INTOX Home Page

Haloperidol

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS
      1.4.2 Other numbers
   1.5 Brand names, Trade names
   1.6 Manufacturers, Importers
   1.7 Presentation, Formulation
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
         3.3.1.1 Colour
         3.3.1.2 State/Form
         3.3.1.3 Description
      3.3.2 Properties of the locally available formulation(s)
   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
      4.1.1 Indications
      4.1.2 Description
   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 AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Macroscopic and microscopic analysis
         8.1.1.2 Toxicological analyses
         8.1.1.3 Biological analyses
         8.1.1.4 Arterial blood gas analysis
         8.1.1.5 Haematological analyses
         8.1.1.6 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Macroscopic and microscopic analysis
         8.1.2.2 Toxicological analyses
         8.1.2.3 Biochemical analyses
         8.1.2.4 Arterial blood gas analysis
         8.1.2.5 Haematological analyses
         8.1.2.6 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Macroscopic and microscopic analysis
         8.1.3.2 Toxicological analyses
         8.1.3.3 Biochemical analyses
         8.1.3.4 Arterial blood gas analysis
         8.1.3.5 Haematological analyses
         8.1.3.6 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 on 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 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 Central nervous system (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)



    1. NAME

       1.1 Substance 

           Haloperidol   (INN)

           (WHO, 1992)

       1.2 Group

           ATC classification index

           Psycholeptics (N05)/Antipsychotics (N05A)/Butyrophone 
           derivatives (N05AD). 

           (WHO, 1992)

       1.3 Synonyms

           Aloperidolo

           Haloperidolum

           (Reynolds, 1993)

           (To be completed by each Centre using local data)

       1.4 Identification numbers

           1.4.1 CAS

                 52-86-8

           1.4.2 Other numbers

                 RTECS      
    
                 EU 1575000

       1.5 Brand names, Trade names

           Monocomponent products
           
           Haldol (UK,Belg., Canad., Fr., Ger., Neth., Norw., Swed., 
           Switz., USA)
           
           Halopidol (Arg.)
           
           Peridol   (Canad.)
           
           Serenace  (UK, Austral., Jap., S.Afr.)
           
           Serenase  (Denm., Ital.)
           
           Halosten  (Jap.)
           
           Sigaperidol (Ger.)
           
           Combination products
           
           Vesadol   (Fr.)
           
           Vesalium  (Ital)
           
           (To be completed by each Centre using local data)

       1.6 Manufacturers, Importers

           Lando Lab
           
           Janssen Lab (France, UK)
           
           Searle (Australia, UK)
           
           Technilab (Canada)
           
           (To be completed by each Centre using local data)

       1.7 Presentation, Formulation

           Oral solution
           
           2 mg/mL
           
           Sterile solution for injection
           
           5 mg/5 mL
           
           Ampoules for injection
           
           5 mg/mL
           
           Tablets
           
           1.5 mg, 5 mg, 10 mg, and 20 mg.
           
           Capsules
           
           0.5 mg
           
           (To be completed by each Centre using local data)

    2. SUMMARY

       2.1 Main risks and target organs

           The main features of severe overdosage are extrapyramidal 
           reactions, hypotension, respiratory difficulty and impairment 
           of consciousness.
           
           Haloperidol acts mainly as a dopamine antagonist.

       2.2 Summary of clinical effects

           Consciousness may be depressed, progressing to coma; 
           paradoxically, some patients manifest confusion, excitement 
           and restlessness.  Tremor or muscle twitching, muscle spasm, 
           rigidity and convulsions are seen.
           
           Extrapyramidal signs can include dystonia, sometimes severe 
           enough to impair swallowing or breathing; torticollis, 
           oculogyric crises and opisthotonos.  The pupils may be 
           constricted or dilated.
           
           Hypotension and tachycardia are common.  Sometimes there can 
           be cardiac arrhythmias, including ventricular fibrillation, 
           conduction defects and cardiac arrest.
 
       2.3 Diagnosis

           Diagnosis is usually on the basis of history and typical 
           extrapyramidal features.
           
           Collect urine and blood samples for biological test. 
           Qualitative drug screens require urine samples.

       2.4 First aid measures and management principles

           Although ipecac syrup is said to be effective in promoting 
           vomiting even after overdoses of phenothiazine 
           tranquillizers, it should not be administered if the patient 
           is already drowsy.  Gastric lavage should be considered up to 
           2 hours after ingestion because gastric motility is greatly 
           reduced.  Use precautions against aspiration. 50 to 100 g of 
           activated charcoal may be administered.
           
           In severe shock, plasma expanders and if necessary dopamine 
           infusion.
           
           Fluid and electrolyte therapy; oxygen and artificial 
           respiration whenever necessary.
           
           Sodium dantrolene, or possibly bromocriptine, may be useful 
           in the malignant neuroleptic syndrome.
           
           Continuously monitor the ECG.
           
           For relief of extrapyramidal signs, antihistaminic/ 
           anticholinergics have been suggested for use in adults 
           (Ellenhorn & Barceloux, 1988). Diphenhydramine (10 to 50 mg) 
           intravenously is said to provide relief from extrapyramidal 
           signs.  The maximum 24 hour dose is 400 mg in children. 
           Diphenhydramine intravenously is effective in children but 
           should not exceed 400 mg in 24 hours.

    3. PHYSICO-CHEMICAL PROPERTIES

       3.1 Origin of the substance

           It is a synthetic product.  Haloperidol is the first of the 
           butyrophenone series of major tranquillizers.

       3.2 Chemical structure

           Structural formula
           
           Molecular formula
           
           C21H23C1FNO2
           
           Molecular weight
           
           375.9
           
           Structural Chemical names
           
           4-[4-(4-Chlorophenyl)-4-hydroxypiperidino]-4'-
           fluorobutyrophenone.
           
           4[4-(4-Chlorophenyl)-4-hydroxy-1-piperidinyl]-1-(4-
           fluorophenyl)-1-butanone.
           
