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Sertraline

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 Colour
      3.3.2 State/Form
      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 EXPOSURE
   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 ANALYSIS AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analysis
         8.1.1.2 Biomedical analysis
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analysis
         8.1.1.5 Other (unspecified) analysis
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analysis
         8.1.2.2 Biomedical analysis
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analysis
         8.1.2.5 Other (unspecified) analysis
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analysis
         8.1.3.2 Biomedical analysis
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analysis
         8.1.3.5 Other (unspecified) analysis
   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 analysis
      8.3.3 Haematological analysis
      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
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system
         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
      10.5.2 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)
    SERTRALINE

    International Programme on Chemical Safety
    Poisons Information Monograph 177
    Pharmaceutical

    1.  NAME

        1.1  Substance

             Sertraline

        1.2  Group

             Psycholeptics (N06)/Antidepressants (N06A)/
             Bicyclic derivatives (N06A B06)

        1.3  Synonyms

             CP-51974-01; CP-51974-1

        1.4  Identification numbers

             1.4.1  CAS number

                    79617-96-2

             1.4.2  Other numbers

                    CAS sertraline hydrochloride: 79559-97-0

        1.5  Main brand names, main trade names

             Zoloft (Australia, Canada, Italy, France, South Africa,
             Switzerland, USA);
             Serlain (Belgium);
             Serad (Italy);
             Tatig (Italy);
             Gladem (Switzerland);
             Lustral (UK)

        1.6  Main manufacturers, main importers

             Pfizer

    2.  SUMMARY

        2.1  Main risks and target organs

             Sertraline is a selective serotonin reuptake inhibitor
             (SSRI). When taken alone it is safer in overdose than most
             other classes of antidepressants. Patients who ingest a
             sertraline overdose generally experience only mild

             neurological and gastroenterological symptoms; significant
             cardiovascular toxicity is unusual.
             The serotonergic effects of sertraline may be enhanced when
             sertraline is combined with tricyclic antidepressants,
             monoamine oxidase inhibitors (MAOIs), carbamazepine, lithium
             or serotonergic substances. A life-threatening serotonin
             syndrome consisting of hyperthermia, tremor and convulsions
             can develop when sertraline is ingested with these
             drugs.

        2.2  Summary of clinical effects

             Lightheadness, drowsiness, tremor in upper extremities;
             nausea, vomiting, diarrhea.

        2.3  Diagnosis

             Diagnosis of sertraline poisoning is clinical and based
             on history of overdose and/or access to sertraline and the
             presence of minor neurological and/or gastroenterological
             symptoms.
             Co-ingestion of tricyclic antidepressants and/or MAOIs should
             be suspected and the diagnosis of the serotonin syndrome
             should be considered in the presence of three or more of the
             following symptoms: behavioural change (confusion or
             hypomania), agitation, myoclonus, ocular clonus, sustained
             ankleclonus, hyperreflexia, sweating, shivering, tremor,
             diarrhea, motor incoordination, muscle rigidity, fever. The
             differential diagnoses include neuroleptic malignant
             syndrome, acute poisoning with strychnine, acute sepsis, or
             severe metabolic disturbance.

        2.4  First aid measures and management principles

             Management of isolated sertraline overdose consists
             primarily of observation and basic supportive care until
             symptoms resolve. Doses of up to 4500 mg produce minimal, if
             any, symptoms in adult patients. Treatment of the serotonin
             syndrome may require aggressive supportive care including
             diazepam, mechanical ventilation, external cooling and if
             necessary, curarization.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Obtained by synthesis

        3.2  Chemical structure

             Structural name:
             (1S, 4S)-4-(3, 4-dichlorophenyl)-1, 2, 3, 4-tetrahydro-1-
             naphtyl (methyl) amine hydrochloride
    

             Molecular formula: C17NCl2H17
    
             Molecular weight: 342.7

        3.3  Physical properties

             3.3.1  Colour

                    White

             3.3.2  State/Form

                    Solid-crystal
                    Solid-powder

             3.3.3  Description

                    Sertraline hydrochloride
                    Solubility:
                    water = 3.8 mg/ml at 25 C, pH 5.3
                    isopropyl alcohol= slightly soluble

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

                    5 years at 20 C

             3.4.2  Storage conditions

                    Keep at a temperature < 30 C, and away from
                    humidity in polyethylene bottles or foil
                    packs.

