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Insulin

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties of the substance
      3.3.2 Properties of the locally available formulation
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Shelf-life of the locally available formulation
      3.4.3 Storage conditions
      3.4.4 Bioavailability
      3.4.5 Specific properties and composition
4. USES
   4.1 Indications
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF ENTRY
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination by route of exposure
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
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
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 CNS
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Relevant laboratory analyses
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life supportive procedures and symptomatic/specific treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
12. Additional information
   12.1 Availability of antidotes
   12.2 Specific preventive measures
   12.3 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    PHARMACEUTICALS
    1. NAME
     1.1 Substance
       Insulin
     1.2 Group
       Antidiabetic agent
     1.3 Synonyms
       Amorph IZS
       Amorphous IZS
       Biphasic Insulin
       Cryst IZS
       Crystalline IZS
       Extended Insulin Zinc Suspension
       Globin Insulin
       Globin Insulin with zinc
       Globin Zinc Injection Insulin
       Globin Zinc Insulin
       GZI
       Injectio Insulini Protaminati cum zinco
       Insulin cum zinco (crystallisati) suspension
       Insulin Hydrochloride
       Insulin Injection
       Insulin lente
       Insulin semilente
       Insulin Ultralente
       Insulin zinc suspension (mixed)
       Insulin zinci crystallisati suspension injectabilis
       Insulini cum zinco (Amorphi) suspension injectabilis
       Insulini cum zinco suspensio composita
       Insulini Isophani Protaminati Suspension injectabilis
       Insulini Solution Injectabilis
       Insulini Zinci Injectabilis Mixta
       Insulini zinci protaminati injectio
       Insulini zinci protaminati suspension injectabilis PZI
       Isophane Insulin
       Isophane Insulin (NPH)
       Isophane Insulin Suspension
       Isophane Protamine Insulin Injection
       IZS
       Neutral Insulin
       NPH Insulin
       Ordinary Insulin
       Prompt Insulin Zinc Suspension
       Protamine zinc injection
       Regular Insulin
       Soluble Insulin
       Unmodified Insulin
     1.4 Identification numbers
       1.4.1 CAS number
             9004-10-8
       1.4.2 Other numbers
             53027-39-7
             8049-62-5 
             8063-29-4
             9004-17-5
             9004-21-1

     1.5 Brand names, Trade names
       Acid Insulin Injection
       
            Hypurin Soluble (CP)
            Regular Iletin (Lily USA)
                 
       Highly purified Animal Insulins
       
            Actrapid MC (Novo UK, Favillon UK)
            Hypurin Neutral (Weddel UK)
            Neusulin (Wellcome UK)
            Nuso Neutral Insulin (Boots UK, Evans Medical UK, 
       Wellcome UK)
            Velosulin (Nordisk UK, Leo UK)
            Velosulin Cartridge (Nordisk, Wellcome)
            Quicksol Boots
            Human Sequence Insulins
            Human Actrapid (Novo)
            Human Actrapid Purified (Novo)
            Human Velosulin (Nordisk, Wellcome)
            Humaline (Lily)
       
       Highly Purified Animal Insulins
       
            Insulin zinc suspension Lente (Evans)
            Hypurin Lente (CP)
            Lentard MC (Novo)
            Tempulin (Boots)
            Human sequence insulins
            Human monotard (Novo)
            Humulin Lente (Lily)
            Semitard MC (Novo)
       
       Human Sequence Insulins
       
            Human ultratard (Novo)
            Humulin zinc (Lily)
            Rapitard MC (Noro)
            Manufacturers - Boots, Evans Medical UK, Wellcome UK.
       
       Highly Purified Animal Insulins
       
            Isophane Insulin Injection (Evans)
            Hypurin Isophane (CP)
            Insulatard (Nordisk, Wellcome)
            Monophane (Boots)
       
       Mixed Highly Purified Animal Insulins
       
            Initard 50/50 (Nordisk, Wellcome)
            Mixtard 30/70 (Nordisk, Wellcome)
       
       Human Sequence Insulins
       
            Human Insulatard (Nordisk, Wellcome)
            Human Protaphane (Novo)

            Humulin (Lily)
       
       Mixed Human Sequence Insulins
       
            Human Actraphane (Noro)
            Human Initard 50/50 (Nordisk, Wellcome)
            Human Mixtard 30/70 (Nordisk, Wellcome)
            Humulin M1 (Lily)
            Humulin M2 (Lily)
            Humulin M3 (Lily)
            Humulin M4 (Lily)
       
       Hypurin Protamine Zinc (Weddel UK)
       
            Also Marketed in Great Britain by Boots, Wellcome, Evans 
       Medical and Weddel
       
       Other Proprietary Names
       
            Protamine Zinc and Iletin
     1.6 Manufacturers, Importers
       Local agents
       
       Insulin   Hayleys (Boots)
                 Morrison Son & Jones (Novo)
                 Robert Hall & Co. (Nordisk)
    2. SUMMARY
     2.1 Main risks and target organs
       Hypoglycaemia is the main risk of insulin overdose.  The brain 
       relies on glucose as its source of energy and hypoglycaemia 
       may lead to coma, convulsions and even death.
     2.2 Summary of clinical effects
       Hypoglycaemia:
       
       The early symptoms of hypoglycaemia are weakness, hunger, 
       giddiness, pallor, sweating, sinking feeling in the stomach, 
       palpitations, irritability, nervousness, headache and tremor.  
       Symptoms resemble those of sympathetic stimulation.
       
