PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Tetanus antitoxin for human use
     1.2 Group
       Immunologic agent
     1.3 Synonyms
       Immunoserum Tetanicum 
       Tetanus antitoxin (BP)
       Tetanus immune globulin
     1.4 Identification numbers
       1.4.1 CAS number
       1.4.2 Other numbers
     1.5 Brand names, Trade names
       Tetanus Antitoxin (USA)
       Tetabulin (Swiss)
       Tetavenine (Swiss)
     1.6 Manufacturers, Importers
       Immunoloski Zavad   (Yugoslavia)
    2. SUMMARY
     2.1 Main risks and target organs
       Acute exposure to tetanus antitoxin occurs when the product is 
       used to provide temporary passive immunity.  The main risks 
       are adverse effects due to intolerance, such as hypotamia, 
       flushing of face, oppressive sensation. Target organs of 
       tetanus vaccine are the skin, central nervous system (CNS), 
       and cardiovascular system.  Anaphylactic shock may occur, but 
       more rarely than serum sickness, hypotension, urticaria, and 
       skin eruptions.  Adverse reactions are more common when the 
       antitoxin is prepared from the serum of animals.  If the 
       antitoxin used is prepared from a pool of human plasma, 
       adverse reactions are less frequent and less significant than 
       those which may occur when toxin of animal origin is used.
     2.2 Summary of clinical effects
       Anaphylactic shock and serum sickness.  Hypotension, flushing 
       of the face, dizziness, urticaria, and skin eruptions.
     2.3 Diagnosis
       Is based on history of antitoxin administration and occurrence 
       of intolerance, characterized in general by flushing of the 
       face, sensation of oppression, hypotenia.  In case of severe 
       intolerance, anaphylactic shock, dizziness, hypotension, cough,
        wheezing, dyspepsia and glottic oedema may occur.
     2.4 First aid measures and management principles
       Therapy for anaphylactic shock: Administer 1 mg adrenaline 
       (1ml of a 1:1000 solution) or 300 to 500 microg noradrenaline 
       (0.3 to 0.5 ml of a 1:1000 solution) by intramuscular (IM) 
       injection.  This dose should be repeated every half an hour 
       until blood pressure is normalized.  Oral antihistamines and 
       intravenous corticosteroids (5 to 100 mg of prednisone IV) 
       should be given at the same time.  Antihistamines should be 
       continued for 10 days after the onset of anaphylactic shock.
       
       Therapy for serum sickness: calcium preparations IV and 
       antihistamines per oral route.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance

       Tetanus antitoxin may be obtained from the serum or plasma of 
       healthy horses immunized against tetanus toxin or, more 
       commonly, from pooled human plasma.  The latter is a 
       lyophilized concentrate which contains immunoglobulins G with 
       a minimum of 100 IU/ml of antitetanus antibodies. Only 
       selected human plasma is used (HIV and HBs negative).
       
       Tetanus antitoxin may also be a refined and concentrated 
       protein, chiefly globulin, containing antitoxin antibodies 
       obtained from the serum or plasma of healthy horses that have 
       been immunized against tetanus toxin or toxoid (USP).  It 
       contains not less than 400 units per ml (Reynolds, 1990).
     3.2 Chemical structure
       Globulin proteins (of human or animal origin).
     3.3 Physical properties
       3.3.1 Properties of the substance
             Tetanus antitoxin occurs as a transparent or 
             slightly opalescent liquid, brownish, yellowish 
             or greenish in colour. It is practically 
             odourless or may have an odour due to the 
             preservative.
       3.3.2 Properties of the locally available formulation
             Immunoglobulins are dissolved in physiological saline 
             solution and 30 to 50 mmol/L phenol or 30 mmol/l 
             tricresol is added as preservative.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             Tetanus antitoxin should be used within 1 or 2 years 
             when the manufacturer's cold storage was 5 or 0°C 
             respectively. Human antitoxin should be kept between +2 
             °C and 8°C
       3.4.2 Shelf-life of the locally available formulation
             Same as section 3.4.1.
       3.4.3 Storage conditions
             Tetanus antitoxin should be refrigerated at 2-9°C and 
             should not be frozen.
       3.4.4 Bioavailability
             Not relevant
       3.4.5 Specific properties and composition
             Tetanus antitoxin contains chlorocresol and glycerol as 
             preservative and stabilizer, respectively.  Human 
             antitoxin preparation consists of 90% gammaglobulins 
             plus glycine (22.5 mg/ml), sodium chloride (3 mg/ml) and 
             thiomersal (0.1 mg/ml).
    4. USES
     4.1 Indications
       Tetanus antitoxin neutralizes the toxin produced by 
       Clostridium tetani; the toxin has high affinity for new 
       cells and antitoxin is unlikely to have an effect on 
       toxin that is no longer circulating. Tetanus antitoxins 
       have been used to provide temporary passive immunity 
       against tetanus but tetanus immunoglobulins are 
       preferred (Reynolds, 1990; McEvoy et al. 1988). Human 
       globulin offers the advantage of greater protection, a 
       lower risk of adverse effects and requires only one-
       tenth of the dosage compared to antitoxin of animal 

