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Promethazine

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
   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 (Hydrochloride)
         3.3.1.2 State/Form (Hydrochloride)
         3.3.1.3 Description (Hydrochloride)
      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(s)
      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 Sample
      8.1.1 Collection
      8.1.2 Storage
      8.1.3 Transport
   8.2 Toxicological Analytical Methods
      8.2.1 Tests for active ingredient
      8.2.2 Tests for biological sample
   8.3 Other laboratory analyses
      8.3.1 Biochemical investigations
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological or Haemostasiological investigations
      8.3.4 Other relevant biomedical analyses
   8.4 Interpretation
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

           Promethazine

           (INN, 1992)

           Promethazine hydrochloride

           (BAN, 1994; USAN, 1994)

           Promethazine theoclate

           (BAN, 1994)

       1.2 Group

           Antihistamines for systemic use (R06)/Phenothiazine
           derivatives (R06AD)
         
           (ATC classification index [WHO] 1992])

       1.3 Synonyms

           Diprazinum; Proazamine Chloride; Promethazini Hydrochloridum; 
           Promethazinium Chloride.

       1.4 Identification numbers

           1.4.1 CAS number

                 Promethazine   60-87-7

                 Promethazine   58-33-3
                 Hydrochloride

                 Promethazine   17693-51-5
                 theoclate

           1.4.2 Other numbers 

                 RTECS 

                 Promethazine   S06825000

                 Promethazine   S08225000
                 hydrochloride

       1.5 Brand names, Trade names

           Monocomponent products
           
           Avomine         Daralix          Fargan
           Meth-zine       Phenergan        Prohist

           Promet          Quadnite         Sayomol 
           Sominex         ZiPan 

           Combination products

           Phensedyl Linctus
           Phenergan with codeine
           Tixylix Linctus
           Phenergan VC
           Phenergan with dextromethorphan

           (To be completed by each Centre using local data)

       1.6 Manufacturers, Importers

           Atosil (Tropon, W.Ger)
           Fenazil (Sella, Ital.)
           Meth-zine (Protea, Austral.)
           Phenergan (May and Baker, Australia, U.K.; Rhone-Poulenc,
           Canada, Denmark, France, Switzerland, Wyeth, U.S.A.)

           (To be completed by each Centre using local data)

       1.7 Presentation, Formulation

           Preparations are usually formulated as promethazine 
           hydrochloride although promethazine theoclate tablets are 
           also available.  The topical cream is formulated as free 
           promethazine. 

           Tablets            12.5 mg to 50 mg
           Syrup              1.25 to 25 mg/5mL
           Injection          25 to 50 mg/mL
           Suppositories      12.5 to 50 mg

           Formulations containing combinations of promethazine 
           hydrochloride and other drugs used to treat the symptoms of 
           coughs and colds are also available, e.g. 

           Phenergan with codeine (Promethazine 6.25 mg and 10 mg 
           codeine per 5 mL syrup) 

           Phenergan VC (Promethazine 6.25 mg and 5 mg phenylephrine per 
           5 mL syrup) 

           Phenergan with dextromethorphan (Promethazine 6.25 mg and 
           15 mg per 5 mL syrup) 

           The above syrups also contain approximately 7% ethanol.

           Phensedyl (Promethazine 3.6 mg, codeine 9 mg, ephedrine 
           7.2 mg per 5 mL) 

           Tixylix (Promethazine 1.5 mg, pholcodine 1.5 mg per 5 mL) 

           (To be completed by each Centre using local data)

    2. SUMMARY

       2.1 Main risks and target organs

           Promethazine is a phenothiazine derivative with potent 
           antihistaminic properties. In therapeutic doses, CNS 
           depression manifested by sedation is a frequent occurrence.  

           In adults, overdosage is usually characterized by CNS 
           depression resulting in sedation and coma sometimes followed 
           by excitement.  

           In young children CNS stimulation is dominant, symptoms 
           include excitation, hallucinations, dystonias and 
           occasionally seizures.  

           Anticholinergic manifestations such as dry mouth, mydriasis 
           and blurred vision are usually present. 

           Overdosage may also present with various cardiorespiratory 
           symptoms such as respiratory depression, tachycardia, 
           hypertension or hypotension and extrasystoles. 

       2.2 Summary of clinical effects

           Toxic Reactions from Promethazine

            Central nervous system
           
           Depression and/or stimulation.  Sedation, coma, confusion,
           disorientation.  Hallucinations, hyperreflexia, toxic
           psychoses, seizures.  CNS excitation predominates in young
           children.

            Respiratory       
           
           Respiratory depression can occur.

            Cardiovascular    
           
           Tachycardia, bradycardia, hypertension, hypotension,
           extrasystoles.

            Dermatological    
           
           Allergic contract dermatitis and photoallergy.

            Head, Eye, Ear, Nose and Throat
           
           Fixed or dilated pupils, blurred vision, diplopia.  Dry 
           mouth, nasal stuffiness. 

            Others            
           
           Urinary retention, constipation.  Hyperpyrexia has been
           reported.

       2.3 Diagnosis

           Antihistamine poisoning must always be considered in patients 
           presenting with a central anticholinergic syndrome. 

           Concentrations of promethazine in blood and urine can be 
           determined by reverse phase HPLC (Taylor & Houston 1982). 

       2.4 First aid measures and management principles

           Symptomatic supportive therapy is indicated including 
           artificial respiration if necessary. Although the 
           anticholinergic actions of promethazine reduce gastric 
           motility, gastric emptying should be considered  should be 
           considered within 1 to 2 hours after ingestion.  

           Although emesis is recommended in many literature reports, 
           and is a useful first aid measure providing the patient is 
           conscious, gastric lavage is preferable as the effectiveness 
           of Ipecac Syrup may be reduced by the anticholinergic actions 
           of promethazine. If the patient is comatose or convulsing,  
           an endotracheal tube with cuff inflated must be in place to 
           prevent aspiration of vomitus. 

           Activated charcoal may also be administered. The use of a 
           cathartic is no longer recommended. 

           Hypotension should be controlled with fluids, posture and 
           pressor drugs such as dopamine or norepinephrine 
           (noradrenaline) if necessary. 

           Seizures may respond to intravenous diazepam.  Phenytoin has 
           also been used. 

           In the presence of severe anticholinergic effects, seizures, 
           hallucinations, delirium, coma, hypertension and arrhythmias 
           have responded to intravenous physostigmine (Cowen, 1979; 
           Cleghorn & Bourke, 1980).  However, the use of physostigmine 
           is considered controversial due to possibly toxic cholinergic 
           effects (see 10.6). 