       Later, symptoms such as depression or euphoria, inability to 
       concentrate, blurring of vision, drowsiness, lack of judgement 
       and self control and amnesia may be present due to 
       neuroglycopenia.  Other features are hemiplegia, ataxia, 
       tachycardia, diplopia and paraesthesia.
       
       If untreated the condition progresses to convulsions, coma and 
       death.
       
       In the precoma stage, Babinski reflex is often present.  
       Pupils are often dilated but react to light.  Later pupils are 
       constricted and no longer react to light.  Hypokalaemia may be 
       present.
       
       Speed of onset of hypoglycaemia varies with the preparation of 
       insulin used.  Symptoms do not usually appear unless the blood 
       glucose concentration falls below 3.5 mmol/l.  Convulsions can 

       occur if the blood glucose concentration falls below 2 mmol/l. 
        In diabetic patients with chronic hyperglycaemia, symptoms of 
       hypoglycaemia may occur at higher blood glucose 
       concentrations.  A few patients may develop hypoglycaemic coma 
       without prior warning symptoms.
       
       Other effects:
       
       Non-specific local reactions such as allergic reactions, 
       atrophy of fat or induration and hypertrophy sometimes occur 
       at the site of injection (usually not a problem with highly 
       purified insulins).
     2.3 Diagnosis
       Early symptoms include weakness, hunger, giddiness, pallor, 
       sweating, sinking feeling in the stomach, palpitations, 
       irritability, nervousness, headache and tremor.
       
       Later, depression or euphoria, inability to concentrate, 
       blurring of vision, drowsiness, lack of judgement and self 
       control and amnesia occur.  Other features are hemiplegia, 
       ataxia, tachycardia, diplopia and paraesthesia.
       
       If untreated the condition progresses to convulsions, coma and 
       death.
       
       In the precoma stage, Babinski reflex is often present.  
       Pupils are often dilated but react to light.  Later pupils are 
       constricted and no longer react to light.  Hypokalaemia may be 
       present.
                 
       
       Estimation of blood glucose level: (see 2.3.1)
       
       Estimation of plasma insulin is usually not relevant.  The 
       serum potassium concentration should be measured explicitly. 
       
       Determination of urinary glucose and ketones for diabetic 
       ketoacidosis.
       
       Serum creatinine, blood urea and serum electrolytes to asses 
       renal function.
     2.4 First aid measures and management principles
       If patient is conscious and cooperative - Oral glucose or 3-4 
       lumps of sugar should be given with water.  This could be 
       repeated in 15 minutes or earlier if symptoms recur.  This 
       should be supplemented by one or more carbohydrate meals until 
       the patient improves.
       
       If unconscious or uncooperative -  Intravenous glucose or 
       intramuscular glucagon should be given at once.  Hospital 
       admission comes later.  50ml of 50% dextrose should be given 
       IV.
       
       NB - It is very important to advise patients and relatives 
       regarding the prevention of hypoglycaemia.  They should know 
       the warning symptoms of hypoglycaemia.

       
       Correction of hypoglycaemia is the most important aspect of 
       management.  If consciousness is impaired even after 
       correction of hypoglycaemia, cerebral oedema should be 
       suspected.  Cerebral oedema should be treated with mannitol 
       and corticosteroids.
    3. PHYSICO-CHEMICAL PROPERTIES
     3.1 Origin of the substance
       Extracted from beta cells of the islets of Langerhans of pork 
       or beef pancreas and purified by crystallisation.
       
       It is also made biosynthetically by recombinant DNA technology 
       using Escherichia coli or semisynthetically by enzymatic 
       modification of porcine material.
     3.2 Chemical structure
       Molecular weight: 6000
       
       Consists of two chains, A and B, of amino acids, joined 
       together by two disulphide bonds.  Insulin is synthesised from 
       a single chain precursor named proinsulin.  On conversion of 
       human proinsulin to insulin, 4 basic amino acids and the 
       remaining connector or C peptide is removed by proteolysis.  
       The resultant insulin molecule has 2 chains.  The acidic or A 
       chain with glycine at the amino terminal residue and the basic 
       or B chain consisting of 30 amino acids with phenylalanine at 
       the amino terminus.  An even larger molecule prepoinsulin has 
       been identified as a precursor of proinsulin.
                      
       Insulin can exist as a dimer, monomer or hexamer.  Two 
       molecules of Zn2+ are coordinated in the hexamer which is 
       stored as granules in the beta cell.
       
       The biologically active form of the hormone is the monomer.
       
       The porcine hormone is most similar to man and differs only by 
       the substitution of an alanine residue for threonine at the 
       carboxy terminus of the B chain.  Bovine insulin differs by 
       three amino acids and therefore is more antigenic than porcine 
       insulin.
     3.3 Physical properties
       3.3.1 Properties of the substance
             White or almost white crystalline powder.  
             Slightly soluble in water.  Practically 
             insoluble in alcohol, chloroform and ether.  
             Soluble in dilute solution of mineral acids and 
             with degradation in solutions of alkali 
             hydroxide.
       3.3.2 Properties of the locally available formulation
             Insulin Injection
             
             This may be prepared by dissolving crystalline insulin 
             containing not less than 23 units/mg in water for 
             injections containing a suitable substance to render the 
             injection iso-osmotic with blood; hydrochloric acid to 
             adjust the pH to 3 to 3.5; and a suitable bactericide.  
             The USP specifies sterile, acidified or neutral solution 

             of insulin USP containing 40, 80, 100 or 500 units per 
             ml as well as 1.4 - 1.8% w/v of glycerol and 0.1 - 0.25% 
             (W/V) of phenol or cresol.
             
             pH of acidified injection 2.5 - 3.5
             pH of neutral injection 7 - 7.8
             
             Insulin injection is a colourless injection or straw 
             coloured liquid practically free from solid matter which 
             deposits on standing.  Contains not more than 40  g 
             zinc/100 units of insulin.  Sterilised by filtration and 
             kept in multidose containers.
             