       origin.
     4.2 Therapeutic dosage
       4.2.1 Adults
             For prophylaxis after injury, non-immune or partially 
             immune persons may be given 3,000 to 5,000 units of 
             tetanus antitoxin subcutaneously or intramuscularly 
             (Reynolds, 1990).
             
             For adults below 30 kg the dosage is 1,500 units.
       4.2.2 Children
             The dose for children of less than 30 kg body weight is 
             usually 1,500 units (Reynolds, 1990).  For children over 
             30 kg in weight the dosage is usually 3,000-5,000 units 
             (McEvoy et al. 1988). Doses of 50,000 to 100,000 units 
             have been given in the treatment of established tetanus; 
             part of this dose is administered by intravenous 
             injection with the remainder being given 
             intramuscularly.  Treatment with tetanus antitoxin 
             should be initiated as soon as possible; the wound 
             should be treated surgically to remove foreign material 
             and exposed to air.
             
             Note:  Sensitivity testing and desensitization: [Prior 
             to use of tetanus antitoxin, an intradermal skin test or 
             a conjunctival test for serum sensitivity should be 
             performed. Adrenaline (epinephrine) should be available 
             during sensitivity testing for immediate treatment of 
             hypersensitivity reactions if they occur]
     4.3 Contraindications
       Sensitivity testing (e.g., skin test, conjunctival test) 
       should be conducted in all individuals, regardless of clinical 
       history, prior to administration of tetanus antitoxin.
    5. ROUTES OF ENTRY
     5.1 Oral
       Not relevant
     5.2 Inhalation
       Not relevant
     5.3 Dermal
       During sensitivity testing and desensitization.
     5.4 Eye
       During sensitivity testing and desensitization.
     5.5 Parenteral
       Most frequent route of exposure: intramuscular, subcutaneous 
       or intravenous.  Intrathecal therapy for tetanus has been 
       carried out with antitetanus immuneglobulin (Abrutyn and 
       Berlin, 1991).
     5.6 Other
       No data available
    6. KINETICS
     6.1 Absorption by route of exposure
       No data available.
     6.2 Distribution by route of exposure
       No data available.
     6.3 Biological half-life by route of exposure
       Human toxin has a long half-life: approximately 21 days
     6.4 Metabolism

       No data available.
     6.5 Elimination by route of exposure
       No data available.
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             No data available.
       7.1.2 Pharmacodynamics
             No data available.
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
             7.2.1.2 Children
       7.2.2 Relevant animal data
             A case of acute hypatic failure in a horse being treated 
             for tetanus was attributed to tetanus antitoxin of 
             equine origin (Step et al, 1991).
       7.2.3 Relevant in vitro data
             No data available.
     7.3 Carcinogenicity
       No data available.
     7.4 Teratogenicity
       Controlled studies have not been done in animals; however, 
       problems in humans have been documented (FDA Pregnancy 
       Category C USP DI 1990). Immune pregnant women confer 
       protection on their infants via placental transmission of 
       maternal antibody.  Pregnant women who are inadequately 
       immunized or unimmunized and who may deliver their infants 
       under unhygienic conditions may expose their infants to 
       neonatal tetanus.   For inadequately immunized or unimmunized 
       pregnant women, it is recommended  that immunization with 
       tetanus antitoxin be initiated or continued during  the last 
       two trimesters. Unimmunized women should receive the first two 
        doses of the primary series before childbirth (USP DI 1990).
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       Medications containing immunosuppressants or radiation therapy 
       should not be administered concomitantly with tetanus toxoid 
       (USP DI 1990). In such cases normal defence mechanisms are 
       suppressed and the patient's antibody response to tetanus 
       toxoid may be decreased.  This precaution does not apply to 
       adrenocorticosteroids used as short-term replacement therapy 
       (less than 2 weeks), as systemic therapy, or by other routes 
       of administration that do not cause immunosuppression.
       
