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Fluoxetine

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 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Properties
         3.3.3.1 Colour
         3.3.3.2 State/Form
         3.3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
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 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
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analyses
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analyses
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analyses
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological analysis and their interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple qualitative test(s)
         8.2.1.2 Advanced qualitative confirmation test(s)
         8.2.1.3 Simple quantitative method(s)
         8.2.1.4 Advanced quantitative method(s)
      8.2.2 Test for biological specimens
         8.2.2.1 Simple qualitative test(s)
         8.2.2.2 Advanced qualitative confirmation test(s)
         8.2.2.3 Simple quantitative method
         8.2.2.4 Advanced quantitative method(s)
         8.2.2.5 Other dedicated method(s)
      8.2.3 Interpretation of toxicological analysis
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analysis and toxicological 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 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 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.6.2 Children
   10.6 Management discussion
11. ILLUSTRATIVE CASES
   11.1 Case reports from literature
12. ADDITIONAL INFORMATION
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    FLUOXETINE

    International Programme on Chemical Safety
    Poisons Information Monograph 651
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Fluoxetine

        1.2  Group

             ATC: Nervous system
             Psychoanaleptic
             Antidepressant
             Selective serotonin reuptake inhibitor
             ATC code: N06AB03

             Straight chain phenylpropylamide structurally unrelated to
             the tricyclic antidepressants.

             (Dista Lab. Prod. Info., 1989).

        1.3  Synonyms

             LY-110140

        1.4  Identification numbers

             1.4.1  CAS number

                    54910-89-3

             1.4.2  Other numbers

                    Fluoxetine hydrochloride CAS number: 59333-67-4

        1.5  Main brand names, main trade names

             Adofen (Spain);
             Docutrix (Spain);
             Fluctin (Germany);
             Fluctine (Australia, Switzerland);
             Flunirin;
             Fluoxeren (Italy);
             Fluoxetin;
             Fluoxetina;
             Fontex;
             Fontisin;
             Ladose;
             Lovan;

             Prozac (Australia, Belgium, Canada, France, Italy,
             Netherlands, South Africa, Spain, U.K., U.S.A.);
             Prozyn (South Africa);
             Reneuron (Spain)

        1.6  Main manufacturers, main importers

             Dista (France)
             Ferrer (Spain)
             Hoechst (Germany)
             Juste (Spain)
             Lilly (U.S.A., Germany, Switzerland, UK)
             Menarini (Italy)

    2.  SUMMARY

        2.1  Main risks and target organs

             Fluoxetine is safer in overdose than most other classes
             of antidepressants. In overdosage, most patients experience
             only mild neurological and gastroenterological symptoms;
             significant cardiovascular toxicity is unusual.
    
             The serotonergic effects of fluoxetine may be enhanced by
             combination with other antidepressants, monoamine oxidase
             inhibitors, carbamazepine or lithium and produce a
             life-threatening serotoninergic syndrome comprising
             hyperthermia, tremor and convulsions.

        2.2  Summary of clinical effects

             Drowsiness, tremor, headache, blurred vision, dizziness,
             restlessness, and rarely, seizures and coma.
    
             Nausea, vomiting, abdominal pain.
    
             Bradycardia, mild hypertension or hypotension.

        2.3  Diagnosis

             Diagnosis of fluoxetine poisoning is clinical and based
             on history of overdose and/or access to fluoxetine, and the
             presence of minor neurological and/or gastroenterological
             symptoms. Alternative diagnoses should be considered when
             significant neurological or cardiovascular symptoms or signs
             are present.
    
             Diagnosis of the serotonergic syndrome should be considered
             in the presence of three or more of the following symptoms:
             behavioural change (confusion or hypomania), agitation,
             myoclonus, hyperreflexia, sweating, shivering, tremor,
             diarrhoea, motor incoordination, fever. The differential
             diagnosis includes neuroleptic malignant syndrome, acute with

             non-specific monoamine oxidase inhibitors or strychnine,
             acute sepsis, or severe metabolic disturbances.