             Neutral insulin BP
             
             Sterile buffered solution of bovine or porcine insulin 
             of potency not less than 23 units/mg;  pH 6.6 - 8 
             colourless liquid.  Contains not more than 20  g 
             zinc/100 units of insulin and a suitable bactericide.  
             Available in multidose containers.
             
             
             
             Insulin Zinc Suspension BP
             
             Sterile buffered suspension of mammalian insulin in the 
             form of a complex obtained by addition of zinc chloride. 
              Insulin is in a form insoluble in water.  Prepared by 
             mixing 3 volumes of insulin zinc suspension (amorphous) 
             and 7 volumes of insulin zinc suspension (crystalline).  
             Contains 40, 80, or 100 units/ml.  White suspension 
             available in multidose containers.  pH 6.9 - 7.5.  
             Complies with a test for prolongation of insulin effect.
             
             Insulin Zinc Suspension BP (Amorphous)
             
             Sterile buffered suspension of mammalian insulin in the 
             form of a complex obtained by addition of zinc chloride. 
              Prepared fromcrystalline insulin containing not less 
             than 23 u almost colourless suspension in which the 
             particles have no uniform shape and rarely exceed 2  m 
             in dimension; pH 6.9 - 7.5. Iso-osmotic with blood.  
             Containing suitable bactericide, the preparation 
             contains 40 and 80 units/ml.
             
             U.S.P. describes a sterile suspension of insulin U.S.P. 
             in buffered water for injection is modified by addition 
             of zinc chloride so that the solid phase of suspension 
             is amorphous.  Contains 40, 80 or 100 units/ml.
             Also contain sodium acetate 0.15 - 0.17%, sodium 
             chloride 0.65 - 0.75%, methyl hydroxy benzoate 0.09 - 
             0.11% and for each 100 units of insulin, 120 - 250  g of 
             zinc. pH 7.2-7.5
             
             Insulin zinc suspension (crystalline) BP
             

             Sterile buffered suspension of bovine insulin to which 
             zinc chloride is added.  Crystalline form is insoluble 
             in water.
             
             Prepared from crystalline insulin containing not more 
             than 23 units/mg.
             
             White or almost colourless suspension.  Particles are 
             mainly crystalline.  Majority of crystals having a 
             maximum diameter greater than 10  m.
             
             pH 6.9 - 7.5 Iso-osmotic with blood.  Preparation 
             contains 40 and 80 units/ml.
             
             U.S.P. - Sterile suspension of insulin contain 40, 80, 
             100 units/ml.  Contains sodium acetate, sodium chloride 
             and methyl hydroxybenzoate (Concentration same as for 
             amorphous insulin) and zinc 120 - 250 ug.  pH 7.2 - 7.5.
             
             Biphasic Insulin BP
             
             Sterile buffered suspension of crystals of bovine 
             insulin containing not less than 23 units/mg. in a 
             solution of porcine insulin of similar potency.  White 
             suspension.  pH 6.6 - 7.2 iso-osmotic with blood.  
             Contained 27.5 - 37.5 ug zinc for each 100 
             units/insulin.  Quarter of insulin in soluble form.  
             Multidose glass container.
             
             Globin zinc Insulin BP
             
             Sterile preparation of mammalian insulin in the form of 
             a complex obtained by addition of suitable globin and 
             zinc chloride.
             
             USP specification: Insulin modified by addition of zinc 
             and globin obtained from beef blood, 40, 80, 100 
             units/ml. Colourless liquid pH 3 - 3.8; iso-osmotic with 
             blood. Each 100 units of insulin also contains 3.6 - 4 
             mg of globin and 250 - 350  g zinc.
             
             USP specification: Also contains as preservatives phenol,
              glycerol and cresol.  Multidose container.
             
             Isophane Insulin
             
             Sterile buffered suspension of insulin in the form of a 
             complex obtained by addition of suitable protamine.  
             Prepared from crystalline insulin.
             
             pH 6.9 - 7.5 iso-osmotic with blood.
             Contains for each 100 units of insulin, 300 - 600  g 
             protamine sulphate and not more than 40  g zinc, a 
             suitable bactericide and sodium phosphate as buffering 
             agent.
             

             USP specification: Sterile suspension of zinc insulin 
             crystalline and protamine sulphate in buffered water for 
             injection. Solid phase contain crystals of insulin 
             protamine and zinc; 40, 80, 100 units/ml.  Contains 
             glycerol, metacresol, phenol sodium phosphate and zinc.
             
