Tetanus Immune Globulin (Systemic)


VA CLASSIFICATION
Primary: IM402


Note: This monograph is specific to the sterile solution of tetanus immune globulin prepared from large pools of plasma obtained from individuals immunized with tetanus toxoid {01} {02}.

Commonly used brand name(s): BayTet.

Another commonly used name is
TIG .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Immunizing agent (passive)—

Indications

General considerations
Tetanus (lockjaw) is a neurologic disease charcterized by severe muscular spasms {14}. It is caused by the neurotoxin produced by the anaerobic bacterium Clostridium tetani in a contaminated wound {14}. Onset is gradual, occurring over 1 to 7 days, and progresses to severe generalized muscle spasms (severe enough to cause spinal fractures), which frequently are aggravated by any external stimulus {14}. Severe spasms persist for 1 week or more and subside in a period of weeks in those who recover {14}. Neonatal tetanus, a common cause of neonatal mortality in developing countries but rare in the U.S., is caused by contamination of the umbilical stump {14}. Local tetanus is manifested by local muscle spasms in areas contiguous to a wound infected with Clostridium tetani {14}.

Wound cleaning, debridement when indicated, and proper immunization are important in the prevention and management of tetanus {10}. The need for tetanus toxoid (active immunization), with or without tetanus immune globulin (passive immunization), depends on both the condition of the wound and the patient's vaccination history {10}.

Determining whether the wound is clean or dirty is extremely important in categorizing patients {09}. A wound is considered to be dirty if it is more than 6 hours old, if there is debris in the wound, if the wound is penetrating or deep, if the instrument that caused the wound is contaminated, if the wound is infected, if the wound is caused by a deep partial- or full-thickness burn, or if it is a crush injury {09}.

A thorough attempt must be made to determine whether a patient has completed primary vaccination. Patients with unknown or uncertain previous vaccination histories should be considered to have had no previous tetanus toxoid doses {10}. Patients who have not completed a primary series may require tetanus toxoid and passive immunization with tetanus immune globulin at the time of wound cleaning and debridement {10}.

Tetanus immune globulin provides protection for a longer time than does antitoxin of animal origin, and causes fewer adverse reactions. Therefore, if passive immunization is needed, tetanus immune globulin is the product of choice {10} {12}.

A recent U.S. serologic survey of tetanus immunity indicated that in the majority of the population, tetanus immunity decreases with time after the recipient's most recent vaccination {05}. If a contraindication to using tetanus toxoid–containing preparations exists for a person who has not completed a primary series of tetanus toxoid immunizations and that person has a wound that is neither clean nor minor, only passive immunization should be given, using tetanus immune globulin {06} {13}.

In the U.S., tetanus is primarily a disease of older adults. Of the 99 tetanus patients with complete information reported to the Centers for Disease Control and Prevention (CDC) during 1987 and 1988, 68% were 50 years of age or older {10}. The age distribution of recent cases and the results of serosurveys indicate that many U.S. adults are not protected against tetanus {07} {10}.

Accepted

Clostridium tetaniinfection (prophylaxis)—Tetanus immune globulin is indicated for prophylaxis against C. tetani infection, and the severe complications that arise from the toxins produced by C. tetani , following injury in patients whose immune status against tetanus is uncertain or incomplete {01} {02}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Tetanus immune globulin is a sterile solution of tetanus hyperimmune immunoglobulin, primarily immunoglobulin G (IgG), containing 15 to 18% protein, of which not less than 90% is gamma globulin. Tetanus immune globulin is prepared from large pools of plasma obtained from individuals immunized with tetanus toxoid. Tetanus immune globulin is stabilized with 0.21 to 0.32 molar glycine and contains no preservative {01} {19}. Tetanus immune globulin is standardized against the U.S. standard antitoxin and the U.S. control tetanus toxin and contains not less than 250 tetanus antitoxin units per vial {01} {11}.
    pH—Adjusted to between 6.4 and 7.2 with sodium carbonate or acetic acid {01} {11}.

Mechanism of action/Effect:

Following intramuscular injection, tetanus immune globulin provides immunity to those individuals who have low or no immunity to the toxin produced by the tetanus organism, Clostridium tetani . The antibodies act to neutralize the free form of the powerful exotoxin, tetanospasmin {01} {19}, produced by this bacterium {01}.