        2.4  First aid measures and management principles

             Management of isolated fluoxetine overdose consists
             primarily of observation and basic supportive care until
             symptoms resolve. Doses of 40 to 800 mg produce minimal, if
             any, symptoms. Administration of activated charcoal is
             recommended following ingestions of greater than 800 mg.
    
             Treatment of the serotonergic syndrome requires more
             aggressive supportive care including diazepam, mechanical
             ventilation and, if necessary, curarization. Although several
             deaths are reported, the symptoms usually resolve within 1 to
             2 days with supportive treatment.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Obtained by synthesis.

        3.2  Chemical structure
    
             Structural formula:

    STRUCTURAL FORMULA 1

    
             Molecular formula:  C17H18F3NO, HCl
    
             Molecular weight:   345.8 (Base: 302.3)
    
             Structural name:    (dl)-N-Methyl-3-phenyl-3-
                                 (alpha,alpha,alpha-trifluoro-p-
                                 tolyloxy)propylamine
                                 hydrochloride.

        3.3  Physical properties

             3.3.1  Properties

                    3.3.3.1  Colour

                             White

                    3.3.3.2  State/Form

                             Crystals. Crystalline powder.

                    3.3.3.3  Description

                             Melting point:157.5 to 158.7C
                             Solubility in: water: 50 mg/mL at 25C
                                            methanol: 250 mg/mL
                                            chloroform: 125 mg/mL
                             Insoluble in hexane, ethyl acetate and
                             benzene.
                             pH 4.35 (aqueous saturated solution).

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    5 years at 15 to 25C.

             3.4.2  Storage conditions

                    Stable at 40C and 75% humidity in polyethylene
                    bottles or foil packs for at least five years.

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

                    Accepted:               Major mental depression
                                            Obsessive compulsive disorder
    
                    Investigational:        Pain syndromes
                                            Panic disorder
                                            Sleep disorders
                                            Eating disorders

        4.2  Therapeutic dosage

             4.2.1  Adults

                    Usual dose: 20 mg daily; doses of up to 80 mg
                    daily in divided doses may be employed if necessary
                    (Dista Lab. Prod. Info., 1989; Reynolds, 1995; Vidal,
                    1996).
    

                    Recommended maximum dose for elderly patients: 60 mg
                    daily.
    
                    Lower doses and/or alternate-day dosing have been
                    recommended in patients with significant hepatic
                    impairment (Reynolds, 1995).

             4.2.2  Children

                    Fluoxetine is presently regarded as
                    contraindicated for use in children. However, some
                    studies suggest it may have a role in the management
                    of major depression, anxiety and obsessive-compulsive
                    disorders in children (Geller et al., 1995).

        4.3  Contraindications

             Absolute:       Hypersensitivity to fluoxetine
                             Children under 15 years old
                             Coadministration of sumatriptan, non-specific
                             monoamine oxidase inhibitors and B-specific
                             monoamine oxidase inhibitors.
    
             Relative:       Combination therapy with A-specific monoamine
                             oxidase inhibitors or other
                             antidepressants
                             Pregnancy
                             Lactation

    5.  ROUTES OF ENTRY

        5.1  Oral

             Fluoxetine is administered orally.

        5.2  Inhalation

             Not relevant.

        5.3  Dermal

             Not relevant.

        5.4  Eye

             Not relevant

        5.5  Parenteral

             Not relevant

        5.6  Other

             No data available.

    6.  KINETICS

        6.1  Absorption by route of exposure

             Fluoxetine hydrochloride is readily absorbed from the
             gastrointestinal tract with peak plasma concentrations
             appearing from 6 to 8 hours after oral administration.
    
             Peak levels for 30 mg, 60 mg, and 75 mg doses were 30.1
             ng/mL, 93.0 ng/mL and 134.6 ng/mL respectively  (Saletu &
             Grunberger, 1985).
    
             The systemic bioavailability is greater than 85 % and does
             not appear to be affected by food (Dista lab. Prod. Inf.,
             1989).

        6.2  Distribution by route of exposure

             Fluoxetine is widely distributed throughout the body. 
             Plasma protein binding is 94 %.
    
