Rabies Immune Globulin (Systemic)


VA CLASSIFICATION
Primary: IM402

Commonly used brand name(s): BayRab; Hyperab; Imogam; Imogam Rabies-HT.

Other commonly used names are
HRIG and RIG . {06}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Immunizing agent (passive)—

Indications

Accepted

Rabies (prophylaxis)—Rabies immune globulin is indicated for post-exposure immunization against rabies infection in persons who have not been previously immunized against rabies with rabies vaccine. Rabies immune globulin is used in conjunction with rabies vaccine. {01} {02} {03} {04} {06} {07} {08} {09}{10}{11}

Unaccepted
Post-exposure prophylaxis is not recommended for persons inadvertently exposed to modified live rabies virus (MLV) vaccines intended for animals. Although vaccine-induced rabies has occurred in animals administered these vaccines, there have been no reported rabies cases among humans resulting from exposure to needle sticks or sprays with licensed MLV vaccines. {06}


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Rabies immune globulin is an antirabies gamma globulin obtained from the plasma of hyperimmunized human donors. It is concentrated by cold ethanol fractionation. The rabies neutralizing antibody content is usually standardized to contain 150 International Units (IU) per mL. {01} {02} {03} {06}{10}{11}
    The solvent/detergent treated immune globulin is isolated from solubilized Cohn Fraction II. The Fraction II solution is adjusted to a final concentration of 0.3% tri-n-butylphosphate; TNBP (solvent) and 0.2% sodium cholate (detergent). The solution is heated to 30°C and maintained at that temperature for not less than 6 hours. After the viral inactivation step, the reactants are removed by precipitation, filtration and finally ultrafiltration and diafiltration. BayRab is formulated as a 15% to 18% protein solution at a pH of 6.4 to 7.2. BayRab is then incubated in the final container for 21 to 28 days at 20 to 27°C. {10}
    A heat treated immune globulin undergoes a heat treatment process step (58 to 60°C for 10 hours) to inactivate viruses that has been added to further reduce any risk of blood-borne viral transmission. The inactivation and removal of model and laboratory strains of enveloped and non-enveloped viruses during the manufacturing and heat treatment process has been validated by spiking experiments. Removal and/or inactivation of the studied enveloped and non-enveloped model viruses was demonstrated at the precipitation II stage of manufacturing. In addition, inactivation was demonstrated during the 10 hour heat treatment process for the studied enveloped and non-enveloped viruses. Imogam Rabies-HT is formulated as a 10% to 18% protein solution at a pH of 6.8 ± 0.4 adjusted with sodium hydroxide or hydrochloric acid. {11}
    One Canadian product is standardized to contain 300 International Units (IU) per mL. {04} The International Unit of potency is equivalent to the U.S. unit of potency. {01}{11}

Mechanism of action/Effect:

Following intramuscular administration, rabies immune globulin provides immediate passive antibodies for a short period of time. This protects the patient until the patient can produce active antibodies from the rabies vaccine. {01} {02} {03} {04} {06}


Protective effect

When the post-exposure prophylaxis regimen has included local wound treatment, passive immunization, and active immunization, 100% effectiveness has been shown. However, rabies has occasionally developed in persons when key elements of the rabies post-exposure prophylaxis regimen were omitted or incorrectly administered. This has occurred outside the United States in cases in which patients' wounds were not cleansed with soap and water or other antiviral agents, rabies vaccine was not administered in the deltoid area but rather in the gluteal area, and passive immunization was not administered around the wound site. {01} {02} {03} {04} {06}{10}{11}


Time to protective effect

An adequate titer of passive antibody is present 24 hours after injection. {01} {02}


Duration of protective effect

Short; rabies immune globulin has a half-life of approximately 21 days. {04} {06}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other human immune globulin products may be sensitive to rabies immune globulin (RIG) also. {01} {02} {03} {04}{10}{11}

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans. Because of the potential consequences of rabies virus infection, and because there is no indication that fetal abnormalities have been associated with use of RIG in pregnant women, pregnancy is not considered to be a contraindication to use.

Studies have not been done in animals.

FDA Pregnancy Category C. {01} {02} {03} {04} {05} {06}{10}{11}

Breast-feeding

Problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of RIG have not been performed in the pediatric population. However, pediatrics-specific problems that would limit the usefulness of this medicine in children are not expected.