Protective effect

Therapeutic passive immunization with tetanus immune globulin decreases fatalities in humans {12}. While the therapeutic dose of tetanus immune globulin does not prevent the effects of toxin already bound to the nerve tissue {19}, it should be given promptly because it may modify the course of toxin that has not yet been bound and later may cause symptoms {12} {19}.


Time to protective effect

Peak blood concentrations of immunoglobulin G (IgG) are obtained approximately 2 days after intramuscular injection {01} {12}.


Duration of protective effect

Short; the half-life of IgG in the circulation of individuals with normal IgG concentrations is approximately 23 days {01}.


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans. However, there is no evidence to suspect that tetanus immune globulin causes problems in pregnant women {15}.

Studies have not been done in animals.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether tetanus immune globulin is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

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


Geriatrics


No information is available on the relationship of age to the effects of tetanus immune globulin in geriatric patients. However, there is no evidence that increasing age enhances the risk or diminishes the efficacy of tetanus immune globulin, or that its effects differ from those in younger persons {15}.

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 in immunoglobulin preparations may interfere with the response to live virus vaccines such as measles, oral poliovirus, and rubella; use of live virus vaccines should be deferred until approximately 3 months after tetanus immune globulin administration {01}; the effect of immune globulin preparations on the response to mumps and varicella vaccines is unknown, but commercial immune globulin preparations contain antibodies to these viruses {04})


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 problem exists
Sensitivity to tetanus immune globulin


Side/Adverse Effects

Note: Sensitization to repeated injections of human immunoglobulin preparations is extremely rare, even though slight soreness at the site of injection and slight temperature elevation may be noted at times {01}.
In the course of routine injections of large numbers of persons with immunoglobulin preparations, there have been a few isolated occurrences of angioneuropathic edema, nephrotic syndrome, and anaphylactic shock after injection {01}.

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
Incidence rare
    
Anaphylactic reaction (difficulty in breathing or swallowing; hives; itching, especially of soles or palms; reddening of skin, especially around ears; swelling of eyes, face, or inside of nose; unusual tiredness or weakness, sudden and severe)
{01}




Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tetanus Immune Globulin (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before receiving this medication
»   Conditions affecting use, especially:
Sensitivity to tetanus immune globulin

Proper use of this medication

» Proper dosing


Side/adverse effects
Signs of potential side effects, especially anaphylactic reaction


General Dosing Information
Skin tests for allergy should not be performed prior to administration of tetanus immune globulin. The intradermal injection of concentrated immunoglobulin G (IgG) solution often causes localized inflammation due to tissue irritation, which can be misinterpreted as a positive allergic reaction. True allergic responses to human IgG are rare {01}.

Although systemic reactions to human immunoglobulin preparations are rare, appropriate precautions should be taken prior to tetanus immune globulin injection to prevent allergic or other unwanted reactions. These should include review of the patient's history regarding possible sensitivity and the ready availability of epinephrine 1:1000 and other appropriate agents used to control immediate allergic reactions {01}.

Tetanus immune globulin is administered intramuscularly {01}. The preferred sites for intramuscular injections are the anterolateral aspect of the upper thigh and the deltoid muscle of the upper arm {04}. It should not be injected intravenously. Intravenous injection of immune globulin intended for intramuscular use can, on occasion, cause a rapid fall in blood pressure. Therefore, injections should only be made intramuscularly; 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 {01}.

It is important to convey immediate passive protection against tetanus, and at the same time begin formation of tetanus antibodies in the injured individual in order to preclude future need for antitoxin. Passive immunization with tetanus immune globulin may be undertaken simultaneously with active immunization using tetanus toxoid in those persons who must receive an immediate injection of tetanus immune globulin and in whom it is desirable to begin or continue (for those patients who have had only one dose of tetanus toxoid) {15} the process of active immunization. {01}.

Since tetanus is actually a local infection, proper initial wound care is of paramount importance {01}. The use of tetanus immune globulin is an adjunct to treatment of the wound. However, in approximately 10% of recent tetanus cases, no wound or other break in the skin or mucous membranes could be implicated. Current recommendations for wound management of patients definitely known to have completed a full tetanus toxoid series indicate only a booster dose of tetanus toxoid if more than 5 to 10 years have elapsed since the last dose of toxoid {01}.

Tetanus immune globulin does not interfere with the immune response to tetanus toxoid. However, the two injections should not be given in the same syringe or injected at the same site, since neutralization of the toxoid may occur {01} {02}.

