Imogam (Rabies Immune Globulin, Pasteurized)

IMOGAM® RABIES PASTEURIZED

Connaught

Rabies Immune Globulin, Pasteurized (Human)

Immunotherapeutic Agent – Passive Immunization

Action And Clinical Pharmacology: Infection with rabies virus characteristically produces an acute illness with rapidly progressive CNS manifestations, including anxiety, dysphagia, and convulsions, and almost invariably progresses to death. Some patients may present with paralysis.

Rabies virus is classified in the Rhabdovirus family.

Rabies virus can infect any warm blooded animal. In North America, it occurs mainly in certain wildlife species and is spread by them to domestic livestock and pets. In recent years, most reported wildlife infections in British Columbia have been in bats; in Alberta, Saskatchewan and Manitoba in skunks; in Ontario and Quebec in foxes and skunks; and in the Northwest Territories in foxes. Rabies has been reported sporadically from New Brunswick and Nova Scotia and recently outbreaks in foxes have been reported in Labrador. Although domestic dogs and cats account for less than 10% of reported animal rabies, bites of these species account for the vast majority of suspected rabies exposures in humans and thus the majority of courses of anti-rabies postexposure treatment.

Airborne transmission has been reported in the laboratory and in bat-infected caves. Transmission has also occurred by transplantation of corneas from patients dying of undiagnosed rabies. Person-to-person transmission by bite has not been documented, although the virus has been isolated from the saliva of patients.

The incubation period in humans ranges from 5 days to more than 1 year; 2 months is the average. Recently, incubation periods of many years have been confirmed by antigenic typing of strains.

Rabies virus is usually transmitted by the bite of a rabid animal but can occasionally penetrate abraded skin contaminated with the saliva of infected animals. Progress of the virus after exposure is believed to follow a neural pathway and the time between exposure and clinical rabies is a function of the proximity of the bite (or abrasion) to the CNS and the dose of virus injected. The incubation period is usually 2 to 6 weeks but can be longer. After severe bites to the face, neck or arms, it may be as short as 10 days. After initiation of the vaccine series (human diploid cell origin), it takes approximately 1 week for development of immunity to rabies; therefore, the value of immediate passive immunization with rabies antibodies in the form of Rabies Immune Globulin (Human) cannot be overemphasized.

Since reporting began in 1925, 21 persons have died of rabies in Canada. A decision on the management of a person who may have been exposed to rabies virus must be made rapidly and judiciously since delay in starting a course of vaccine reduces its effectiveness and the infection is almost always fatal. Close to 3 000 persons in Canada receive postexposure treatment each year because of exposure to rabid or suspect rabid animals.

Rabies antibody provides passive protection when given immediately to individuals exposed to rabies virus. Rabies Immune Globulin (Human) of adequate potency was used in conjunction with Rabies Vaccine of duck embryo origin. When a globulin 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, Pasteurized (Human) administered with the first of 5 doses of Inactivated Human Rabies Vaccine Mérieux confirmed that passive immunization with 20 IU/kg of Rabies Immune Globulin (Human) provides maximum circulating antibody with minimum interference with the active immunization.

A recent study indicates that the neutralizing antibody levels following administration of Rabies Immune Globulin, Pasteurized (Human) with and without Rabies Vaccine (HDCV) are not significantly different from that observed following Rabies Immune Globulin (not heat treated) administered in the same manner.

A double-blind trial was conducted in 64 healthy veterinary student volunteers randomized into 4 parallel groups of 16 each, to compare the safety and antibody levels achieved following i.m. injection of Rabies Immune Globulin, Pasteurized (Human) and Rabies Immune Globulin, nonheat treated (Human). Each immune globulin was administered on day 0, either alone or in combination with the Human Diploid Cell Rabies Vaccine using the standard postexposure prophylactic schedule of day 0, 3, 7, 14 and 28.

The dosage corresponded to the postexposure recommended dose of 20 IU/kg of Rabies Immune Globulin and was administered in 3, equally divided i.m. 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 Rabies Immune Globulin, Pasteurized (Human) and Rabies Immune Globulin, nonheat treated (Human) groups. By day 3, 60% of each group had detectable antibody titers of ³0.05 IU/mL. By day 14, the geometric mean titres (with 95% confidence interval) were 19 IU/mL (11 to 38) in the Rabies Immune Globulin, Pasteurized (Human) + vaccine group and 31 IU/mL (20 to 48) in the Rabies Immune Globulin, nonheat-treated (Human) + vaccine group. These differences were not statistically different.

Both Rabies Immune Globulin, Pasteurized (Human) and Rabies Immune Globulin, nonheat-treated (Human) were safe and without serious adverse events or allergic reactions.

Indications And Clinical Uses: Rabies Immune Globulin, Pasteurized (Human) is indicated for individuals suspected of exposure to rabies, with one exception: persons who have been previously immunized with Human Diploid Cell Rabies Vaccine, (HDCV) in a pre- or postexposure treatment series receive only vaccine.

Persons previously vaccinated with a vaccine other than HDCV in whom adequate antibody levels have not been demonstrated should receive full postexposure prophylaxis with HDCV and RIG.

