure Immunization: Rabies Vaccine Inactivated (Diploid Cell Origin), Dried administered as 1 mL injections i.m. on day 0, 3, 7, 14 and 28 evoked detectable antibody in vaccinees by day 7. Antibody levels continued to rise reaching peak values at day 28.

Testing of vaccinees at day 90 showed some decline from peak antibody levels but all were many times above the accepted protective level.

When Rabies Immune Globulin (Human) in a dosage of 20 IU per kg of bodyweight was administered at the same time as the initial vaccine injection, serum rabies antibody was demonstrable 2 days following the injection. Significantly higher antibody levels were present on days 2, 3, and 7 than when rabies vaccine only was administered indicating the importance of rabies immune globulin in providing antibody in the early period following exposure. There was no significant difference in antibody levels following rabies vaccine with and without rabies immune globulin at 14, 28, 49 and 90 days indicating that rabies immune globulin did not suppress the response to vaccine.

Indications And Clinical Uses: Pre-exposure immunization, both primary series and periodic reinforcement, and for postexposure immunization against rabies.

Pre-exposure Immunization: Pre-exposure rabies vaccination is an elective procedure and should be offered to persons at potentially high risk of contact with rabid animals, e.g., certain laboratory workers, veterinarians, animal control and wildlife workers, spelunkers, forest rangers, conservation officers, and certain travellers including those: working (even for a short time) in a rabies-infected country, if their activities may involve exposure to some special risk; spending time (e.g., 1 month or more) in a foreign country where rabies is a constant threat; or travelling in such a country, for any length of time, far away from a major medical centre. Three doses of Human Diploid Cell Vaccine (HDCV) are required, one on days 0, 7 and 21.

Reinforcement Immunization: Persons with continuing high risk of exposure such as certain veterinarians should have their serum tested every 2 years; others working with live rabies virus in laboratories or vaccine-production facilities and who are at risk of inapparent exposure should be tested every 6 months. Those with inadequate titers should be given a booster dose of HDCV. Persons previously immunized with other vaccines should be given sufficient doses of HDCV to produce an adequate antibody response. An acceptable antibody titer is considered to be 1:32 by the rapid fluorescent-focus inhibition test.

Postexposure Immunization: A decision on the management of a person who has been exposed to the risk of rabies infection must be made rapidly and judiciously since delay in starting a course of vaccine reduces its effectiveness, and the disease once established is almost always fatal.

Rabies prophylaxis must be considered in every incident where potential exposure to rabies virus has occurred. The following factors should be taken into consideration.

Species of Animal: The animals in Canada most often proven rabid are foxes, skunks, cattle, dogs, cats and bats. The distribution of animal rabies and the species involved vary considerably across Canada so it is important to consult the local medical officer of health or government veterinarian. Human exposures to livestock are usually confined to salivary contamination, with the exception of horses and swine in which biting incidents have been reported. Risk of infection following exposure to rabid cattle is low, and only about 30 cases have ever been recorded. Squirrels, hamsters, guinea-pigs, gerbils, chipmunks, rats, mice, other rodents or rabbits and hares are rarely found to be infected with rabies and are not known to cause human rabies in Canada and the U.S.; their bites seldom, if ever, call for rabies prophylaxis.

Incident: Each incident requires full investigation including an assessment of the risk of rabies in the animal species involved and the behavior of the particular animal. An unprovoked attack is more apt to indicate that the animal is rabid. Nevertheless, rabid cats and dogs may become uncharacteristically quiet. Bites inflicted on a person attempting to feed or handle an apparently healthy animal should generally be regarded as provoked.

Type of Exposure: Exposure to rabies virus is considered to have occurred when the animal's teeth break the skin in a bite or if the animal's saliva or other potentially infectious material (such as brain tissue) comes into contact with an open wound or mucous membrane. If the virus-containing material is dry, the virus can be considered to be non-infectious. Contact with blood, urine or feces or petting a rabid animal does not constitute an exposure and is not an indication for prophylaxis. The occurrence of rabies following exposure to virus-laden aerosols in a laboratory and in a bat-infested cave has been reported. The only known cases of human-to-human transmission of rabies occurred in patients who received corneal transplants from persons who had died of unrecognized rabies. Tissues from persons who die of encephalitis of unknown etiology should not be used as donor transplants.