    3. PHYSICO-CHEMICAL PROPERTIES 

       3.1 Origin of the substance 

           Synthesised from 10-phenothiazinepropyl chloride and 
           dimethylamine in the presence of Cu (U.S. patent 2,530,451; 
           1950 to Rhone-Poulenc).  From Grignard complexes of 
           dimethylaminopropyl halide and phenothiazine (U.S. patent 
           2,607,773;1952 to Rhone-Poulenc), (Merck Index, 1983). 

       3.2 Chemical structure 

           Structural formula 

           Molecular formula 

           Promethazine      C17H20N2S 

           Promethazine       C17H20N2S,HCl
           Hydrochloride 

           Promethazine      C17H20N2S,C7H7ClN4O2 
           theoclate

           Molecular weight

           Promethazine      284.4

           Promethazine      320.9
           Hydrochloride 

           Promethazine       499.0
           theoclate

           Chemical names

           1,N,N-Trimethyl-2-(phenothiazin-10-yl)ethylamine.

           10-[2-(Dimethylamino)propyl]-phenothiazine monohydrochloride. 

           N,N,alpha-Trimethyl-10H-phenothiazine-10-ethanamine.

           10-(2-dimethylamino-2-methylethyl)phenothiazine.

           N-(2'-dimethylamino-2'-methyl)ethylphenothiazine.
          
           (Martindale, 1993; Merck Index, 1993)

       3.3 Physical properties 

           3.3.1 Properties of the substance

                 3.3.1.1 Colour (Hydrochloride)

                         White or faintly yellow. On prolonged exposure 
                         to air it is slowly oxidised, becoming blue in 
                         colour. 

                 3.3.1.2 State/Form (Hydrochloride)

                         Crystalline powder

                 3.3.1.3 Description (Hydrochloride)

                         Odourless or almost odourless.  

                         A 10% solution in water has a pH of 4.0 to 5.0.

                         Solubility

                         1 in 0.6 of water
                         1 in 9 of alcohol
                         1 in 2 of chloroform.
                         Practically insoluble in ether and acetone.

                         Melting point is about 222 C.

                         Melting point (promethazine) is about 60 C.

                         (Martindale, 1993)

           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

                 Expiry dates of the commercially available preparation 
                 vary between 2 to 5 years. 

           3.4.2 Shelf-life of the locally available formulation(s)

                 Expiry dates of commercially available preparations 
                 vary between 2 to 5 years depending on dosage form and 
                 manufacturer (AHFS, 1988). 

                 (To be completed by each Centre using local data).

           3.4.3 Storage conditions

                 All preparations should be protected from light.  Oral 
                 and parenteral preparations of the drug should be 
                 stored at a temperature of 15 to 30 C, and the rectal 
                 suppositories at 2 to 8 C.  

                 Freezing of the oral solution and injection should be 
                 avoided. 

                 The tablets and solutions of promethazine should be 
                 stored in tightly closed, light resistant containers 
                 and the rectal suppositories stored in well closed 
                 containers. (AHFS, 1988) 

           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 

                 Promethazine is used for the treatment of allergic 
                 symptoms, often given at night because of its marked 
                 sedative effects. Drug hypersensitivity reactions have 
                 also been treated with promethazine (Weil, 1968).  
                 Promethazine is usually given orally for the treatment 
                 of allergic conditions but can be given by deep 
                 intramuscular injection or slow intravenous injection 
                 in emergencies. 

                 Promethazine is sometimes used for its sedative effects 
                 and in some countries is marketed for this purpose, 
                 including the sedation of young children. 

                 Promethazine is used as an anaesthetic premedication to 
                 produce sedation, reduce anxiety and also to reduce 
                 post operative nausea and vomiting.  The drug is often 
                 given in conjunction with an opiate analgesic such as 
                 pethidine, particularly in obstetrics. 

                 Taken before travelling, promethazine is effective in 
                 preventing motion sickness.  Vomiting from other causes 
                 can be treated with higher or more frequent doses. 

                 Other less common uses  

                 Promethazine has been used to control extrapyramidal 
                 disorders in children caused by metoclopramide 
                 (Stonham, et al., 1984) and levodopa induced 
                 dyskinesias in patients with Parkinson's disease (Tarsy 
                 et al., 1975). 

                 In young children undergoing dental procedures it has 
                 been suggested (Houpt et al., 1985) that promethazine 
                 be used in conjunction with chloral hydrate to produce 
                 sedation as there was a lower incidence of nausea than 
                 when chloral hydrate was administered alone.  

                 In some countries, promethazine is available as a 2% 
                 cream for the treatment of allergic skin conditions, 
                 however topical use is not recommended due to skin 
                 sensitization reactions (Martindale, 1989). 

           4.1.2 Description

                 Not relevant

       4.2 Therapeutic dosage

           4.2.1 Adults 

                 Oral

                  Hypersensitivity reactions (hydrochloride) 

                 25 mg to 75 mg as a single dose at night; or 

                 Up to 60 mg per day in divided doses. 

                  Hypnotic (hydrochloride) 

                 20 mg at night. 

                  Nausea and vomiting (hydrochloride, theoclate) 

                 Up to 25 mg every 4 to 6 hours. 

                 Rectal 

                 Doses similar to oral doses. 

                 Parenteral 

                  All indications except nausea and vomiting 
                  (hydrochloride) 

                 25 to 50 mg (Maximum of 100 mg per 24 hours) 
                 (Intravenously/Intramuscularly). 

                  Nausea and vomiting (hydrochloride) 
                
                 12.5 to 25 mg every 4 hours (Maximum of 100 mg per 24 
                 hours) (Intravenously/Intramuscularly). 

                 (Martindale , 1993) 
            
           4.2.2 Children

                 Oral

                  Hypersensitivity reactions (hydrochloride)

                 2 to 5 years  5 to 15 mg daily.
                 5 to 10 years 10 to 25 mg daily.
    
                  Hypnotic (hydrochloride)

                 2 to 5 years  15 to 20 mg at night.
                 5 to 10 years 20 to 25 mg at night.

                  Motion sickness(hydrochloride)

                 2 to 5 years  5 mg
                 5 to 10 years 10 mg

                  Motion sickness(theoclate)

                 5 to 10 years 12.5 mg

                 Parenteral

                  Intramuscular

                  All indications (hydrochloride)

                 5 to 10 years 6.25 to 12.5 mg 

                 (Martindale, 1993)

                  Intravenous

                 A suggested maximum recommended intravenous dose for 
                 patients under the age of seventeen is 0.5 mg/kg/dose 
                 (ASHP, 1984). 
                
       4.3 Contraindications

           Newborn and premature infants 

           Lactation 

           As a treatment for asthma 

           Patients receiving large doses of other CNS depressants or 
           patients who are comatose. 

