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Flupenthixol

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
         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 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 Others
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 and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
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 Eyes, ears, 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 Other
      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
 
             Flupenthixol
 
             Note: The International Nonproprietary Name (INN) for this 
             substance is flupentixol. However, the British Approved Name 
             (BAN) is flupenthixol and as it is generally marketed under 
             that name, the drug and its derivatives will be referred to 
             as such in this document. 
 
             (WHO, 1992; British Pharmacopoeia Commission, 1994) 
 
        1.2  Group
 
             ATC classification index 
 
             Psycholeptics(N05)/Antipsychotics(N05A)/ 
             Thioxanthene derivatives (N05AF)
 
             (WHO,1992) 
 
        1.3  Synonyms
 
             Flupenthixol
 
             Flupentixol
 
             Flupenthixol hydrochloride
 
             Flupenthixol dihydrochloride
             Flupentixol hydrochloride
 
             Flupenthixol decanoate
 
             (Z)-Flupenthixol decanoate
             cis-Flupenthixol decanoate
             Flupentixol decanoate
 
             (Budavari, 1989; Reynolds, 1993) 
 
        1.4  Identification numbers
 
             1.4.1  CAS number
 
                    Flupenthixol                2709-56-0
 
             1.4.2  Other numbers
 
                    Other CAS numbers 
 
                    Flupenthixol decanoate      30909-51-4
 
 
 
                    Flupenthixol hydrochloride  2413-38-9
 
                    RTECS 
 
                    TL9900000 (Flupenthixol) 
 
                    Other 
 
                    LC-44  (Flupenthixol) 
                    N-7009 (Flupenthixol) 
 
             1.5  Brand names, Trade names
 
             Depixol Injection
             Depixol-Conc Injection
             Depixol Tablets
             Fluanxol Tablets
 
             (To be completed by each Centre using local data)
 
        1.6  Manufacturers, Importers
 
             Lundbeck Ltd., 48 Park Street, Luton LU1 3HS
             Tel: (0582) 411482
 
        (To be completed by each Centre using local data)
 
        1.7  Presentation, Formulation 
 
             Depixol Injection
             
             Sterile, straw-coloured solution containing cis(Z)- 
             flupenthixol decanoate 20 mg/mL in thin vegetable oil. 
             Ampoules and syringes, 1 mL (20 mg) and 2 mL (40 mg).  Vials, 
             10 mL (200 mg)
             
             Depixol-Conc Injection
             
             Sterile, straw-coloured solution containing cis(Z)- 
             flupenthixol decanoate 100 mg/mL in thin vegetable oil. 
             Ampoules, 1 mL (100 mg).  Vials, 5 mL (500 mg)
             
             Depixol Tablets
             
             Round, biconvex, yellow sugar-coated tablets with Lundbeck 
             logo in black on one face; diameter 9 mm. Tablets contain 
             racemic flupenthixol hydrochloride 3 mg.  Bottles of 100 
             tablets
 
 
 
             
             Fluanxol Tablets
             
             0.5 mg tablet; 'Lundbeck' in black; Round, biconvex, red 
             sugar-coated tablets, diameter 6 mm. Tablets contain racemic 
             flupenthixol hydrochloride 0.5 mg.  Bottles of 100 tablets 1 
             mg tablet; 'Lundbeck' in white; diameter 8 mm. Tablets 
             contain racemic flupenthixol hydrochloride 1 mg. Packs of 60 
             tablets, as 6 x 10 tablet blister strips.
             
             (To be completed by each Centre using local data)
 
    2.  SUMMARY
 
        2.1  Main risks and target organs
 
             Acute poisoning
             
             Main risks
             
             Coma with respiratory depression, hypotension, convulsions 
             and extrapyramidal effects.
             
             Target organs
             
             Major target organs are the Central Nervous System (CNS) and 
             cardiovascular system.
             
             Chronic poisoning
             
             Main risks
             
             Extrapyramidal side-effects, tardive dyskinesia and 
             neuroleptic malignant syndrome (NMS).
             
             Sudden death has also occurred; cause unknown.
             
             Target organs
             
             Major target organ is the CNS; also kidneys as a result of 
             rhabdomyolysis in severe NMS.
 
        2.2  Summary of clinical effects
 
             Acute poisoning
 
             Initially, drowsiness, sinus tachycardia, hypotension, 
             miosis.
             
             Drowsiness may progress to coma (in agitated or aggressive 
             patients, hallucinations), possibly with respiratory 
             depression.
             
 
 
 
             Tonic-clonic convulsions, muscle spasms.
             
             Hypothermia or hyperthermia.
             
             Extrapyramidal effects may include acute dystonic reactions 
             such as protruding tongue, torticollis and opisthotonos; or 
             Parkinsonian symptoms.
             
             Chronic poisoning
             
             Extrapyramidal effects
             
             Hyperkinesis (i.e. acute dystonic reactions such as 
             protruding tongue, torticollis and opisthotonos); or 
             hypokinesis (e.g. Parkinsonism, akinesias).
             
             Tardive dyskinesia
             
             Symptoms include a range of involuntary, repetitive movements 
             involving the jaws, lips and tongue (orofacial dyskinesia), 
             and possibly more generalised movements including limb- 
             jerking and hyperextension of neck and trunk. Symptoms often 
             persist despite cessation of therapy.
             
             Neuroleptic malignant syndrome (NMS)
             
             Initially, withdrawal and hypoactivity progressing to 
             drowsiness and coma.
             
             This is followed by severe extrapyramidal dysfunction, 
             including akinesia, lead-pipe rigidity progressing to 
             opisthotonos, tremor, oculogyric crisis and increased muscle 
             tone possibly resulting in dysphagia and dyspnoea.
             
             In severe cases symptoms include fluctuating blood pressure, 
             tachycardia, dysuria or incontinence, peripheral 
             vasoconstriction, dyspnoea, sweating and hyperpyrexia. Renal 
             failure may occur secondary to rhabdomyolysis.
 
        2.3  Diagnosis
 
             Clinical diagnosis of poisoning by flupenthixol is 
             difficult, but must be considered in patients with impaired 
             consciousness and extrapyramidal features.
             
             Flupenthixol may be measured in plasma, but levels are of 
             little use in the management of acute overdose.
 
        2.4  First aid measures and management principles
 
             Life support 
 
             Normal supportive management of the unconscious patient, 
             including stable side position or intubation and ventilation 
 
 
 
             if necessary.
             
             Treat hypotension with intravenous fluids/plasma expanders. 
             Monitor arterial blood pressure and central venous pressure, 
             if unresponsive give alphamimetic agents such as dopamine(see 
             Section 10.7).
             
             If patient agitated, hallucinating or convulsing, give 
             diazepam 0.1 mg/kg intravenously.
             
             Gut decontamination
             
             Give activated charcoal (50 g in adults, or 1 to 2 g/kg in 
             children) for any amount taken in a child and for more than 
             10 mg in an adult.
             
             Do not give emetic because of potential for flupenthixol 
             induced coma which may result in the loss of ability to 
             protect airway, causing aspiration pneumonitis.
             
             Gastric lavage should only be considered in rare cases 
             following recent ingestion of life-threatening amounts in 
             adults.
             
             Symptomatic treatment
             
             Neuroleptic malignant syndrome (NMS)
             
             Institute cooling measures. In mild hyperthermia, diazepam 
             0.1 mg/kg intravenously may suffice. If severe (>40░C), give 
             dantrolene 1 to 10 mg/kg intravenously (see separate antidote 
             monograph).
             
             Maintain urine output to protect renal function. Consider 
             alkalinizing urine in cases of rhabdomyolysis.
             
             Extrapyramidal effects treatment
             
             For mild extrapyramidal dysfunction, give diazepam 0.05 to 
             0.1 mg/kg intravenously.
             
             If severe, give procyclidine or benztropine or orphenadrine 
             or diphenhydramine.
             
             Tardive dyskinesia treatment
             
             Withdraw flupenthixol if possible (but beware temporary 
             worsening of symptoms) and treat symptomatically. 
             Diltiazem(max. 360 mg/day) may be useful.
             
             Elimination
             
 
 
 
             Active methods of elimination are of no use in flupenthixol 
             poisoning. However, repeated dose activated charcoal should 
             be considered in serious overdose (see Section 10.4).
             
             In NMS, haemodialysis may be required for renal failure.
 
    3.  PHYSICO-CHEMICAL PROPERTIES
 
        3.1  Origin of the substance
 
             Flupenthixol is wholly synthetic. Thioxanthone is 
             converted to an activated butadiene by a Grignard reaction 
             followed by dehydration. Flupenthixol is formed by 1,4 
             addition to the activated butadiene followed by heating or 
             treatment with strong alkali(Petersen et al., 1977).
 