    4.  USES

        4.1  Indications

             4.1.1  Indications

                    Psychoanaleptic Antidepressant
                    Bicyclic antidepressant

             4.1.2  Description

                    Accepted:
                    Major mental depression.
                    Prevention of relapse and recurrence of depression.
                    Investigational:
                    Obsessive compulsive disorders (Greist et al., 1995).
                    Headache (Solomon & Pearson, 1994).
                    Sexual disfunction (Mendels et al., 1995).
                    Eating disorder (Robert & Lydiard, 1993).
    

                    Mental retardation and autistic disorder (Hellings et
                    al., 1996).
                    Premenstrual dysphoric disorder (Yonkers et al.,
                    1996).

        4.2  Therapeutic dosage

             4.2.1  Adults

                    For the treatment of depression and prevention
                    of its recurrence, usual initial dosage is 50 mg daily
                    by mouth, as a single dose, after food, in the morning
                    or the evening. This may be increased gradually if
                    necessary in 50 mg increments, at intervals of at
                    least 1 week, to 200 mg daily.
                    Doses of 150 mg daily or more should not be given for
                    longer than 8 weeks. Once the optimal therapeutic
                    response is obtained, dosage should be reduced to the
                    lowest effective level for maintenance, which is
                    usually 50 mg daily (Reynolds, 1996).
                    No specific dosage adjustments are required in elderly
                    patients, but more careful clinical monitoring is
                    recommended at the beginning of the treatment.
                    Dosage should be reduced by half the normal dosage in
                    patients with significant hepatic impairment (Pfizer
                    lab., 1996).

             4.2.2  Children

                    Not indicated

        4.3  Contraindications

             Absolute:
             Hypersensitivity to sertraline.
             Children less than 15 years old.
             Co-administration of sumatriptan, non selective monoamine
             oxidase inhibitor (MAOI) and MAOI B-selective
             antidepressants.
             Relative:
             Co-administration of MAOI A-selective antidepressants.
             Pregnancy (absence of available data)
             Breast feeding (Pfizer lab., 1996).

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             Sertraline is available as capsules, thus ingestion is
             the most common route of exposure.

        5.2  Inhalation

             Not relevant

        5.3  Dermal

             Not relevant

        5.4  Eye

             Not relevant

        5.5  Parenteral

             No data available

        5.6  Other

             No data available

    6.  KINETICS

        6.1  Absorption by route of exposure

             Sertraline is slowly and completely absorbed from the
             gastrointestinal tract.
             Peak plasma concentrations (Cmax) occur between 4.5 and 8.5
             hours after ingestion of a single 100 mg dose.
             The presence of food slightly increases sertraline
             bioavailability and Cmax increases by 25 % (Murdoch & Mac
             Tavish, 1992).
             Sertraline undergoes extensive first pass metabolism in the
             liver.

        6.2  Distribution by route of exposure

             Widely distributed throughout body tissues and highly
             bound to plasma proteins (about 98 %). The apparent volume of
             distribution is 20 L/kg.
             The plasma sertraline level was reported to be 20 to 48 g/L
             after at least 1 week of treatment with 100 mg sertraline
             daily, and it ranged from 40 to 187 g/L after 200 mg (Gupta
             & Dziurdzy, 1994). Plasma sertraline concentrations increase
             proportionally to the administered dose, unlike fluoxetine
             and paroxetine (Preskorn, 1994).
             Cmax and area under the plasma concentration-time curve
             values are increased, and elimination half-life is prolonged
             in elderly patients but these changes do not appear to
             warrant dose adjustment in this patient group (Murdoch & Mac
             Tavish, 1992; Pfizer lab., 1996).