           Hypersensitivity to promethazine and other phenothiazines. 

           Patients receiving therapy with monoamine oxidase inhibitors 
           (MAOI). 

           Patients with narrow angle glaucoma, stenosing peptic ulcer, 
           pyoloroduodenal obstruction, symptomatic prostatic 
           hypertrophy, bladder neck obstruction. 

           Because of a possible link between phenothiazine use and 
           Sudden Infant Death Syndrome of infant sleep apnoea, 
           authorities in the U.S. have stated that promethazine is 
           contraindicated in children under two years of age. 

           Precautions 

           Promethazine should be used with caution in patients with 
           impaired liver function, a history of bronchial asthma, 
           increased intraocular pressure, hyperthyroidism, 

           cardiovascular disease, hypertension and diabetes.  Epileptic 
           patients may experience an increase in the severity of 
           seizures when treated with promethazine and the drug may be 
           contraindicated in these patients. 

           The drug should be used in dehydrated children or children 
           with acute infections due to increased susceptibility to 
           dystonias (AFHS, 1988). 

           Concurrent administration of promethazine with alcohol or 
           other CNS depressants will cause increased drowsiness. 

           Promethazine should be used in pregnancy only when the 
           potential benefits justify the possible risks to the foetus. 

    5. ROUTES OF ENTRY 

       5.1 Oral

           Tablets
           Solution
           Syrup
           Elixir

       5.2 Inhalation

           No data available.

       5.3 Dermal

           Topical cream.

       5.4 Eye

           No data available.

       5.5 Parenteral

           Preparations available for intramuscular and intravenous 
           injection. 

       5.6 Other

           Rectal suppositories are available in some countries.

    6. KINETICS

       6.1 Absorption by route of exposure

           The drug is well absorbed from the gastrointestinal tract. 

           Peak plasma concentrations occur after 2 to 3 hours when 
           promethazine is administered orally (25 to 50 mg) or 
           intramuscularly (25 mg) (Digregorio & Ruch, 1980;  Moolenaar 
           et al., 1981;  Schwinghammer et al., 1984(i)).  

           Following rectal administration of promethazine in a 
           suppository formulation, peak plasma concentrations were 
           observed after about 8 hours (Schwinghammer et al., 1984(i)). 

           Oral bioavailability is approximately 25% (Taylor et al., 
           1983).  Rectal bioavailability has been reported at 23% 
           (Schwinghammer et al., 1984(i)). 

       6.2 Distribution by route of exposure 

           Promethazine is widely distributed in body tissues and has a 
           large apparent volume of distribution following oral and 
           intramuscular administration (DiGregorio & Ruch, 1980).  In a 
           study involving seven adults the steady state volume of 
           distribution following intravenous administration was 
           reported to be 970 L (Taylor et al., 1983). 

           Promethazine has been reported to be 93% protein bound when 
           determined by gas chromatography (Quin & Calvert, 1976) and 
           as 76 to 80% protein bound when determined by HPLC 
           (Digregorio & Ruch, 1980).  

           Promethazine rapidly crosses the placenta, appearing in the 
           cord blood within 1.5 minutes when given intravenously at 
           term (Moya et al., 1963). 

           Promethazine crosses the blood brain barrier (Quach et al., 
           1979). 

       6.3 Biological half-life by route of exposure 

           The elimination half life of promethazine following oral 
           administration has been estimated to be within the range of 
           12 to 15 hours (Taylor et al., 1979).  

           After intravenous administration of 12.5 mg, blood 
           concentrations of promethazine declined biexponentially with 
           a terminal elimination half life of 12 hours (Taylor et al., 
           1983). 

       6.4 Metabolism 

           Promethazine is metabolized principally to promethazine 
           sulphoxide and to a lesser degree desmethylpromethazine.  In 
           a study of 7 subjects, peak plasma concentrations of the 
           sulphoxide metabolite occurred earlier after oral 
           administration than after intravenous administration.  It was 
           concluded that the major site of metabolism is the liver and 
           that the drug is subjected to extensive first-pass hepatic 
           biotransformation, explaining the oral bioavailability of 
           25%. Metabolism also occurs in the gut wall but to a lesser 
           degree than earlier postulated.  The sulphoxide metabolite 
           has not been detected after intramuscular dosing as 
           circulating levels are probably below analytical detection 
           limits, due to a combination of slow absorption, lower dose 

           (50% of oral) and bypass of first pass metabolism in the 
           liver (Taylor et al., 1983). 

       6.5 Elimination by route of exposure 

           Elimination of promethazine is primarily due to hepatic 
           metabolism (see 6.4).  In eight subjects given oral doses of 
           25 mg, only 0.6% of an administered dose was excreted 
           unchanged in the urine within 24 hours, while 10.3% was 
           excreted as promethazine sulphoxide (the major metabolite). 
           The renal clearance of the sulphoxide approached the GFR 
           being 90 mL/min while that of promethazine was only 
           5.9 mL/min, suggesting significant tubular reabsorption of 
           promethazine (Taylor et al., 1983).  Most oxidised 
           metabolites of other phenothiazines are biologically inactive 
           (Goodman & Gilman, 1980).  No evidence was found to suggest 
           that metabolites of promethazine are pharmacologically or 
           toxicologically active. Promethazine has not been reliably 
           detected in breast milk (Briggs et al., 1986). 

    7. PHARMACOLOGY AND TOXICOLOGY 

       7.1 Mode of action 

           7.1.1 Toxicodynamics 

                 The pharmacology of promethazine is complex and for 
                 this reason toxicological mechanisms are not completely 
                 understood.  Most reference texts suggest that the 
                 toxicity of promethazine is mainly due to its 
                 anticholinergic actions at muscarinic receptors.  Many 
                 of the signs and symptoms of poisoning are similar to 
                 those observed with atropine.  In the presence of 
                 anticholinergic effects, serious manifestations such as 
                 seizures, hallucinations, hypertension and arrhythmias 
                 have been reversed (in some cases) by the 
                 administration of physostigmine. 

                 As well as anticholinergic effects, promethazine can 
                 also exhibit toxic effects typical of antipsychotic 
                 phenothiazines.  Hypotension and extrapyramidal signs 
                 may be attributable to antidopaminergic actions of 
                 promethazine. 