Vaccination Status of Biting Animal: A small number of vaccinated animals have developed rabies. Therefore, symptoms suggesting rabies, even in a vaccinated animal, must be carefully evaluated. The vaccination history in itself should not influence the need for post-exposure treatment nor the need to sacrifice the animal for assessment.

The following recommendations are intended as a guide for the management of persons following possible exposure to rabies and may need to be modified in accordance with the specific circumstances of the exposure to rabies.

Local Treatment of Wounds: Immediate washing and flushing with soap and water, detergent, or water alone is imperative and is probably the most effective procedure in the prevention of rabies. Suturing the wound should be avoided if possible. Tetanus prophylaxis and antibacterial drugs should be given as required.

Immunizing Agents: There are 2 types of immunizing products: Vaccines, which contain inactivated virus and induce an active immune response beginning in 7 to 10 days and persisting for at least a year; and Rabies Immune Globulin (RIG), which provides rapid protection that persists for only short period of time (half-life about 21 days).

Vaccine and immune globulin should be used concurrently for optimum post-exposure prophylaxis against rabies, except in certain previously immunized persons, as indicated below.

Vaccine: Postexposure prophylaxis should be started as soon as possible after exposure and should be offered to exposed persons regardless of the elapsed interval. Prophylaxis may be started as late as 6 or more months after exposure.

Five doses of HDCV should be given: The first dose (on day 0) as soon as possible after exposure, and additional doses on each of days 3, 7, 14 and 28 days after the first dose. A single dose of RIG should also be given on day 0 as described below. Routine follow-up antibody determination is unnecessary, except in the case of persons with immunodeficiency or those receiving immunosuppressive therapy.

Indication for Discontinuation of Postexposure Prophylaxis: A course of vaccine may be discontinued if fluorescent antibody tests on the brain of an animal killed at the time of attack prove to be negative.

Postexposure Therapy of Previously Immunized Persons: Persons previously vaccinated with HDCV should receive 2 vaccine doses, 1 immediately and another 3 days later. RIG should not be given in these cases. Antibody determination is not helpful because two booster doses are recommended whatever the result.

If vaccine other than HDCV had been used for previous immunization and seroconversion has not been demonstrated, full post-exposure rabies prophylaxis with HDCV including rabies immune globulin should be started. A serum sample may be collected before vaccine is given and if adequate antibody is demonstrated, the course can be discontinued provided that the 2 doses of vaccine indicated above have been given.

Contra-Indications: There are no specific contraindications to the use of Rabies Vaccine Inactivated (Diploid Cell Origin), Dried in the postexposure situation; however, care should be taken if the vaccine is to be administered to persons known to be sensitive to bovine serum, polymyxin, neomycin or thimerosal, as even trace amounts may cause an allergic reaction in such individuals.

General: Pre-exposure immunization with Rabies Vaccine Inactivated (Diploid Cell Origin), Dried should be deferred in the presence of any acute illness, including febrile illness.

Absolute Contraindications: Allergy to any component of Rabies Vaccine Inactivated (Diploid Cell Origin), Dried, or an allergic or anaphylactic reaction to a previous dose of Rabies Vaccine Inactivated (Diploid Cell Origin), Dried are contraindications to pre-exposure vaccination.

Manufacturers' Warnings In Clinical States: Local and/or mild systemic reactions may occur after vaccine injection but these are usually transient and do not contraindicate continuing immunization.

This vaccine must not be used s.c. or intradermally.