Geriatrics


No information is available on the relationship of age to the effects of RIG in geriatric patients.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

Live virus vaccines    (antibodies contained in RIG may interfere with the body's immune response to certain live virus vaccines; live virus vaccines, such as measles, mumps, and rubella, should be administered at least 14 days prior to, or at least 3 months after, administration of RIG {01} {02} {03})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Immunoglobulin A (IgA) deficiencies, in patients who have known antibody to IgA    (small amounts of IgA may be present in RIG and may cause a severe allergic reaction in patients with antibody to IgA {01} {02} {03} {04})


Sensitivity to RIG
Sensitivity to thimerosal    (some RIG available in the U.S. and Canada contain thimerosal {01} {02} {03} {04})




Side/Adverse Effects

Note: Severe systemic adverse effects to rabies immune globulin (RIG) are rare. {01} {02} {03}
Although not reported with RIG, anaphylaxis, angioneurotic edema, and nephrotic syndrome have been reported rarely with other immune globulin products. {01} {02} {03} {06}{10}{11}
If necessary, physicians should consult with the state public health department, the Centers for Disease Control (CDC), Canadian National Advisory Committee on Immunization (NACI), and/or the World Health Organization (WHO) regarding the management of serious adverse reactions. {04} {06}
There is no evidence that hepatitis B virus (HBV), human immunodeficiency virus (HIV), or other viruses have been transmitted by commercially available RIG in the U.S. {03} {06}
Since RIG is given in conjunction with rabies vaccine, adverse effects generally associated with rabies vaccine have also been temporally associated with RIG. {04}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Fever
    
pain, soreness, tenderness, or stiffness of the muscles at the place(s) of injection — may persist for several hours following injection {01} {02} {03} {04} {06}{10}{11}





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Rabies Immune Globulin (Systemic) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to rabies immune globulin, other human immune globulins, or thimerosal
Other medical problems, especially immunoglobulin A (IgA) deficiencies

Proper use of this medication

» Proper dosing


General Dosing Information
The recommended dose of rabies immune globulin (RIG) is 20 International Units (IU) per kg of body weight. Since RIG may partially suppress active production of rabies antibody, it is recommended that no more than the recommended dose be administered. {01} {02} {03} {04} {06}{10}{11}

If anatomically feasible, up to one-half of the dose of RIG should be thoroughly infiltrated into the area(s) around the wound(s) and the rest should be administered intramuscularly in the gluteal area. {01} {02} {03} {04} {06}{10}{11} Because of risk of injury to the sciatic nerve, the central region of the gluteal area should be avoided; only the upper, outer quadrant should be used. {10}

Care should be taken to avoid injection of RIG into or near blood vessels or nerves. {01} {02} {03} {04} {06}

RIG should not be administered intravenously because of the potential for serious reactions. {10} Although systemic reactions are rare, epinephrine should be available for the treatment of acute anaphylactic reactions. {10}{11}

All post-exposure therapy should begin with immediate and thorough cleansing of all the patient's wounds with soap and water. Studies have shown that wound cleansing greatly reduces the likelihood of rabies. {01} {02} {03} {04} {06}{10}{11}

Appropriate management of persons who may have been exposed to rabies depends on the assessment of the risk of infection. The incubation period for rabies infection varies with respect to the location and severity of the bite. The incubation period is usually 2 to 6 weeks, but can be longer. For bites to the face or extensive bites elsewhere on the body, the incubation period may be as short as 10 to 17 days. Decisions about management should be made promptly. Persons who have been bitten by animals suspected of being, or proven, rabid should begin therapy within 24 hours. If necessary, physicians should consult with the local or state public health department, the Centers for Disease Control (CDC), the Canadian National Advisory Committee on Immunization (NACI), and/or the World Health Organization (WHO) regarding the need for rabies prophylaxis. {01} {03} {04} {06}

The essential components of the rabies post-exposure prophylaxis regimen are local wound treatment, passive immunization with RIG (unless the patient has been previously immunized against rabies), and active immunization with rabies vaccine. Rabies has occasionally developed in persons when key elements of this regimen were omitted or incorrectly performed. In addition, tetanus prophylaxis and antibacterial medications may be administered as required. Both passive immunization with RIG (except for patients who have been previously immunized against rabies) and active immunization with rabies vaccine are required regardless of the interval between exposure and initiation of therapy. However, RIG should not be administered in the same syringe or into the same body site as the rabies vaccine. {01} {02} {03} {04} {06}{10}{11}

Persons are considered to have been previously immunized against rabies (and as such should not receive RIG as part of the post-exposure therapy) if they have previously received complete regimens of pre- or post-exposure rabies prophylaxis with human diploid cell rabies vaccine (HDCV) or rabies vaccine adsorbed (RVA) or if they have been documented to have had an adequate antibody response to another rabies vaccine, such as duck embryo rabies vaccine. Regardless of the antibody titer that is present before post-exposure therapy occurs, an anamnestic antibody response should occur following the administration of the next dose of rabies vaccine. {01} {02} {03} {06}{10}{11}