        3.2  Chemical structure
 
             Structural formulae
             
             Flupenthixol;flupenth.bmp
             
             Note: Flupenthixol exists as two geometric isomers, the 
             cis(Z) and trans(E) forms. Only cis(Z)-flupenthixol is 
             pharmacologically active.
             
             Molecular formulae
             
             Flupenthixol                   C23H25F3N2OS
             
             Flupenthixol decanoate         C33H43F3N2O2S
             
             Flupenthixol hydrochloride     C23H25F3N2OS.2HCl
             
             Molecular weights
             
             Flupenthixol    434.5
             
             Flupenthixol decanoate         588.8
             
             Flupenthixol hydrochloride     507.4
 
 
 
             
             Structural Names
             
             Flupenthixol
             
             2-{4-[3-(2-Trifluoromethylthioxanthen-9-ylidene)propyl]- 
             piperazin-1-yl}-ethanol
             
             2-Trifluoromethyl-9-{3-[4-(▀-hydroxyethyl)-1-piperazinyl]-propylidene} 
             thioxanthene
             
             4-{3-[2-(Trifluoromethyl)-9H-thioxanthen-9-ylidene]propyl}-1- 
             piperazineethanol
             
             Flupenthixol decanoate
             
             2-{4-[3-(2-Trifluoromethylthioxanthen-9-ylidene)propyl]- 
             piperazin-1-yl}-ethyl decanoate
             
             Flupenthixol hydrochloride
             
             2-{4-[3-(2-Trifluoromethylthioxanthen-9-ylidene)propyl]- 
             piperazin-1-yl}-ethanol dihydrochloride
             
             (Budavari, 1989; Reynolds, 1993)
 
        3.3  Physical properties
 
             3.3.1  Properties of the substance
 
                    3.3.1.1 Colour
 
                             Flupenthixol decanoate
                             
                             Yellow
                             
                             Flupenthixol hydrochloride 
                             
                             White or yellowish-white
 
                    3.3.1.2 State/Form
 
                             Flupenthixol decanoate
                             
                             Oil
                             
                             Flupenthixol hydrochloride 
                             
                             Powder
 
                    3.3.1.3 Description
 
                             Flupenthixol decanoate
                             
                             Slight odour
 
 
 
                             
                             Very slightly soluble in water; soluble in 
                             ethanol; freely soluble in chloroform and 
                             ether.
                             
                             Flupenthixol hydrochloride 
                             
                             Soluble in water and ethanol; very slightly 
                             soluble in chloroform; virtually insoluble in 
                             ether.
                             
                             (Budavari, 1989; Reynolds, 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
 
                    <3.4.1  Shelf-life>No data available.
 
             3.4.2  Shelf-life of locally available formulation(s)
 
                    Depixol Injection: Depixol-Conc Injection - Two years
                    
                    Depixol Tablets - Five years
                    
                    Fluanxol Tablets 0.5 mg - Five years; 1 mg - Three years
                    
                    (To be completed by each Centre using local data)
 
             3.4.3  Storage conditions
 
                    Depixol Injection; Depixol-Conc Injection - 
                    Store at room temperature and protect from light.
                    
                    Depixol Tablets; Fluanxol Tablets - Protect from light 
                    and moisture.
                    
                    (To be completed by each Centre using local data)
 
             3.4.4  Bioavailability
 
                    (To be completed by each Centre using local data)
 
 
 
                    3.4.5.  (Specific properties and composition)
 
                    <3.4.5.> Formulations of flupenthixol decanoate 
                    intended for intramuscular injection (Depixol 
                    Injection and Depixol-Conc Injection) are based on 
                    Viscoleo, a light vegetable oil.
                    
                    (To be completed by each Centre using local data)
 
    4.  USES
 
        4.1  Indications
 
             4.1.1  Indications
 
             4.1.2 Description
 
                    Flupenthixol decanoate
                    
                    For treatment and maintenance in schizophrenia and 
                    related psychoses (as a depot injection), especially 
                    in patients whose compliance with oral medication is 
                    suspect.
                    
                    Flupenthixol hydrochloride
                    
                    Used orally in schizophrenia and related psychoses, 
                    particularly with apathy and withdrawal (but not mania 
                    or psychomotor hyperactivity); short-term adjunctive 
                    treatment of severe anxiety; and depressive illness 
                    (with or without anxiety).
 
        4.2  Therapeutic dosage
 
             4.2.1  Adults
 
                    Depixol Injection (20 mg/ml); Depixol-Conc Injection (100mg/ml)
                    
                    Test dose 20 mg, then after 5 to 10 days 20 to 40 mg, 
                    repeated at intervals of 2 to 4 weeks, adjusted 
                    according to response. Maximum dose 400 mg weekly.
                    
                    Depixol-Conc Injection is indicated when the patient 
                    requires a high dose which could not otherwise be 
                    given due to the large volume of the injection.
                    
                    Note: Given by deep injection into the gluteal 
                    muscle.
                    
                    Depixol Tablets (3 mg)
                    
                    Initially 3 to 9 mg twice daily, adjusted according to 
                    response. Maximum dose 18 mg daily.
                    
                    Fluanxol Tablets (0.5 mg; 1 mg)
                    
 
 
 
                    Initially 1 mg (0.5 mg in elderly) in the morning, 
                    increased after 1 week to 2 mg (1 mg in elderly) if 
                    necessary.  Maximum dose 3 mg (2 mg in elderly) daily; 
                    divide doses above 2 mg (1 mg in elderly) into 2 
                    portions, the second portion given before 1600 hours. 
                    (Reynolds, 1993)
 
             4.2.2  Children
 
                    Not recommended.
 
        4.3  Contraindications
 
             Flupenthixol decanoate
             
             Depot flupenthixol decanoate is not recommended for excitable 
             or hyperactive patients as it may exacerbate these 
             features.
             
             It is also contraindicated in Parkinsonism, severe 
             arteriosclerosis, senile confusional states and severe renal, 
             hepatic or cardiovascular disease.
             
             Flupenthixol is best avoided in pregnancy, though there is no 
             evidence of teratogenicity or foetotoxicity.  There is no 
             reason why treatment should not continue (at least after the 
             first trimester) in a previously unrecognised pregnancy 
             (Lundbeck Ltd., 1989).
             
             Flupenthixol hydrochloride
             
             Oral flupenthixol hydrochloride should be used with caution 
             in Parkinsonism, severe arteriosclerosis, senile confusional 
             states and severe renal, hepatic or cardiovascular 
             disease.
             
             It is contraindicated in excitable or hyperactive patients in 
             doses below 6 mg/day as it may exacerbate these features.
             
             Flupenthixol is best avoided in pregnancy, though there is no 
             evidence of teratogenicity or foetotoxicity.  There is no 
             reason why treatment should not continue (at least after the 
             first trimester) in a previously unrecognised pregnancy 
             (Lundbeck Ltd, 1989).
             
             Oral flupenthixol hydrochloride is not recommended for the 
             treatment of severe depression requiring electroconvulsive 
             therapy and/or hospitalisation.
 
    5.  ROUTES OF ENTRY
 
        5.1  Oral
 
             This is the main route of entry in acute poisonings.
 
 
 
        5.2  Inhalation
 
             Not applicable.
 
        5.3  Dermal
 
             Not applicable.
 
        5.4  Eye
 
             Not applicable.
 
        5.5  Parenteral
 
             Chronic poisoning and especially NMS has been mostly 
             reported after parenteral administration.
 
        5.6  Others
 
             No data available.
 
    6.  KINETICS
 
        6.1  Absorption by route of exposure
 
             Oral
             
             Absorption of flupenthixol is fairly slow and incomplete, 
             with a bioavailability in humans of about 50% (Jorgensen 
             1980; Jorgensen, 1982). It is probable that flupenthixol 
             undergoes first-pass metabolism, either in the gut wall or 
             the liver, as does fluphenazine, the analogous phenothiazine 
             (Curry et al.,1979). 
             
             In human studies using tritiated flupenthixol hydrochloride, 
             Jorgensen & Gottfries (1972) found that peak serum 
             radioactivity occurred at 3 to 8 hours. Subjects (5) were all 
             post-menopausal female schizophrenics already stabilised on 
             flupenthixol.
             
             This was confirmed in a later study with unlabelled 
             flupenthixol (Jorgensen 1980) using human volunteers (N = 3; 
             healthy male adults), where the time to peak (tmax) was 3 to 
             6 hours. In patients, average tmax was quoted as 4 hours 
             (Jorgensen et al., 1982).
             
