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 µg/L
after at least 1 week of treatment with 100 mg sertraline
daily, and it ranged from 40 to 187 µg/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 œ 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 37.3°C 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)