       Where possible, immunosuppressive therapy should be 
       interrupted when immunization is required because of a tetanus-
       prone wound (USP DI 1990).
     7.7 Main adverse effects
       Hypersensitivity reactions are liable to occur after the 
       injection of any serum of animal origin, i.e., serum sickness, 
       anaphylaxis, hypotension, urticaria and shock.
       
       Serum sickness may develop up to several weeks following 
       administration of tetanus antitoxin and is characterized by: 

       urticaria, malaise, lymphadenopathy, arthralgia, and fever, 
       vomiting diarrhoea, bronchospasm. There may also be nephritis, 
       myocarditis, polyarthritis, neuritis and ureitis (Reynolds, 
       1990; McEvoy, 1988).
       
       Minor reactions include: skin eruptions, local pain, numbness 
       and occasional joint pains which may appear up to several days 
       following administration of tetanus antitoxin.  However, these 
       reactions appear to be brief in duration and insignificant.  
       Local pain or local erythema and urticaria may occur without 
       systemic effects 7-10 days following administration of tetanus 
       antitoxin and may last for about 2 days (McEvoy, 1988).
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
             8.1.1.2 Biomedical analyses
             8.1.1.3 Arterial blood gas analysis
             8.1.1.4 Haematological analyses
             8.1.1.5 Other (unspecified) analyses
       8.1.2 Storage of laboratory samples and specimens
             8.1.2.1 Toxicological analyses
             8.1.2.2 Biomedical analyses
             8.1.2.3 Arterial blood gas analysis
             8.1.2.4 Haematological analyses
             8.1.2.5 Other (unspecified) analyses
       8.1.3 Transport of laboratory samples and specimens
             8.1.3.1 Toxicological analyses
             8.1.3.2 Biomedical analyses
             8.1.3.3 Arterial blood gas analysis
             8.1.3.4 Haematological analyses
             8.1.3.5 Other (unspecified) analyses
     8.2 Toxicological Analyses and Their Interpretation
       8.2.1 Tests on toxic ingredient(s) of material
             8.2.1.1 Simple Qualitative Test(s)
             8.2.1.2 Advanced Qualitative Confirmation Test(s)
             8.2.1.3 Simple Quantitative Method(s)
             8.2.1.4 Advanced Quantitative Method(s)
       8.2.2 Tests for biological specimens
             8.2.2.1 Simple Qualitative Test(s)
             8.2.2.2 Advanced Qualitative Confirmation Test(s)
             8.2.2.3 Simple Quantitative Method(s)
             8.2.2.4 Advanced Quantitative Method(s)
             8.2.2.5 Other Dedicated Method(s)
       8.2.3 Interpretation of toxicological analyses
     8.3 Biomedical investigations and their interpretation
       8.3.1 Biochemical analysis
             8.3.1.1 Blood, plasma or serum
             8.3.1.2 Urine
             8.3.1.3 Other fluids
       8.3.2 Arterial blood gas analyses
       8.3.3 Haematological analyses
       8.3.4 Interpretation of biomedical investigations
     8.4 Other biomedical (diagnostic) investigations and their 
       interpretation
     8.5 Overall Interpretation of all toxicological analyses and 
       toxicological investigations
     8.6 References
    9. CLINICAL EFFECTS
     9.1 Acute poisoning
       9.1.1 Ingestion
             Not relevant
       9.1.2 Inhalation
             Not relevant
       9.1.3 Skin exposure
             No data available.
       9.1.4 Eye contact
             No data available.
       9.1.5 Parenteral exposure
             No data available.
       9.1.6 Other
             No data available.
     9.2 Chronic poisoning
       9.2.1 Ingestion
             No data available.
       9.2.2 Inhalation
             No data available.
       9.2.3 Skin exposure
             No data available.
       9.2.4 Eye contact
             No data available.
       9.2.5 Parenteral exposure
             No data available.
       9.2.6 Other
             No data available.
     9.3 Course, prognosis, cause of death
       Adverse reactions to antitoxin of human origin are not 
       frequent.  They consist of transient tenderness and 
       inflammation at the site of injection and other local 
       reactions.  Allergic reactions are rare and usually self-
       limited.  Tetanus antitoxin prepared from the serum of animals 
       may induce anaphylaxis, with hypotension, dyspnoea, orticaria 
       and shock.  Serum sickness may occur 7 to 10 days after 
       injection, with fever, vomiting, diarrhoea, bronchospasm and 
       urticaria (rarely, nephritis and myocarditis, polyarthritis, 
       neuritis and uveitis may be observed) (Reynolds, 1990).
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Tachycardia may be seen in case of intolerance to be 
             toxin.
       9.4.2 Respiratory
             Neuritis may result from severe serum sickness.
       9.4.3 Neurological
             9.4.3.1 CNS
                     No data available.
             9.4.3.2 Peripheral nervous system
                     Neuritis may result from severe serum sickness.
             9.4.3.3 Autonomic nervous system
                     No data available
             9.4.3.4 Skeletal and smooth muscle
                     No data available
       9.4.4 Gastrointestinal