             Intramuscular
             
             Flupenthixol decanoate is slowly released from the depot 
             site, with a half-life of 3 to 8 days (Jorgensen, 1980). The 
             decanoate ester is then rapidly hydrolysed intracellularly to 
             flupenthixol, with only traces of decanoate remaining in the 
             bloodstream (Jorgensen et al., 1971). The serum tmax for 
             intramuscular flupenthixol decanoate is 3 to 5 days 
             (Jorgensen, 1980).
 
 
 
        6.2  Distribution by route of exposure
 
             Flupenthixol is highly protein-bound (99%), and hence 
             has a large volume of distribution, Vd, of 14.1 L/kg; i.e. 
             987 L for a 70 kg person (Jorgensen 1980). In general, the 
             highest levels of flupenthixol are found in parenchymatous 
             organs such the lungs and liver, with much lower 
             concentrations in the CNS.  This appears to be the case 
             irrespective of the route of administration.
             
             Oral
             
             In the rat, Jorgensen et al. (1969) found that, following 
             oral administration of tritiated flupenthixol, tissue 
             radioactivity at 8 hours post-ingestion (i.e. close to tmax) 
             10 mg/kg, was as follows:
 
                                  Concentration       Percentage
                                  Micrograms/gram     of dose
             
             Lungs                  33.1                2.3
             Liver                  24.8                9.3
             Spleen                 12.7                0.5
             Kidneys                10.2                0.9
             Heart                   4.6                0.2
             Epididymal fat          3.1                0.2
             Brain                   1.7                0.3
             
             This order did not vary significantly with time.
             
             Intramuscular
             
             Following intramuscular 3H-flupenthixol decanoate in Viscoleo 
             (a light vegetable oil) to rats, Jorgensen et al. (1971) 
             found the following tissue radioactivity levels at 1 day 
             post-injection:
             
                                Concentration          Percentage
                                Micrograms/gram        of dose
             
             Lungs                   1.5                 0.3
             Liver                   1.5                 1.6
             Kidneys                 0.6                 0.1
             Spleen                  0.4                 -
             Heart                   0.12                -
             Epididymal fat          0.1                 0.1
             Brain                   0.09                -
             
             A further 19.2% of the injected dose was still present at the 
             depot site.
 
 
        6.3  Biological half-life by route of exposure
 
             The kinetics of flupenthixol are complex, involving at 
             least a three-compartment model.
             
             Oral
             
 
 
 
             The mean biological half-life in the terminal phase (i.e. 
             beyond about 24 hour post-ingestion) is 19 to 39 hours, 
             (Jorgensen, 1980).
             
             Intramuscular
             
             The mean biological half-life in the terminal phase (i.e. 
             beyond about 14 days after injection) is 19 to 39 hours 
             (Jorgensen, 1980). Elimination half-life, however, was found 
             be from 5 to 113 days (Jorgensen et al., 1982).  Depot 
             flupenthixol decanoate thus undergoes 'flip-flop' kinetics 
             (i.e. ka << ke). The significance of this is that the 
             terminal slope (and half-life) of the concentration/time 
             curve is dependent on absorption rate constant, ka, not 
             elimination rate constant, ke.
 
        6.4  Metabolism
 
             Flupenthixol has no active metabolites (Jorgensen, 1978a).
             
             The metabolism of flupenthixol follows three main routes in 
             animals, regardless of the route of administration (Jorgensen 
             et al., 1969). These are:
 
                     Sulphoxidation
                     Side-chain N-dealkylation
                     Glucuronic acid conjugation
 
             The major metabolites found in plasma are N- 
             desalkylflupenthixol and flupenthixol sulphoxide, both 
             inactive (Jorgensen et al., 1969, Jorgensen, 1980). However, 
             no compounds other than flupenthixol itself are found in the 
             brain, even after intramuscular injection of the decanoate 
             (Jorgensen, 1978a).
             
             More N-desalkylflupenthixol is formed following oral 
             administration than from intramuscular, presumably because N- 
             dealkylation is a product of first-pass metabolism in the gut 
             wall and liver (Muusze et al., 1977, cited in Jorgensen, 
             1978b).
 
        6.5  Elimination and excretion 
 
             Oral
             
             In rats, 63% of a 3H-flupenthixol dose (10 mg/kg) was found 
             in the faeces (54% between 8 and 24 hours after ingestion); 
             17.4% in urine; and 2.2% remained in the body after 10 days 
             (Jorgensen et al., 1969).
             
             Intramuscular
             
             In dogs, 7 to 37% of a radiolabelled dose of flupenthixol 
             decanoate intramuscular appeared in urine and 21 to 54% in 
             faeces.  Traces of drug were also found in bile (Jorgensen et 
             al., 1971).
             
 
 
 
             In rats, only 71.4% of the dose had been excreted by 28 days, 
             indicating that significant amounts of drug were still 
             present (Jorgensen et al., 1971).
             
             Peak urinary excretion was at about 8 days; faecal at between 
             3 and 6 days (Jorgensen et al., 1971). The major excretion 
             products were flupenthixol sulphoxide and N- 
             desalkylflupenthixol.
             
             Intravenous
             
             In rats, 59.3% of a 3H-flupenthixol dose (10 mg/kg) was found 
             in the faeces; 16.4% in urine; and 14.4% remained in the body 
             after 5 days (Jorgensen et al., 1969). The same author also 
             found that 12.6% of the dose was excreted in bile, suggesting 
             that enterohepatic circulation occurs.
             
             Note: Systemic clearance, Cls, following intravenous infusion 
             was calculated by Jorgensen (1980) as 0.46 L/min (▒ 2.5 
             L/min) in healthy volunteers.  This is slightly higher than 
             Cls for intramuscular depot administration in psychiatric 
             patients (Stauning et al., 1979), 0.31 L/min.  This is not 
             surprising, since the area under the curve (AUC) is higher 
             for the intramuscular preparation, giving a lower calculated 
             clearance.  Small amounts of flupenthixol are excreted in 
             breast milk (see 9.4.15).
 
    7.  PHARMACOLOGY AND TOXICOLOGY
 
        7.1  Mode of action
 
             7.1.1  Toxicodynamics
 
                    There is little data on the activity of 
                    flupenthixol or other thioxanthenes in overdose. By 
                    analogy with phenothiazines, however, and drawing on 
                    descriptions of clinical findings in the literature 
                    and internal case reports, it is likely that toxicity 
                    is caused by the same mechanisms as those producing 
                    its therapeutic effects:  that is, by dopamine and 
                    alpha-adrenergic receptor blockade.  Flupenthixol 
                    appears devoid of anticholinergic activity.
 
             7.1.2  Pharmacodynamics
 
                    Neuroleptics such as flupenthixol act in 
                    psychosis by blockage of postsynaptic dopamine 
                    receptors in the brain (Ban & Lehmann, 1974; 
                    Richelson, 1984).  Flupenthixol is a powerful 
                    antagonist of both D1 and D2 dopamine receptors, but 
                    is no more potent a neuroleptic than other agents 
 
 
 
                    (e.g. haloperidol) which are D2 antagonists only 
                    (Ehmann et al., 1987). This would suggest that the 
                    antipsychotic activity of neuroleptics is mediated by 
                    D2 receptors, but not by D1.
                    
                    Flupenthixol is an alpha-adrenergic receptor 
                    antagonist and also depresses many hypothalamic and 
                    hypophyseal hormones. It blocks prolactin inhibitory 
                    factor (PIF), resulting in an increase in pituitary 
                    prolactin secretion (Fielding & Lal, 1978).
                    
                    Unlike the phenothiazines, flupenthixol resembles the 
                    tricyclic antidepressants in some of its actions, 
                    though not in anticholinergic activity (Kato et al., 
                    1969), and at low doses (1 to 2 mg/day orally) is an 
                    effective and well-tolerated antidepressant and 
                    anxiolytic in its own right, although contraindicated 
                    in agitated patients (Poeldinger & Sieberns, 
                    1983).
                    
                    Like many antipsychotic drugs, flupenthixol also has 
                    an additive effect when given with tricyclic 
                    antidepressants (Reiter, 1969). The additive effect 
                    may be clinically useful (Connelly & Naylor, 1987) or 
                    potentially dangerous (Siris et al. 1978).
 
        7.2  Toxicity
 
             7.2.1  Human data
 
                    7.2.1.1  Adults 
 
                             An acute oral dose of approximately 
                             29 mg (0.41 mg/kg) caused coma and 
                             respiratory depression in a 67-year-old male 
                             who subsequently died (NPIS London: data on 
                             file). Cause of death was a coronary 
                             thrombosis, with flupenthixol overdose as a 
                             possible contributory factor.
                             