           4[4-(p-Chlorophenyl)-4-hydroxypiperidino]-4'-
           fluorobutyrophenone.
           
           (Reynolds, 1993; Budavari, 1989)

       3.3 Physical properties

           3.3.1 Properties of the substance

                 3.3.1.1 Colour

                         White to faintly yellowish

                 3.3.1.2 State/Form
                         
                         Amorphous or microcrystalline powder

                 3.3.1.3 Description

                         Odourless
                         
                         Practically insoluble in water; soluble in 
                         approximately 1:60 in alcohol, 1:20 in 
                         chloroform and slightly soluble in ether.  
                         Freely soluble in methanol-acetone, benzene and 
                         acids.
                         
                         pKa    8.3
                         
                         The B.P. injection has a pH of 2.8 to 3.6

           3.3.2 Properties of the locally available formulation(s)

                 To be completed by each Centre using local data.

       3.4 Other characteristics

           3.4.1 Shelf-life of the substance

           3.4.2 Shelf-life of the locally available formulation

                 To be completed by each Centre using local data.

           3.4.3 Storage conditions

                 Store in airtight containers.  Protect from light.

           3.4.4 Bioavailability

                 To be completed by each Centre using local data.

           3.4.5 Specific properties and composition

                 To be completed by each Centre using local data.

    4. USES

       4.1 Indications

           4.1.1 Indications

                 Haloperidol is indicated for use in the management of 
                 manifestations of psychotic disorders such as 
                 schizophrenia and mania.
                 
                 It is indicated for the control of tics and vocal 
                 utterances of Tourette's Disorder in children and 
                 adults.
                 
                 It is effective for the treatment of severe behaviour 
                 problems in children of combative, explosive 
                 hyperexcitability.
                 
                 It is also used in the management of Gilles de La 
                 Tourette's syndrome, intractable hiccup and as an anti-
                 emetic.
                 
                 ((Physician's Desk Reference, 1987)

           4.1.2 Description
     
                 Not relevant.

       4.2 Therapeutic dosage

           4.2.1 Adults

                 Oral
                 
                 Psychoses and associated behavioural disorders
                 
                 0.5 to 5 mg twice or three times daily.
                 
                 Severe psychoses
                 
                 Up to 100 mg daily.
                 
                 In very high dose therapy, 200 mg daily has been used.
                 
                 Parenteral
                 
                  Intramuscular
                 
                 Doses vary from 2 to 30 mg depending on the condition 
                 being treated.
                 
                 Long-acting decanoate ester may be given in doses 
                 ranging from 100 to 300 mg.
                 
                  Intravenous
                 
                 Up to 30 mg for emergency control of disturbed 
                 patients.
                 
                 (Reynolds, 1993)

           4.2.2 Children

                 Oral
                 
                 A suggested dose in children over 3 years of age is 25 
                 to 50 ug/kg per bodyweight daily, and increased 
                 cautiously, if necessary up to 150 ug/kg daily.
                 
                 (Reynolds, 1993)

       4.3 Contraindications

           Severe dystonic reactions have followed the use of 
           haloperidol, particularly in children and adolescents.  It 
           should therefore be used with extreme care in children.
           
           Haloperidol may also cause severe neurotoxic reactions in 
           patients with hyperthyroidism and in patients receiving 
           lithium.
           
           (Reynolds, 1989)
           
           Haloperidol is contraindicated in severe toxic central 
           nervous system depression or comatose states from any cause 
           and individuals who are hypersensitive to this drug or have 
           Parkinson's disease (Physician's Desk Reference, 1987).
           
           Also contraindicated in late pregnancy because of dystonic 
           reaction in the neonate.  Infants should not be nursed during 
           drug treatment (Physician's Desk Reference, 1987).

    5. ROUTES OF ENTRY

       5.1 Oral

           It is the main route of administration.

       5.2 Inhalation

           Not relevant.

       5.3 Dermal

           Not relevant.

       5.4 Eye

           Not relevant.

       5.5 Parenteral

           Through intravenous and intramuscular injection.

       5.6 Other

           Not relevant.

    6. KINETICS

       6.1 Absorption by route of exposure

           Haloperidol is readily absorbed from the gastrointestinal 
           tract.  Owing to the first-pass effect of metabolism in the 
           liver, plasma concentrations following oral administration 
           are lower than those following intramuscular administration.  
           Moreover, there is wide intersubject variation in plasma 
           concentration of haloperidol and its therapeutic effects.
           
           The decanoate ester of haloperidol is very slowly absorbed 
           from the site of injection and is therefore suitable for 
           depot injection.  It is gradually released into the 
           bloodstream where it is rapidly hydrolysed to haloperidol.
           
           (Reynolds, 1989)

       6.2 Distribution by route of exposure

           Haloperidol is very extensively bound to plasma proteins 
           (90%).  It is widely distributed in body and crosses the 
           bloodbrain barrier. The volume of distribution is 18 L/kg).
           
           (Reynolds, 1989; Gilman et al., 1990)

       6.3 Biological half-life by route of exposure

           The plasma half-life in therapeutic doses is reported to 
           range from about 13 to nearly 40 hours (Reynolds, 1989), with 
           a mean of 20 hours. Gilman et al.(1990) gives a similar 
           average value of 18 hours.
        
       6.4 Metabolism

           Haloperidol is metabolized in the liver and the paths of 
           metabolism include oxidative N-dealkylation (Reynolds, 1989).

       6.5 Elimination by route of exposure

           The total systemic clearance of the drug from plasma is 
           11.8 mL/min/kg. This rate increases in children and decreases 
           in aged patients (Gilman et al., 1990).
           
           After metabolism, haloperidol is excreted in the urine, via 
           the bile and in the faeces, there is evidence of 
           enterohepatic recycling by 40%.  About 26% was excreted in 
           the urine by the healthy subjects and 20% by the patients in 
           the first 5 days; by the third day about 15% had been 
           excreted in the faeces (Johnson, 1967).  It takes 28 days to 
           fully eliminate a single oral dose.