             No data available
       9.4.5 Hepatic
             No data available
       9.4.6 Urinary
             9.4.6.1 Renal
                     No data available
             9.4.6.2 Other
                     No data available
       9.4.7 Endocrine and reproductive systems
             No data available
       9.4.8 Dermatological
             Skin eruptions, local pain, local erythema and urticaria 
             may occur.
       9.4.9 Eye, ear, nose, throat: local effects
             Glottic oedema may occur in case of anaphylaxis
       9.4.10 Haematological
              No data available.
       9.4.11 Immunological
              Nephritis, myocarditis, polyarthritis, neuritis and 
              uveitis  may occur after serum sickness.
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       No data available.
              9.4.12.2 Fluid and electrolyte disturbances
                       No data available.
              9.4.12.3 Others
                       No data available.
       9.4.13 Allergic reactions
              The risk of hypersensitivity reactions, (anaphylaxis, 
              serum sickness) remains significant for several weeks 
              following administration of tetanus antitoxin (see also 
              7.7).
       9.4.14 Other clinical effects
              No data available
       9.4.15 Special risks
              Pregnancy: human antitoxin may be used during 
              pregnancy.
              
              Breastfeeding: problems in humans have not been 
              documented.
              
              Enzyme deficiencies: no data available.
     9.5 Other
       No data available.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Management principles consist of control of anaphylactic 
         shock, serum sickness and hypotension.
         In case of intolerance to the antitoxin its administration 
         should be stopped immediately.
         Antihistamines, corticosteroids and sympathomimetics may 
         have to be used to counteract the adverse reaction.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                No data available

         10.2.2 Biomedical analysis
                No data available
         10.2.3 Toxicological analysis
                No data available
         10.2.4 Other investigations
                No data available
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         In case of anaphylaxis, epinephrine (1:10.000) should be 
         administered intravenously.  An antihistamine may be 
         indicated for mild allergic reactions.  For anaphylactic 
         reactions, adrenaline (epinephrine) with maintenance of 
         vital functions is necessary.
         
         Adult dosage:  If anaphylaxis occurs, give 0.2 to 0.5 mg of 
         adrenaline intramuscularly or subcutaneously; the dose 
         should be repeated every 10 to 15 min as needed and if 
         necessary increased up to a maximum of 1 mg per dose.  If 
         analphylactic shock occurs, give 0.5 mg of adrenaline 
         intramuscularly or subcutaneously, followed by a slow 
         intravenous adminstration of adrenaline or 0.0025 to 0.005 
         mg.  The dose may be repeated every 5 to 15 min as required.
         