        6.3  Biological half-life by route of exposure

             After oral doses, plasma half-life is 24 to 26 hours.

        6.4  Metabolism

             Sertraline is extensively metabolized in the liver to
             N-desmethylsertraline, whose half-life is 2 to 3 times longer
             than sertraline. N-desmethylsertraline is 10 times less
             active as an inhibitor of serotonin re-uptake in vitro, and
             has almost no activity in animal models (Ronfeld et al.,
             1988).

        6.5  Elimination and excretion

             N-desmethylsertraline is oxidatively deaminated to
             desmethylsertraline ketone which, in turn, undergoes
             hydroxylation to an alpha-hydroxyketone and alcohol; these
             metabolites are then conjugated and excreted in equal amounts
             in the urine and faeces; a small amount of unchanged drug
             (less than 0.2 %) is excreted in the urine (Murdoch & Mac
             Tavish, 1992).
             There are few data about the excretion of sertraline and its
             metabolites in breast milk; Altshuler et al. (1995) did not
             detect sertraline in the serum of an infant exclusively
             breastfed by his mother, after 3 weeks and 7 weeks of
             treatment, although sertraline could be detected in breast
             milk.

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

                    Sertraline 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.
                    Sertraline, like the other SSRIs fluoxetine and
                    paroxetine, can inhibit in vivo and in vitro, the
                    hepatic isoenzyme 2D6 of the cytochrome P450 system
                    (CYP2D6), which is involved in the oxidative
                    metabolism of numerous drugs (Riesenman, 1995).
                    Caution should be used when combining sertraline with
                    CYP2D6 substrates (desipramine, nortriptyline,
                    haloperidol, thioridazine, flecainide, codeine,
                    propranolol, metoprolol), as sertraline can cause a
                    significant increase in the serum concentrations of
                    these drugs.
    

                    In vitro studies suggest that sertraline may be a
                    substrate for, but does not inhibit another hepatic
                    isoenzyme of the cytochrome P450 sytem, CYP3A3/4
                    (Rapeport et al., 1996), which is involved in the
                    metabolism of carbamazepine. A study performed in
                    healthy volunteers showed no evidence of a
                    pharmacodynamic drug-drug interaction between
                    sertraline and carbamazepine (Rapeport et al.,
                    1996).

             7.1.2  Pharmacodynamics

                    Sertraline specifically inhibits central
                    nervous system neuronal re-uptake of serotonin, thus
                    increasing the concentration of the serotonin at the
                    synapse and enhancing of serotonergic neuronal
                    transmission. The increased availability of serotonin
                    is thought to be linked with the improvement in
                    depression accounted for by sertraline treatment.
                    Sertraline has no direct effect on the re-uptake of
                    noradrenaline, dopamine or GABA. Unlike most tricyclic
                    antidepressants, it has no significant affinity for
                    alpha1-adrenergic, H1-histamine, and muscarinic
                    receptors. Furthermore, sertraline does not show
                    significant affinity for D1 and D2 dopaminergic,
                    alpha2 and  adrenergic, benzodiazepine and opioid
                    receptors. The selectivity of sertraline may account
                    for the lower incidence of some adverse effects such
                    as sedation, orthostatic hypotension and
                    anticholinergic effects (Pfizer lab., 1996).
                    Like tricyclic antidepressants, MAOIs, and other
                    SSRIs, sertraline significantly reduces REM (rapid eye
                    movement) sleep density, REM time and the REM
                    percentage of total sleep time in patients with major
                    depression (Murdoch & Mac Tavish, 1992).

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Overdoses up to 4500 mg of
                             sertraline alone produced mild drowsiness and
                             serious toxicity did not develop in the 48
                             patients described by Myers et al.
                             (1993).

                    7.2.1.2  Children

                             In a case series of pediatric
                             overdoses (Myers et al., 1995), sertraline
                             caused no symptoms in 10 children less than
                             5-year old ingesting 50 to 250 mg; 8 of these
                             received gastrointestinal decontamination.