The optimum therapeutic dose for the treatment of tetanus infection has not been established. However, the Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) recommends a single dose of 3000 to 6000 units of tetanus immune globulin for the treatment of tetanus infection {14} {16} {18}.

Antibodies in immune globulin preparations may interfere with the response to live virus vaccines such as oral poliovirus, and rubella. Therefore, use of live virus vaccines should be deferred until approximately 3 months after tetanus immune globulin administration {01}. The concurrent administration of tetanus immune globulin should not interfere with the immune response to oral typhoid vaccine {04}.

Recent evidence suggests high doses of immune globulin can inhibit the immune response to measles vaccine for more than 3 months after administration {04} {06}. Administration of immune globulin can also inhibit the response to rubella vaccine {04}. The effect of immune globulin preparations on the response to mumps and varicella vaccines is unknown, but commercial immune globulin preparations contain antibodies to these viruses {04}.

Blood-containing products, such as immune globulins, can diminish the immune response to measles, mumps, and rubella virus vaccine live or its individual component vaccines. Therefore, after an immune globulin preparation is received, these vaccines should not be administered before the recommended interval {04}. However, the postpartum vaccination of rubella-susceptible women with rubella virus vaccine live or measles, mumps, and rubella virus vaccine live should not be delayed because immune globulin was received during the last trimester of pregnancy or at delivery {04}. These women should be vaccinated immediately after delivery and, if possible, tested at least 3 months later to ensure immunity to rubella and, if necessary, to measles {04}.

If administration of an immune globulin preparation becomes necessary because of imminent exposure to disease, measles, mumps, and rubella virus vaccine live or its individual component vaccines can be administered simultaneously with the immune globulin preparation, although vaccine-induced immunity could be compromised {04}. The vaccine should be administered at an injection site remote from that chosen for the immune globulin inoculation. Unless serologic testing indicates that specific antibodies have been produced, vaccination should be repeated after the recommended interval {04}.

If administration of an immune globulin preparation becomes necessary after measles, mumps, and rubella virus vaccine live or its individual component vaccines have been administered, interference can occur {04}. Usually, vaccine virus replication and stimulation of immunity will occur 1 to 2 weeks after vaccination. Thus, if the interval between administration of any of these vaccines and subsequent administration of an immune globulin preparation is less than 14 days, vaccination should be repeated after the recommended interval, unless serologic testing indicates that antibodies were produced {04}.

Immune globulin preparations interact less with inactivated vaccines and toxoids than with live virus vaccines {04}. Therefore, administration of inactivated vaccines and toxoids either simultaneously with, or at any interval before or after, receipt of immune globulins should not substantially impair the development of a protective antibody response {04}. The vaccine or toxoid and the immune globulin preparation should be administered at different injection sites using the standard recommended dose of vaccine. Increasing the vaccine dose or number of vaccinations for inactivated vaccines or toxoids is not indicated or recommended {04}.

Immunocompromised persons, including those infected with human immunodeficiency virus (HIV), should receive tetanus immune globulin for the same indications and in the same doses as immunocompetent persons {01} {03}.
For emergency tetanus prophylaxis of wounds

   • If uncertain of number or less than three primary doses of tetanus toxoid have been administered: For clean, minor wounds, tetanus and diphtheria toxoids should be administered as soon as possible. For children younger than 7 years of age, diphtheria and tetanus toxoids adsorbed (for pediatric use), diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP), or a combination DTP and poliovirus vaccine should be given as part of the routine childhood immunization. For all other wounds, tetanus immune globulin also should be administered {01} {10} {13}.
   • If three or more doses of tetanus toxoid have been administered alone or in combination with other vaccines such as DTP {15}: For clean, minor wounds, if more than 10 years have passed since the last dose of tetanus toxoid, tetanus and diphtheria toxoids should be administered as soon as possible. For other, more severe tetanus-prone wounds {15}, if more than 5 years have passed since the last dose of tetanus toxoid, tetanus and diphtheria toxoids should be administered as soon as possible. Generally, tetanus immune globulin is not required in either case {01} {10} {13}.

For treatment of adverse effects
Recommended treatment consists of the following:
   • For mild hypersensitivity reaction—Administering antihistamines, and, if necessary, corticosteroids {08}.
   • For severe hypersensitivity or anaphylactic reaction—Administering epinephrine. Antihistamines or corticosteroids also may be administered as required {08}.