                             An adult patient (age and weight not stated) 
                             took 90 mg flupenthixol and suffered only 
                             mild extrapyramidal signs (Mann, 1976).
                             
                             0.367 mg/kg/day for 12 days caused 
                             wakefulness, muscle weakness and headache 
                             (NIOSH, 1989).
 
 
 
                    7.2.1.2  Children
 
                             18 to 20 mg (0.9 mg/kg) flupenthixol 
                             in a 3┤-year-old girl caused Grade III coma, 
                             followed after 23 hours by episodes of 
                             extrapyramidal signs, which persisted for 
                             over 10 hours (Bailie et al., 
                             1981).
 
             7.2.2  Relevant animal data
 
                    Species  Route             LD50
                                               (mg/kg)
 
                    Mouse    Oral               300
                    Mouse    Subcutaneous       425
                    Mouse    Intraperitoneal    150
                    Mouse    Intravenous         87
                    Rat      Oral               791
                    Rat      Subcutaneous       258
                    Rat      Intravenous         37
                    
                    (NIOSH, 1989)
 
             7.2.3  Relevant in vitro data
 
                    None.
 
        7.3  Carcinogenicity
 
             None known.
 
        7.4  Teratogenicity
 
             Flupenthixol crosses the placenta, with foetal serum and 
             amniotic fluid concentrations about one quarter the maternal 
             serum level (Kirk & Jorgensen, 1980). Four patients in this 
             study were receiving depot flupenthixol, the other one oral. 
             No effects were seen on foetuses.
 
        7.5  Mutagenicity
 
             None known.
 
 
 
        7.6  Interactions
 
             Tricyclic antidepressants 
 
             Flupenthixol appears to have an additive or synergistic 
             effect with tricyclic antidepressants (TCA), unrelated to its 
             antipsychotic activity. The mechanism is unclear, as only 
             anecdotal reports have been published, but appears to be 
             associated with elevated serum TCA levels (Cook et al., 
             1986).
             
             A 28-year-old paranoid schizophrenic received imipramine 150 
             mg/day plus depot flupenthixol 40 mg intramuscularly every 
             two weeks and trihexyphenydil (benzhexol) 2 mg/day. 
             Imipramine + desipramine levels were mildly elevated (180 to 
             710 nmol/L), and there was a sinus tachycardia which 
             disappeared on withdrawal of medication (Cook et al., 
             1986).
             
             A 31-year-old woman suffering from severe, unipolardepressive 
             psychosis with suicidal and homicidal hallucinations had 
             previously been stabilised on clomipramine 300 mg/day, L- 
             tryptophan 1 g twice daily and thioridazine 100 mg, but 
             without clinical improvement (Connelly & Naylor, 1987). 20 mg 
             flupenthixol decanoate were given intramuscularly, followed 
             by 40 mg after 3 days. There was immediate improvement in 
             socialisation, hallucinations and sleep pattern, but she then 
             had several cycles of relapses and improvements coinciding 
             with the fortnightly depot flupenthixol injections, despite 
             their being gradually increased to 80 mg.  Rechallenge with 
             flupenthixol produced an improvement after 23 days; 
             rechallenge with 20 mg every two weeks produced continued 
             improvement until discharge 6 weeks thereafter, with the L- 
             tryptophan and thioridazine  withdrawn. A relapse then 
             occurred after noncompliance with clomipramine, corrected 
             when it was restarted at 150 mg/day.  The patient's response 
             was thought to be due to an interaction between clomipramine 
             and flupenthixol, not involving the antipsychotic effects of 
             the latter.
             
             Ethanol
             
             A double-blind study showed impairment of performance in 
             tests (choice reaction, co-ordination, attention) with 
             flupenthixol 0.5 mg three times daily for three weeks plus 
             ethanol 0.5 g/kg.  This did not occur with flupenthixol 
             alone, or with single-dose haloperidol either with or without 
             ethanol (Linnoila, 1973; Linnoila et al., 1975).  The 
             deterioration in performance was sufficient to severely 
             impair driving or handling machinery.
             
 
 
 
             The mechanism of this interaction is unknown, but is presumed 
             to be additive CNS depression.
             
             Eproxindine
             
             Eproxindine is a novel Class I antiarrhythmic agent.  Sudden 
             cardiorespiratory arrest and death occurred in a clinical 
             trial volunteer who was later found to have been given 
             flupenthixol decanoate intramuscularly 40 mg at a psychiatric 
             clinic, one day before receiving eproxindine 400 mg (Darragh 
             et al., 1985).
             
             It is possible that this interaction was due to competition 
             for protein binding sites: since flupenthixol is 99% protein- 
             bound, a 1% reduction in binding would cause a doubling in 
             free fraction. This is, however, open to question as 
             flupenthixol has a very large volume of distribution (14.1 
             L/kg) and plasma drug levels would therefore not rise greatly 
             (Simister & Jorgensen, 1985).
             
             Arecoline
             
             Chewing by two patients of betel nut, Areca catechu (Palmae), 
             was accompanied by exacerbation of extra-pyramidal side- 
             effects (see Section 7.7) from both depot flupenthixol and 
             depot fluphenazine (Deahl, 1987).  This was thought due to 
             the cholinergic activity  of arecoline, a tertiary amine 
             found in the nut, which would antagonise the effect of 
             procyclidine, given to both patients to control 
             extrapyramidal signs.
             
             Monoamine oxidase inhibitors (MAOI)
             
             No published evidence could be found for an interaction 
             between flupenthixol and MAOI. However, MAOI could 
             theoretically affect flupenthixol pharmacodynamics, so it may 
             be advisable to allow 7 days between cessation of MAOI 
             therapy and commencement of flupenthixol (Lundbeck Ltd., 
             1989).
 
        7.7  Main adverse effects
 
             Sudden death
             
             Sudden death occurred in three patients aged 23-29 receiving 
             depot flupenthixol decanoate, which was the sole medication 
             in two.  None was receiving the drug for the first time.  The 
             last doses given were 30 mg, 20 mg and 40 mg, with death 
             occurring 1 day, 1 week and 1 week respectively after the 
             final dose (Turbott & Smeeton, 1984).
             
 
 
 
             The causes of death were unknown in all cases, and postmortem 
             findings were unremarkable. A possible clue may be that the 
             deaths occurred at about the same time post-dose as the 
             highest incidence of extrapyramidal symptoms, and close to 
             tmax for intramuscular flupenthixol decanoate.  Similar cases 
             have been reported with phenothiazines (Whyman, 1976; 
             Solomon, 1977).
             
             Extrapyramidal signs & symptoms
             
             The dopamine antagonist activity of flupenthixol (and other 
             neuroleptics) is also responsible for its extrapyramidal side 
             effects, which occur in approximately 25% of patients 
             (British National Formulary, 1989).  They are caused by 
             disturbance of the dopamine-acetylcholine balance in the 
             basal ganglia (Carlsson, 1978).
             
             This may cause an acetylcholinergic excess, resulting in 
             hyperkinesis (i.e. acute dystonic reactions such as 
             protruding tongue, torticollis and opisthotonos); or 
             dopaminergic excess leading to hypokinesias (e.g. 
             Parkinsonism, akinesias) (Bell et al., 1980).
             
             Extrapyramidal symptoms appear rapidly after oral 
             administration, and within 1 to 3 days of depot injection. 
             They may persist for about five days (Lundbeck Ltd., 
             1989).
             
             Neuroleptic malignant syndrome
             
             Neuroleptic malignant syndrome (NMS) is a rare but serious 
             side- effect of many neuroleptic drugs (Szabadi, 1984). It 
             may be caused by flupenthixol (Bates & Courtenay-Evans, 1984; 
             Tomson, 1986). 
             
             There are three groups of symptoms:
             
             Catatonic (usually the earliest to appear)
             
             Withdrawal and hypoactivity progressing to drowsiness and 
             coma (Weinberger & Kelly, 1977).
             
             Extrapyramidal 
             
             Akinesia; lead-pipe rigidity (NPIS London: case report 
             77/118) progressing to opisthotonos; tremor; oculogyric 
             crisis; increased muscle tone possibly resulting in dysphagia 
             and dyspnoea (Weinberger & Kelly, 1977).
             
 
 
 
             Autonomic 
             
             Fluctuating blood pressure; tachycardia; peripheral 
             vasoconstriction; dyspnoea; sweating; dysuria or 
             incontinence; hyperpyrexia (Weinberger & Kelly, 1977).
             
             This combination of extrapyramidal signs with hyperpyrexia 
             should be diagnostic.
             