             7.2.2  Relevant animal data

                    Acute toxicity

                    In mice
                    LD 50 (oral):
                    548 mg/kg in male
                    419 mg/kg in female
    
                    LD 50 (intraperitoneal):
                    73 mg/kg in male
    
                    In rats:
                    LD 50 (oral):
                    1591 mg/kg in male
                    1327 mg/kg in female
    
                    LD 50 (intraperitoneal):
                    79 mg/kg in male
    
                    Symptomatology: decreased food intake, hyperactivity,
                    muscular weakness, convulsions.
                    The oral LD50 in mice and rats is equivalent to 150
                    and 500 times greater than the maximum daily
                    recommended dose in humans (i.e. 3 mg/kg),
                    respectively.
    
                    Chronic toxicity
                    Dogs were administered oral doses of 10, 30 and 90
                    mg/kg for 6 and 12 months; several adverse effects
                    occurred during the first weeks, including
                    hypersalivation, abnormal movements of the head,
                    disorientation, agitation; the dosage of 90 mg/kg
                    resulted in convulsions in 2 dogs; all of these
                    effects where temporary and resolved spontaneously
                    despite continuation of sertraline administration. An
                    increase of liver weight associated with a rise in
                    plasma alkaline phosphatase enzymes was noted, due to
                    the properties of enzyme induction of sertraline
                    (Pfizer lab., 1996).

             7.2.3  Relevant in vitro data

                    No data available

        7.3  Carcinogenicity

             Animal studies:
             In rats a slight increase in the number of follicular and
             thyroid adenomas was observed in relation with hepatic enzyme
             induction; these findings cannot be extrapolated to man,
             because of species differences in the metabolic mechanisms
             (Pfizer lab., 1996).

        7.4  Teratogenicity

             Animal studies:
             Fertility in rats was not affected.
             Sertraline did not show embryotoxic or teratogenic properties
             in rat and rabbit models. However, in the rat, sertraline
             caused a delay in fetal ossification and a delay in
             apparition of teeth in the young. A decrease in food intake
             inducing a delay in growth in the young, proportional to the
             administered dose, sometimes associated with hyperactivity,
             was also observed (Dosage not stated), (Pfizer lab., 1996).

        7.5  Mutagenicity

             In vitro and in vivo: sertraline did not show
             mutagenicity for chromosomes and genes (Pfizer lab., 1996).

        7.6  Interactions

             Co-administration of drugs increasing the level of
             serotonin: tricyclic antidepressants, other SSRIs, MAOIs,
             reversible inhibitors of monoamine oxidase (RIMAs), lithium,
             may cause a serotonin syndrome (Graber et al., 1994; Alderman
             & Cheum Lee, 1996; Mason & Blackburn, 1997).
             At least 2 weeks should elapse after discontinuing a MAOI
             before starting therapy with sertraline. Sertraline should be
             stopped at least 1 week before beginning MAOI therapy.
             Sumatriptan: the manufacturer recommends to not prescribe
             sertraline concomitantly with sumatriptan, which is a
             selective agonist at serotonin type 1D receptors, because of
             possible hypertensive crises and severe coronary
             vasoconstriction, and advises a washout period of 1 week
             after cessation of sertraline. However, a clinical study
             performed by Blier & Bergeron (1995) involving 103 episodes
             of migraine in patients taking any SSRIs, did not show
             evidence of significant adverse effects.
             Cimetidine inhibits the metabolism of sertraline, leading to
             increased plasma concentrations; close clinical monitoring
             and/or reduced sertraline doses are recommended (Pfizer lab.,
             1996).
    

             By extrapolation from data available for fluoxetine, drug
             interactions with oral anticoagulants and carbamazepine might
             occur, though in vitro and in vivo studies performed with
             carbamazepine did not show evidence of interactions and
             though no cases have been reported to date (Pfizer lab.,
             1996; Rapeport et al., 1996).
             Treatment with sertraline was associated with worsening
             and/or recurrence of the lysergide (LSD) flashbacks in two
             adolescents with a long history of polydrug abuse. They had
             stopped taking LSD 10 months before sertraline therapy
             (Markel et al., 1994).

