TETANUS IMMUNOGLOBULIN
DESCRIPTION:
Tetanus Immune Globulin (Human)- Tetglob treated with solvent/detergent is a
sterile solution of tetanus hyperimmune immune globulin for intramuscular
administration; it contains no preservative. Tetglob is prepared by cold ethanol
fractionation from the plasma of donors immunized with tetanus toxoid. The
immune globulin is isolated from solubilized Cohn Fraction II. The Fraction II
solution is adjusted to a final concentration of 0.3% tri-n-butyl phosphate
(TNBP) and 0.2% sodium cholate. After the addition of solvent (TNBP) and
detergent (sodium cholate), the solution is heated to 30 deg 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. Tetglob is formulated as a 15-18% protein
solution at a pH of 6.4-7.2 in 0.21-0.32 M glycine. Tetglob is then incubated in
the final container for 21-28 days at 20-27 deg C. The product 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 container.
The removal and inactivation of spiked model enveloped and non-enveloped viruses
during the manufacturing process for Tetglob has been validated in laboratory
studies. Human Immunodeficiency Virus, Type 1 (HIV-1), was chosen as the
relevant virus for blood products; Bovine Viral Diarrhea Virus (BVDV) was chosen
to model Hepatitis C virus; Pseudorabies virus (PRV) was chosen to model
Hepatitis B and the Herpes viruses; and Reo virus type 3 (Reo) was chosen to
model non-enveloped viruses and for its resistance to physical and chemical
inactivation. Significant removal of model enveloped and non- enveloped viruses
is achieved at two steps in the Cohn fractionation process leading to the
collection of Cohn Fraction II: the precipitation and removal of Fraction III in
the processing of Fraction II + IIIW suspension to Effluent III and the
filtration step in the processing of Effluent III to Filtrate III. Significant
inactivation of enveloped viruses is achieved at the time of treatment of
solubilized Cohn Fraction II with TNBP/sodium cholate.
ACTIONS/CLINICAL PHARMACOLOGY:
The occurrence of tetanus in the United States has decrease dramatically from
560 reported cases in 1947, when national reporting began, to a record low of 48
reported cases in 1987. (Ref. 1) The decline has resulted from widespread use if
tetanus toxoid and improved wound management, including use of tetanus
prophylaxis in emergency rooms. (REF. 2)
Tetglob supplies passive 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 produced by
this bacterium. Historically, such passive protection was provided by antitoxin
derived from equine or bovine serum; however, the foreign protein in these
heterologous products often produced severe allergic manifestations, even in
individuals who demonstrated negative skin and/or conjunctival tests prior to
administration. Estimates of the frequency of these foreign protein reactions
following antitoxin of equine origin varied from 5%-30%. (REF. 3-6) If passive
immunization is needed, human tetanus immune globulin (TIG) is the product of
choice. It provides protection longer than antitoxin of animal origin and causes
few adverse reactions. (REF. 2)
Several studies suggest the value of human tetanus antitoxin in the treatment of
active tetanus. (REF. 7,8) In 1961 and 1962, Nation et al, (REF. 7) using Tetglob
treated 20 patients with tetanus using single doses of 3,000 to 6,000 antitoxin
units in combination with other accepted clinical and nursing procedures. Six
patients, all over 45 years of age, died of causes other than tetanus. The
authors felt that the mortality rate (30%) compared favorably with their
previous experience using equine antitoxin in larger doses and that the results
were much better than the 60% national death rate for tetanus reported from 1951
to 1954. (REF. 9) Blake et al, (REF. 10) however, found in a data analysis of
545 cases of tetanus reported to the Centers for Disease Control from 1965 to
1971 that survival was no better with 8,000 units of human tetanus immune
globulin (TIG) than with 500 units; however, an optimal dose could not be
determined.
Serologic tests indicate that naturally acquired immunity to tetanus toxin does
not occur in the United States. Thus, universal primary vaccination, with
subsequent maintenance of adequate antitoxin levels by means of appropriately
timed boosters, is necessary to protect persons among all age groups. Tetanus
toxoid is a highly effective antigen; a completed primary series generally
induces protective levels of serum antitoxin that persist for (>/=) 10 years.
(REF. 2)
Passive immunization with Tetglob may be undertaken concomitantly with active
immunization using tetanus toxoid in those persons who must receive an immediate
injection of tetanus antitoxin and in whom it is desirable to begin the process
of active immunization. Based on the work of Rubbo, (REF.11) McComb and Dwyer,
(REF. 12) and Levine et al, (REF. 13) the physician may thus supply immediate
passive protection against tetanus, and at the same time begin formation of
active immunization in the injured individual which upon completion of a FULL
TOXOID SERIES will preclude future need for antitoxin.