             NMS carries a 20% mortality rate (Caroff, 1980), hyperpyrexia 
             (or complications secondary to it, e.g. respiratory failure) 
             being the major cause of death.  NMS-induced hyperpyrexia may 
             be more prevalent in hot climates (Singh, 1983).
             
             NMS is thought to be caused by excessive dopamine receptor 
             blockade (Burke et al., 1981; Henderson, 1981).  However, 
             some other precipitating factor (e.g. concurrent lithium 
             therapy, which would prevent compensating up-regulation of 
             dopamine receptors in neuroleptic therapy) is probably 
             required (Szabadi, 1984).
             
             Tardive dyskinesia
             
             Tardive dyskinesia is a serious extrapyramidal side effect of 
             neuroleptic drug therapy. It usually occurs in patients on 
             long- term depot medication, and has been seen with both 
             flupenthixol and fluphenazine (Barnes & Wiles, 1983).
             
             Symptoms include a range of involuntary, repetitive movements 
             involving the jaws, lips and tongue (orofacial dyskinesia), 
             and possibly more generalised movements including limb- 
             jerking and hyperextension of neck and trunk (Dick & 
             Saunders, 1981).  Symptoms often persist despite cessation of 
             therapy.
             
             The syndrome is thought to be caused by chronic dopaminergic 
             blockade, leading to up-regulation of receptors and 
             hypersensitivity (Klawans, 1973), a theory supported by the 
             fact that severity of symptoms is inversely related to plasma 
             flupenthixol levels (Barnes & Wiles, 1983).  The same authors 
             also found that severity correlated with patient age.
 
 
 
    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
 
    9.  CLINICAL EFFECTS
 
        9.1  Acute poisoning
 
             9.1.1  Ingestion
 
                    Drowsiness, sinus tachycardia, hypotension, 
                    miosis. Progressive coma (in agitated or aggressive 
                    patients, hallucinations); possibly respiratory 
                    depression. Tonic-clonic convulsions, muscle spasms. 
                    Hypothermia or hyperthermia.
                    
                    Extrapyramidal effects are hyperkinesis (i.e. acute 
                    dystonic reactions such as protruding tongue, 
                    torticollis and opisthotonos) or hypokinesis (e.g. 
                    Parkinsonism, akinesia).
 
             9.1.2  Inhalation
 
                    Not known.
 
             9.1.3  Skin exposure
 
                    Not known.
 
             9.1.4  Eye contact
 
                    Not known.
 
             9.1.5  Parenteral exposure
 
                    Not known from acute overdose, but would be as 
                    for ingestion. Onset of symptoms could be delayed for 
                    several days (tmax for intramuscular depot 
                    flupenthixol is 3 to 5 days):
                    
                    Drowsiness, sinus tachycardia, hypotension, miosis. 
                    Progressive coma (in agitated or aggressive patients, 
                    hallucinations); possibly respiratory depression. 
                    Tonic-clonic convulsions, muscle spasms. Hypothermia 
                    or hyperthermia.
                    
                    Extrapyramidal effects
                    
                    Hyperkinesis (i.e. acute dystonic reactions such as 
                    protruding tongue, torticollis and opisthotonos); or 
                    Hypokinesis (e.g. Parkinsonism, akinesia)
                    
 
 
 
                    Accidental intravenous injection of intramuscular 
                    flupenthixol preparations has not been reported, but 
                    due to the oily nature of the preparation, there could 
                    be a risk of embolus formation.
 
             9.1.6  Other
 
                    Not known.
 
        9.2  Chronic poisoning
 
             9.2.1  Ingestion
 
                    Extrapyramidal effects
                    
                    Hyperkinesis (i.e. acute dystonic reactions such as 
                    protruding tongue, torticollis and opisthotonos);  or 
                    Hypokinesis (e.g. Parkinsonism, akinesias).
                    
                    Tardive dyskinesia
                    
                    Normally only seen in patients on long-term therapy, 
                    and therefore unlikely to affect patients receiving 
                    oral flupenthixol only.  However, in the event of this 
                    occurring, symptoms would include a range of 
                    involuntary, repetitive movements involving the jaws, 
                    lips and tongue (orofacial dyskinesia), and possibly 
                    more generalised movements including limb-jerking and 
                    hyperextension of neck and trunk. Symptoms often 
                    persist despite cessation of therapy.
                    
                    Neuroleptic malignant syndrome (NMS)
                    
                    Normally only seen in patients on long-term, high-dose 
                    therapy, and therefore unlikely to affect patients 
                    receiving oral flupenthixol only.  However, in the 
                    event of its occurring, symptoms would include:
                    
                    Catatonic (usually the earliest to appear): 
                    Withdrawal and hypoactivity progressing to drowsiness 
                    and coma.
                    
                    Extrapyramidal: Akinesia; lead-pipe rigidity 
                    progressing to opisthotonos; tremor; oculogyric 
                    crisis; increased muscle tone possibly resulting in 
                    dysphagia and dyspnoea.
                    
                    Autonomic: Fluctuating blood pressure; tachycardia; 
                    peripheral vasoconstriction; dyspnoea; sweating; 
                    dysuria or incontinence; hyperpyrexia.
                    
 
 
 
                    NMS carries a 20% mortality rate. Hyperpyrexia (or 
                    complications secondary to it, e.g. cerebrovascular 
                    injury) is the major cause of death.  This combination 
                    of extrapyramidal signs with hyperpyrexia should be 
                    diagnostic.
 
             9.2.2  Inhalation
 
                    Not known
 
             9.2.3  Skin exposure
 
                    Not known
 
             9.2.4  Eye contact
 
                    Not known
 
             9.2.5  Parenteral exposure
 
                    Extrapyramidal effects
                    
                    Hyperkinesis (i.e. acute dystonic reactions such as 
                    protruding tongue, torticollis and opisthotonos);  or 
                    Hypokinesis (e.g. Parkinsonism, akinesias).
                    
                    Tardive dyskinesia
                    
                    Symptoms include a range of involuntary, repetitive 
                    movements involving the jaws, lips and tongue 
                    (orofacial dyskinesia), and possibly more generalised 
                    movements including limb-jerking and hyperextension of 
                    neck and trunk. Symptoms often persist despite 
                    cessation of therapy.
                    
                    Neuroleptic malignant syndrome (NMS)
                    
                    Normally only seen in patients on long-term, high-dose 
                    therapy, but it is rare.Symptoms include:
                    
                    Catatonic (usually the earliest to appear): 
                    Withdrawal and hypoactivity progressing to drowsiness 
                    and coma.
                    
                    Extrapyramidal: Akinesia; lead-pipe rigidity 
                    progressing to opisthotonos; tremor; oculogyric 
                    crisis; increased muscle tone possibly resulting in 
                    dysphagia and dyspnoea.
                    
                    Autonomic: Fluctuating blood pressure; tachycardia; 
                    peripheral vasoconstriction; dyspnoea; sweating; 
                    dysuria or incontinence; hyperpyrexia.
                    
 
 
 
                    NMS carries a 20% mortality rate. Hyperpyrexia (or 
                    complications secondary to it, e.g. cerebrovascular 
                    injury) is the major cause of death.  This combination 
                    of extrapyramidal signs with hyperpyrexia should be 
                    diagnostic.
 
             9.2.6  Other
 
                    Not known.
 
        9.3  Course, prognosis, cause of death
 
             Mild poisoning
             
             Drowsiness, sinus tachycardia, hypotension, miosis.
             
             Moderate poisoning
             
             Drowsiness progresses to coma (in agitated or aggressive 
             patients, hallucinations).  Hypothermia, muscle spasms.
             
             Extrapyramidal effects
             
             Hyperkinesis (i.e. acute dystonic reactions such as 
             protruding tongue, torticollis and opisthotonos);  or 
             hypokinesis (e.g. Parkinsonism, akinesias).  Symptoms may 
             persist for up to 48 hours after oral overdose.
             
             Severe poisoning
             
             Deep coma, possibly respiratory depression. Tonic-clonic 
             convulsions.
             
             No fatalities have been reported from overdose of 
             flupenthixol alone. However, in acute overdose the most 
             likely cause of death would be anoxic brain damage or other 
             lesions caused by respiratory depression, or cardiac arrest 
             due to "torsades de pointes" arrhythmias..
             
             Neuroleptic malignant syndrome (NMS), which is seen in 
             patients on long-term, high-dose treatment, carries a 20% 
             mortality rate. Hyperpyrexia (or complications secondary to 
             it, e.g. cerebral injury) is the major cause of death. 
             Hyperpyrexia should therefore be regarded seriously, 
             especially in chronic or acute-on-chronic poisoning, as it 
             may presage the onset of NMS. The combination of extra- 
             pyramidal signs with hyperpyrexia should be diagnostic.
             