           7.1.2 Pharmacodynamics 

                 Promethazine is a phenothiazine antihistamine, 
                 antagonizing the central and peripheral effects of 
                 histamine medicated by histamine H1 receptors.  The 
                 drug does not antagonize histamine at H2 receptors. 
                 Antihistamines competitively antagonize most of the 
                 smooth muscle stimulating actions of histamine on the 
                 H1 receptors of the gastrointestinal tract, uterus, 
                 large blood vessels and bronchial muscle.  Increased 
                 capillary permeability and oedema formation, flare and 

                 pruritus, resulting from actions of histamine on H1 
                 receptors, are also effectively antagonized.  
                 Promethazine appears to act by blocking H1 receptor 
                 sites, preventing the action of histamine on the cell.  
                 Promethazine rapidly crosses the blood brain barrier 
                 and it is thought that the sedative effects of 
                 antihistamines are due to blockade of H1 receptors in 
                 the brain (Quach et al., 1979).  

                 Promethazine is not used clinically for its 
                 antipsychotic properties but in common with other 
                 phenothiazines exhibits antidopaminergic properties.  
                 The antiemetic effect of promethazine may be due to 
                 blockade of dopaminergic receptors in the Chemoreceptor 
                 Trigger Zone (CTZ) of the medulla.  

                 Promethazine has strong anticholinergic properties, 
                 blocking the responses to acetylcholine that are 
                 mediated by muscarinic receptors.  These atropine-like 
                 actions are responsible for most of the side effects 
                 observed in clinical use of the drug.  Promethazine 
                 also has anti-motion sickness properties which may be 
                 due to central antimuscarinic action.  

                 In concentrations several times higher than those 
                 required to antagonize histamine, promethazine exhibits 
                 local anaesthetic effects.  Promethazine has also been 
                 shown to inhibit calmodulin (Levin & Weiss, 1976).  
                 Authors have suggested (Peachell & Pearce, 1985) that 
                 calmodulin inhibition by promethazine could be a 
                 mechanism involved in the blockade of histamine 
                 secretion at cellular level. 

       7.2 Toxicity 

           7.2.1 Human data 

                 7.2.1.1 Adults 
                      
                         Minimum lethal exposure and maximum tolerated 
                         exposure have not been clearly defined in human 
                         subjects, due mainly to the lack of data on the 
                         exact amount ingested in cases of overdosage. 

                         Peak plasma levels following therapeutic oral  
                         doses of 30 to 50 mg in adults have ranged from 
                         11 to 23 ng/mL (Wallace et al., 1981). 

                         Adverse effects following intramuscular 
                         injection were associated with plasma levels of 
                         48 ng/mL (Schwinghammer et al., 1984(i)). 
            
                 7.2.1.2 Children 

                         Promethazine is readily available in syrup form 
                         which is often administered to sedate young 
                         children.  It is likely that in many cases the 
                         dose is excessive, leading to symptoms of 
                         toxicity. 

                         CNS toxicity with survival has been reported in 
                         children aged 5 to 12 years after accidental 
                         ingestion of 200 to 500 mg of promethazine 
                         (12.5 to 28 mg/kg).  (Leak & Carroll, 1967; 
                         Cleghorn & Bourke, 1980.) 

                         Death was reported in a two-year-old child with 
                         a history of ingesting 200 mg of promethazine 
                         as tablets (Dominikovich, 1962). 
                       
                         Death was reported in an infant with a post 
                         mortem blood level of 156 ng/mL (Degouffe & 
                         Rice, 1982). 

                         TDLo (child, oral)     20 mg/kg 
                                                Behavioral (excitement, 
                                                change in motor 
                                                activity, stiffness) 

                         TDLo (Human)           3500 ug/kg/D.
                                                Behavioral (sleep, 
                                                convulsions, rigidity)
            
           7.2.2 Relevant animal data

                 LD50 (mouse, intravenous)55 mg/kg

           7.2.3 Relevant in vitro data

                 No data available.

       7.3 Carcinogenicity
            
           Long-term animal studies to determine the carcinogenic 
           potential of promethazine have not been performed at the time 
           of preparation of this Monograph.  There are no human or 
           animal data concerning the carcinogenic potential of the 
           drug. As phenothiazines induce prolactin secretion by 
           inhibiting dopamine, investigations have been carried out to 
           ascertain whether there is a correlation between chronic 
           phenothiazine administration and the development of pituitary 
           tumours.  In two studies, (Asplund et al., 1982; Lilford et 
           al., 1984) the results were inconclusive and further in-depth 
           studies are necessary to evaluate the potential for 
           phenothiazines to induce pituitary adenomas. 

       7.4 Teratogenicity 

           A number of investigations have been performed to assess the 
           teratogenic potential of promethazine (Heinonen et al., 1977; 
           Wheatley, 1964; Greenberg et al., 1977).  These studies 
           failed to show and association between promethazine exposure 
           in the first trimester of pregnancy and malformations.  
           Current opinions is that these studies were not adequate or 
           sufficiently controlled to establish whether promethazine is 
           safe to use in pregnancy with respect to possible adverse 
           effects on the fetus (AHFS 1988).  Use late in pregnancy may 
           result in EEG changes in the neonate (Borgstedt & Rosen, 
           1968).  Promethazine has not been shown to be teratogenic in 
           rats receiving oral doses of 6.25-12.5 mg/kg daily (2-4 times 
           the maximum recommended human dosage) (AHFS, 1988). 
           Promethazine should be used in pregnancy only when the 
           potential benefits justify the possible risks to the fetus. 

       7.5 Mutagenicity 

           There was no evidence of promethazine induced mutagenesis in 
           the Ames microbial mutagen test (AHFS, 1988).  No relevant 
           human or animal data available to date. 

       7.6 Interactions 

           Concomitant administration of promethazine and other CNS 
           depressants (ethanol, narcotics, other phenothiazines and 
           antihistamines, barbiturates and benzodiazepines) may lead to 
           excessive CNS depression and possible respiratory depression. 
           The combination of promethazine and tricyclic antidepressant 
           drugs (e.g. amitriptyline, doxepin) or other drugs with 
           anticholinergic actions, may result in additive 
           anticholinergic effects (Hansten & Horn, 1989).  Many 
           preparations containing promethazine also contain other 
           drugs, such as codeine, dextromethorphan, phenylephrine and 
           ephedrine.  The toxic effects of these drugs must be 
           considered if compound preparations have been ingested. 

       7.7 Main adverse effects 

           Sedation, ranging from mild drowsiness to deep sleep, is 
           probably the most common adverse effect. 

           Anticholinergic effects such as dryness of the mouth, nose 
           and throat, blurred vision, mydriasis, poor accommodation, 
           sweating and thickening of bronchial secretions are frequent. 

           Dizziness, lassitude, disturbed co-ordination and muscular 
           weakness have all be reported. 

           Gastrointestinal effects including epigastric distress, 
           nausea, diarrhoea or constipation can occur. 

           Promethazine can also cause immunoallergic  reactions. 