             Protamine Zinc Insulin
             
             Sterile buffered suspension of mammalian insulin to 
             which protamine and zinc chloride are added.
             White suspension.  pH 6.9 - 7.5 iso-osmotic with blood.  
             Contains for each 100 units of insulin, 1 - 1.7 mg of 
             protamine sulphate and zinc chloride equivalent to 200 
             per  g of zinc, 10 - 11 mg of sodium phosphate.
             
             USP specification: Buffered sterile suspension to which 
             zinc chloride and protamine sulphate are added.  40, 80, 
             100 units/ml.  Also contain glycerol, cresol, phenol, 
             sodium phosphate for each 100 units of insulin in 
             addition to protamine and zinc.
     3.4 Other characteristics
       3.4.1 Shelf-life of the substance
             Up to 2 years at storage conditions of 2 - 8C
       3.4.2 Shelf-life of the locally available formulation
             Up to 2 years at storage conditions of 2 - 8C
       3.4.3 Storage conditions
             Store at 2 - 8C.  Avoid freezing.
       3.4.4 Bioavailability
             To be added by PCC using the monograph
       3.4.5 Specific properties and composition
             To be added by PCC using the monograph
    4. USES
     4.1 Indications
       (a)  Diabetes mellitus
       
       (b)  Complications of diabetes mellitus
            eg.  Hyperglycaemic ketoacidotic coma
                 Hyperglycaemic hyperosmolar non-ketotic coma
       
       (c)  Hyperkalaemia
       
       (d)  Insulin hypoglycaemia can be used as a test of anterior 
       pituitary function and to test completeness of vagotomy in 
       reducing gastric secretion.
     4.2 Therapeutic dosage
       4.2.1 Adults
             Blood sugar < 16.5 mmol/l (300 mg%): 20 units.
             Blood suger 11 - 16.5 mmol/l (200 - 300 mg%): 10 units.
       4.2.2 Children
             Dose is than adjusted according to the usual monitoring 
             of blood and/or urine glucose.  Daily dose increments 
             should be 4 units.  When stabilised, two-thirds of the 
             daily dose is generally given 30 minutes before 
             breakfast and one-third 30 minutes before the evening 
             meal.
             

             If only one injection per day is required, 10 - 14 units 
             of an intermediate-acting insulin can be given.  Dose 
             increment is 4 units given on alternate days.  Soluble 
             or neutral may be added or special mixed insulins used 
             according to the patient's response.
     4.3 Contraindications
       Absolute  Hypoglycaemia
       
       Relative  Allergic reactions may occur to beef or porcine 
       insulins. 
       
       Precautions:  Differing immunological response to bovine and 
       porcine insulin have been reported and hypoglycaemia has been 
       reported in patients changing from bovine to porcine insulin.  
       Care is recommended to avoid inadvertant change of insulin 
       from one species to another.  Care may be necessary in 
       changing over to a highly purified insulin.
       
       The hypoglycaemia caused by insulin may be enhanced by alcohol,
        monoamine oxidase inhibitors and propranolol and other beta 
       blockers.  Propranolol may mask the symptoms of hypoglycaemia.
       
       NB - Any deterioration in renal function and severe hepatic 
       disease may reduce insulin clearance and may result in 
       hypoglycaemia.
    5. ROUTES OF ENTRY
     5.1 Oral
       When taken orally insulin has no hypoglycaemic effect since it 
       is inactivated in the gastrointestinal tract (Reynolds, 1982)
     5.2 Inhalation
       Not relevant
     5.3 Dermal
       Not relevant
     5.4 Eye
       Not relevant
     5.5 Parenteral
       Insulin is administered by subcutaneous, intramuscular or 
       intravenous injections and poisoning can occur only through 
       this route.
     5.6 Other
       Not relevant
    6. KINETICS
     6.1 Absorption by route of exposure
       Insulin must be injected SC, IM or IV.  It is absorbed into 
       the blood and peak plasma insulin concentration with 
       subcutaneous insulin occurs at 60 - 90 min. Absorption is 
       slower if there is peripheral vascular disease or smoking, and 
       faster if the patient is vasodilated eg. by a hot bath or 
       ultraviolet exposure or exercise.
       
       Any changes in mode of administration either accidentally (eg. 
       accidental IM or IV injection) or deliberately (eg. constant 
       subcutaneous insulin infusion) may potentiate the absorption 
       and action of insulin, leading to hypoglycemia.  Severe 
       hypoglycaemia may occur during constant infusion and several 
       deaths have been reported (Paterson et al, 1983).

       
       Absorption of insulin from injection site affected by insulin 
       lipodystrophy is very unpredictable and rapid absorption may 
       lead to hypoglycaemia.
     6.2 Distribution by route of exposure
       A fraction of endogenous or exogenous insulin in plasma may be 
       associated with certain proteins but the bulk appears to 
       circulate in blood and lymph as the free hormone.  The volume 
       of distribution of insulin approximates the volume of 
       extrecellular fluid.
       
       Insulin is inactivated in the liver and kidneys (about 40% in 
       a single passage).  About 10% appear in the urine.
     6.3 Biological half-life by route of exposure
       The plasma half-life is:
        
       intravenous injection    10 minutes
       subcutaneous injection   4 hours
       intramuscular injection  2 hrs.
     6.4 Metabolism
       Metabolism occurs mainly in the liver and kidneys;  10% of the 
       dose appears in the urine.  Insulin is normally filtered at 
       the glomeruli and then completely reabsorbed or destroyed at 
       the proximal tubule.  In patients with impaired renal tubular 
       function, urinary clearance approaches glomerular filtration 
       rates.  50% of insulin that reaches the liver via the portal 
       vein is destroyed in a single passage, never reaching the 
       general circulation.  Proteolytic degradation of insulin 
       occurs both at cell surfaces and in the lysosomes.  A 
       proteolytic enzyme that degrades insulin has been purified 
       from muscle.  An enzyme, glutathione insulin transhydrogenase, 
       which utilises reduced glutathione to reduce disulfide bridges 
       of insulin and produce separate chains, has been implicated.
       