             Symptoms include:
             
 
 
 
             Catatonic (usually the earliest to appear): Withdrawal and 
             hypoactivity progressing to drowsiness and coma.
             
             Extrapyramidal: Akinesia; lead-pipe rigidity progressing to 
             opisthotonos; tremor; oculogyric crisis; increased muscle 
             tone possibly resulting in dysphagia and dyspnoea.
             
             Autonomic: Fluctuating blood pressure; tachycardia; 
             peripheral vasoconstriction; dyspnoea; sweating; dysuria or 
             incontinence; hyperpyrexia.
 
        9.4  Systematic description of clinical effects
 
             9.4.1  Cardiovascular
 
                    Acute
                    
                    Shock and hypotension are likely in significant 
                    overdose (NPIS London, data on file).  Cardiotoxic 
                    effects such as conduction defects and ventricular 
                    dysrhythmias have not been reported with flupenthixol 
                    or other thioxanthenes.  However, these do occur after 
                    over-dosage with other neuroleptics such 
                    asthioridazine, chlorpromazine and haloperidol 
                    (Niemann et al., 1981; Lumpkin et al., 1979). 
                    Further, flupenthixol does not cause the 
                    anticholinergic effects associated with tricyclic 
                    antidepressants (Mann, 1976).
                    
                    "Torsades de pointes" type arrhythmia may be observed 
                    in severe poisoning with coma. (Jacobsen D, personal 
                    communication).
                    
                    Chronic
                    
                    None known.
                    
                    Acute-on-chronic
                    
                    Hypertension or hypotension may occur as a feature of 
                    the neuroleptic malignant syndrome (NMS). One patient 
                    in NMS had blood pressure varying between 100/60 and 
                    170/120 (Tomson, 1986); another had intermittent 
                    hypotension associated with sweating and tachypnoea 
                    (Bates & Courtenay-Evans, 1984).
 
             9.4.2  Respiratory
 
                    Acute
                    
                    Respiratory depression occurred in a patient who took 
                    an overdose of 29 mg flupenthixol (NPIS London, data 
                    on file).
 
 
 
                    
                    Chronic
                    
                    None known.
                    
                    Acute-on-chronic
                    
                    Hypoxia due to decreased chest wall compliance in NMS 
                    (Tomson, 1986)
 
             9.4.3  Neurological
 
                    9.4.3.1  Central nervous system (CNS)
 
                             Acute
                             
                             Drowsiness progressing to coma (NPIS London, 
                             data on file; Bailie et al., 1981). 
                             Hallucinations have occurred in agitated or 
                             aggressive patients with phenothiazine 
                             overdose (Barry et al., 1973), so might 
                             conceivably occur with flupenthixol.
                             
                             Tonic-clonic convulsions have occurred in a 5 
                             year old child (NPIS London, case 
                             76/18193).
                             
                             Extrapyramidal effects: Hyperkinesis (i.e. 
                             acute dystonic reactions such as protruding 
                             tongue, torticollis and opisthotonos) (Bailie 
                             et al., 1981); or hypokinesis (e.g. 
                             Parkinsonism, akinesias) (NPIS London, case 
                             77/118).
                             
                             Chronic
                             
                             Tardive dyskinesia:  Symptoms include a range 
                             of involuntary, repetitive movements 
                             involving the jaws, lips and tongue 
                             (orofacial dyskinesia), and possibly more 
                             generalised movements including limb-jerking 
                             and hyperextension of neck and trunk (Dick & 
                             Saunders, 1981).  Symptoms often persist 
                             despite cessation of therapy, and severity 
                             appears to be inversely proportional to serum 
                             flupenthixol levels (Barnes & Wiles, 
                             1983).
                             
 
 
 
                             Long-term, high-dose flupenthixol may lead to 
                             paradoxical excitability, restlessness and 
                             aggression (Barnes & Bridges, 1980). 
                             Wakefulness and  headache was caused by 
                             0.367 mg/kg/day for 12 days (NIOSH, 
                             1989).
                             
                             Acute-on-chronic
                             
                             NMS:  Withdrawal and hypoactivity progressing 
                             to drowsiness and coma (Weinberger & Kelly, 
                             1977). Extrapyramidal symptoms include 
                             akinesia; lead-pipe rigidity (NPIS London: 
                             case report 77/118) progressing to 
                             opisthotonos; tremor; oculogyric crisis 
                             (Weinberger & Kelly, 1977).
 
                    9.4.3.2  Peripheral nervous system
 
                             Acute
                             
                             None known.  Chlorpromazine and other 
                             phenothiazines have local anaesthetic 
                             properties, probably associated with membrane 
                             stabilising activity (Seeman, 1972), but this 
                             has not been reported with flupenthixol.
                             
                             Chronic
                             
                             None known.
                             
                             Acute-on-chronic
                             
                             None known.
 
                    9.4.3.3  Autonomic nervous system
 
                             Acute
                             
                             Shock and hypotension may occur (NPIS London, 
                             data on file).
                             
                             Acute
                             
                             Shock
                             Chronic
                             
                             None known.
                             
 
 
 
                             Acute-on-chronic
                             
                             NMS: Fluctuating blood pressure; tachycardia; 
                             peripheral vasoconstriction; sweating; 
                             hyperpyrexia (Weinberger & Kelly, 1977).
                             
                             Acute
                             
                             Shock
 
                    9.4.3.4  Skeletal and smooth muscle
 
                             Acute
                             
                             Extrapyramidal effects may cause hyperkinesis 
                             (i.e. acute dystonic reactions such as 
                             protruding tongue, torticollis and 
                             opisthotonos), or hypokinesis (e.g. 
                             Parkinsonism, akinesias) (Bell et al., 
                             1980).
                             
                             Chronic
                             
                             Tardive dyskinesia:  Symptoms include a range 
                             of involuntary, repetitive movements 
                             involving the jaws, lips and tongue 
                             (orofacial dyskinesia), and possibly more 
                             generalised movements including limb-jerking 
                             and hyperextension of neck and trunk (Dick & 
                             Saunders, 1981).  Symptoms often persist 
                             despite cessation of therapy.
                             
                             0.367 mg/kg/day for 12 days caused muscle 
                             weakness (NIOSH, 1989).
                             
                             Acute-on-chronic
                             
                             In NMS, increased muscle tone may occur, 
                             possibly resulting in dysphagia and dyspnoea 
                             (Weinberger & Kelly, 1977).  Elevated CPK 
                             levels have been reported in several cases 
                             (McAllister, 1978; Henderson & Wooten, 1981), 
                             possibly reflecting rhabdomyolysis after 
                             muscle hypertonia.
                             
                             Laryngo-pharyngeal dystonia has been 
                             suggested as a possible mechanism in sudden 
                             death from depot flupenthixol (Turbott & 
                             Smeeton, 1984).
 
 
 
             9.4.4  Gastrointestinal
 
                    Acute
                    
                    None known.  Nausea and vomiting do not appear to be a 
                    feature of overdose.
                    
                    Chronic 
                    
                    None known.
                    
                    Acute-on-chronic
                    
                    None known. Acute intestinal dilation has been 
                    reported in a fatal case(Turbott & Smeeton, 
                    1984).
 
             9.4.5  Hepatic
 
                    Acute
                    
                    One patient became jaundiced after recovery from a 
                    multiple overdose of flupenthixol, amylobarbitone and 
                    ethanol (NPIS London, case 77/118). It is not known 
                    whether flupenthixol played any part in this.
                    
                    Chronic
                    
                    None known.  Flupenthixol does not appear to possess 
                    the potential for hepatotoxicity of some 
                    phenothiazines, such as chlorpromazine.
                    
                    Acute-on-chronic
                    
                    Elevated AST, LDH and alkaline phosphatase levels have 
                    been reported in neuroleptic malignant syndrome (Smego 
                    & Durack, 1982).  The mechanism is unknown, but may be 
                    secondary to hyperthermia.
 
             9.4.6  Urinary
 
                    9.4.6.1  Renal
 
                             Acute
                             
                             None known.
                             
                             Chronic
                             
                             None known.
                             
 
 
 
                             Acute-on-chronic
                             
                             Acute renal failure has been reported in 
                             neuroleptic malignant syndrome (NMS) from 
                             flupenthixol (Tomson, 1986), thought to be 
                             due to rhabdomyolysis after muscle 
                             hypertonia.  Elevated CPK levels have been 
                             reported in several other cases of NMS 
                             (McAllister, 1978; Henderson & Wooten, 
                             1981).
 
                    9.4.6.2  Other
 
                             Acute
                             
                             None known.
                             