             The volume of distribution is highly variable, ranging from
             11 to 88 L/kg.

        6.3  Biological half-life by route of exposure

             Fluoxetine has a relatively long and highly variable
             half-life ranging from 1 to 4 days after a single dose and
             averaging nearly 70 hours; patients receiving high doses over
             long periods of time may exhibit prolonged elimination
             half-lives.
    
             The half-life of its active metabolite, norfluoxetine, is
             about 7 to 9 days.

        6.4  Metabolism

             Fluoxetine is extensively metabolized in the liver to a
             desmethyl metabolite, norfluoxetine, which has activity
             similar to fluoxetine.
    
             Peak plasma concentrations of the active metabolite,
             norfluoxetine, occur around 76 hours after ingestion.

        6.5  Elimination and excretion

             The primary route of elimination appears to be further
             hepatic metabolism to inactive metabolites which are
             conjugated and then excreted in the urine.

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1   Mode of action

             7.1.1  Toxicodynamics

                    Fluoxetine is a potent inhibitor of serotonin
                    re-uptake by Central Nervous System neurones and may
                    interact with other drugs or circumstances which cause
                    serotonin release. The enhancement of the serotonergic
                    effects may produce a life-threatening serotonin
                    syndrome.

             7.1.2  Pharmacodynamics

                    Fluoxetine specifically inhibits neuronal
                    re-uptake of serotonin, thus increasing the
                    concentration of the serotonin at the synapse and
                    reinforcing of serotonergic neuronal transmission.
    
                    Fluoxetine has little effect on other
                    neurotransmitters.
    
                    Fluoxetine has no direct effect on the heart (Dista
                    lab. Prod. Inf., 1989). 
    
                    Fluoxetine inhibits liver drug-metabolising enzymes
                    including CYP IID6, CYP IA2 and CYP IIIA4 (Lane et
                    al., 1995).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Estimated minimum lethal exposure:
                             1200 to 2000 mg (Kincaid et al., 1990).
    
                             Maximum tolerated exposure: 300 to 400 mg
                             with no co-ingestant.

                    7.2.1.2  Children

                             A 12-year-old boy ingested 1888 mg 
                             (26 mg/kg) and experienced seizures and

                             minimal ECG changes (Riddle et al.,
                             1989).
    
                             A 4-year-old child ingested 43 mg/kg and
                             experienced unresponsiveness, sinus
                             tachycardia, moderate psychomotor agitation
                             and dyskinesia (Feierabend, 1995).
    
                             The highest dose at which no toxicity was
                             observed is 3.6 mg/kg (Borys et al.,
                             1990).

             7.2.2  Relevant animal data

                    Lethal seizures occurred in 50% of various
                    animals given 200 to 700 mg/kg. The exact dose needed
                    is species dependent (Dista lab. Prod. Inf.,
                    1989).

             7.2.3  Relevant in vitro data

                    No data available.

        7.3  Carcinogenicity

             Human studies: there is no evidence of carcinogenicity
             in patients taking fluoxetine.
    
             Animal studies: fluoxetine was not carcinogenic in rats and
             mice at doses ten times the recommended daily dose for 24
             months (Dista lab. Prod. Info., 1989).

        7.4  Teratogenicity

             Animal studies: in rats, fluoxetine and norfluoxetine
             cross the placenta and distribute within the fetus during the
             periods of organogenesis and postorganogenesis (Pohland et
             al., 1989). Levels in fetal tissue are approximately half the
             corresponding maternal concentrations.
    
             Fluoxetine does not impair the fetal growth in rats or
             rabbits at doses nine and eleven times the maximum daily
             human dose respectively (Dista lab. Prod. Info., 1989).
    
             Human studies: a study of 128 women exposed to fluoxetine
             during the first trimester showed no increase in major fetal
             malformations. It is not known, however, if the drug is a
             human teratogen (Pastuszak et al., 1993).
    

             A neonate whose mother had been taking fluoxetine during most
             of her pregnancy sufferred tachypnoea, emesis, continuous
             crying, irritability, tremor and increased muscle tone; the
             symptoms resolved within 96 hours (Spencer, 1993).
    