    7. PHARMACOLOGY AND TOXICOLOGY

       7.1 Mode of action

           7.1.1 Toxicodynamics

                 The same mechanism of action applies to both 
                 pharmacodynamics and toxicodynamics.

           7.1.2 Pharmacodynamics

                 Dopamine receptors currently are classified as D-
                 1(stimulate adenylate cyclase) and D-2(inhibit 
                 adenylate cyclase).  Neuroleptic drugs block both D-1 
                 and D-2 receptors but the significance of the ratio 
                 remains unclear.  The therapeutic dose of neuroleptic 
                 drug appears to correlate with its affinity for brain 
                 dopamine D-2 receptors (Richelson, 1984).
                 
                 Neuroleptic drugs also block a number of other 
                 receptors including H1 and H2 histamine, alfa 1 and 
                 alfa 2 adrenergic, muscarinic and serotoninergic 
                 receptors.

       7.2 Toxicity

           7.2.1 Human data

                 7.2.1.1 Adults

                         Deaths from massive haloperidol ingestion have 
                         not been reported (Ellenhorn & Barceloux, 
                         1988).
                         
                         Three cases of sudden death after taking 20 to 
                         140 mg daily for one to four days (Gosselin et 
                         al., 1984).

                 7.2.1.2 Children

                         A 29-month-old girl and an 11 month old boy who 
                         divided 265 mg of haloperidol between them 
                         developed lethargy, hypothermia, hyperreflexia, 
                         neuromuscular rigidity, unsteady gait and 
                         intention tremors (Scialli, 1978).

           7.2.2 Relevant animal data

                 LD50 (oral) rat   850 mg/kg (Gosselin, 1984).

           7.2.3 Relevant in vitro data

                 No data available.

       7.3 Carcinogenicity

           Carcinogenicity studies using oral haloperidol were conducted 
           in Wistar rats (dosed at up to 5 mg/kg daily for 24 months) 
           and in Albino swiss mice (dosed at up to 5 mg/kg daily for 18 
           months).
           
           In the rat study, survival was less than optimal in all dose 
           groups, reducing the number of rats at risk for developing 
           tumours.  However, although a relatively greater number of 
           rats survived to the end of the study in high dose male and 
           female groups, these animals did not have a greater incidence 
           of tumours than control animals.
           
           Therefore, although not optimal, this study does suggest the 
           absence of haloperidol related increase in the incidence of 
           neoplasia in rats at doses up to 20 times the usual daily 
           human dose for chronic  patients.
           
           In female mice at 5 to 20 times the highest initial daily
           dose for chronic patients, there was a statistically
           significant increase in mammary gland neoplasia and total
           tumour incidence; at 20 times the same daily dose there was
           a statistically significant increase in pituitary gland
           neoplasia.  In male mice, no statistically significant
           differences in incidence of total tumours or specific
           tumour types were noted.  Neuroleptic drugs elevate
           prolactin levels; the elevation persists during chronic
           administration.  Tissue culture experiment indicate that
           approximately one-third of human breast cancers are
           prolactin dependent "in vitro", a factor of potential
           importance if the prescription of these drugs is
           contemplated in a patient with a previously detected breast
           cancer.  Although disturbances such as galactorrhoea,
           amenorrhea, gynaecomastia, and impotence have been
           reported, the clinical significance of elevated serum
           prolactin levels is unknown for most patients.  An increase
           in mammary neoplasms has been found in rodents after
           chronic administration of neuroleptic drugs.  Neither
           clinical studies nor epidemiological studies conducted to
           date, however, have shown an association between chronic
           administration of these drugs and mammary tumorigenesis;
           the available evidence is considered too limited to be
           conclusive at this time (Physician's Desk Reference, 1987).

       7.4 Teratogenicity

           Rodents given 2 to 20 times the usual maximum human dose of 
           haloperidol by oral or parenteral routes showed an increase 
           in incidence of resorption, reduced fertility, delayed 
           delivery and pup mortality.  No teratogenic effect has been 
           reported in rats, rabbits or dogs at dosages within this 
           range, but cleft palate has been observed in mice given 15 
           times the usual maximum human dose.  Cleft palate in mice 
           appears to be a non-specific response to stress or 
           nutritional imbalance as well as to a variety of drugs, and 
           there is no evidence to relate this phenomenon to predictable 
           human risk for most of this agents (Physician's Desk 
           Reference, 1987).
           
           There are no well controlled studies with haloperidol in 
           pregnant women.  There are reports, however, of cases of limb 
           malformations observed following maternal use of haloperidol 
           along with other drugs which have suspected teratogenic 
           potential during the first trimester of pregnancy.  Causal 
           relationships were not established in these cases.  Since 
           such experience does not exclude the possibility of fetal 
           damage due to haloperidol;  this drug should be used during 
           pregnancy or in women likely to become pregnant only if the 
           benefit clearly justifies a potential risk to the fetus 
           (Physician's Desk Reference, 1987).

       7.5 Mutagenicity

           No mutagenic potential of haloperidol was found in the Ames 
           Salmonella microsomal activation assay (Physicians Desk 
           Reference, 1987).

       7.6 Interactions

           The use of alcohol with this drug should be avoided due to 
           possible additive effects and hypotension.
           
           An encephalopathic syndrome (characterised by weakness, 
           lethargy, fever, tremulousness and confusion, extrapyramidal 
           symptoms, leucocytosis, elevated serum enzymes, BUN, and FBS)  
           followed by irreversible brain damage has occurred in a few 
           patients treated with lithium plus haloperidol.  A casual 
           relationship between these events and the concomitant 
           administration of lithium and haloperidol has not been 
           established; however, patients receiving such combination 
           therapy should be monitored closely for early evidence of 
           neurological toxicity and treatment discontinued promptly if 
           such signs appear (Physician's Desk Reference, 1987).
           