Corticosteroids, other immunosuppressive agents, antimalarials, and immunosuppressive illnesses can interfere with the development of active immunity after vaccination and may predispose the patient to rabies. Pre-exposure prophylaxis should be administered to such persons with the awareness that the immune response may be inadequate. Immunosuppressive agents should not be administered during post-exposure therapy unless essential for the treatment of other conditions. When rabies post-exposure prophylaxis is administered to persons receiving steroids or other immunosuppressive therapy, or who are immunosuppressed, it is important that a serum sample be tested for rabies antibody to ensure that an acceptable antibody response has developed.

Corticosteroid therapy can result in immunosuppression although the exact dose and duration of therapy required to suppress the immune system is not well defined. Persons treated with high doses of systemic steroids, e.g., ³2 mg/kg/day of prednisone orally for more than 2 weeks, should be considered to have a compromised immune system.

As with any vaccine, immunization with Rabies Vaccine Inactivated (Diploid Cell Origin), Dried may not protect 100% of susceptible individuals.

Since the vaccine contains traces of bovine serum, polymyxin, neomycin and thimerosal, the possibility of allergic reactions in individuals sensitive to these substances should be borne in mind when considering the use of this vaccine.

Precautions: General: The possibility of allergic reactions in individuals sensitive to components of the vaccine should be evaluated. Epinephrine HCl solution (1:1 000) and other appropriate agents should be available for immediate use in case an anaphylactic or acute hypersensitivity reaction occurs. Before an injection of any vaccine, all appropriate precautions should be taken to prevent adverse reactions. This includes a review of the patient's history with respect to possible hypersensitivity to the vaccine or similar vaccine, determination of previous immunization history, and the presence of any contraindications to immunization.

Special care should be taken to ensure that the product is not injected into a blood vessel.

A separate, sterile syringe and needle, or a sterile disposable unit, must be used for each individual patient to prevent the transmission of infectious agents. There have been case reports of transmission of HIV and hepatitis by failure to scrupulously observe sterile technique.

Do not recap needles.

If the vaccine is administered to persons with immunodeficiency or receiving immunosuppressive therapy the expected antibody response may not be obtained.

Pregnancy: The safety of Rabies Vaccine in pregnancy has not been established. Because of the potential consequences of inadequately treated rabies exposure and limited data that indicate that fetal abnormalities have not been associated with rabies vaccination, pregnancy is not considered a contraindication to postexposure prophylaxis. If there is a substantial risk of exposure to rabies, pre-exposure prophylaxis may also be indicated during pregnancy.

Adverse Reactions: Local reactions which may occur include redness, soreness, hardness, swelling, pain and itching at the site of injection. Generalized reactions such as fever, chills, malaise, headache, abdominal pain and joint pain may also occur. These reactions are usually of short duration lasting a few hours to 1 to 2 days and have onset within a few hours of vaccine injection.

In a simulated post-exposure clinical trial done in Texas in 1984, 31 persons each received 5 doses of rabies vaccine on days 0, 3, 7, 14 and 28. These persons were not given rabies immune globulin. Local reactivity was mild and subsided within 24 to 48 hours. Systemic reactivity was infrequent, mild and usually consisted of headache, dizziness and malaise. There were no severe reactions reported. The incidence of adverse events following any dose are shown in Tables I and II.

Neurological events have been reported following administration of rabies vaccine of human diploid cell origin. These have included 3 cases of neurologic illness resembling Guillain Barré syndrome and a few other subacute central and peripheral nervous system disorders.

Systemic allergic reactions characterized by generalized urticaria and accompanied in some cases by arthralgia, angioedema, fever, nausea and vomiting have been reported following administration of Human Diploid Cell Rabies Vaccines (HDCV). These reactions are uncommon in persons receiving primary immunization but have occurred in up to 7% of persons receiving a booster dose, with onset after 2 to 21 days. These reactions have been shown to follow the development of IgE antibodies to beta propiolactone-altered human serum albumin in the vaccine. Vaccines purified by zonal centrifugation appear to be less likely to be associated with such reactions. Immediate anaphylactic reactions have occurred in 1 in 10 000 persons given HDCV. In clinical trials with this vaccine, no immune-complex-like reactions have been reported.