           Leucopenia and agranulocytosis (Engel, 1979) have occurred 
           rarely, and usually in patients receiving promethazine in 
           combination with other drugs known to cause these effects. 

           Jaundice and thrombocytopenic purpura have been reported 
           rarely.  

           Extrapyramidal effects can occur, especially at high doses. 

           Cardiovascular side effects are occasionally seen after 
           injection;  tachycardia, bradycardia, mild transient 
           hypertension and hypotension have all been noted (Martindale, 
           1989).  

           Venous thrombosis has been reported at the site of 
           intravenous injections.  Arteriospasm and gangrene may follow 
           inadvertent intra-arterial injection (Mostafavi & Samimi, 
           1971).  

           Respiratory depression, sleep apnoea and sudden infant death 
           syndrome (SIDS) have occurred in a number of infants or young 
           children who were receiving usual doses of promethazine. 
           (Kahn & Blum, 1979 and 1982; Kahn et al., 1985).  These 
           reports suggest that promethazine and other CNS depressants 
           may cause sudden death, especially in apnoea prone infants, 
           and that these drugs should be avoided in infants even though 
           a causal relationship has been established. 

    8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS 
    
       The treatment of promethazine poisoning is symptomatic and 
       evaluation of drug level sin body fluids is not useful in guiding 
       therapy.  Promethazine is unstable in aqueous and organic 
       solvents (Meaking et al., 1978) and, due to its large volume of 
       distribution, is present in very low concentrations in body 
       fluids.  These factors have presented difficulties when 
       developing methods of the determination of promethazine in serum. 
       Gas chromatographic methods with flame ionization have been used 
       to detect toxic concentrations of the drug in serum (Wells et 
       al., 1975).  Although increased sensitivity is obtained with 
       nitrogen specific gas chromatographic methods (Dadisch et al., 
       1977).  HPLC methods have been developed in order to carry out 
       pharmacokinetics studies (Digregorio & Ruch, 1980; Taylor & 
       Houston, 1982). 

       8.1 Sample 

           8.1.1 Collection 

                 Blood should be placed in heparinised polycarbonate 
                 tubes. 

           8.1.2 Storage 

                 Blood and urine sample should be protected from light 
                 and frozen at -20C until assay. 

           8.1.3 Transport 

                 Samples should be frozen and protected from light. 

       8.2 Toxicological Analytical Methods 

           8.2.1 Tests for active ingredient 

                 Qualitative and quantitative tests are described in the 
                 USP(XXII).  Infra-red spectroscopy for identification 
                 and non-aqueous titration with perchloric acid for 
                 quantitative assay.  Test and assay procedures should 
                 be carried out rapidly and under subdued light. 

           8.2.2 Tests for biological sample 

                 Simple urine colour tests are available to 
                 qualitatively determine the presence of phenothiazines 
                 in urine. Although these tests are not specific for 
                 promethazine they may be useful in helping to confirm a 
                 diagnosis. Test solution (FPN universal);  5 parts 5% 
                 ferric chloride;  45 parts 20% perchloric acid;  50 
                 parts 50% nitric acid.  Mix 1 ml urine with l ml test 
                 solution; read immediately;  disregard all colours 
                 appearing after a delay of 10 seconds or more.  
                 Phenothiazines give colours ranging from peach, pink, 
                 rose to purple and dark gray. An approximate 
                 correlation is the darker the colour then the higher 
                 the daily dose of phenothiazine (Ellenhorn & Barceloux, 
                 1989).  Promethazine and its metabolites can be 
                 quantitatively determined in blood and urine by reverse 
                 phase HPLC (Taylor & Houston, 1982). 

                 Measuring blood levels of promethazine is not 
                 considered to be of practical assistance in the 
                 clinical management of promethazine poisoning. 

       8.3 Other laboratory analyses 

           8.3.1 Biochemical investigations 

                 Regular laboratory investigations should be performed 
                 to assure that liver function tests and electrolytes 
                 remain within normal limits. 

           8.3.2 Arterial blood gas analyses 

                 Not normally indicated. 

           8.3.3 Haematological or Haemostasiological investigations 

                 Not specifically indicated. 

           8.3.4 Other relevant biomedical analyses 

                 ECG may be useful if arrhythmias are suspected. 

       8.4 Interpretation 
         
    9. CLINICAL EFFECTS 

       9.1 Acute poisoning 

           9.1.1 Ingestion 

                 Overdosage may result in CNS depression followed by 
                 stimulation (excitation, agitation, hyperreflexia).  In 
                 young children or teenagers, CNS stimulation is usually 
                 dominant.  Symptoms resemble anticholinergic overdose 
                 and may include fixed and dilated pupils, flushed face, 
                 fever, dry mouth, excitation, hyperreflexia, dystonias, 
                 hallucinations and tonic-clonic seizures.  Periods of 
                 excitation may alternate with somnolence and catatonia. 
                 Hypertension or hypotension may be noted in agitated or 
                 comatose patients respectively. Tachycardia and 
                 extrasystoles have been reported (Shawn & McGuigan, 
                 1984). 

                 While coma appears to occur more frequently in adults, 
                 it may do so because of co-ingestion of ethanol 
                 (Jacobsen D, Personal communication). 

           9.1.2 Inhalation 

                 No data available. 

           9.1.3 Skin exposure 

                 Topical application of promethazine has resulted in 
                 systemic toxic effects, especially in young children 
                 (Shawn & McGuigan, 1984; Pan et al., 1989).  Symptoms 
                 reported include visual hallucinations, peripheral 
                 anticholinergic signs, drowsiness, agitation, 
                 irritability, tachycardia and myoclonus.  

                 Topical application of promethazine may cause contact 
                 dermatitis. 

           9.1.4 Eye contact 

                 No data available. 

           9.1.5 Parenteral exposure 

                 Rapid intravenous administration of promethazine may 
                 cause hypotension (AHFS, 1988).  Tachycardia, 
                 bradycardia and faintness have all been reported with 
                 parenteral promethazine. 

                 Chemical irritation and necrotic lesions have resulted 
                 on rare occasions following subcutaneous injection of 
                 promethazine and the drug should not be administered by 
                 this route.  Extravasation should also be avoided. 
                 Accidental intra-arterial injection can cause chemical 
                 irritation and arteriospasm leading to impaired 
                 circulation and gangrene.  There are case reports of 
                 amputation as a result of intra-arterial injection of 
                 promethazine (Heber & Helmig, 1976). 

           9.1.6 Other 

                 No data available. 

       9.2 Chronic poisoning 

           9.2.1 Ingestion 

                 Promethazine has rarely been associated with 
                 obstructive jaundice which is usually reversible if the 
                 drug is discontinued (AHFS, 1988). 