        7.7  Main adverse effects

             The most common adverse effects reported with
             therapeutic doses of sertraline are primarily nausea,
             diarrhea, dyspepsia, dry mouth, insomnia, somnolence, tremor,
             dizziness, headache and male sexual dysfunction (delayed
             ejaculation). These adverse effects are reported to occur in
             10 to 20 % of patients, and they cause patients to stop
             therapy in approximately 1 to 4 % of cases (Murdoch & Mac
             Tavish, 1992).
             Manic episodes may be provoked in patients with bipolar
             disorders. If this occurs, sertraline should be discontinued
             and a sedative antipsychotic drug should be administered
             (Heimann & March, 1996; Reynolds, 1996).
             Less common adverse effects include, pruritus, alopecia
             (Bourgeois, 1996), and extrapyramidal symptoms (Cano &
             Roquer, 1995).
             Several cases of hyponatremia and the syndrome of
             inappropriate secretion of antidiuretic hormone (SIADH) have
             been reported, mainly in elderly patients (Liu et al.,
             1996).
             Galactorrhoea developed in a 40-year-old woman receiving
             sertraline 150 mg/day during 11 weeks (Lesaca, 1996).
             Several cases of stuttering have been described (Brewerton et
             al., 1996; Christensen et al., 1996).
             Bruxism causing significant physical consequences was
             associated with sertraline and other SSRIs in a case series
             reported by Fitzgerald & Healy (1995).
             A case of anisocoria was reported by Barrett (1994).
             Increase in serum AST and ALT levels has occurred, and
             returned to normal after treatment was stopped (Pfizer lab.,
             1996).
             Sertraline caused prolonged bleeding time in one patient
             (Calhoun & Calhoun, 1996); agranulocytosis was also reported
             by Trescoli-Serrano & Smith (1996).

    8.  TOXICOLOGICAL ANALYSIS AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analysis

                    8.1.1.2  Biomedical analysis

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analysis

                    8.1.1.5  Other (unspecified) analysis

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analysis

                    8.1.2.2  Biomedical analysis

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analysis

                    8.1.2.5  Other (unspecified) analysis

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analysis

                    8.1.3.2  Biomedical analysis

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analysis

                    8.1.3.5  Other (unspecified) analysis

        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 analysis

             8.3.3  Haematological analysis

             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

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    The ingestion of sertraline alone causes
                    nausea, vomiting, diarrhea, tremor, confusion,
                    drowsiness or agitation, bradycardia occuring within 2
                    to 4 hours (Brown & Kerr, 1994; Caracci, 1994; Klein-
                    Schwartz & Anderson, 1996; Lau & Horowitz, 1996).
                    Similarly to other SSRIs, more serious toxicity may be
                    expected with the co-ingestion of tricyclic

                    antidepressants, MAOIs, or SSRIs, and may result in a
                    life-threatening serotonin syndrome, although no cases
                    have been reported.
                    To date no fatalities have been reported after
                    overdoses of sertraline either alone, or in
                    combination with other antidepressants.

             9.1.2  Inhalation

                    Not relevant

             9.1.3  Skin exposure

                    No data available

             9.1.4  Eye contact

                    Not relevant

             9.1.5  Parenteral exposure

                    No data available

             9.1.6  Other

                    No data available

        9.2  Chronic poisoning

             9.2.1  Ingestion

                    A case of sertraline abuse has been reported by
                    D'Urso (1996) in a 19-year-old man who ingested 11.3 g
                    of sertraline almost daily for a period of 6 months:
                    soon after ingestion, he experienced relaxation and
                    euphoria, followed 1 hour later by intense excitement
                    and a marked tremor. Then he experienced visual and
                    auditory hallucinations. Eight hours after ingestion,
                    the intense effects decreased, but hallucinations
                    often persisted for several days.