                             Chronic
                             
                             Urinary incontinence has occurred with long- 
                             term depot treatment with flupenthixol (and 
                             fluphenazine).  Enuresis occurred within 
                             seven days of each injection, stopped after 
                             withdrawal of treatment, and recurred on re- 
                             challenge.  All patients were women under 35 
                             years (Shaikh, 1978).
                             
                             Acute-on-chronic
                             
                             None known.
 
             9.4.7  Endocrine and reproductive systems
 
                    Acute
                    
                    None known.
                    
                    Chronic
                    
                    Flupenthixol depresses many hypothalamic and 
                    hypophyseal hormones.  It blocks prolactin inhibitory 
                    factor (PIF), resulting in an increase in pituitary 
                    prolactin secretion (Fielding & Lal, 1978).
                    
                    Priapism has been reported with other neuroleptics 
                    (thioridazine, fluphenazine, chlorpromazine, 
                    trifluoperazine; haloperidol), but not with 
                    flupenthixol (Fishbain, 1985).
                    
 
 
 
                    Acute-on-chronic
                    
                    None known.
 
             9.4.8  Dermatological
 
                    Acute
                    
                    None known.
                    
                    Chronic
                    
                    Not known from flupenthixol. Some phenothiazines have 
                    caused photosensitisation.
                    
                    Acute-on-chronic
                    
                    Sweating may occur in NMS (Bates & Courtenay-Evans, 
                    1984).
 
             9.4.9  Eyes, ears, nose, throat: local effects
 
                    Acute
                    
                    Hypersalivation was reported in a 3-year-old who had 
                    taken 18 to 20 mg flupenthixol 33 hours previously 
                    (Bailie et al., 1981)
                    
                    Acute
                    
                    Hypersalivation
                    Chronic
                    
                    None known from flupenthixol. However, long-term 
                    treatment with thiothixene (another thioxanthene) may 
                    cause fine lenticular pigmentation (Haase et al., 
                    1967; Mason, 1977).  Only very mild visual problems 
                    were noted, shortly after the start of treatment.
                    
                    Acute-on-chronic
                    
                    Dry cough has been reported in NMS (Bates & Courtenay- 
                    Evans, 1984).
                    
                    Acute
                    
                    Hypersalivation
 
 
 
             9.4.10  Haematological
 
                    Acute
                    
                    None known.
                    
                    Chronic
                    
                    None known from flupenthixol. Blood dyscrasias 
                    progressing to agranulocytosis have occurred with some 
                    phenothiazines (DuComb & Baldessarini, 1977).
                    
                    Acute-on-chronic
                    
                    Leucocytosis of 12-30 x 109 cells/L may occur in NMS 
                    (Smego & Durack, 1982; Bates & Courtenay-Evans, 1984; 
                    Tomson, 1986).
 
             9.4.11  Immunological
 
                    Acute
                    
                    None known.
                    
                    Chronic
                    
                    None known.
                    
                    Acute-on-chronic
                    
                    None known
 
             9.4.12  Metabolic
 
                    9.4.12.1  Acid-base disturbances
 
                             Acute
                             
                             Acidosis is possible if respiratory 
                             depression occurs.
                             
                             Chronic
                             
                             None known.
                             
                             Acute-on-chronic
 
                             In neuroleptic malignant syndrome, 
                             respiratory or metabolic acidosis is possible 
                             because of respiratory depression or 
                             rhabdomyolysis.
 
 
 
                    9.4.12.2  Fluid and electrolyte disturbances
 
                             Acute
                             
                             None known.
                             
                             Chronic
                             
                             None known.
                             
                             Acute-on-chronic
                             
                             Hyperkalaemia may occur secondary to NMS.
                             
                             A patient with NMS had marked hyponatraemia. 
                             However, this was possibly not related to 
                             flupenthixol as he also had psychogenic 
                             polydipsia (Tomson, 1986)
 
                    9.4.12.3  Other
 
                             Acute
                             
                             None known.
                             
                             Chronic
                             
                             None known.
                             
                             Acute-on-chronic
                             
                             Patients with NMS may develop marked 
                             hyperpyrexia (Bates & Courtenay-Evans, 1984; 
                             Tomson, 1986).
 
             9.4.13  Allergic reactions
 
                    Acute
                    
                    None known.
                    
                    Chronic
                    
                    None known.
                    
                    Acute-on-chronic
                    
                    None known.
 
 
 
             9.4.14  Other clinical effects
 
                    None known.
 
             9.4.15  Special risks
 
                    Pregnancy
                    
                    Flupenthixol crosses the placenta, with foetal serum 
                    and amniotic fluid concentrations about one quarter 
                    the maternal serum level (Kirk & Jorgensen, 1980). 
                    Four patients in this study were receiving depot 
                    flupenthixol, the other one oral. No effects were seen 
                    on the foetuses, confirming the findings of animal 
                    studies (Lundbeck Ltd., 1989).
                    
                    Breast feeding
                    
                    Kirk & Jorgensen (1980) found that flupenthixol was 
                    excreted in breast milk at a concentration about 30% 
                    higher than the maternal serum level.  However, 
                    Mathesen & SkjŠraasen (1988) found that milk levels 
                    closely paralleled maternal serum levels, except when 
                    milk triglyceride levels were elevated. Given the 
                    lipophilicity of flupenthixol, this is not 
                    surprising.
                    
                    Flupenthixol was detectable in the child on only one 
                    occasion in the two studies, and was not thought by 
                    either authority to be a hazard.
                    
                    Enzyme deficiency
                    
                    None known.
 
        9.5  Other
 
             Sudden death occurred in three patients aged 23-29 
             receiving depot flupenthixol, which was the sole medication 
             in two. None was receiving the drug for the first time. The 
             last doses given were 30 mg, 20 mg and 40 mg, with death 
             occurring 1 day, 1 week and 1 week respectively after the 
             final dose (Turbott & Smeeton, 1984).
             
             The causes of death were unknown in all cases, and postmortem 
             findings were unremarkable. A possible clue may be that the 
             deaths occurred at about the same time post-dose as the 
             highest incidence of extrapyramidal symptoms, and close to 
             tmax for intramuscular flupenthixol decanoate. Similar cases 
             have been reported with phenothiazines (Whyman, 1976; 
             Solomon, 1977).
 
 
 
        9.6  Summary
 
             Not applicable
 
    10.  MANAGEMENT
 
        10.1  General principles
 
             Flupenthixol appears to be relatively safe in overdose. 
             A series of 28 overdoses followed up by NPIS London (Crome et 
             al, 1978) failed to show any serious toxicity.
             
             Since flupenthixol is fairly slowly absorbed from the gut, 
             with tmax = 3 to 6 hours (Jorgensen, 1980; Jorgensen et al., 
             1982), initial management of acute overdose should be aimed 
             primarily at prevention of absorption.
             
             The major symptoms seen in acute overdose are likely to be 
             CNS depression, with the possibility of respiratory 
             depression (NPIS London, data on file), especially if alcohol 
             has also been taken. Extrapyramidal effects are also probable 
             (Mann, 1976; Bailie et al., 1981).
             
             There is a danger of shock and hypotension in significant 
             overdose. However, flupenthixol does not cause the 
             cardiotoxic effects seen after overdosage with other 
             neuroleptics such as thioridazine, chlorpromazine and 
             haloperidol (Niemann et al., 1981; Lumpkin et al., 1979); nor 
             does it cause the anticholinergic effects associated with 
             tricyclic antidepressants (Mann, 1976).
             
             Further treatment should therefore be basically supportive, 
             with particular attention to maintaining adequate ventilation 
             and blood pressure. Antiparkinsonian drugs should be given as 
             required.
             
             Methods of active removal, such as haemodialysis or 
             haemoperfusion, are unlikely to be of use, since flupenthixol 
             is highly protein-bound and has a large volume of 
             distribution (Jorgensen, 1980).
 
        10.2  Relevant laboratory analyses
 
             10.2.1  Sample collection
 
                    For flupenthixol analysis, blood should be 
                    collected into EDTA tubes, and the plasma separated 
                    and frozen pending analysis. For monitoring of 
                    therapy, samples for quantitative analysis should be 
                    taken not less than 10 hours post-dose (Balant- Gorgia 
                    et al., 1985b).
 
 
 
             10.2.2  Biomedical analysis
 
                    None specifically relevant in acute overdose. 
                    Arterial blood gases (pO2, pH) should be monitored in 
                    unconscious patients.
                    
                    If neuroleptic malignant syndrome suspected, monitor 
                    temperature, arterial blood gases (pO2, pH), serum 
                    electrolytes, glucose and CPK.
 