           Other reported interactions involve the following drugs and 
           adverse effects:
           
           Beta-blockers (Severe hypotension or pulmonary arrest).
           
           Methyldopa (Dementia, psychomotor retardation, memory 
           impairment and inability to concentrate)
           
           Indomethacin (Severe drowsiness and confusion).
           
           (Reynolds, 1989; Ellenhorn & Barceloux, 1988)
           
       7.7 Main adverse effects

           In general, the symptoms of overdose would be an exaggeration 
           of known pharmacological effects and adverse reactions.
           
           Anticholinergic side effects and sedation occur less often 
           than with aliphatic phenothiazines, but extrapyramidal 
           reactions are more common. Administration of antidopaminergic 
           and anticholinergics may worsen or bring forward the onset of 
           extrapyramidal effects.
           
           Idiosyncratic reaction producing severe drowsiness when used 
           with indomethacin (Reynolds, 1989; Ellenhorn & Barceloux, 
           1988).

    8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
     
       8.1 Material sampling plan
     
           Blood levels do not correlate well with clinical effects in 
           part because of the large number of active metabolites.  
           Chlorpromazine appears unstable in plasma but more stable in 
           erythrocytes.
     
           8.1.1 Sampling and specimen collection
     
                 8.1.1.1 Macroscopic and microscopic analysis
     
                 8.1.1.2 Toxicological analyses
     
                 8.1.1.3 Biological analyses
     
                 8.1.1.4 Arterial blood gas analysis

                 8.1.1.5 Haematological analyses

                 8.1.1.6 Other (unspecified) 
                 analyses

           8.1.2 Storage of laboratory samples and specimens
     
                 8.1.2.1 Macroscopic and microscopic analysis

                 8.1.2.2 Toxicological analyses

                 8.1.2.3 Biochemical analyses

                 8.1.2.4 Arterial blood gas analysis

                 8.1.2.5 Haematological analyses

                 8.1.2.6 Other (unspecified) analyses

           8.1.3 Transport of laboratory samples and specimens

                 8.1.3.1 Macroscopic and microscopic analysis
                
                 8.1.3.2 Toxicological analyses

                 8.1.3.3 Biochemical analyses

                 8.1.3.4 Arterial blood gas analysis

                 8.1.3.5 Haematological analyses

                 8.1.3.6 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 on biological specimens

                 8.2.2.1 Simple qualitative test(s)

                         Phenistix testing of the urine also may suggest 
                         the presence of phenothiazines.  The 
                         persistence of the positive violet colour upon 
                         addition of 50% H2SO4 to the strip confirms the
                         presence of phenothiazines.
                         
                         The ferric chloride urine test also is a quick 
                         qualitative screen for phenothiazines (25 mg of 
                         phenothiazine per 100 ml of urine is necessary 
                         for a positive reaction).  The 10% ferric 
                         chloride solution should be kept in a dark 
                         bottle in a dark cabinet.
                         
                         One millilitre of urine added to 10 to 15 drops 
                         of 10% ferric chloride solution will yield a 
                         deep burgundy, port wine colour if sufficient 
                         phenothiazines are present.
     
                 8.2.2.2 Advanced qualitative confirmation test(s)
     
                 8.2.2.3 Simple quantitative method(s)
     
                         The Forrest colorimetric test provides a 
                         relative quick semi-quantitative urine 
                         screening test for phenothiazines (test 
                         solution: 20 parts 5% ferric chloride; 80 parts 
                         10% sulphuric acid).
                         
                         Performance of test:  mix 1 ml urine with 1 ml 
                         test solution: read within 20 seconds.
                         
                         Resulting test colours and daily dosage (mg)
                         
                         Pink      Purple     Dark blue     Dark grey
                         
                         +         ++         +++           ++++
                         
                         100-300   300-600    600-900       > 900
     
                 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 Blood, plasma or serum
     
                 Serum electrolytes, glucose, creatine kinase should be 
                 performed in symptomatic patients.
                 
                 "Basic analyses"
                 "Dedicated analyses"
                 "Optional analyses"
     
                 8.3.1.2 Urine
     
                         "Basic analyses"
                         "Dedicated analyses"
                         "Optional analyses"
     
                 8.3.1.3 Other fluids
     
           8.3.2 Arterial blood gas analyses
     
                 Monitor arterial blood gases in particular with 
                 respiratory symptoms with malignant hyperthermia.
     
           8.3.3 Haematological analyses
     
                 Serial blood counts should be performed, especially in 
                 patients who have history of prolonged use.
                 
                 "Basic analyses"
                 "Dedicated analyses"
                 "Optional analyses"
     
           8.3.4 Interpretation of biomedical investigations
     
       8.4 Other biomedical (diagnostic) investigations and their 
           interpretation 
     
           Continuous ECG monitoring should be performed for patients 
           with suspected or overt cardiac arrhythmia.
     
       8.5 Overall interpretation of all toxicological analyses and 
           toxicological investigations 
     
           Chlorpromazine has produced haematological disorders, 
           including agranulocytosis, eosinophilia, leucopenia, 
           haemolytic anaemia, aplastic anaemia, thrombocytopenic 
           purpura and pancytopenia.
           
           Hyperglycaemia, hypoglycaemia and glycosuria have also been 
           reported.
     
       8.6 References
        
    9. CLINICAL EFFECTS

       9.1 Acute poisoning
    
           9.1.1 Ingestion

                 In general, the symptoms of overdosage would be an 
                 exaggeration of known pharmacologic effects and adverse 
                 reactions, the most prominent of which would be as 
                 follows:
                 
                 Coma with respiratory depression and hypotension which 
                 could be severe enough to produce a shock-like state.
                 
                 The extrapyramidal reaction would be manifest by 
                 muscular weakness or rigidity and a generalized or 
                 localized tremor.
                 
                 Paradoxical effects such as hypertension or agitation 
                 may occur, especially in children.
                 