       Severe impairment of renal function appears to affect the rate 
       of disappearance of circulating insulin to a greater extent 
       than does hepatic disease.
     6.5 Elimination by route of exposure
       About 10% of the drug appears in urine.
    7. PHARMACOLOGY AND TOXICOLOGY
     7.1 Mode of action
       7.1.1 Toxicodynamics
             Insulin in overdose causes hypoglycaemia.  Hypoglycaemia 
             deprives the brain of substrate glucose upon which it is 
             almost exclusively dependent for its oxidative 
             metabolism.  During insulin coma, oxygen consumption in 
             the human brain decreases by nearly half.
             
             A prolonged period of hypoglycaemia causes irreversible 
             damage to the brain as evidenced in experimental animals 
             by histological changes in the cortex, basal ganglia and 
             rostral parts of the medulla.  Convulsions, coma, mental 
             retardation, hemiparesis, ataxia, incontinence, aphasia, 
             choreiform movements, and parkinsonism may occur in man.
       7.1.2 Pharmacodynamics
             Insulin binds to a receptor on the surface of the target 

             cell and probably also enters the cell in this state. 
             The receptors vary in number inversely with the insulin 
             concentration to which they are exposed.
             
             The receptor becomes phosphorylated on addition of 
             insulin and ATP. The cellular mechanism of action of 
             insulin after combination with the receptor is 
             uncertain;  the complex may activate a "second 
             messenger" which in turn causes the release of third 
             messenger Ca++ ions.  Insulin also has a membrane effect 
             in increasing gluose uptake and utilization, especially 
             by muscle and adipose tissue.  Its effects include the 
             following:
             
             a)   Reduction in blood sugar due to increased glucose 
             uptake in the peripheral tissues which convert it to 
             glycogen or fat, and reduction of hepatic output 
             (diminished breakdown of glycogen and diminished 
             gluconeogenesis).  When blood glucose falls below renal 
             threshold (180 mg/100 ml or 10 mmol/l) glycosuria ceases 
             as does the osmotic diuresis of water and electrolytes.  
             Polyuria and excessive thirst are thus alleviated.  If 
             blood glucose falls much below normal levels, appetite 
             is stimulated.
             
             b)   Other metabolic effects: Insulin stimulates the 
             transit of amino acids and potassium into the cells.  
             Insulin regulates utilization of carbohydrate and energy 
             products and enhances protein synthesis.
             
             c)   Insulin increases concentrations of the active form 
             of the enzyme pyruvate dehydrogenase.  Hence pyruvate is 
             oxidized or converted to fat and is unavailable for 
             glucose formation.  In addition to enhanced synthesis of 
             fat, insulin increases the activity of membrane bound 
             lipoprotein lipase which makes fatty acids derived from 
             circulating lipoproteins available to the cell.
     7.2 Toxicity
       7.2.1 Human data
             7.2.1.1 Adults
                     In most normal adults, 0.1 - 0.2 Units/kg 
                     intravenously is sufficient to cause profound 
                     hypoglycaemia.  However, in insulin dependent 
                     diabetics, it is not possible to indicate the 
                     amount of insulin necessary to cause toxicity 
                     because the level of hypoglycaemia and its 
                     duration are the important factors.  For example,
                      patients who have taken 80 to 500 times of the 
                     normal dose taken for suicidal purposes have 
                     recovered (Martin et al, 1977).
             7.2.1.2 Children
                     No data available.
       7.2.2 Relevant animal data
             No data available.
       7.2.3 Relevant in vitro data
             No data available.

     7.3 Carcinogenicity
       Development of cancer at the site of long term insulin 
       injection has been reported.  (Eisenbad and Walter, 1975).
     7.4 Teratogenicity
       Congenital malformations occurred in 17 of 117 babies born to 
       diabetic mothers taking insulin at the time of conception (Pay 
       and Insley, 1976).
     7.5 Mutagenicity
       No data available.
     7.6 Interactions
       Alcohol, beta blockers, salicylates, oxytetracycline and 
       monoamine oxidase inhibitors potentiate the hypoglycaemic 
       effects of insulin.  Bezafibrate and clofibrate may improve 
       glucose tolerance and have an additive effect. Corticosteroids,
        corticotrophin, diazoxide, diuretics like bumetanide, 
       furosemide and thiazides and oral contraceptives antagonise 
       the effects of insulin.  Lithium may occasionally impair 
       glucose tolerance.
     7.7 Main adverse effects
       (a)  Hypoglycaemia - symptoms are directly related to duration 
       and depth of hypoglycaemia.  Initial sympathetic overactivity 
       is followed by signs of neuroglycopenia.
       
       (b)  Non specific local reactions at site of injection eg. 
       pain, oedema.
       
       (c)  Allergic reactions
       
       (d)  Lipoatrophy or induration and hypertrophy at the site of 
       injection is asociated with chronic use.
       