             Fluoxetine and norfluoxetine are excreted in breast milk
             (Burch & Wells, 1992); the effects on the infant are
             uncertain. Caution should be exercised when fluoxetine is
             administered to a nursing mother (Dista lab. Prod.Info.,
             1989).

        7.5  Mutagenicity

             In vitro: fluoxetine and norfluoxetine did not show
             mutagenicity in the Ames test. There was no induction of
             sister-chromatid exchange in the bone marrow of the chinese
             hamster (Dista lab. Pro.Info., 1989).

        7.6  Interactions

             Drug interactions with fluoxetine have been reported
             with L-tryptophan, L-dopa; monoamine oxidase inhibitors:
             selegiline, tranylcypromine; tricyclic antidepressants;
             selective serotonin re-uptake inhibitors: trazodone,
             zimeldine; benzodiazepines: alprazolam, diazepam; buspirone,
             lithium, anticonvulsants: carbamazepine, phenytoin,
             valproate; pentazocine, dextromethorphan, fenfluramine,
             calcium channel blockers, benztropine, cyproheptadine,
             clarithromycin (Pollak et al., 1995), and substances of
             abuse: cannabis, ethanol, LSD (Jackson & Hornfeldt, 1991;
             Messiha, 1993).
    
             At least 14 days should elapse between discontinuing a
             MAO-inhibiting antidepressant and introducing fluoxetine. 
             Conversely, because of the long half-life of fluoxetine and
             its metabolite, norfluoxetine, it is recommended that at
             least 5 weeks should elapse between discontinuation of
             fluoxetine and the introduction of a MAO inhibitor (Dista
             lab. Prod. Info., 1989).

        7.7  Main adverse effects

             The major adverse effects reported with therapeutic
             doses of fluoxetine are primarily those of headache,
             insomnia, nausea, and nervousness, with a prevalence of 15 to
             23 %. Less common adverse effects include tremors, sweating,
             dry mouth, anxiety, drowsiness, and diarrhoea, with a
             prevalence of 10 to 14 % (Messiha, 1993).

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                             Toxic ingredient: liquids, capsules,
                             scene residues
                             In case of ingestion: 
                                            Vomitus: total amount
                                            Gastric aspirate: total amount
                                            (or gastric lavage: first
                                            portion: 100 mL)
                             Whole blood without additives: 10 mL
                             Urine: random specimen: 50 mL

                    8.1.1.2  Biomedical analyses

                             Plasma (lithium heparin as
                             anticoagulant) or serum and urine for
                             standard biochemical analyses.

                    8.1.1.3  Arterial blood gas analyses

                             Heparinized arterial blood sample
                             (in severe cases).

                    8.1.1.4  Haematological analyses

                             Anticoagulated blood (e.g. EDTA) for
                             standard haematological analyses and
                             differential blood picture.

                    8.1.1.5  Other (unspecified) analyses

                             No further materials.

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                             Serum, urine and other materials in
                             a refrigerator (4C).

                    8.1.2.2  Biomedical analyses

                             No special requirements, but as
                             usually performed.

                    8.1.2.3  Arterial blood gas analyses

                             No special requirements, but as
                             usually performed.

                    8.1.2.4  Haematological analyses

                             No special requirements, but as
                             usually performed.

                    8.1.2.5  Other (unspecified) analyses

                             Not applicable.

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                             No special requirements, but as
                             usually performed.

                    8.1.3.2  Biomedical analyses

                             No special requirements, but as
                             usually performed.

                    8.1.3.3  Arterial blood gas analyses

                             No special requirements, but as
                             usually performed.

                    8.1.3.4  Haematological analyses

                             No special requirements, but as
                             usually performed.

                    8.1.3.5  Other (unspecified) analyses

                             Not applicable.