                 (Physician's Desk Reference, 1987)
                 
                 Note: While overdosage is likely to occur with a 
                 parenteral rather than with an oral medication, 
                 information pertaining to haloperidol is presented, 
                 modified only to reflect the extended duration of 
                 action of haloperidol decanoate.
     
           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

                 Usually iatrogenic with signs and symptoms similar to 
                 oral except that the decanoate salt has a prolonged 
                 duration of action.

           9.1.6 Other

       9.2 Chronic poisoning

           9.2.1 Ingestion 

                 Chronic poisoning by ingestion may induce neurological 
                 syndromes, the most severe of which are parkinsonism, 

                 akathisia and tardive dyskinesia (Reynolds, 1989).

           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

                 No data available

           9.2.6 Other

                 Not relevant

       9.3 Course, prognosis, cause of death

           Cases of sudden and unexpected death have been reported in 
           association with the administration of haloperidol.  The 
           nature of the evidence makes it impossible to determine 
           definitively what role, if any, haloperidol played in the 
           outcome of the reported cases.  The possibility that 
           haloperidol caused death cannot, of course, be excluded, but 
           it is to be kept in mind that sudden and unexpected death may 
           occur in psychotic patients when they go untreated or when 
           they are treated with other neuroleptic drugs (Reynolds, 
           1993).

       9.4 Systematic description of clinical effects

           9.4.1 Cardiovascular

                 Cardiac arrhythmia, hypotension, hypertension and ECG 
                 changes are usually secondary to acute overdose 
                 (Reynolds, 1989; Physician's Desk Reference, 1987).

           9.4.2 Respiratory

                 In acute overdose, respiratory depression secondary to 
                 CNS depression is common.
                 
                 Laryngospasm and bronchospasm have been reported 
                 (Physician's Desk Reference, 1987).
                 
                 Bronchopneumonia can occur and is commonly due to 
                 aspiration.
                 
                 It has been postulated that lethargy and decreased 
                 sensation of thirst due to central inhibition may lead 
                 to dehydration, haemoconcentration and reduced 
                 pulmonary ventilation.

           9.4.3 Neurological

                 9.4.3.1 Central nervous system (CNS)

                          Acute
                         
                         Acute effects include CNS depression, coma, 
                         acute dystonia.  Neuroleptic malignant syndrome 
                         can occur after acute overdose or chronic 
                         therapy.
                         
                          Extrapyramidal reactions
                         
                         Neuromuscular (extrapyramidal) reactions during 
                         the administration of haloperidol have been 
                         reported frequently, often during the first few 
                         days of treatment.
                         
                         In most patients, these reactions involved 
                         Parkinson-like symptoms which, when first 
                         observed, were usually reversible.  Other types 
                         of neuromuscular reactions such as motor 
                         restlessness, dystonia and tardive dystonia, 
                         akathisia, hyperreflexia, opisthotonos, 
                         oculogyric crises have been reported far less 
                         frequently, but were often more severe.
                         
                         Severe extrapyramidal reactions have been 
                         reported to occur at relatively low doses. 
                         Generally the occurrence and severity of most 
                         extrapyramidal symptoms are dose related since 
                         they occur at relatively high doses and have 
                         been shown to disappear or become less severe 
                         when the dose is reduced.
                         
                         As with all antipsychotic agents haloperidol 
                         has been associated with persistent dyskinesia. 
                         Tardive dyskinesia, a syndrome consisting of 
                         potentially irreversible, involuntary, 
                         dyskinetic movements, may appear in some 
                         patients on long-term therapy or may occur 
                         after drug therapy has been discontinued.  The 
                         risk appears to be greater in elderly patients 
                         on high dose therapy, especially females.  The 
                         symptoms are persistent and in some patients 
                         appear irreversible.  The syndrome is 
                         characterized by rhythmical involuntary 
                         movements of tongue, face, mouth or jaw (e.g. 
                         protrusion of tongue, puffing of cheeks of 
                         mouth, chewing movements).  Sometimes these may 

                         be accompanied by involuntary movements of 
                         extremities.
                         
                         It has been reported that fine vermicular 
                         movement of the tongue may be an early sign of 
                         the syndrome and if the medication is stopped 
                         at that time the syndrome may not develop.

                 9.4.3.2 Peripheral nervous system

                         Not relevant

                 9.4.3.3 Autonomic nervous system

                         Dry mouth, blurred vision, urinary retention 
                         and diaphoresis.  This is an important 
                         component of neuroleptic malignant syndrome.

                 9.4.3.4 Skeletal and smooth muscle

                         (see 9.4.3.1 and 9.4.14)

           9.4.4 Gastrointestinal

                 Anorexia, constipation, hypersalivation, dyspepsia, 
                 nausea and vomiting.

           9.4.5 Hepatic

                 Impaired liver function and/or jaundice have been 
                 reported.

           9.4.6 Urinary
    
                 9.4.6.1 Renal

                         Urinary retention can occur in acute overdose 
                         and chronic haloperidol administration.

                 9.4.6.2 Other

                         No data available

           9.4.7 Endocrine and reproductive systems

                 Endocrine disorders may occur with chronic treatment. 
                 Lactation, breast engorgement, mastalgia, menstrual 
                 irregularities, gynaecomastia, impotence, increased 
                 libido, hyperglycaemia, hypoglycaemia and 
                 hyponatraemia.

           9.4.8 Dermatological

                 Maculopapular and acneiform skin reactions and isolated 
                 cases of photosensitivity and loss of hair have been 

                 reported in chronic therapy.

           9.4.9 Eye, ear, nose, throat: local effects

                 Cataracts, retinopathy and visual disturbances (PDR, 
                 1987).
            
           9.4.10 Haematological

                  In chronic therapy there are rare reports of mild 
                  haematological abnormalities, usually transient 
                  leucopenia or leucocytosis.

           9.4.11 Immunological

                  No data available.

           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

                           Decreased serum cholesterol has been reported 
                           (Physician's Desk Reference, 1987).