       (e)  Insulin resistance.
    8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
     8.1 Material sampling plan
       8.1.1 Sampling and specimen collection
             8.1.1.1 Toxicological analyses
                     Type of Plasma Insulin   a)   Bioassay
                                              b)   Immunoassay
                                    
                     Plasma insulin estimated by bioassay is called 
                     insulin-like activity (ILA) and plasma insulin 
                     estimated by immunoassay is called 
                     immunoreactive insulin (IRI); ILA and IRI differ 
                     qualitatively and quantitatively.  In vivo 
                     bioassays depend on lowering of blood glucose in 
                     rabbits or production of convulsions in mice.  
                     Several in vitro methods have become popular due 
                     to high degrees of sensitivity and relative 
                     simplicity of execution.  One method is based on 
                     the capacity of insulin to increase the glycogen 
                     content and glucose uptake of rat diaphragm.  
                     Adipose tissue assays are based on the capacity 
                     of insulin to stimulate glucose metabolism by 
                     the epididymal fat pad of the rat or by a 
                     suspension of isolated fat cells.
                     

                     The sensitivity of radio-immunoassay is greater 
                     than that of other assays.
                     
                     The following could be determined by radio-
                     immunoassay.
                     
                          a.   Total immunoreactive insulin (IRI)
                     
                          b.   NEIRI - nonextracted immunoreactive 
                     plasma           insulin
                     
                          c.   Free plasma insulin ('Free' IRI)
                     
                          d.   I125 insulin binding in vitro
                     
                          e.   Acute insulin sensitivity (KITT)
                     
                          f.   Half-time of immunoreactive insulin    
                            disappearance (Gilman and Goodman, 1985; 
                     Martin et al,           1977).
                     
                     Blood glucose estimation
                     
                          Concentration of plasma IRI of normal 
                     persons after      an overnight fast is under 20 
                     microunits/ml.
             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
             Not relevant
       9.1.4 Eye contact
             Not relevant
       9.1.5 Parenteral exposure
             0.4 units of monocomponent insulin injected 
             subcutaneously three times a day into each quadrant of a 
             pitted scar did not cause hypoglycaemia (Amroiwalla, 
             1977).  Insulin toxicity causes hypoglycaemic symptoms.
       9.1.6 Other
     9.2 Chronic poisoning
       9.2.1 Ingestion
             Not relevant
       9.2.2 Inhalation
             Not relevant
       9.2.3 Skin exposure
             Not relevant
       9.2.4 Eye contact
             Not relevant
       9.2.5 Parenteral exposure
             Not relevant
       9.2.6 Other
             Not relevant
     9.3 Course, prognosis, cause of death
       Symptoms do not usually appear unless the blood glucose 
       concentration falls below 3.5 mmol/l.  Convulsions can occur 
       if the blood glucose concentration falls below 2 mmol/l.  Mild 
       hypoglycaemia is usually relieved rapidly by ingestion of 
       carbohydrates.
       
       Even when the level of consciousness is impaired, parenteral 
       admiistration of glucose or glucagon will lead to full 
       recovery.  Sometimes brain damage is irreversible.
       
       Severe or prolonged neuroglycopenia may respond only slowly to 
       restoration of the plasma glucose concentration as concomitant 
       cerebral oedema may itself depress the level of consciousness. 
        Prolonged hypoglycaemia may cause irreversible cerebral 

       damage as manifested by chronically impaired cognitive 
       functions, convulsions and hemiparesis, eventually causing 
       death.
     9.4 Systematic description of clinical effects
       9.4.1 Cardiovascular
             Acute - Hypoglycaemia promotes the release of adrenalin 
             which causes palpitations and tachycardia.  When 
             hypoglycaemia is severe, angina, arrhythmias, premature 
             beats and coronary thrombosis may occur.
       9.4.2 Respiratory
             Shallow breathing is present in severe, prolonged 
             hypoglycaemic coma.
       9.4.3 Neurological
             9.4.3.1 CNS
                     Signs of neuroglycopenia due to prolonged 
                     hypoglycaemia include intellectual impairment, 
                     irrational behaviour, blurring of vision, 
                     diplopia, headache, confusion, abnormal and 
                     often aggressive behaviour, mental retardation, 
                     hemiparesis, ataxia, incontinence, aphasia, 
                     choreiform movements, parkinsonism, epilepsy, 
                     convulsions, drowsiness and coma.
             9.4.3.2 Peripheral nervous system
                     Numbness of lips, nose or fingers.
             9.4.3.3 Autonomic nervous system
                     Initial sympathetic overactivity is observed due 
                     to hypoglycaemia as a result of the release of 
                     adrenaline.
                     
                     Symptoms include anxiety, hunger, sweating, 
                     weakness, pallor, palpitations and tremors.
             9.4.3.4 Skeletal and smooth muscle
       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
                     Urinary incontinence.
       9.4.7 Endocrine and reproductive systems
             No data available.
       9.4.8 Dermatological
             Cutaneous bullae occur due to prolonged coma (similar to 
             those associated with barbiturate poisoning).
             