        8.2  Toxicological analysis and their interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple qualitative test(s)

                    8.2.1.2  Advanced qualitative confirmation test(s)

                    8.2.1.3  Simple quantitative method(s)

                    8.2.1.4  Advanced quantitative method(s)

             8.2.2  Test for biological specimens

                    8.2.2.1  Simple qualitative test(s)

                    8.2.2.2  Advanced qualitative confirmation test(s)

                    8.2.2.3  Simple quantitative method

                    8.2.2.4  Advanced quantitative method(s)

                    8.2.2.5  Other dedicated method(s)

             8.2.3  Interpretation of toxicological analysis

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             Sodium, potassium, chloride,
                             calcium, magnesium Glucose, amylase, creatine
                             kinase, creatinine (urea) Optional:
                             bicarbonate (or total CO2), uric
                             acid

                    8.3.1.2  Urine

                    8.3.1.3  Other fluids

                             No dedicated test.

             8.3.2  Arterial blood gas analyses

                    pH, pCO2, pO2, base excess, actual HCO3-,
                    and O2-saturation.

             8.3.3  Haematological analyses

                    Complete blood count, including platelets,
                    haematocrit.
                    Differential blood picture.

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

             Serum electrolytes, urea and creatinine, liver function
             tests, amylase, creatine kinase and arterial blood gases are
             useful to optimize supportive care.

        8.5  Overall interpretation of all toxicological analysis and
             toxicological investigations

             Analysis of Materials
    
             Fluoxetine is not easily detected in materials by simple
             physicochemical tests. The UV spectrum in methanol gives
             deltamax  at 227 nm; A| = 372 (Risley & Bopp, 1990).  Using
             thin layer chromatography, the drug can be visualized with
             Mandelin's reagent (pale grey). In methanol ammonia (100:1.5)
             the Rf is 0.24, and in ethyl acetate / methanol / ammonia
             (85:15:5) the Rf is 0.50 (personal experience). Gas
             chromatography is also useful, and the retention index for
             fluoxetine is 1950 on SE54, SE30, OV1 or HP5 or similar.
             Flame ionization detection has sufficient sensitivity for
             residues; electron capture or nitrogen-phosphorus detection
             give improved selectivity.
    
             Analysis of Biological Specimens
    
             Confirmation of the presence of fluoxetine may be useful in
             some instances to confirm the diagnosis of intoxication, or
             to explain the occurrence of serotonergic syndrome. 
             Measurement of serum concentrations is not usual clinical
             practice.  There are no commonly-available immunoassay kits
             for drug testing (including those for tricyclic
             antidepressants) which respond to fluoxetine. Extraction of
             fluoxetine and norfluoxetine from biological specimens is
             easily achieved by pH adjustment to 8 to 12, and addition of
             an organic solvent (ethyl acetate, hexane / iso-amyl alcohol
             etc.).  Cleaning by back-extraction into dilute sulphuric
             acid may be necessary for low concentrations.  Thin layer
             chromatography is applicable to the analysis of gastric
             contents and urine. In methanol / ammonia (100:1.5) the Rf of
             fluoxetine is 0.24, and 0.30 for norfluoxetine; in ethyl
             acetate / methanol / ammonia (85:15:5) the Rf is 0.50 for
             both compounds (personal experience).  Both compounds can be
             visualized with Mandelin's reagent (pale grey), and give a
             positive iodoplatinate reaction. 
    
             Advanced Methods of Analysis
    
             Gas chromatography can be performed without derivatization by
             many methods which are suitable for analysis of other
             antidepressant drugs, from which both fluoxetine and
             norfluoxetine are well separated (run earlier than
             amitriptyline).  Care should be taken to ensure separation
             from caffeine, especially on nitrogen-phosphorus detection. 
             Isothermal analysis on OV1 or HP1 gives good separation at

             180C within 5 minutes (Rohrig & Prouty, 1989).  DB5 and DB17
             are also useful.  FID is adequate for overdose concentrations
             (0.02 mg/L), but nitrogen-phosphorus (Kincaid et al., 1990;
             Fontanille et al., 1997) and electron capture detection
             (Dixit et al., 1991) both give improved sensitivity (0.001 to
             0.005 mg/L from 1 mL sample).  Derivatization of both
             compounds with butyric anhydride gives more characteristic
             spectra on GCMS, particularly for fluoxetine (Kincaid et al.,
             1990).
    