           9.4.13 Allergic reactions

                  Maculopapular and acneiform skin reactions and 
                  isolated cases of photosensitivity.

           9.4.14 Other clinical effects

                  Neuroleptic Malignant Syndrome
                 
                 As with other neuroleptic drugs, a symptom complex 
                 sometimes referred to as neuroleptic malignant syndrome 
                 (NMS) has been reported.  Cardinal features of NMS are 
                 hyperpyrexia, muscle rigidity, altered mental status 
                 (including catatonic signs), and evidence of autonomic 
                 instability (irregular pulse or blood pressure). 
                 Additional signs may include elevated CPK, 
                 myoglobinuria (rhabdomyolysis) and acute renal failure. 
                 NMS is potentially fatal, requires intensive 
                 symptomatic treatment discontinuation of neuroleptic 
                 treatment.
                 
                 Hyperpyrexia and heat stroke, not associated with the 
                 above symptom complex, have also been reported.
                 
                 Cases of photosensitivity have been reported.
                 
           9.4.15 Special risks

                   Pregnancy
                  
                  There are no adequate well-controlled studies in 
                  pregnant women.  There are reports, however, of two 
                  cases of limb malformations observed following 
                  maternal use of haloperidol along with other drugs 
                  which have suspected teratogenic potential during the 
                  first trimester of pregnancy.  Use with caution in 
                  pregnancy or in women likely to become pregnant only 
                  if the benefit clearly justifies a potential risk to 
                  the fetus.
                  
                   Breast-feeding
                  
                  Since haloperidol is excreted in human breast milk, 
                  infants should not be nursed during drug treatment 
                  with haloperidol.

       9.5 Other

           Withdrawal Emergent Neurological Signs
           
           Generally, patients receiving short term therapy 
           experience no problems with abrupt discontinuation of 
           antipsychotic drugs.  However, some patients on maintenance 
           treatment experience transient dyskinetic signs after abrupt 
           withdrawal. In certain of these cases the dyskinetic 
           movements are indistinguishable from the syndrome described 
           under "Tardive Dyskinesia" except for duration.  It is not 
           known whether gradual withdrawal of antipsychotic drugs will 
           reduce the rate of occurrence of withdrawal emergent 
           neurological signs but until further evidence becomes 
           available, it seems reasonable to withdraw the use of 
           haloperidol gradually.
           
           Insomnia, restlessness, anxiety, euphoria, agitation, 
           drowsiness, depression, lethargy, headache, confusion, 
           vertigo, grand mal seizures, exacerbation of psychotic 
           symptoms including hallucinations, and catatonic-like 
           behavioural states may occur which may be responsive to drug 
           withdrawal and/or treatment with anticholinergic drugs.

       9.6 Summary

           Not relevant.

    10. MANAGEMENT

        10.1 General principles

             In acute overdosage the mainstay of treatment is supportive 

             care.  Patients with a history of significant neuroleptic 
             ingestion should receive gut decontamination, and 
             monitoring of vital signs and ECG.  Symptomatic patients 
             (e.g. hypotension, conduction delay, dysrhythmia) should be 
             admitted until the ECG is normal for 24 hours. Asymptomatic 
             patients can be released after a 4 hour observation period.

        10.2 Relevant laboratory analyses

             10.2.1 Sample collection

                    Collect urine and blood samples for toxicology and 
                    biomedical analysis.

             10.2.2 Biomedical analysis

             10.2.3 Toxicological analysis

                    Blood levels do not correlate well with clinical 
                    effects.

             10.2.4 Other investigations

                    ECG monitoring.

        10.3 Life supportive procedures and symptomatic/specific
             treatment

             Patients with vital signs or cardiac abnormalities should 
             receive cardiac monitoring.  Hypotension is the most common 
             sign and should initially be treated with plasma expanders. 
             Additional appropriately titrated doses of dopamine may be 
             required. Pure beta agonists are contraindicated because 
             they may worsen the hypotension.
             
             In cases of arrhythmia, correction of acidosis, 
             hypokalaemia and hypoxia should be done. Intractable 
             ventricular dysrhytmias ("torsades de pointes") may require 
             overdrive pacing, or isoprenaline infusion if precipitated 
             by bradycardia.
             
             Tardive Dyskinesia
             
             Once this syndrome has developed, treatment is difficult. 
             About 50% of patients may eventually recover if the 
             neuroleptics are withdrawn.  Anticholinergic drugs used in 
             acute dystonic reactions do not improve this condition and 
             in fact may worsen it.  The use of diltiazem in doses up to 
             360 mg daily has been associated with immediate clinical 
             improvement lasting for weeks in an initial study (Ross et 
             al., 1987).
             
             Thermal Dysregulation
             
             Hypothermia invariably is mild unless the patient has been 


    
             exposed to low ambient temperature; it is usually 
             responsive to measures used to correct other vital signs 
             and to passive rewarming.  True hyperthermia represents a 
             greater risk and the development of the neuroleptic 
             malignant syndrome requires prompt treatment.  Careful 
             attention should be directed toward maintaining fluid and 
             electrolyte balance and controlling seizures.  Cooling 
             blankets or ice packs are helpful but antipyretics probably 
             are not.  Haloperidol and other anticholinergic drugs 
             should be stopped.  The development of myoglobinuria 
             indicates the need for alkaline diuresis to prevent acute 
             tubular necrosis.
             
             For malignant hyperthermia, dantrolene may be administered 
             at an initial intravenous dose of 2.5 mg/kg up to a maximum 
             of 10 mg/kg/day. (See the IPCS antidote monograph on 
             dantrolene for more details). Monitor arterial blood gases 
             (PO2, pH) serum electrolytes, glucose and creatine kinase 
             carefully.  Bromocriptine may be required.  Patients should
             receive appropriate hydration.
             
             Seizures
             
             Diazepam and phenytoin are the anticonvulsant drugs of 
             choice.  Persistence of seizures for an hour is an 
             indication for intubation, curarization, and thiopental 
             general anaesthesia.  Urine myoglobin and serum muscle 
             enzyme levels should be checked in all patients with 
             prolonged muscle rigidity or seizures.
             