             Lipodystrophy - Fat atrophy and hypertrophy usually 
             occur with prolonged use of non purified insulins.
       9.4.9 Eye, ear, nose, throat: local effects
             Eye - Pupils are initially dilated and react to light.  
             Later pupils are constricted and cease to react to 
             light.
       9.4.10 Haematological
              Hypercoagulation has been reported.
       9.4.11 Immunological

              Immediate hypersensitivity: this occurs most frequently 
              during first few weeks of therapy.  Following an 
              injection a 'wheal and flare' response occurs around 
              injection site within 2 hours.  Local swelling is 
              maximal at 6 - 12 hrs but the reaction usually settles 
              within 24 - 48 hrs.
              
              Rarely, a widespread general hypersensitivity reaction 
              with widespread urticaria, gastrointestinal 
              disturbances and angioneurotic oedema will occur.
              
              Immediate hypersensitivity is mediated by IgE 
              antibodies.
              
              Delayed hypersensitivity may occur shortly after 
              introducing insulin therapy.
              
              Erythema occurs around injection site 2 - 24 hrs after 
              injection and settles slowly over 2 - 3 days.  Rarely, 
              local residual scarring may occur.
              
              Type IV hypersensitivity is mediated by lymphocytes.
              
              These reactions subside spontaneously and are rarely 
              generalized but occasionally they may persist and 
              necessitate a change in insulin therapy. Most cases 
              occur with non-highly purified bovine insulin.
              
              Acute anaphylaxis to insulin is extremely rare.
       9.4.12 Metabolic
              9.4.12.1 Acid-base disturbances
                       Hypoglycaemic coma may lead to respiratory 
                       depression and anoxia with consequent 
                       acidosis.
              9.4.12.2 Fluid and electrolyte disturbances
                       Hyperinsulinaemia may itself cause 
                       hypokalaemia and hypoglycaemia provokes the 
                       release of adrenalin, which may also cause 
                       hypokalaemia     
              9.4.12.3 Others
       9.4.13 Allergic reactions
              see 9.4.11.
       9.4.14 Other clinical effects
       9.4.15 Special risks
              Hypoglycaemia, severe in 17 cases, occurred during the 
              first 6 hours of life in 22 of 34 infants born to 
              diabetic mothers who received insulin.  Clinical 
              features were present only in two (Martin et al, 1975).
              
              Pregnancy: It is unclear whether insulin causes 
              congenital malformations, though diabetes certainly 
              does.  Neonatal hypoglycaemia is caused by neonatal 
              pancreatic hyperstimulation when diabetic mothers have 
              been hyperglycaemic.  Alcohol is an important risk 
              factor - and most cases of death from insulin have been 
              associated with alcohol.

     9.5 Other
       No data available.
     9.6 Summary
    10. MANAGEMENT
      10.1 General principles
         Correction of hypoglycaemia and the maintenance of normal 
         blood glucose concentration are the most important aspects 
         in management.  In conscious, cooperative patients, oral 
         therapy with a few lumps of sugar or glucose is adequate.
         
         Patients who have large subcutaneous depots of insulin 
         continue to absorb it over several days, and may need 
         glucose infusions.
      10.2 Relevant laboratory analyses
         10.2.1 Sample collection
                Venous blood glucose concentration is measured on a 
                fresh sample taken into a tube containing fluoride-
                acetate.  A volume of 1-2 ml of whole blood is 
                sufficient.  If measurement is likely to be delayed, 
                the sample should be stored at 4C, though even at 
                this temperature there is some glucose consumption.  
                Where assay within a few hours is impossible, a 
                reliable result can be obtained by separating the 
                plasma and then freezing it at -20C.
                
                Diagnosis of hypoglycaemia is suggested by a low 
                glucose oxidase strip reading.
                
                Insulin assay is not helpful in patients with 
                antibodies, unless free insulin concentration can be 
                measured.
         10.2.2 Biomedical analysis
                The blood glucose concentration should be measured.  
                Hypokalaemia can be detected by assay of serum 
                potassium.
         10.2.3 Toxicological analysis
                Refer to section 8.
         10.2.4 Other investigations
      10.3 Life supportive procedures and symptomatic/specific 
         treatment
         If the patient is conscious and cooperative, give oral 
         glucose or sucrose (3-4 sugar lumps) and repeat after 15 
         minutes or earlier if symptoms recur.  This should be 
         supplemented by a carbohydrate meal until blood sugar is 
         stable.
         
         If the patient is unconscious or uncooperative, give 50 ml 
         of 50% dextrose (25 g of glucose) IV.  If there is no 
         response within 15 minutes repeat the dose; glucagon 1 mg IM 
         or IV or SC is a less reliable alternative. This can also be 
         repeated but failure of the first glucagon injection is 
         unlikely to be followed by success with further doses.
         
                   
         For children give approximately 1 ml/kg of 50% glucose and 
         repeat if there is no response.  A 10% glucose infusion via 

         a peripheral vein may be enough, but commonly 20% glucose 
         has to be given by the central vein.  
         
         If the patient is still unconscious despite this treatment 
         and blood sugar is normal or above normal then cerebral 
         oedema is likely and should be treated with 20% mannitol.  
         (Unless contraindicated due to cardiovascular disease).
         
         Blood glucose concentration should be measured every 15 - 30 
         minutes and the rate of infusion altered to keep the blood 
         glucose concentration within the range of 5 - 10 mmol/l.
         
         Give dexamethasone 10 mg IV followed by 16 mg daily in four 
         divided doses.  Give oxygen.
         
         Treatment with parenteral dextrose at doses up to 25 g/hr 
         may be necessary for protracted periods, depending on the 
         preparation of insulin injected.  Initially, 1% - 20% 
         solution via a large central vein may be necessary to 
         supplement oral carbohydrate ingestion.
         