             9.2.2  Inhalation

                    Not relevant

             9.2.3  Skin exposure

                    No data available

             9.2.4  Eye contact

                    Not relevant

             9.2.5  Parenteral exposure

                    No data available

             9.2.6  Other

                    No data available

        9.3  Course, prognosis, cause of death

             Pure sertraline overdoses usually have a fairly benign
             course. To date no fatalities have been reported.

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

             Bradycardia (Klein-Schwartz & Anderson, 1996).

             9.4.2  Respiratory

                    No data

             9.4.3  Neurological

                    9.4.3.1  Central nervous system

                             Confusion, drowsiness, agitation,
                             tremor (Lau & Horowitz, 1996); euphoria,
                             visual and auditory hallucinations (D'Urso,
                             1996).

                    9.4.3.2  Peripheral nervous system

                             No data available.

                    9.4.3.3  Autonomic nervous system

                             No data available.

                    9.4.3.4  Skeletal and smooth muscle

                             No data available.

             9.4.4  Gastrointestinal

                    Nausea, vomiting; diarrhea (Brown & Kerr, 1994).

             9.4.5  Hepatic

                    No data available.

             9.4.6  Urinary

                    No data available.

                    9.4.6.1  Renal

                             No data available.

                    9.4.6.2  Other

                             No data available.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatological

                    No data available.

             9.4.9  Eye, ear, nose, throat: local effects

                    No data available.

             9.4.10 Haematological

                    No data available.

             9.4.11 Immunological

                    No data available.

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                             No data available.

                    9.4.12.2 Fluid and electrolyte disturbances

                             No data available.

                    9.4.12.3 Others

                             No data available.

             9.4.13 Allergic reactions

                    No data available.

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    A case of sertraline abuse has been reported
                    by D'Urso (1996) in a 19-year-old man who ingested
                    11.3 g of sertraline almost daily for a period of 6
                    months: soon after ingestion, he experienced
                    relaxation and euphoria, followed 1 hour later by
                    intense excitement and a marked tremor. Then he
                    experienced visual and auditory hallucinations. Eight
                    hours after ingestion, the intense effects decreased,
                    but hallucinations often persisted for several
                    days.
                    Sertraline is excreted in breast milk; Kent & Laidlaw
                    (1995) reported withdrawal symptoms in a baby who had
                    been breastfed by his mother taking 200 mg sertraline
                    daily. Conversely, Ratan & Friedman (1995) reported no
                    adverse effects in a baby whose mother was started on
                    sertraline 150 mg daily when 20 weeks pregnant and
                    breastfed for 11 days while on the same dose.
                    As the effects on the infant are uncertain, caution
                    should be exercised when sertraline is administered to
                    a pregnant woman or a nursing mother (Pfizer lab.,
                    1996).

        9.5  Other

             Sertraline, like other SSRIs can cause adverse effects
             after withdrawal, either from a reduction in dosage or from
             the abrupt cessation of the drug. The most frequent symptoms
             include vertigo, dizziness, paresthesia (shock-like
             sensations, tingling and burning sensations); less frequent
             symptoms include irritability, anxiety, headache, orthostatic
             hypotension, sleep disturbances. The symptoms usually occur
             within 48 hours after stopping sertraline and they last about
             two weeks (Frost & Lal, 1995; Amsden & Georgian, 1996;
             Coupland et al., 1996; Rosenstock, 1996).

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             The primary management of sertraline overdoses consists
             of the institution of careful observation and supportive
             care. In most cases, this consists of no more than careful
             observation of vital signs and neurological status and
             supportive care until signs and symptoms resolve. Intravenous
             access should be established as soon as practical.
             In more severe intoxications or when other substances have
             also been ingested, 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

             In pure sertraline overdoses, intensive supportive care
             has not been required to date. Measures that may infrequently
             be required based on the clinical presentation include:
             endotracheal intubation and assisted ventilation if coma is
             present, intravenous fluid resuscitation if hypotension is
             present, pharmacological control of seizures, cooling if
             hyperthermia is present.