                 Leucopenia and agranulocytosis have been reported 
                 rarely, usually in conjunction with other agents known  
                 to have caused these effects. 

                 Thrombocytopenic purpura has also been reported (AHFS, 
                 1988).  As with other phenothiazines, promethazine can 
                 cause photosensitivity reactions.  Long-term use of the 
                 antipsychotic phenothiazines has been associated with 
                 many adverse reactions including, blood dyscrasias, 
                 hepatotoxicity, ocular changes, dermatological 
                 disorders and allergic reactions.  The possibility that 
                 these could occur with prolonged administration of 
                 promethazine should not be ruled out. 

           9.2.2 Inhalation 

                 No data available. 

           9.2.3 Skin exposure 

                 Topical administration of promethazine can cause 
                 allergic reactions (contact dermatitis, pruritic), 
                 inflammation and also photosensitivity. 

           9.2.4 Eye contact 

                 No data available. 

           9.2.5 Parenteral exposure 

                 Venous thrombosis has been reported at the site of 
                 intravenous injections (Martindale, 1989). 

           9.2.6 Other 

                 No data available. 

       9.3 Course, prognosis, cause of death 

           Mild cases of overdosage may manifest simply as excessive 
           drowsiness or mild CNS excitation in children or teenagers. 
           With increasing dose coma may develop, or more frank symptoms 
           of CNS excitation, for example, hallucinations, delirium, 
           hyperreflexia.  There is little indication in the literature 
           that the severity of the poisoning can be related to the 
           appearance of signs and symptoms such as extrapyramidal 
           effects, hypertension or hypotension.  

           Treatment is symptomatic and the appearance of specific 
           effects cannot be relied upon when assessing the severity of 
           poisoning.  It is generally agreed that as the severity of 
           the poisoning increases serious anticholinergic effects 
           usually appear along with seizures, hypertension and 
           arrhythmias, delirium or coma.  Death due to respiratory 
           arrest has been reported in association with promethazine 
           poisoning (Dominikovich, 1962). 

       9.4 Systematic description of clinical effects 

           Since formulations containing promethazine in combination 
           with other drugs are available, it may alter the clinical 
           picture from the following description. 

           9.4.1 Cardiovascular 

                 Acute Tachycardia and extrasystoles have been reported 
                 (Pan et al., 1989).  Hypotension, or even cardiac shock 
                 may develop after antihistamine overdose.  Hypertension 
                 has also occurred. 

           9.4.2 Respiratory 

                  Acute 

                 Stridor, wheezing and bronchospasm have been reported 
                 after a single 25 mg dose (ADRAC, 1982). 

                 Respiratory arrest has been reported following overdose 
                 (Darwish et al., 1980; Dominikovich, 1962). 

                  Acute or chronic  

                 The observation that promethazine (and other 
                 phenothiazines) may increase the number of central and 
                 obstructive sleep apnoeas has lead to speculation that 
                 some cases of sudden infant death syndrome (SIDS) may 
                 be related to promethazine therapy (Kahn & Blum, 1982).  
                 The available data are suggestive, but inconclusive 

                 that a causal relationship exists between therapeutic 
                 promethazine administration and SIDS. 

           9.4.3 Neurological

                 9.4.3.1 Central nervous system (CNS)

                         Acute CNS depression commonly occurs early in 
                         cases of overdosage.  Drowsiness, confusion and 
                         coma have all been reported (Leak & Carroll, 
                         1967).  Periods of CNS excitation may alternate 
                         with somnolence and catatonia (Mantz et al., 
                         1964).  Coma can occur in promethazine 
                         overdose.  A 14 year old boy became comatose 
                         after ingesting 200 mg of promethazine (Pan et 
                         al., 1989).  CNS excitation often predominates 
                         in children at the onset of poisoning and may 
                         occur in adults, usually as the patient emerges 
                         from coma.  Patients may become agitated, 
                         hyperreflexic, restless, delirious and nervous 
                         (Leak & Carroll, 1967).  Acute psychoses and 
                         neurological reactions have been reported 
                         following therapeutic use of promethazine 
                         (Swaiman, 1960).  A dose of 12.5 mg was 
                         administered intramuscularly to a five-year-old 
                         child, eighteen hours later the patient became 
                         lethargic and experienced visual hallucinations 
                         and muscular incoordination.  Eventually the 
                         child became comatose, a condition which 
                         persisted for 28 hours.  Another report (Jones 
                         et al., 1973) cites the case of child given a 
                         pre-operative dose of 20 mg of promethazine.  
                         Within hours, the child experienced confusion, 
                         hallucinations, agitation and complained of 
                         worms crawling on the bedsheets.  Visual and 
                         tactile hallucinations have been associated 
                         with promethazine toxicity (Shawn & McGuigan, 
                         1984;  Leak & Carroll, 1967).  Similar symptoms 
                         have been described after therapeutic use in 
                         children (Kalikow & Kisco, 1988) and in adults 
                         with renal failure (McAllister et al., 1978).  
                         Acute extrapyramidal reactions following single 
                         doses of promethazine have been reported.  
                         Parkinsonism like symptoms were induced in an 
                         adult male following an oral dose of 50 mg 
                         (Schwinghammer et al., 1984(ii)). 
                         Extrapyramidal reactions are more likely to 
                         occur with high doses (AHFS, 1988).  Seizures 
                         can be a complication of promethazine 
                         overdosage. 

                         Cases of seizures have been reported in 
                         children who received higher than recommended 
                         doses of promethazine as an anaesthetic 
                         premedication (Waterhouse, 1967). 

                         Acute dystonic reactions including 
                         opisthotonos, oculogyric crisis and facial 
                         dyskinesias have occurred following 
                         promethazine overdose.  In one report, onset of 
                         dystonias was delayed for 24 hours after a 
                         large promethazine overdose (Darwish et al., 
                         1980).  Other neurological effects associated 
                         with promethazine poisoning:-

                         Extensor plantar reflexes (Leak & Carroll, 
                         1967). Encephalopathy (25 mg rectal dose to a 
                         five year old child) (Fisher, 1972). 

                         Choreoathetosis.  In one case movements did not 
                         occur until 24 hours following overdosage 
                         (Cleghorn & Bourke, 1980). 

                 9.4.3.2 Peripheral nervous system 

                         No data available. 

                 9.4.3.3 Autonomic nervous system 

                         No data available. 

                 9.4.3.4 Skeletal and smooth muscle 

                         No data available. 
                              
           9.4.4 Gastrointestinal 

                 The anticholinergic properties of the drug may cause 
                 dry mouth and slow the rate of gastric emptying. 