             HPLC is commonly used for quantitative serum measurements. 
             Good chromatography over 8 minutes was obtained using C8
             column with a mobile phase of triethylamine acetate (10 mL/L,
             pH to 5.5 with glacial acetic acid) / acetonitrile (65:35)
             mobile phase (Nichols et al., 1994), or with 0.067M potassium
             dihydrogenphosphate buffer / acetonitrile (70:30) (Thomare et
             al., 1992).  Both methods use UV detection at 228 nm and give
             sensitivity of 0.01 mg/L and 0.002 mg/L respectively. 
             Alternatively, excellent separation was seen over 12 minutes
             on a C18 column with high sensitivity (<0.005 mg/L) by
             pre-column derivatization with dansyl chloride and
             fluorescence detection (Suckow et al., 1992).
    
             Chiral analysis of fluoxetine and norfluoxetine is possible
             after derivatization with the chiral reagent,
             (S)-(-)-N-trifluoroacetylprolyl chloride followed by gas
             chromatography on DB5 with electron capture detection
             (Torok-Both et al., 1992).
    
             Toxicity is not well correlated with fluoxetine
             concentration, and toxicity can often be attributed to other
             causative agents.  Serotonergic syndromes may occur with
             relatively low fluoxetine concentrations (<0.1 mg/L).  As a
             guide, typical concentrations of fluoxetine in serum are:
    
                                                                       
                                                mg/L         mol/L
             Peak after single oral dose
             (30 - 75 mg)
             6 - 8 hours                        0.03 - 0.13  0.1- 0.43
             Steady-state in therapy
                    fluoxetine                  <0.3         <1.0
                    norfluoxetine               <0.7         <2.33
             Serious toxicity possible          >0.5         >1.67
                                                                       
    
             Serum concentrations of 1 to 2 mg/L have been reported
             without serious toxicity.
    

             Serum electrolytes, urea and creatinine and arterial blood
             gases are useful to optimize supportive care.

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Blurred vision, nausea, vomiting, abdominal
                    pain, diarrhoea, lethargy, dizziness, insomnia,
                    tremors, and rarely, seizures and coma.
    
                    Significant cardiovascular toxicity is unusual. 
                    Effects have included mild hypo- or hypertension,
                    tachycardia, and ventricular dysrhythmia.
    
                    Co-ingestion of serotonin-reuptake inhibitors can
                    result in aggressive behaviour, confusion, tremor,
                    restlessness, shivering, diaphoresis, hyperthermia,
                    diarrhoea, and myoclonus.

             9.1.2  Inhalation

                    Not relevant.

             9.1.3  Skin exposure

                    Not relevant.

             9.1.4  Eye contact

                    Unknown.

             9.1.5  Parenteral exposure

                    No data available.

             9.1.6  Other

                    No data available.

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    No data available.

             9.2.2  Inhalation

                    Not relevant.

             9.2.3  Skin exposure

                    Not relevant.

             9.2.4  Eye contact

                    No data available.

             9.2.5  Parenteral exposure

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             The clinical course of fluoxetine poisoning is generally
             very mild in nature and of short duration. Complete and rapid
             recovery is the rule. A few deaths have been reported in the
             forensic literature, seemingly after ingestion of very high
             doses.  Most involved co-ingestants and all are poorly
             documented (Kincaid et al., 1990).

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

                    Sinus tachycardia, bradycardia (Feder, 1991),
                    hypotension, mild hypertension, ECG changes especially
                    QT interval prolongation and ventricular dysrhythmias. 
                    Patients with preexisting cardiovascular disease or
                    taking cardiac medications may be at greater risk of
                    developing fluoxetine cardiotoxicity (Ellison et al.,
                    1990).

             9.4.2  Respiratory

                    Dyspnea, cough and flu-like symptoms have been
                    reported (Kim & Pentel, 1989).
    