Peak blood levels of IgG are obtained approximately 2 days after intramuscular
injection. The half-life of IgG in the circulation of individuals with normal
IgG levels is approximately 23 days. (REF. 14)
CLINICAL STUDIES:
In a clinical study in eight healthy human adults receiving another hyperimmune
immune globulin product treated with solvent/detergent, Rabies Immune Globulin
(Human), BayRab(TM), prepared by the same manufacturing process, detectable
passive antibody titers were observed in the serum of all subjects by 24 hours
post injection and persisted through the 21 day study period. These results
suggest that passive immunization with immune globulin products is not affected
by the solvent/detergent treatment.
INDICATIONS AND USAGE:
Tetanus Immune Globulin (Human), Tetglob is indicated for prophylaxis against
tetanus following injury in patients whose immunization is incomplete or
uncertain (see below). It is also indicated, although evidence of effectiveness
is limited, in the regimen of treatment of active cases of tetanus. (REF.
7,8,15)
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 and toxoid doses.
Persons who had military service since 1941 can be considered to have received
at least one dose, and although most of them may have completed a primary series
of tetanus toxoid, this cannot be assumed for each individual. Patients who have
not completed a primary series may require tetanus toxoid and passive
immunization at the time of wound cleaning and debridement. (REF. 2)
The following table is a summary guide to tetanus prophylaxis in wound
management:
GUIDE TO TETANUS PROPHYLAXIS IN WOUND MANAGEMENT (REF. 2)
HISTORY OF TETANUS IMMUNIZATION CLEAN, MINOR WOUNDS ALL OTHER WOUNDS(1)
(DOSES) ---------------------------------------------------------------------------------
TD(2) TIG(3) TD TIG
-----------------------------------------------------------------------------------------------------------------------------------------------------
UNCERTAIN OR LESS THAN 3 YES NO YES YES
3 OR MORE(4) NO(5) NO NO(6) NO
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(1) Such as, but not limited to, wounds contaminated with dirt, feces, soil,
and saliva; puncture wounds; avulsions; and wounds resulting from missiles,
crushing, burns and frostbite.
(2) Adult type tetanus and diphtheria toxoids. If the patient is less than 7
years old, DT or DTP is preferred to tetanus toxoid alone. For persons (>/=) 7
years of age, Td is preferred to tetanus toxoid alone. (See Dosage and
Administration)
(3) Tetanus Immune Globulin (Human).
(4) If only three doses of fluid tetanus toxoid have been received, a fourth
dose of toxoid, preferably an absorbed toxoid, should be given.
(5) Yes if more than 10 years since the last dose.
(6) Yes if more than 5 years since the last dose. (More frequent boosters are
not needed and can accentuate side effects.)
CONTRAINDICATIONS:
None known.
WARNINGS:
Tetglob should be given with caution to patients with a history of prior systemic
allergic reactions following the administration of human immunoglobulin
preparations.
In patients who have severe thrombocytopenia or any coagulation disorder that
would contraindicate intramuscular injections, Tetglob should be given only if
the expected benefits outweigh the risks.
PRECAUTIONS:
GENERAL
BAY-TET SHOULD NOT BE GIVEN INTRAVENOUSLY. Intravenous injection of
immunoglobulin intended for intramuscular use can, on occasion, cause a
precipitous fall in blood pressure, and a picture not unlike anaphylaxis.
Injections should only be made INTRAMUSCULARLY 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. Intramuscular injections are preferably
administered in the anterolateral aspects of the upper thigh and the deltoid
muscle of the upper arm. The gluteal region should not be used routinely as an
injection site because of the risk of injury to the sciatic nerve. If the
gluteal region is used, the central region MUST be avoided; only the upper,
outer quadrant should be used. (REF. 16)
Chemoprophylaxis against tetanus is neither practical nor useful in managing
wounds. Wound cleansing, debridement when indicated, and proper immunization are
important. The need for tetanus toxoid (active immunization), with or without
TIG (passive immunization), depends on both the condition of the wound and the
patient's vaccination history. Rarely, has tetanus occurred among persons with
documentation of having received a primary series of toxoid injections. (REF. 2)
See table under INDICATIONS AND USAGE.
SKIN TESTS SHOULD NOT BE DONE. The intradermal injection of concentrated IgG
solutions often causes a localized area of inflammation which can be
misinterpreted as a positive allergic reaction. In actuality, this does not
represent an allergy; rather, it is localized tissue irritation.
Misinterpretation of the results of such tests can lead the physician to
withhold needed human antitoxin from a patient who is not actually allergic to
this material. True allergic responses to human IgG given in the prescribed
intramuscular manner are rare.