           9.4.5 Hepatic 

                 Chronic promethazine has rarely been associated with 
                 obstructive jaundice which is usually reversible 
                 following discontinuance of the drug (AHFS, 1988). 

           9.4.6 Urinary 

                 9.4.6.1 Renal 

                         Acute urinary retention due to anticholinergic 
                         actions have been reported with promethazine 
                         toxicity (Shawn & McGuigan, 1984). 

                 9.4.6.2 Other 

                         Promethazine overdose has reported to produce a 
                         characteristic rose coloration of urine, 
                         however this was due to haematuria in one case  
                         (Cliche, 1961). 

           9.4.7 Endocrine and reproductive systems 

                 Promethazine was considered to be unsafe in patients 
                 with acute porphyria although there is conflicting 
                 experimental evidence on porphyrinogenicity 
                 (Martindale, 1989). 

           9.4.8 Dermatological 

                  Acute or chronic 

                 Urticaria has been reported following oral ingestion 
                 (ADRAC, 1982).  Photosensitivity (principally 
                 photoallergic dermatitis) can occur following topical 
                 or systemic administration of antihistamines, including 
                 promethazine.  The reaction may manifest as eczema, 
                 pruritic, papular rash or erythema.  Promethazine may 
                 also cause sensitization following topical use, giving 
                 rise to an allergic contact dermatitis (AHFS, 1988). 

           9.4.9 Eye, ear, nose throat: local effects

                  Acute 

                 Anticholinergic effects on the eye include, mydriasis, 
                 fixed pupils, blurred vision, diplopia and general 
                 visual disturbances (Cowen, 1979;  Shawn & McGuigan, 
                 1984). Oculogyric crisis has been reported following 
                 overdose (Darwish et al., 1980). 

                 Dryness of the nose and nasal stuffiness have been 
                 noted (Dominikovich, 1962; Leak & Carroll, 1967). 
                 Anticholinergic effects include dryness of the mouth 
                 and throat.  Facial erythema has been noted (Cliche, 
                 1961). 

           9.4.10 Haematological

                  Chronic leucopenia and agranulocytosis have been 
                  reported rarely in patients receiving promethazine in 
                  combination with other drugs known to cause these 
                  effects. Thrombocytopenic purpura has been reported 
                  with promethazine (AHFS, 1988).  A case of allergic 
                  agranulocytosis has been reported (Engel, 1976), 
                  however this patient was taking larger than normal 
                  doses, up to 400 mg per day, for approximately four 
                  weeks. Discontinuing the promethazine resulted in the 
                  eventual complete recovery of the patient. 

                  Serious blood dyscrasia have occurred with the 
                  antipsychotic phenothiazines and the possibility that 
                  these could occur with promethazine should not be 
                  discounted. 

           9.4.11 Immunological 

                  There is a report of an acute anaphylactoid reaction 
                  involving promethazine and temazepam (Mills, 1988) 
                  although it was not established whether promethazine 
                  was the causative agent. 

                  Chronic promethazine is a potent sensitiser 
                  particularly following topical application.  
                  Promethazine can exert immunosuppressive effects 
                  resulting in potentially adverse reactions, e.g. 
                  infections (Descotes, 1988). 

           9.4.12 Metabolic 

                  9.4.12.1 Acid-base disturbances 

                           No data available. 

                  9.4.12.2 Fluid and electrolyte disturbances 

                           Hypokalaemia has been reported (Mantz et al., 
                           1964). 

                  9.4.12.3 Others 

                           Hyperthermia following promethazine ingestion 
                           has been reported (Dollberg, 1980). 
                
           9.4.13 Allergic reactions 

                  Photoallergic dermatitis can occur following topical 
                  or systemic administration of promethazine.  Topically 
                  applied promethazine can cause allergic contact 
                  dermatitis. 

           9.4.14 Other clinical effects 

                  No data available. 

           9.4.15 Special risks 

                  Pregnancy 

                  Promethazine is commonly used in obstetrics as an 
                  adjunct to opiate analgesia and as a sedative.  The 
                  drug rapidly crosses the placenta, appearing in cord 
                  blood within one and a half minutes of an intravenous 
                  dose (Moya & Thorndike, 1963).  The use of 
                  promethazine during labour has been associated rarely 
                  with neonatal respiratory depression (Hall, 1987).  
                  Transient behavioral and EEG changes have also been 
                  described in neonates (Borgstedt & Rosen, 1986).  
                  Promethazine has been shown to markedly impair 
                  platelet aggregation in the newborn but less so in the 

                  mother (Corby & Shulman, 1971; Whaun et al., 1980).  

                  Immunological disturbances have been described in a 
                  few infants whose mothers had been treated with 
                  promethazine during pregnancy (Descotes, 1988).  The 
                  clinical significance of these effects are unknown. 

                  A number of studies have been performed to assess the 
                  teratogenic potential of promethazine (Heinonen et 
                  al., 1977; Wheatley, 1964).  The safe use of 
                  promethazine during pregnancy has not been 
                  established.  The drug should only be used when the 
                  potential benefits justify the possible risks to the 
                  foetus. 

       9.5 Other

           No data available.

       9.6 Summary

           Not relevant

    10. MANAGEMENT

        10.1 General principles

             Symptomatic supportive therapy is indicated and general 
             measures such as maintenance of adequate ventilation and 
             cardiovascular function must be instituted if necessary. 
             Gastric emptying may be successful, even if delayed for up 
             to 2 hours.  Emesis should probably not be induced due to 
             the risk of coma or psychosis developing in the patient. 
             Administration of activated charcoal would be preferred. 
             The use of a cathartic is no longer recommended.  In the 
             absence of seizures, gastric lavage (with endotracheal tube 
             with cuff inflated in place to prevent aspiration of 
             gastric contents) may be beneficial.  
            
             Seizures may be controlled with intravenous diazepam 
             (preferred) or phenytoin.  Unless severe, hypotension 
             should be treated with posture; severe cases can be treated 
             with fluids, or pressor agents. 

             In severe hypertension, parenteral sodium nitroprusside may 
             be required.  Dystonic reactions frequently respond to 
             intravenous diphenhydramine.  In the presence of severe 
             anticholinergic effects, physostigmine by slow intravenous 
             injection, has been administered. However, the use of 
             physostigmine is considered controversial. 

        10.2 Relevant laboratory analyses 

             Treatment is symptomatic and supportive and measurement of 
             promethazine levels in body fluids is not useful in guiding 

             treatment of overdosage.  No specific investigations are 
             indicated. 

             10.2.1 Sample collection 

                    Venous blood samples are placed in heparinised 
                    polycarbonate tubes and frozen at -20C until assay. 
                    Urine samples should be protected from light and 
                    also stored at -20C (Taylor et al., 1983) 

             10.2.2 Biomedical analysis 

                    Concentrations of promethazine in blood and urine 
                    can be determined by reverse phase HPLC (Taylor & 
                    Houston 1982). 