                    Induction of dyspnoea and coughing in a female smoker
                    has been attributed to a fluoxetine-nicotine
                    interaction. Dyspnoea, cough and flu-like symptoms
                    have been reported (Bass & Colebatch, 1992).

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                             Drowsiness, headache, restlessness,
                             delirium, insomnia, ataxia, extrapyramidal
                             syndrome (Baldwin et al., 1991; Eisenhauer &
                             Jermain, 1993), coma and seizures.
    
                             Psychiatric: manic and hypomanic states.  It
                             has also been suggested that fluoxetine may
                             induce suicidal ideation in a small subset of
                             patients (Crundwell, 1993; Tueth,
                             1994).

                    9.4.3.2  Peripheral nervous system

                             Blurred vision.

                    9.4.3.3  Autonomic nervous system

                             Bradycardia or tachycardia.

                    9.4.3.4  Skeletal and smooth muscle

                             Tremor, myoclonus, dystonia.

             9.4.4  Gastrointestinal

                    Abdominal pain, nausea, vomiting, diarrhoea. 
                    Anorexia leading to weight loss.

             9.4.5  Hepatic

                    Mild liver enzyme disturbances are reported
                    (Bobichon et al., 1993; Castiella & Arenas,
                    1994).

             9.4.6  Urinary

                    9.4.6.1  Renal

                             No data available.

                    9.4.6.2  Other

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    Fluoxetine may alter glycaemic control in
                    diabetic subjects.
    

                    Fluoxetine is associated with the syndrome of
                    inappropriate secretion of antidiuretic hormone
                    (Staab, 1990).
    
                    Sexual disorders: anorgasmia, penile anaesthesia,
                    sexual arousal (Modell, 1989; Morris, 1991; Measom,
                    1992).

             9.4.8  Dermatological

                    Skin rash, pruritus, urticaria, psoriasis,
                    photosensitivity reactions, alopecia (Hemlock et al.,
                    1992; Gupta et al., 1993; Ogilvie, 1993; Gaufberg &
                    Ellison, 1995; O'Brien, 1995; Roger et al.,
                    1995).

             9.4.9  Eye, ear, nose, throat: local effects

                    Voice disorder (Murray, 1995).

             9.4.10 Haematological

                    Abnormal platelet aggregation, prolongation of
                    the bleeding time (Humphries et al., 1990; Alderman et
                    al., 1992; Aranth & Lindberg, 1992).

             9.4.11 Immunological

                    Skin rashes (Gupta et al., 1993), angioedema,
                    serum sickness and anaphylactoid reactions have been
                    reported (Roger et al., 1995).

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             Acidosis is expected in association
                             with coma and/or convulsions.

                    9.4.12.2 Fluid and electrolyte disturbances

                             Several cases of hyponatraemia,
                             hypo-osmolarity and syndrome of inappropriate
                             secretion of antidiuretic hormone have been
                             reported (Staab, 1990).

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    Skin rashes.

             9.4.14 Other clinical effects

                    Stuttering (Guthrie & Grunhaus, 1990).

             9.4.15 Special risks

                    The safety of fluoxetine during pregnancy and
                    lactation is not established (see section
                    7.4).

        9.5  Other

             Several cases of fluoxetine withdrawal syndrome have
             been described, occurring from one to seven days after
             discontinuation of the medication.  Symptoms included
             vertigo, dizziness, light-headedness, irritability, anxiety,
             headache, sweating, and nausea (Einbinder, 1995; Berlin,
             1996).

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             The primary management of isolated fluoxetine overdose
             consists of institution of appropriate observation and
             supportive care.  In most cases, this consists of no more
             than careful observation of vital signs and neurological
             status until signs and symptoms resolve.  Intravenous access
             should be established as soon as practicable.  In more severe
             intoxications or where there is a co-ingestion, more
             aggressive measures such as establishment of an airway,
             ventilation, administration of intravenous fluids, control of
             seizures, and control of hyperthermia may be
             necessary.