         Occasionally neurological deficits recover after several 
         days if full supportive care is maintained.
         
         Frequent blood sugar estimations (venous or capillary) may 
         be necessary, particularly initially, according to the 
         clinical condition.  Plasma insulin estimations do not help 
         in the management.
         
         Treat hypokalaemia with potassium supplements.  Intravenous 
         potassium chloride 20 - 60 mEq per litre of fluid may be 
         given.
      10.4 Decontamination
         Not relevant
      10.5 Elimination
         Not relevant
      10.6 Antidote treatment
         10.6.1 Adults
                No specific antidotes are available
         10.6.2 Children
                No specific antidotes are available
      10.7 Management discussion
         Glucagon 1 mg IM is useful to correct hypoglycaemia.  
         However, there is a risk that glucagon-induced insulin 
         secretion may be a complication (Marri et al, 1968).
         
         Excision of the skin and fat of an insulin injection site 
         under a local anaesthetic has been performed in the 
         management of insulin overdose (McIntyre et al, 1986).
         
         Hypoglycaemia may develop later than predicted from the 
         duration of action of various insulin preparations (Haskell 
         and Stapezyriski, 1983).
    11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
         Kaminer and Robbins (1988) reported a case of a 16 year old 

         girl with insulin-dependent diabetes mellitus who gave 
         herself an injection of 600 units of regular insulin in a 
         suicidal attempt.  She lost consciousness for 12 hours and 
         was found confused and disoriented.  She recovered fully.
         
         Martin et al (1977) reported a case of a young man with a 
         prior history of depressive illness who was found 
         unconscious about 12 hours after self-administration of 
         about 1,600 units of NPH insulin along with a large amount 
         of alcohol and barbiturates.  Despite the intravenous 
         administration of a large amount of glucose and 20% fructose 
         solution, hypoglycaemia recurred and his conscious state 
         deteriorated after an episode of respiratory obstruction.  
         He did not require further insulin for 6 days by which time 
         the blood glucose level had risen to 15 mmol/l.  Improvement 
         in his conscious state was slow and he had evidence of 
         marked mental impairment and emotional lability.
      11.2 Internally extracted data on cases
      11.3 Internal cases
    12. Additional information
      12.1 Availability of antidotes
      12.2 Specific preventive measures
         Patients should be advised regarding the correct dose and 
         injection technique. They should have an adequate knowledge 
         of early features of hypoglycaemia so that they can take 
         glucose or sugar immediately.
      12.3 Other
    13. REFERENCES
    Amroliwalla FK (1977). Br Med J 1: 1389 - 90
    
    British National Formulary (1988).  British Medical Association 
    and the Pharmaceutical Society of Great Britain.
    
    Dukes MNG (1988). Meyler's Side Effects of Drugs.  Amsterdam, 
    Elsevier Scientific Publishers.
    
    Eisenbad E, Walter RM (1975). J Am Med Ass 233: 985.
    
    Gilman AG, Goodman LS, Rall TW, Murad F (1985) ed. In: The 
    Pharmacological Basis of Therapeutics 7th Ed. Pergamon. p 1490 - 
    1504.
    
    Haskell RJ, Stapezynski JS (1983).  Intravenous glucose for the 
    treatment of intentional insulin overdoses.  Ann Emerg Med 12: 
    260.
    
    Kaminer Y, Robbins DR (1988).  Attempted suicide by insulin 
    overdose in insulin-dependent diabetic adolescents.  Paediatrics 
    81: 526 - 528.
    
    Laurence DR, Bennett PN. Clinical Pharmacology. Churchill 
    Livingstone. Edinburgh.
    
    McIntyre AS, Woolf VJ, Burnhem WR (1986).  Local excision of 
    subcutaneous fat in the management of insulin overdose.  Br J 
    Surg 73: 538.

    
    Martin FIR, Hansen N, Warne GL (1977).  Attempted suicide by 
    insulin overdose in insulin-requiring diabetics.  Med J Austr 1: 
    58-60.
    
    Martin FIR et al (1975). Arch Dis Child 130: 998
    
    Paterson KR, Paice BJ, Lawson DH, (1983).  Undesired effects of 
    insulin therapy.  Adv Drug React Ac Pois Rev 2: 219-234
    
    Pay IR, Insley J (1976). Arch Dis Child 51: 935
    
    Reynolds JEF (1982) ed. Martindale, The Extra Pharmacopoeia. 28th 
    ed. The Pharmaceutical Press, London. p. 2025.
    
    Trevor M. Avery's Drug Treatment. 3rd ed.  ADIS Press. Auckland. 
    p. 530-535
    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
    ADDRESS(ES)
    Author(s):Dr Ravindra Fernando 
              Dr (Mrs) Geetha Fernando 
              National Poisons Information Centre
              General Hospital
              Colombo 8
              Sri Lanka
      
              Tel: 94-1-94016
              Fax: 94-1-599231
    
    Date:     April 1990
    
    Reviewer: Dr R. Ferner
              West Midlands Poisons Unit
              Dudley Road Hospital
              Birmingham B18 7QH
              United Kingdom
    
              Tel: 44-21-5543801
              Fax: 44-21-5236526
    
    Date:     February 1991
    
    Peer review: Adelaide, Australia, April 1991



    See Also:
       Toxicological Abbreviations