RIG, when indicated, is administered only once, usually at the beginning of the post-exposure therapy regimen. RIG provides immediate passive antibodies until the patient can produce active antibodies from the rabies vaccine. If not given on the first day, RIG may be given any time up through the 7th day of the therapy regimen. Beyond the 7th day, RIG is not indicated, since an active antibody response to the rabies vaccine is presumed to have begun, and passive antibody may interfere with the body's active response. {01} {02} {03} {06}{10}{11}

If post-exposure prophylaxis is administered outside the U.S., additional prophylaxis may be desirable when the patient returns to the U.S. Physicians should contact the state public health department or the CDC for specific advice. This is important, since treatment regimens and products vary from country to country. {06}


Parenteral Dosage Forms

RABIES IMMUNE GLOBULIN (HUMAN) (RIG) USP

Usual adult and adolescent dose
Immunizing agent (passive)
Intramuscular: 20 International Units (IU) per kg of body weight. If anatomically feasible, up to one-half of the dose should be thoroughly infiltrated into the area(s) around the wound(s) and the rest should be administered intramuscularly in the gluteal area. {01} {02} {03} {06}{10}{11} Because of risk of injury to the sciatic nerve, the central region of the gluteal area should be avoided; only the upper, outer quadrant should be used.{10}


Note: Rabies immune globulin (RIG) is used in conjunction with rabies vaccine and should be administered at the time of the first rabies vaccine dose or no later than the 7th day of rabies vaccine therapy. {01} {02} {03} {06}{10}{11}


Usual pediatric dose
See Usual adult and adolescent dose. {01} {02} {03} {06}

Strength(s) usually available
U.S.—


150 International Units (IU) per mL (Rx) [BayRab (preservative-free ) (glycine, 0.21 to 0.32 M)] [Imogam (thimerosal)] [Imogam Rabies-HT (preservative-free) (glycine, 0.3M)] [Hyperab (thimerosal)]{01}{02}{10}{11}

Canada—


150 International Units (IU) per mL (Rx) [Imogam (thimerosal )] [Hyperab ( thimerosal)]{02}{03}


300 International Units (IU) per mL (Rx)[Generic](may contain thimerosal){04}

Note: The International Unit of potency is equivalent to the U.S. unit of potency. {01} {02}{11}


Packaging and storage:
Store between 2 and 8 °C (35 and 46 °F), unless otherwise specified by manufacturer. Do not freeze. {01} {02} {03} {04}{10}{11}

Stability:
The solution should be discarded if it has been frozen. {02}

The solution should not be used if it is discolored or contains particulate matter. {01} {02} {03} {04}

Rabies immune globulin (RIG) should not be heated. It may be warmed slightly by holding the vial in one's hands, but it should not be placed in warm water or an incubator. {01} {02} {03} {04}

Incompatibilities:
RIG should not be administered in the same syringe or into the same body site as the rabies vaccine. {06}

Auxiliary labeling:
   • Store in refrigerator. {01} {02} {03} {04}
   • Do not freeze. {01} {02} {03} {04}
   • Discard if vaccine has been frozen. {02}



Revised: 11/04/1999



References
  1. Imogam package insert (Connaught—US), Rev 7/91, Rec 5/94.
  1. Hyperab package insert (Cutter—US and Canada), Rev 9/91, Rec 5/94.
  1. Imogam (Connaught). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 596.
  1. Generic (Rabies Immune Globulin, Human—Connaught). In: Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 29th ed. Ottawa: Canadian Pharmaceutical Association, 1994: 1114.
  1. Chabala S, Williams M, Amenta R, et al. Confirmed rabies exposure during pregnancy: treatment with human rabies immune globulin and human diploid cell vaccine. Am J Med 1991 Oct; 91: 423-4.
  1. Centers for Disease Control and Prevention. Rabies prevention-United States, 1991: recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991 Mar 22; 40(RR-3): 1-19.
  1. Frenia ML, Lafin SM, Barone JA. Features and treatment of rabies. Clin Pharm 1992 Jan; 11(1): 37-47.
  1. Baevsky RH, Bartfield JM. Human rabies: a review. Am J Emerg Med 1993 May; 11(3): 279-86.
  1. Groleau G. Rabies. Emerg Med Clin North Am 1992 May; 10(2): 361-8.
  1. Product Information: BayRab™, rabies immune globulin (human). Bayer Corporation, Elkhart, IN, USA, April 1998.
  1. Product Information: Imogam® Rabies-HT, rabies immune globulin (human). Pasteur Mérieux Connaught, Swiftwater, PA, USA, April 1997.
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