             Acute Dystonic reactions
             
             Intravenous diphenhydramine (2 mg/kg up to 50 mg over 
             several minutes) and intramuscular benztropine mesylate (2 
             mg in adults) are the drugs of choice and should relieve 
             symptoms in 5 and 15 to 20 minutes respectively.  Mild 
             sedation is the main side effect.  Follow up treatment with 
             an anticholinergic agent (e.g. diphenhydramine 50 mg oral 
             three times daily or trihexylphenidyl 2 mg oral twice 
             daily) should be given over 2 to 3 days because of the long 
             half-life of major tranquillizers.  Doses of benztropine 
             mesylate exceeding 8 mg in one day should be avoided 
             because of the possibility of severe anticholinergic 
             symptoms.  Haloperidol should be discontinued.
             
             Akathisias and Parkinsonianlike syndrome
             
             These may be relieved by reduction of the dose, or addition 
             or antiparkinsonian drugs (e.g. benztropine).  Often 
             akathisias appear resistant to anticholinergic drugs and 
             benzodiazepines.  Recent trial of low dose propranolol 
             suggest that beta adrenergic blockers may be efficacious 
             (Adler, 1986).

        10.4 Decontamination

             Haloperidol delays gastric emptying.  Obtunded patients 
             theoretically may benefit from gastric decontamination up 
             to several hours post-ingestion. However, lavage is 
             generally not recommended later than 2 hours following 
             ingestion. Instead, activated charcoal should be given and 
             may be repeated later.

        10.5 Elimination

             Because of the high protein binding and large volumes of 
             distribution, haemodialysis and forced diuresis are 
             ineffective.  Haemoperfusion has not been well studied, but 
             is unlikely to be efficacious.

        10.6 Antidote treatment

             10.6.1 Adults

                    There are no antidotes.

             10.6.2 Children

                    There are no antidotes.

        10.7 Management discussion 

             In the absence of any specific antidote the mainstay of 
             treatment is supportive care. Physostigmine has been used 
             to treat the effects of mixed phenothiazine and tricyclic 
             antidepressants (Weisdorf, 1978), but its use is 
             controversial and is not recommended, due to serious 
             adverse reactions.
             
             Gut decontamination (where appropriate), and monitoring 
             vital signs and ECG are recommended.  Symptomatic patients 
             (e.g. hypotension, conduction delay, dysrthythmia) should 
             be admitted until the ECG is normal for 24 hours. 
             Appropriate therapy (as per section 10.3) to counter the 
             adverse effects is also recommended.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Case 1
             
             A 29-month-old girl ingested an indeterminate amount out of 
             53 x 5 mg haloperidol tablets and was admitted with 
             impaired consciousness, hypotension, and general 
             hypotonia.Intravenous mannitol was given to increase 
             diuresis. 12 hours after admission she showed signs of 
             bradycardia, sinus arrhythmia and hypothermia, as well as 
             tremor and rigidity of the upper extremities, unsteady gait 

             and dystonic movements around the eyelids and mouth. 
             Diphenhydramine intravenously partly relieved the dystonic 
             movements. Symptoms resolved without sequelae 4 days after 
             admission. (Scialli et al, 1978).
             
             Case 2
             
             11-month-old boy (brother of girl in Case 1) also ingested 
             an indeterminate amount out of 53 x 5 mg haloperidol 
             tablets and showed symptoms of bradycardia, arrhythmia, 
             hypothermia and hypotension as well as impaired 
             consciousness and rigidity of the extremities with 
             hyperreflexia. Generalised tremors developed, with 
             flushing, hypersalivation and cogwheel rigidity in all 
             extremities. Intravenous diphenhydramine improved the 
             symptomology and the patient was symptom free after 7 
             days.(Scialli & Thornton, 1978).
             
             Case 3
             
             Report of severe arrhythmia and mild parkinsonism in a 
             patient treated for mania with high dose haloperidol (90 mg 
             the first day, 60 mg second day and 10 mg the third day). 
             The patient was treated with lidocaine (lignocaine),  
             followed by procainamide and on day 13 the ECG was normal 
             and mild parkinsonism was still evident. (Mehta et al., 
             1979)
             
             Case 4
             
             Brief clinical report of latent onset of hypertension in 
             22-month-old girl who had swallowed 15 to 20 mg of 
             haloperidol and had developed systolic pressures up to 180 
             mm Hg after 8 hours after admission. After 5 days of 
             antihypertensive therapy (hydrallazine) the patient had 
             recovered. (Cummingham & Challapalli, 1979)
             
             Case 4
             
             Sinaniotis et al. (1978) describe 3 cases of young children 
             (3.5-year-old girl, 6-year-old boy and 5-year-old girl who 
             had ingested unknown quantities of haloperidol (later 
             confirmed by spectrophotometric analysis of the blood). 
             Prominent toxicity features were dysarthric speech, 
             difficulty in swallowing and extrapyramidal symptoms. 
             Akathisia was present in one child. Biperiden was 
             administered to all three patients and in each case the 
             extrapyramidal symptoms subsided in a few hours.
             
             Case 5
             
             Adverse drug report by the Australian Adverse Drug Reaction 
             Advisory Committee (ADRAC) of malignant ventricular 
             tachycardia in a 46-year-old woman treated in hospital with 
             haloperidol 60 to 100 mg daily for 10 days. Antiarrhythmic 

             drug (lignocaine) was unsuccessful against the tachycardia 
             and cardioversion was required. (Bett & Holt, 1983).
             
             Case 6
             
             Report of a 54-year-old hospitalised male who developed the 
             syndrome of inappropriate secretion of antidiuretic hormone 
             (SIADH), after taking clinical doses of haloperidol which 
             led to significant hyponatraemia (Peck & Shenkman, 1979).
             