        10.2 Life supportive procedures and symptomatic/specific
             treatment

             Intensive supportive care is rarely required.  Measures
             that may occcasionally be required are: endotracheal
             intubation and/or artificial ventilation if coma is present,
             intravenous fluid resuscitation if hypotension is present,
             control of seizures, cooling if hyperthermia is present
             (refer to appropriate treatment guides for more detailed
             management guidance).

        10.3 Decontamination

             Gastrointestinal decontamination by administration of a
             single dose of oral activated charcoal may be indicated
             following ingestion of more than 800 mg of fluoxetine by an
             adult presenting within two hours, or where there has been a
             significant co-ingestion.

        10.4 Enhanced elimination

             There are no effective methods known to enhance the
             elimination of fluoxetine.

        10.5 Antidote treatment

             10.5.1 Adults

                    No data available.

             10.6.2 Children

                    No data available.

        10.6 Management discussion

             Although of theoretical benefit, the role of dantrolene
             in the management of the serotonergic syndrome has yet to be
             evaluated.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             A 15-year-old female ingested forty five 20 mg
             fluoxetine tablets.  Ten hours later, she was found jerking,
             frothing at the mouth and with a staring gaze.  On arrival at
             hospital thirty minutes later, she had a normal level of
             consciousness.  She denied the ingestion of any other
             medications and had no previous history of seizures or
             trauma.  Physical examination and all routine laboratory
             studies were unremarkable.  Comprehensive drug screening did
             not detect the presence of any other substances.  Serum
             fluoxetine and norfluoxetine concentrations were 1956 ng/mL
             and 416 ng/mL respectively (Braitberg & Curry, 1995).
    
             A 4-year-old child ingested 43 mg/kg of fluoxetine.  Toxic
             effects consisted of a brief period of unresponsiveness,
             sinus tachycardia and moderate psychomotor agitation and
             dyskinesia.  The child recovered completely with supportive
             care (Feierabend, 1995).
    

             A 40-year-old female developed a classical serotoninergic
             syndrome with severe hyperthermia (43C) eight hours after
             ingesting 340 mg fluoxetine, 6000 mg moclobemide, 300 mg
             clomipramine and 12 mg clonazepam. She died from the
             subsequent complications of fulminant disseminated
             intravascular coagulation and multiple organ failure (Power
             et al., 1995).
    
             A patient being treated with carbamazepine 200 mg/day for an
             affective disorder, developed a serotonergic syndrome 14 days
             following institution of fluoxetine therapy at a dose of 20
             mg/day.  In addition to features of the serotonergic
             syndrome, she reported dizziness, experienced an oculogyric
             crisis, and developed leucopenia and thrombocytopenia.  She
             made a complete recovery within 72 hours of the
             discontinuation of fluoxetine (Dursun et al., 1993).

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

        12.2 Other

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

        Author:     M.O. Rambourg Schepens,
                    Centre Anti-Poisons,
                    Hpital Maison Blanche,
                    45 Rue Cognacq-Jay
                    F-51092 REIMS Cedex, France,
    
                    Tel:     33-326862686
                    Fax:     33-326865548
                    E-mail:  marie-odile.rambourg@wanadoo.fr
    
        Date:       August 1996.

        Reviewer:   L.M. Murray,
                    Department of Emergency Medicine,
                    Prince of Wales Hospital,
                    Randwick, NSW, Australia.
    
        Peer
        review:     Cardiff, United Kingdom, September 1996
                    (A. Borges, R. Ferner, M. Hanafy, M. Kowalczyk, L.
                    Murray, M.O. Rambourg Schepens)

    
        Author
        Section 8:  Dr S. Dawling
                    Center for Clinical Toxicology
                    Vanderbilt University Medical Center
                    501 Oxford House
                    1161 21st Avenue South
                    Nashville, TN 37232-4632
                    United States of America
    
                    Tel:     1-615-9360760
                    Fax:     1-615-9360756
                    E-mail:  sheila.dawling@mcmail.vanderbilt.edu
    
        Date:       March 1998
    
        Editors:    Dr M. Ruse (April 1997); Mrs J. Dumnil (May 1999)
    


    See Also:
       Toxicological Abbreviations