Parenteral Dosage Forms

TETANUS IMMUNE GLOBULIN INJECTION USP

Usual adult and adolescent dose
Immunizing agent (passive)
Deep intramuscular injection, 250 units {01} {10} {13}.


Note: In cases of severe or highly contaminated wounds, or when treatment is delayed for more than twenty-four hours, a dose of 500 units may be required. If the threat of tetanus infection persists, repeat doses of tetanus immune globulin can be given at four-week intervals {01}.


Usual pediatric dose
Immunizing agent (passive)
See Usual adult and adolescent dose.


Note: The pediatric dose is the same as for adults. Alternatively, in children younger than 7 years of age, tetanus immune globulin can be given in doses of 4 units per kilogram of body weight {01} {02}.


Strength(s) usually available
U.S.—


Not less than 250 units in each prefilled disposable syringe (Rx) [BayTet]{01}{19}

Canada—


Not less than 250 units in each prefilled disposable syringe (Rx)[Generic]{01}{19}

Packaging and storage:
Store between 2 and 8 ºC (36 and 46 ºF), unless otherwise specified by manufacturer {11}.

Stability:
Tetanus immune globulin should not be used if exposed to freezing temperatures {01} {02}.

Incompatibilities:
Do not administer in the same syringe or at the same body site as tetanus toxoid.

Auxiliary labeling:
   • Do not freeze {01} {02}.



Developed: 06/27/1997



References
  1. BayTet package insert (Bayer—US), Rev 8/96, Rec 4/97.
  1. Krogh CME, editor. CPS Compendium of pharmaceuticals and specialties. 31st ed. Ottawa: Canadian Pharmaceutical Association; 1996. p. 1451-2.
  1. Centers for Disease Control and Prevention. Recommendations of the Advisory Committee on Immunization Practices (ACIP): use of vaccines and immune globulins in persons with altered immunocompetence. MMWR Morb Mortal Wkly Rep 1993; 42(RR-4): 1-18.
  1. Centers for Disease Control and Prevention. Recommendations of the Advisory Committee on Immunization Practices (ACIP): general recommendations on immunization. MMWR Morb Mortal Wkly Rep 1994; 43(RR-1): 1-38.
  1. Centers for Disease Control and Prevention. Recommendations of the Advisory Committee on Immunization Practices (ACIP): recommended childhood immunization schedule—United States, 1995. MMWR Morb Mortal Wkly Rep 1995; 44(RR-5): 1-9.
  1. Centers for Disease Control and Prevention. Recommendations of the Advisory Committee on Immunization Practices (ACIP): update—vaccine side effects, adverse reactions, contraindications, and precautions. MMWR Morb Mortal Wkly Rep 1996; 45(RR-12): 1-35.
  1. Dal-Ré R, Gil A, González A, et al. Does tetanus immune globulin interfere with the immune response to simultaneous administration of tetanus-diphtheria vaccine? A comparative clinical trial in adults. J Clin Pharmacol 1995; 35: 420-5.
  1. Fisher M. Treatment of acute anaphylaxis. BMJ 1995; 311: 731-3.
  1. Giangrasso J, Smith RK. Misuse of tetanus immunoprophylaxis in wound care. Ann Emerg Med 1985; 14: 573-9.
  1. Centers for Disease Control and Prevention. Recommendations of the Advisory Committee on Immunization Practices (ACIP): diphtheria, tetanus, and pertussis: recommendations for vaccine use and other preventive measures. MMWR Morb Mortal Wkly Rep 1991; 40(RR-10): 1-25.
  1. The United States pharmacopeia. The national formulary. USP 23rd revision (January 1, 1995). NF 18th ed (January 1, 1995). Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1994. p. 1502.
  1. Passen EL, Andersen BR. Clinical tetanus despite a “protective” level of toxin-neutralizing antibody. JAMA 1986; 225(9): 1171-3.
  1. American College of Emergency Physicians. Tetanus immunization recommendations for persons seven years of age and older. Ann Emerg Med 1986; 1111-2.
  1. American Academy of Pediatrics (AAP). Tetanus. In: Peter G, editor. 1994 Red Book: report of the Committee on Infectious Diseases. 23rd ed. Elk Grove Village, IL: American Academy of Pediatrics, 1994. p. 458-63.
  1. Panel comment, 4/97.
  1. Panel comment, 3/97.
  1. Panel comment, 3/97.
  1. Panel comment, 3/97.
  1. Manufacturer comment, 4/97.
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