If indicated, Rabies Immune Globulin, Pasteurized (Human) should be administered as promptly as possible after exposure. If initiation of treatment is delayed for any reason, Rabies Immune Globulin, Pasteurized (Human) should still be given, regardless of the interval between exposure and treatment. Since vaccine-induced antibody begins to appear within 1 week, there is no value in administering rabies immune globulin more than 8 days after the first dose of a rabies vaccine course.

Recommendations for passive and/or active immunization after exposure to an animal suspected of having rabies have been outlined by the W.H.O. and by the Canadian National Advisory Committee on Immunization (NACI).

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 noninfectious. 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.

Because some bat bites may be less severe, and therefore more difficult to recognize, than bites inflicted by larger mammalian carnivores, rabies postexposure treatment should be considered for any physical contact with bats when bite or mucous membrane contact cannot be excluded.

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 postexposure 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; Rabies Immune Globulin (RIG) , which provides rapid protection that persists for only a short period of time (half-life about 21 days).

Vaccine and immune globulin should be used concurrently for optimum postexposure prophylaxis against rabies , except in persons previously vaccinated with human diploid cell rabies vaccine (HDCV).

Postexposure Treatment Guide: The following recommendations are only a guide (see Table I). They should be applied in conjunction with knowledge of the animal species involved, circumstances of the bite or other exposure, vaccination status of the animal, and presence of rabies in the region. Local and provincial public health officials should be consulted if questions arise about the need for rabies prophylaxis.

Contra-Indications: Should not be administered in repeated doses once vaccine treatment has been initiated. Repeating the dose may interfere with maximum active immunity expected from the vaccine.

Manufacturers’ Warnings In Clinical States: Rabies Immune Globulin, Pasteurized (Human) is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. An alcohol fractionation procedure used to purify the immunoglobulin component removes and/or inactivates both enveloped and nonenveloped viruses. An added heat treatment process (60° C, 10 hours) further inactivates both enveloped and nonenveloped viruses (see Supplied). Despite these measures, it is still theoretically possible that known or unknown infectious agents may be present. All infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other health care provider to the Medical Director, Connaught Laboratories Limited, 1755 Steeles Avenue West, Toronto, Ontario, Canada, M2R 3T4. The physician should discuss the risks and benefits of this product with the patient. This should include information that cases of rabies have been attributed to omission of passive immunization in persons who have received rabies vaccine.

Rabies Immune Globulin, Pasteurized (Human) should be given with caution to patients with a history of prior systemic allergic reactions following the administration of human immune globulin preparations.

Persons with specific IgA deficiency have increased potential for developing antibodies to IgA and could have anaphylactic reactions to subsequent administration of blood products containing IgA.

Precautions: General: There is no contraindication to the use of rabies vaccine or rabies immune globulin if indicated following exposure to a proven rabid animal. Hypersensitive individuals should be vaccinated only under strict medical supervision.

Infiltration of wounds in some anatomical sites (finger tips) must be carried out with care in order to avoid increased pressure in the tissue compartment (compartment syndrome).

The possibility of allergic reactions in individuals sensitive to components of the product 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. Health care providers should be familiar with current recommendations for the initial management of anaphylaxis in nonhospital settings, including proper airway management.

Before administration of any product, 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 product or similar product, determination of previous immunization history, and the presence of any contraindications, current health status, and a current knowledge of the literature concerning the use of the product under consideration.

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

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

A separate sterile needle and syringe, 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.

Needles should not be recapped and should be disposed of properly.

Before administration of Rabies Immune Globulin, Pasteurized (Human), health care personnel should inform the patient, parent or guardian of the benefits and risks of immunization, and also inquire about the recent health status of the patient to be injected.

Rabies Immune Globulin, Pasteurized (Human) should not be administered i.v because of the potential for serious reactions. Injection should be made i.m. and care should be taken to draw back on the plunger of the syringe before injection in order to be certain that the needle is not in a blood vessel. Although systemic reactions to immunoglobulin preparations are rare, epinephrine (1:1 000) should be available for treatment of acute anaphylactoid reactions. As with all preparations given i.m., bleeding complications may be encountered in patients with bleeding disorders.

Drug Interactions: Live virus vaccine such as measles vaccine should not be given for 4 months following Rabies Immune Globulin, Pasteurized (Human) administration because antibodies in the globulin preparation may interfere with the immune response to the vaccination. Interference may also occur if the administration of Rabies Immune Globulin, Pasteurized (Human) becomes necessary within a short time after the administration of a live viral vaccine, and if the time interval between the 2 is very short (less than 14 days), vaccination may have to be repeated.

Pregnancy: Pregnancy is not a contraindication to rabies postexposure therapy. Based on limited data, there have been no fetal abnormalities associated with rabies vaccination. Clinical experience with other immunoglobulin preparations suggests that there are no known adverse effects on the fetus from immune globulin, but there are no reported studies indicating whether or not such adverse effects occur. Specifically animal reproduction studies have not been conducted with Rabies Immune Globulin, Pasteurized (Human). It is also not known whether Rabies Immune Globulin, Pasteurized (Human) can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Rabies Immune Globulin, Pasteurized (Human) should be given to a pregnant woman only if clearly needed.