             Case 7
             
             Suspected idiosyncratic neuroleptic malignant syndrome in a 
             58-year-old woman who developed sinus tachycardia and 
             hyperthermia (above 40 0C) accompanied by muscle rigidity 
             and opisthotonos after a single intramuscular injection of 
             5 mg of haloperidol. Treatment with oral dantrolene (25 to 
             150 mg daily) had to be withdrawn after 6 days due to 
             hepatotoxicity, whilst supportive treatment was continued. 
             Complete recovery from suspected syndrome after 29 days 
             (Konikoff et al., 1984)
             
             Case 8
             
             Brief clinical report of a 60-year-old woman with no 
             history of cardiac disease seen in a hospital emergency 
             department 30 minutes after ingesting 1000 mg of 
             haloperidol. Eighteen hours after admission she had several 
             episodes of torsades de pointes which was successfully 
             controlled with ventricular overdrive pacing (Zee-Cheng et 
             al., 1985)
     
        11.2 Internally extracted data on cases

             No data available.

        11.3 Internal cases

             To be completed by each Centre using local data.

    12. ADDITIONAL INFORMATION

        12.1 Availability of antidotes

             No antidote is available.

        12.2 Specific preventive measures

             No data available.

        12.3 Other

             Not relevant.

    13. REFERENCES

        Adler L et al. (1986) A controlled study of propranolol in the 
        treatment of neuroleptic-induced akathisia.  Br J Psychiatry, 
        149:42-45.
        
        Budavari S ed. (1989) The Merck index, an encyclopedia of 
        chemicals, drugs, and biologicals, 11th ed. Rahway, New Jersey, 
        Merck and Co., Inc., p 725.
        
        Bett JHN & Holt GW (1983) Malignant ventricular tachycardia and 
        haloperidol. Br med J, 287:1264
        
        Cummingham DG & Challapalli M (1979) Hypertension in acute 
        haloperidol poisoning. J pediatr, 95:489-90
        
        Dollery C ed.(1991) Therapeutic drugs. Edinburgh, Churchill and 
        Livingstone.
        
        Ellenhorn MJ and Barceloux DG (1988) Medical toxicology, 
        diagnosis and treatment of human poisoning. New York, Elsevier 
        Science Publishing Co, pp 478-490, 75-76.
        
        Gilman AG, Rall TW, Nies AS & Taylor P eds.(1990) Goodman and 
        Gilman's the pharmacological basis of therapeutics, 8th ed. New 
        York, Pergamon Press, p 1683.
        
        Gosselin RE, Smith RP & Hodge HC (1984) Clinical toxicology of 
        commercial products, 5th ed. Baltimore, Williams & Wilkins, 
        p 109.
        
        Johnson PC et al. (1967) in Reynolds JEF ed. (1989) Martindale, 
        the extra pharmacopoeia, 29th ed. London, The Pharmaceutical 
        Press, pp 743-746.
        
        Konikoff F, Kuritzky A, Jerushalmi Y, & Theodor E (1984) 
        Neuroleptic malignant syndrome induced by a single injection of 
        haloperidol. Br Med J, 289:1228-1229
        
        Mehta D, Mehta S, Petit J, & Shriner W (1979) Cardiac arrhythmia 
        and haloperidol. Am J Psychiatry, 136:1468-69
        
        Peck, V & Shenkman L (1979) Haloperidol-induced syndrome of 
        inappropriate secretion of antidiuretic hormone. Clin pharmacol, 
        26:442-4
        
        Physicians' Desk Reference (1987) 41st ed. Ordell NJ, Medical 
        Economics, pp 1189-1192.
        
        Reynolds JEF ed. (1989) Martindale, the extra pharmacopoeia, 
        29th ed. London, The Pharmaceutical Press. pp 743-746.
        
        Reynolds JEF ed. (1993) Martindale, the extra pharmacopoeia, 
        30th ed. London, The Pharmaceutical Press. pp 599-600.
        
        Richelson E (1984)  Neuroleptic affinities for human brain 
        receptors and their use in predicting adverse effects. J Clin 
        Psychiatry  45:331-336. 
        
        Ross JL et al.(1987) Diltiazem for tardive dyskinesia.  Lancet 
        1:268.
        
        RTECS/NIOSH (1985) Registry of toxic effects of chemical 
        substances, 1983-84 cumulative supplement to the 1981-82 ed., 
        Cincinnati, Ohio, US National Institute for Occupational Safety 
        and Health (Publication No. DHHS (NIOSH)) 2:1352.
        
        Scialli JUK & Thornton WE (1978)  Toxic reactions from a 
        haloperidol overdose in two children.  Thermal and cardiac 
        manifestations. Jama, 239:48-49.
        
        Sinaniotis CA, Spyrides P, Vlachos P, & Papadatos C (1978) Acute 
        haloperidol poisoning in children. J pediatr 93:1038-9
        
        Weisdorf D et al. (1978) Physostigmine for cardiac and 
        neurological manifestations of phenothiazine poisoning.  Clin 
        Pharmacol Ther, 24:663-667.
        
        WHO (1992) Anatomical Therapeutic Chemical (ATC) classification 
        index. Oslo, WHO Collaborating Centre for Drug Statistics 
        Methodology, p 81.
        
        WHO (1992) International nonproprietary names (INN) for 
        pharmaceutical substances. Geneva, World Health Organisation, 
        p 256.
        
        Zee-Cheng CS, Mueller CE, Seifert CF, & Gibbs HR (1985) Ann 
        Intern Med, 102:418

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author       Dr Julia Higa de Landoni
                     Division Toxicologia
                     Hospital de Clinicas San Martin
                     Avda. Cordoba 2351
                     1120-Buenos Aires
                     Argentina
        
        Date         13 August 1992
        
        Peer Review  Drs Deng, Ferner, Landoni, Maramba, Shintani &
                     Wickstrom.
        
        Date and     10 September 1992,
        Place




See Also:
        HALOPERIDOL (UK PID)