             10.2.3 Toxicological analysis 

                    Not relevant 

             10.2.4 Other investigations 

                    Not relevant 

        10.3 Life supportive procedures and symptomatic/specific 
             treatment 

             General measures such as maintenance of ventilation and 
             cardiovascular function must be instituted if necessary. 

             Arrhythmias 

             Sinus tachyarrhythmias do not need to be routinely treated 
             unless the patient demonstrates signs or symptoms of 
             haemodynamic instability.  Tachyarrhythmias may respond to 
             intravenous propranolol or another beta-blocker. 

             Seizures 

             Administer diazepam intravenously. If seizures are not 
             controlled or recur administer, intravenous phenytoin. 

             Dystonic reactions 

             Usually respond to intravenous diphenhydramine(to be used 
             only to treat severe reactions). 

        10.4 Decontamination

             Following oral ingestion and parenteral exposure 

             The anticholinergic properties of promethazine slow gastric 
             motility, therefore gastric emptying may be considered up 
             to two hours following the ingestion. 

             Activated charcoal may be administered. 

             Following dermal exposure  

             The exposed area should be washed thoroughly with soap and 
             water. 

        10.5 Elimination

             No reports in the literature were found to suggest that 
             forced diuresis, haemoperfusion or dialysis were of any 
             value. 

        10.6 Antidote treatment

             10.6.1 Adults

                    Physostigmine has been used intravenously to control 
                    coma, hallucinations and delirium inpatients with 
                    severe anticholinergic signs and symptoms (Cleghorn 
                    & Bourke, 1980; Cowen, 1979).  The use of 
                    physostigmine is considered controversial due to the 
                    possibility of hazardous cholinergic effects, 
                    including convulsions (Meredith et al., 1984). It 
                    should be considered if severe (central) 
                    anticholinergic features are present. Atropine 
                    should be readily available in case unwanted 
                    cholinergic side-effects develop. 

             10.6.2 Children

                    As above, in 10.6.1.

        10.7 Management discussion

             Most authorities no longer recommend the use of 
             physostigmine as an antidote although there appears to be 
             some controversy in the literature. 

             Promethazine toxicity may well be an unrealized problem of 
             significant proportions, especially in developing countries 
             where promethazine containing preparations can be bought 
             and freely administered to young children.  There is 
             probably scope for research into the significance of this 
             problem; methods of preventions and education of patients 
             and health care workers. 

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature 

             Case 1    (Oral ingestion, child) 

             A two-year-old ingested up to 200 mg of promethazine in 
             tablet form.  On admission he had a two-hour history or 

             rigidity and alternate tightening and loosening of the 
             hands. Restlessness, irritability, purposeless limb 
             movements and nasal congestion was also noted.  Gastric 
             lavage was performed two and a half hours after admission 
             with no return of tablets.  Three hours later the child 
             died of respiratory failure (Dominikovich, 1962). 

             Case 2    (Oral ingestion, child) 

             A twelve-year-old male developed delirium and 
             hallucinations four hours after the ingestion of 200 mg of 
             promethazine. Slurred speech, violent activity, 
             restlessness, agitation, tachycardia, dry mouth and nasal 
             stuffiness were also noted. Hallucination and extensor 
             plantar reflexes resolved 22 hours after onset (Leak & 
             Carroll, 1967). 

             Case 3    (Oral ingestion, adult) 
     
             A forty-year-old woman ingested an unknown amount of 
             promethazine.  The patient was comatose on admission, 
             responding slightly to pain, with mydriasis and extensor 
             plantar reflexes.  Six hours after admission she was 
             arousable but restless and aggressive.  Twenty four hours 
             after admission she was experiencing hallucinations, 
             delirium and confusion which were resolved following a dose 
             of 0.5 mg physostigmine intramuscularly.  By the following 
             day all symptoms had resolved (Cowen, 1979). 

             Case 4    (Topical application, child) 

             Application of 26 mg/kg of promethazine to 30% of total 
             body surface area to a sixteen-month-old boy resulted in 
             drowsiness within thirty minutes.  The patient awoke two 
             hours after application but was irritable and ataxic.  Six 
             hours later signs and symptoms included irritability, 
             drowsiness, agitation and tachycardia.  All manifestations 
             resolved eighteen hours after exposure.  A urine specimen 
             taken ten hours post-exposure did not contain promethazine 
             (Shawn & McGuigan, 1984). 

             Case 5    (Topical application, adolescent) 

             A fourteen-year-old boy presented unconscious five hours 
             after topical application of 90 g of 2% promethazine cream 
             to the entire body.  Signs and symptoms on admission 
             included disorientation, agitation, myoclonus and dry 
             mouth.  Blood and urine specimens on admission showed 
             140 ng/ml and 80 ng/ml or promethazine respectively.  All 
             manifestations resolved within twenty four hours (Pan et 
             al., 1989). 

             Case 6    (Oral ingestion, adult, fatality)

             A twenty-seven-year-old man died after taking a massive 
             overdose of promethazine tablets.  Promethazine levels in 
             the body were approximately on thousand times the 
             therapeutic level.  No other drugs or alcohol were detected 
             in the stomach contents or urine (Pharm J 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

             To be completed by each Centre using local data.

        12.2 Specific preventive measures

             Store in air-tight containers protected from light, in 
             child resistant packaging away from the sight and reach of 
             children. 

        12.3 Other

             No data available.
             
    13. REFERENCES
    
        American Hospital Formulary Service (AHFS)(1988) Drug 
        information. 

        McEvoy GK ed. American Society of Hospital Pharmacists, 
        Bethesda, MD. pp 2222. 

        Adverse Drug Reactions Advisory Committee (ADRAC) (1982)  Seven 
        case studies: Antihistamine. Med J Aust, 1: 522. 

        American Society of Hospital Pharmacists (ASHP)(1984)  
        Guidelines for the Administration of Medications to Pediatric 
        Patients, 2nd ed. Bethesda, MD. 

        Asplund K, Hagg E, & Lindqvist M, et al, (1982) Phenothiazine 
        drugs and pituitary tumours (letter). Ann Intern Med, 96:533. 

        Borgstedt AD & Rosen MG (1986) Medication during labour 
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    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE 
        ADDRESS(ES) 
        
        David J. WOODS  BSc.  MRPharmS. 
        Pharmacy Department 
        University of Otago Medical School 
        P.O. Box 913 
        Dunedin New Zealand 


        29th June 1990

  







    See Also:
       Toxicological Abbreviations