Adverse Reactions: In a recent clinical trial involving 16 volunteers in each of 4 treatment groups, 2 subjects reported severe headaches, 1 in the Rabies Immune Globulin, Pasteurized (Human) + placebo group and one in the Rabies Immune Globulin, nonheat-treated (Human) and the Human Diploid Cell Rabies Vaccine group. One third of the volunteers reported moderately systemic reactions (headache and malaise). These were equally distributed among the 4 treatment groups with no significant differences between the groups.

Local or mild systemic adverse reactions to the globulin are infrequent and may be treated symptomatically.

Local tenderness, soreness or stiffness of the muscles may occur at the injection site and may persist for several hours after injection. Urticaria and angioedema may occur. Anaphylactic reactions although rare, have been reported following injection of human immune globulin preparations. Fever, skin reactions or chills have been reported following human rabies immunoglobulins. Rare cases of nausea, vomiting, hypotension, tachycardia and allergic-type reactions have been reported. In very rare cases, anaphylactic shock has been observed.

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: 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.

Rabies Immune Globulin, Pasteurized (Human) should be used in conjunction with rabies human diploid cell vaccine (HDCV). The recommended dose of Rabies Immune Globulin, Pasteurized (Human) is a single i.m. administration of 20 IU/kg (0.133 mL/kg) of body weight at the time of administration of the first vaccine dose. If possible up to half the dose should be used to infiltrate the wound, and the rest administered i.m., preferably in the gluteal or deltoid region. Two injections would be given in the gluteal region if the volume is greater than 5 mL.

Rabies Immune Globulin, Pasteurized (Human) should never be administered in the same syringe or into the same anatomical site as the vaccine. HDCV is never to be administered in the gluteal region. Because Rabies Immune Globulin, Pasteurized (Human) may partially suppress active production of antibody, no more than the recommended dose should be given.

The dose of 20 IU/kg body weight is the same for children and adults. The dose of Rabies Immune Globulin, Pasteurized (Human), especially following multiple wounds, may be diluted 2-to 3-fold in a solution of 0.9% sodium chloride in order to provide the full amount of human rabies immunoglobulin required for good infiltration of sites at risk of rabies.

Do not heat by placing in warm water or incubator.

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 (see Precautions).

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

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 product, date given, dose, manufacturer and lot number.

Availability And Storage: Imogam Rabies Pasteurized is a sterile solution of antirabies immunoglobulin (10 to 18% protein) for i.m. administration. It is prepared by cold alcohol fractionation from pooled venous plasma of individuals immunized with Rabies Vaccine prepared from human diploid cells (HDCV). The product is stabilized with 0.3 M glycine. The globulin solution has a pH of 6.8±0.4 adjusted with sodium hydroxide or hydrochloric acid. No preservatives are added.

Imogam Rabies Pasteurized is a colorless to light opalescent liquid.

A heat-treatment process step (58 to 60° C, 10 hours) to inactivate viruses has been added to further reduce risk of blood-borne viral transmission. The inactivation and removal of model and laboratory strains of enveloped and nonenveloped viruses during the manufacturing and heat treatment processes for Imogam Rabies Pasteurized has been validated by spiking experiments. Human immunodeficiency virus, type 1 (HIV-1) and type 2 (HIV-2) were selected as relevant viruses for plasma derived products. Bovine viral diarrhea virus and Sindbis virus were chosen to model hepatitis C virus. Porcine pseudorabies virus was selected to model hepatitis B virus and herpes virus. Avian reovirus was used to model nonenveloped RNA viruses and for its relative resistance to inactivation by chemical and physical methods. Finally, porcine parvovirus was selected to model human parvovirus B19 and its notable resistance to inactivation by heat treatment.

Removal and/or inactivation of the studied enveloped and nonenveloped model viruses was demonstrated at the precipitation III stage of manufacturing. In addition, inactivation was demonstrated to occur during the 10-hour (58 to 60° C) heat treatment process for the studied enveloped and nonenveloped viruses.

The product is standardized against a Standard Rabies Immune Globulin of known potency in IU for rabies antibody. Each vial is formulated to contain at least 150 IU/mL. Each mL contains: human proteins 100 to 180 mg containing (IgG-class) human rabies immunoglobulins with a minimum titre of 150 IUmL. Nonmedicinal ingredients: glycine, sodium chloride and water for injection. Vials of 2 mL – 300 IU (150 IU/mL) which is sufficient for a child weighing 15 kg; and 10 mL – 1 500 IU (150 IU/mL) which is sufficient for an adult weighing 75 kg.

Titre determined by the Rapid Fluorescent Focus Inhibition Test (RFFIT) technique.

Store at refrigerator temperature (2 to 8° C). Do not freeze. Product that has been exposed to freezing should not be used. Imogam Rabies Pasteurized contains no preservatives and unused portions must be discarded immediately. Do not use after expiration date.

IMOGAM® RABIES PASTEURIZED Connaught Rabies Immune Globulin, Pasteurized (Human) Immunotherapeutic Agent – Passive Immunization

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