Although systemic reactions to human immunoglobulin preparations are rare,
epinephrine should be available for treatment of acute anaphylactic reactions.
DRUG INTERACTIONS
Antibodies in immunoglobulin preparations may interfere with the response to
live viral vaccines such as measles, mumps, polio, and rubella. Therefore, use
of such vaccines should be deferred until approximately 3 months after Tetanus
Immune Globulin (Human), Tetglob administration.
No interactions with other products are known.
PREGNANCY CATEGORY C
Animal reproduction studies have not been conducted with Tetglob. It is also not
known whether Tetglob can cause fetal harm when administered to a pregnant woman
or can affect reproduction capacity. Tetglob should be given to a pregnant woman
only if clearly needed.
PEDIATRIC USE
Safety and effectiveness in pediatric population have not been established.
DRUG INTERACTIONS:
Antibodies in immunoglobulin preparations may interfere with the response to
live viral vaccines such as measles, mumps, polio, and rubella. Therefore, use
of such vaccines should be deferred until approximately 3 months after Tetanus
Immune Globulin (Human), Tetglob administration.
No interactions with other products are known.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
Slight soreness at the site of injection and slight temperature elevation may be
noted at times. Sensitization to repeated injections of human immunoglobulin is
extremely rare.
In the course of routine injections of large numbers of persons with
immunoglobulin there have been a few isolated occurrences of angioneurotic
edema, nephrotic syndrome, and anaphylactic shock after injection.
OVERDOSAGE:
Although no data are available, clinical experience with other immunoglobulin
preparations suggests that the only manifestations would be pain and tenderness
at the injection site.
DOSAGE AND ADMINISTRATION:
Routine Prophylactic Dosage Schedule:
Adults And Children 7 Years And Older: Tetglob, 250 units should be given by deep
intramuscular injection (see PRECAUTIONS). At the same time, but in a different
extremity and with a separate syringe, Tetanus and Diphtheria Toxoids Adsorbed
(For Adult Use) (Td) should be administered according to the manufacturer's
package insert. Adults with uncertain histories of a complete primary
vaccination series should receive a primary series using the combined Td toxoid.
To ensure continued protection, booster does of Td should be given every 10
years. (REF. 2)
Children Less Than 7 Years Old: In small children the routine prophylactic dose
of Tetglob may be calculated by the body weight (4.0 units/kg). However, it may
be advisable to administer the entire contents of the vial or syringe of Tetglob
(250 units) regardless of the child's size, since theoretically the same amount
of toxin will be produced in the child's body by the infecting tetanus organism
as it will in an adult's body. At the same time but in a different extremity and
with a different syringe, Diphtheria and Tetanus Toxoids and Pertussis Vaccine
Adsorbed (DTP) or Diphtheria and Tetanus Toxoids Adsorbed (For Pediatric Use)
(DT), if pertussis vaccine is contraindicated, should be administered per the
manufacturer's package insert.
Note: The single injection of tetanus toxoid only initiates the series for
producing active immunity in the recipient. The physician must impress upon the
patient the need for further toxoid injections in 1 month and 1 year. Without
such, the active immunization series is incomplete. If a contraindication to
using tetanus toxoid-containing preparations exists for a person who has not
completed a primary series of tetanus toxoid immunization and that person has a
wound that is neither clean nor minor, Only passive immunization should be given
using tetanus immune globulin. (REF. 2) See table under INDICATIONS AND USAGE.
Available evidence indicates that complete primary vaccination with tetanus
toxoid provides long lasting protection (>/=) 10 years for most recipients.
Consequently, after complete primary tetanus vaccination, boosters--even for
wound management--need be given only every 10 years when wounds are minor and
uncontaminated. For other wounds, a booster is appropriate if the patient has
not received tetanus toxoid within the preceding 5 years. Persons who have
received at least two doses of tetanus toxoid rapidly develop antibodies.
(REF.2) The prophylactic dosage schedule for these patients and for those with
incomplete or uncertain immunity is shown on the table in INDICATIONS AND USAGE.
Since tetanus is actually a local infection, proper initial wound care is of
paramount importance. The use of antitoxin is adjunctive to this procedure.
However, in approximately 10% of recent tetanus cases, no wound or other breach
in skin or mucous membrane could be implicated. (REF. 17)
Treatment Of Active Cases Of Tetanus:
Standard therapy for the treatment of active tetanus including the use of Tetglob
must be implemented immediately. The dosage should be adjusted according to the
severity of the infection. (REF. 7,8)
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.
They should not be used if particulate matter and/or discoloration are present.
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