             10.2.3  Toxicological analysis
 
                    Analysis of flupenthixol in body fluids is 
                    difficult, as (in common with other neuroleptics) the 
                    drug is administered in small doses and has a very 
                    large volume of distribution, giving low serum 
                    concentrations even in overdose.
                    
                    Detection
                    
                    Colour tests:
                    Refer to Section 8.1.1.
                    
                    Thin-layer chromatography:
                    Refer to Section 8.1.2.
                    
                    Quantitative analysis
                    
                    Refer to Section 8.1.3. Plasma levels are unlikely to 
                    affect the management of acute overdose.
                    
                    It should be borne in mind that oral preparations of 
                    flupenthixol contain a racemic mixture of the cis(Z) 
                    and trans(E) isomers. Since GLC cannot distinguish 
                    between them, results obtained by this method should 
                    be halved to give the concentration of active drug. 
                    This does not apply to depot preparations.
 
             10.2.4  Other investigations
 
                    Not relevant.
 
        10.3  Life supportive procedures and symptomatic/specific treatment
 
             Life support
             
             CNS and respiratory depression
             
             Normal supportive management of the unconscious patient. 
             Measure arterial blood gases (pO2, pH) and/or respiratory 
             rate; intubate and ventilate if necessary.
 
 
 
             
             Hypotension
             
             Although flupenthixol itself does not cause acute 
             cardiotoxicity, patients who overdose on it frequently also 
             have access to cardiotoxic drugs such as tricyclic 
             antidepressants.  If this is suspected, monitor ECG.
             
             For hypotension, give intravenous fluids or plasma expanders 
             initially. This may be all that is required to restore 
             adequate blood pressure.
             
             If hypotension is unresponsive to intravenous fluids, give 
             alphamimetic agents such as dopamine.
             
             Other
             
             For agitation, hallucinations or convulsions give diazepam 
             0.1 mg/kg.
             
             Symptomatic treatment
             
             Neuroleptic Malignant Syndrome
             
             If NMS suspected, monitor temperature, arterial blood gases 
             (pO2, pH), serum electrolytes, glucose and CPK.
             
             Cooling measures should be instituted, e.g. diazepam 0.1 
             mg/kg may be sufficient in mild hyperthermia (Smego & Durack, 
             1982). If severe (>40░C), dantrolene 1 to 10 mg/kg may be 
             effective, as it relieves muscle rigidity in malignant 
             hyperthermia (Cameron & Borthwick, 1983). Treat 
             extrapyramidal effects conventionally.  Give procyclidine 5 
             to 10 mg intravenously, repeated as necessary (maximum dose 
             in 24 hours 20 mg), or benztropine 2 mg intravenously or 
             intramuscularly stat.  Orphenadrine 20 mg intramuscularly 
             stat was also effective in a child (Bailie et al., 1981).
             
             Because of the risk of secondary renal damage due to 
             rhabdomyolysis, adequate fluid balance should be maintained. 
             Consider alkalizing urine. Haemodialysis may be required in 
             renal failure (Tomson, 1986).
             
             Extrapyramidal effects
             
             If extrapyramidal signs are mild (e.g. neck stiffness only), 
             and are not causing the patient distress, diazepam 0.05 to 
             0.1 mg/kg may suffice.
             
             For more severe symptoms, give procyclidine 5 to 10 mg 
             intravenously, repeated as necessary (maximum dose in 24 
             hours 20 mg), or benztropine 2 mg (adults) intravenously or 
 
 
 
             intramuscularly stat. Orphenadrine 20 mg intramuscularly stat 
             was also effective in a child (Bailie et al., 1981). 
             Diphenhydramine 2 mg/kg (maximum 50 mg) intravenously stat 
             relieves symptoms rapidly, but may cause further sedation and 
             should be given with caution in drowsy patients.
             
             Smaller doses of all these agents may be required in mixed 
             overdose with tricyclic antidepressants, due to the 
             possibility of anticholinergic symptoms.
             
             After initial control of the acute dystonic reaction, oral 
             antiparkinsonian therapy should continue for 48 to 72 hours 
             to prevent recurrence of symptoms due to the long half-life 
             of flupenthixol.  This may be given on an outpatient basis 
             (Corre et al., 1984).  Suitable oral dosages are benztropine 
             1 to 2 mg twice daily, or diphenhydramine 50 mg three times 
             daily.
             
             Tardive dyskinesia
             
             Tardive dyskinesia has only been seen in long-term 
             neuroleptic therapy.  It is therefore unlikely to be seen in 
             acute overdose, or with oral therapy.
             
             No truly effective treatment for tardive dyskinesia has yet 
             been established (Dick & Saunders, 1981). Current 
             recommendations consist of cessation of the drug and 
             symptomatic management of side- effects. Withdrawal of 
             flupenthixol is likely to lead initially to worsening of the 
             symptoms, though these tends to improve after some months. 
             Diltiazem in doses up to 360 mg/day may be effective in 
             relieving tardive dyskinesia, but requires further 
             investigation (Ross et al., 1987).
 
        10.4  Decontamination
 
             Activated charcoal
             
             The efficacy of activated charcoal in flupenthixol overdose 
             has not been established, but it is probably useful since it 
             is effective with phenothiazines.
             
             Give activated charcoal (50 g in adults, 1 to 2 mg/kg in 
             children) for any amount taken in a child and for more than 
             10 mg in an adult.
             
             Due to possible enterohepatic recycling, repeated-dose 
             activated charcoal may be useful in large overdoses 
             (Jorgensen et al., 1969).
             
 
 
 
             Emesis and gastric lavage
             
             Gastric lavage should only be considered in rare cases 
             following recent ingestion of life-threatening amounts in 
             adults.
             
             Do not give emetic because of potential for flupenthixol- 
             induced coma which may result in the loss of ability to 
             protect airway, causing aspiration pneumonitis.
 
        10.5  Elimination
 
             Active methods of elimination (forced diuresis, 
             haemoperfusion, haemodialysis, alteration of urinary pH) are 
             ineffective due to flupenthixol's large volume of 
             distribution, and a high degree of protein binding 
             (Jorgensen, 1980).
             
             In patients with neuroleptic malignant syndrome, 
             haemodialysis or peritoneal dialysis may be required for 
             renal failure (Tomson, 1986).
 
        10.6  Antidote treatment
 
             10.6.1  Adults
 
                    Not applicable.
 
             10.6.2  Children
 
                    Not applicable.
 
        10.7  Management discussion
 
             No discussion.
 
    11.  ILLUSTRATIVE CASES
 
        11.1  Case reports from literature
 
             (Note: There are very few cases of flupenthixol 
             overdose reported in the literature, and those tend to be 
             anecdotal. Other reports of overdose are available from NPIS 
             London's case files).
             
             Case 1
             
             Flupenthixol 18 to 20 mg (0.9 mg/kg) in a 3┤- year-old girl 
             caused drowsiness after 90 minutes, progressing to Grade III 
             coma after 3 hours. Gastric lavage was performed, without 
             result (following attempted emesis with salt water). 
             Consciousness improved over the next 20 hours without further 
             treatment.
 
 
 
             
             At 23 hours post-ingestion she started suffering a series of 
             episodes of extrapyramidal effects, which persisted for over 
             10 hours. These initially included neck extension and 
             catalepsy; then festinating gait and facial and body 
             rigidity; and finally (at 33 hours) dysphagia and salivation, 
             treated with orphenadrine 20 mg.  Recovery was complete by 48 
             hours (Bailie et al., 1981).
             
             Case 2
             
             An adult patient (age and weight not stated) took 90 mg 
             flupenthixol and suffered only mild extrapyramidal signs 
             (Mann, 1976).
 
        11.2  Internally extracted data on cases
 
             To be completed by each Centre using local data.
 
        11.3  Internal cases
 
             To be completed by each Centre using local data
 
    12.  ADDITIONAL INFORMATION
 
        12.1  Availability of antidotes
 
             Not applicable.
 
        12.2  Specific preventive measures
 
             No data available.
 
        12.3  Other
 
             Not applicable.
 
 
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    14.  AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), 
    COMPLETE ADDRESS(ES)
 
        Author      Mr N. Thompson MSc (Med Sci) DipInfSci BA
                    National Poisons Unit
                    Avonley Road
                    London SE14 5ER
                    United Kingdom
        
        Date                 March 1990
        
        Peer Review          Strasbourg, France, April 1990
        
        Update Peer Review   Berlin, Germany, October 1995
                             (Group members: Dr A. Jaeger, Dr C. Pulce, 
                             Dr G Volans)
 
    


    See Also:
       Toxicological Abbreviations