         Children's dosage:  If anaphylaxis occurs, give adrenaline 
         0.01 mg/kg body weight or 0.3 mg per square metre of body 
         surface, up to a maximum of 0.5 mg per dose, by subcutaneous 
         injection; repeat every 15 minutes for two doses, then every 
         four hours as needed.  If anaphylactic shock occurs, give 
         0.3 mg adrenaline intramuscularly or intravenously; repeat 
         every 15 minutes for three or four doses, if necessary.
      10.4 Decontamination
         Not relevant.
      10.5 Elimination
         Not relevant.
      10.6 Antidote treatment
         10.6.1 Adults
                No antidote available.
         10.6.2 Children
                No antidote available.
      10.7 Management discussion
         No data available.
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         A severe and irreversible case of perceptive deafness was 
         reported following the administration of antitoxin for 
         tetanus prophylaxis (Pantazoupoulos, 1966, reported in 
         Martindale, 1982).  A rare case of bilateral perceptive 
         deafness following clinical tetanus was reported in a 15 day-
         old neonate treated with tetanus antitoxin (human gamma 
         globulins) and penicillin. Although the mechanism of 
         auditory  nerve damage was not clear, the authors attributed 
         it to the tetanus toxin  and not to the antitoxin (Skevas et 
         al., 1991).
      11.2 Internally extracted data on cases
         No data available.
      11.3 Internal cases

         To be completed by the poisons centre.
    12. Additional information
      12.1 Availability of antidotes
         Not relevant.
      12.2 Specific preventive measures
         No data available.
      12.3 Other
         Rare cases of agammaglobulinemia may have secondary 
         reactions to antitoxin of human origin.
    13. REFERENCES
    Abrutyn E, Berlin JA (1991).  Lutrathecal therapy in tetanus,  
    meta-analysis. JAMA Oct 23-30; 266 (16): 2262-7.
    
    Briggs GG, Freeman RK, Yaffe SJ (1986).  Tetanus/diphtheria 
    toxoids (adult). Drugs in pregnancy and lactation.  A reference 
    guide to foetal and neonatal risk. Second Edition.  Williams & 
    Wilkins, Baltimore, 423/t.
    
    McEvoy GK et al (1988).  Serums, Toxoids and Vaccines Tetanus 
    antitoxin.  American Hospital Formulary Service Drug Information 
    88. American Society of the Hospital Pharmacists, Montgomery 
    Avenue, Bethesda, (1871-1969).
    
    Reynolds JEF, ed. (1990)  Martindale, the Extra Pharmacopoeia, 
    30th Edition. Pharmaceutical Press, London.
    
    Skevas A, Kastanioudakis I, Exarchakos G, Assimakopoulos D, 
    (1992); Perceptive bilateral deafness collowing clinical tetanus 
    to a neanate. Int J. Pediatr-Otorhinolaryngol.  Mar; 23(2); 177-
    80.
    
    Step DL, Blue JT, Dill SG (1991).  Penicillin-induced hemolytic 
    anaemia and acute hepatic failure following treatment of tetanus 
    in a horse.  Cornell Vet. Jan 1981 (1): 13-8.
    
    The United States Pharmacological Convention Inc., (1990).  
    Tetanus toxoid.  USP Drug Information for Health Care 
    Professionals. Vol. I. 1580-2583.
    
    Zink GL (1990).  Immunizing agents and diagnostic antigens.   In: 
    Osol Arthur, Remington's Pharmaceutical Sciences, 16th Edition, 
    Mack Publishing Company, Easton, Pennsylvania, 1324-1340.
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Authors:  Dr O.J. Kasilo
              Drug and Toxicology Information Service, (DaTIS),
              Department of Pharmacy
              University of Zimbabwe Medical School
              P.O.Box A178
              Avondale
              Harare
              Zimbabwe
    
              Dr C.F.B. Nbachi
              Department of Clinical Pharmacology and Toxicology
              University of Zimbabwe Medical School

              P.O.Box A178
              Avondale
              Harare
              Zimbabwe
    
              Tel: 263-4-790233/791631 Ext. 117/172
              Fax: 263-4-303 292
              Telex:    265801 UNIV ZW.
    
         Date:          April 1990
    
         Peer review:   Strasbourg, France, April 1990
    
         Review:   IPCS, May 1994

    See Also:
       Toxicological Abbreviations