        10.3 Decontamination

             For doses of up to 4500 mg, gastrointestinal
             decontamination by administration of a single oral dose of
             activated charcoal should be considered. Gastric lavage
             followed by activated charcoal should be advocated in
             patients who have ingested higher doses and/or when there has
             been a significant co-ingestion.

        10.4 Enhanced elimination

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

        10.5 Antidote treatment

             10.5.1 Adults

                    No data

             10.5.2 Children

                    No data

        10.6 Management discussion

             No prospective studies have been performed to evaluate
             the treatment of the serotonin syndrome, and treatment
             strategies are primarily based on case reports. Non specific
             serotonin receptor antagonists such as methysergide and
             cyproheptadine have been used successfully (Lappin &
             Auchincloss, 1994). Propranolol which blocks serotonin 1A
             receptors has also been used (Lejoyeux et al., 1994).
             Benzodiazepines can reduce the muscular rigidity. Dantrolene
             which is a direct skeletal muscle relaxant has also been
             found to be useful by Graber et al. (1994). The efficacy of
             these agents has yet to be evaluated.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

             Caracci (1994) described a 32-year-old woman who
             ingested 4000 mg of sertraline. The patient experienced
             tremors, nausea, and dizziness for 2 days and recovered
             uneventfully.
    
             A classic serotonin syndrome developed in a 39-year-old man
             12 hours after starting sertraline therapy and 36 hours after
             discontinuation of tranylcypromine. The patient initially
             experienced drowsiness, restlessness, tremor, global
             hypertonia, hyperreflexia and sinus tachycardia; then his
             condition deteriorated and he experienced increased
             confusion, myoclonus, fixed pupils, profuse sweating, and
             flushed skin; his temperature increased to 38.8 C and his
             respiratory rate was 40/minute with marked chest-wall
             rigidity. Following paralysis and sedation, the man was
             ventilated and within 30 minutes of the onset of paralysis,
             his temperature was 37.3C and the sweating, tachycardia and
             flushing had resolved; 36 hours after his admission he was
             extubated and he was discharged after a further 4 hours
             clinical monitoring (Corkeron, 1995).
    
             Kaminski et al. (1994) described a severe intoxication
             consistent with a serotonin syndrome in a 9-year-old boy,
             with a history of attention deficit disorder, after ingestion
             of an unknown amount of sertraline. The patient exhibited
             prolonged tachycardia (200 bpm), hypertension,
             hallucinations, coma, hyperthermia (42.2 C), tremors of all
             extremities and skin flushing. After intensive supportive
             care, the child recovered uneventfully, 76 hours after the
             onset of symptoms. Plasma sertraline concentrations were 68
             ng/mL and 32 ng/mL, respectively, 9 and 26 hours after
             ingestion. They did not support a sertraline overdose, and
             the authors suggest that this may have been a serotonin
             syndrome. The child had been taking methylphenidate twice
             daily for his ADD (treatment duration not stated), until 9
             days before admission.
             Though the authors did not consider a possible interaction
             between sertraline and long term treatment with
             methylphenidate, as an alternative explanation to the severe
             symptoms experienced by the patient, this hypothesis must not
             be disregarded.

    12. ADDITIONAL INFORMATION

        12.1 Specific preventive measures

             No data

        12.2 Other

             No data

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

        Author: MO Rambourg Schepens
        Centre Anti-Poisons de Champagne Ardenne
        Centre Hospitalier Universitaire
        F-51092 REIMS cedex
        FRANCE
    
        e-mail: marie-odile.rambourg@wanadoo.fr
    
        Reviewer: WA Watson
        Emergency Medicine
        Truman Medical Center
        2301 Holmes Street
        Kansas City, MO,
        USA
    
        e-mail: wawatson@CCTR.UMKC.EDU
    
        Date: JUNE 1997
    
        Peer review: Oslo (2 July, 1997) Members of group: Marie-Odile
        Rambourg, Bill Watson, Rob Dowsett, Barbara Groszek, Michael
        Ruse
    
        Editor: Dr. M. Ruse (August, 1997)
    


    See Also:
       Toxicological Abbreviations