Physicians, nurses, and pharmacists should report any adverse occurrences temporally related to the administration of the product in accordance with local requirements and to the Medical Director, Connaught Laboratories Limited, 1755 Steeles Avenue West, Toronto, Ontario, Canada, M2R 3T4.

Dosage And Administration: Do not inoculate in the gluteal area.

Pre-exposure Immunization: Three injections each of 1 mL each of Rabies Vaccine Inactivated (Diploid Cell Origin), Dried should be administered i.m. into the deltoid muscle on days 0, 7 and 21.

Reinforcement Immunization: The booster dose of 1 mL of vaccine should be administered i.m. into the deltoid muscle.

Postexposure Immunization: Five dose of 1 mL of HDCV should be given by i.m. injection into the deltoid muscle in adults or into the anterolateral zone of the thigh in small children; the first dose (on day 0) as soon as possible after exposure, and additional doses on each of days 3, 7, 14 and 28 after the first dose. A single dose of RIG should also be given on day 0 as described below.

Rabies Immune Globulin: A dose of 20 IU/kg of RIG should be administered on one occasion, as soon as possible after exposure. Up to one half the dose should be infiltrated around the wound if practical; the remainder should be given i.m. using a separate syringe and needle. Because of interference with active antibody production, the recommended dose should not be exceeded.

Since vaccine-induced antibody begins to appear within 1 week, there is no value in administering RIG more than 8 days after initiating a vaccine course.

Under no circumstances should vaccine be administered in the same syringe or at the same site as RIG.

Parenteral biological products should be inspected visually for extraneous particulate matter and/or discoloration before administration. If these conditions exist, the product should not be administered.

Shake the vial to distribute uniformly the suspension before withdrawing each dose. When administering a dose from a rubber-stoppered vial, do not remove either the rubber stopper or the metal seal holding it in place. Aseptic technique must be used for withdrawal of each dose.

Before injection, the skin over the site to be injected should be cleansed with a suitable germicide.

Administer the vaccine i.m. The preferred site is into the anterolateral aspect of the mid-thigh (vastus lateralis muscle) or into the deltoid muscle. After insertion of the needle, aspirate to ensure that the needle has not entered a blood vessel.

Do not inject i.v.

Each person who is immunized should be given a permanent personal immunization record. In addition, it is essential that the physician or nurse record the immunization history in the permanent medical record of each patient. This permanent office record should contain the name of the vaccine, date given, dose, manufacturer and lot number.

Availability And Storage: Rabies Vaccine Inactivated (Diploid Cell Origin), Dried is a sterile diploid cell culture rabies virus vaccine for human use. It is a purified and concentrated suspension of "fixed" rabies virus (CL-77) adapted to and prepared in monolayers of MRC-5 human diploid cells grown in a defined medium. The viral harvest is inactivated with b-propiolactone. The inactivated material is clarified by membrane filtration and further processed by continuous gradient zonal centrifugation and dialysis. In addition to the presence of viral protein, human albumin is added to a concentration of 2% as a stabilizer. Traces of bovine serum, polymyxin, neomycin and proteins originating from the cell substrate may also be present.

The potency of the vaccine is equal to or greater than 2.5 IU of rabies antigen per dose as established by testing in parallel with the Standard Rabies Vaccine in the NIH mouse potency test (FDA).

The vaccine is freeze-dried in single dose vials for reconstitution to 1 mL with the sterile diluent provided. The sterile diluent contains thimerosal 0.01% as a preservative. The reconstituted vaccine is orange to red in color due to phenol red indicator.

Packages of 1 single dose vial of vaccine and 1 vial of sterile diluent for reconstitution of a single dose.

The freeze-dried vaccine and sterile diluent should be stored and transported between 2 and 8°C. Do not freeze. The vaccine should be used immediately after reconstitution. Product which has been exposed to freezing should not be used. Do not use vaccine beyond the expiry date.