SETRAL is indicated for the treatment of:
 Major depressive episodes. Prevention of recurrence of major
depressive episodes.
 Panic disorder, with or without agoraphobia.
 Obsessive compulsive disorder (OCD) in adults and paediatric
patients aged 6-17 years.
 Social anxiety disorder.
 Post traumatic stress disorder (PTSD).

Posology
Initial treatment
 Depression and OCD
Sertraline treatment should be started at a dose of 50 mg/day.
 Panic Disorder, PTSD, and Social Anxiety Disorder
Therapy should be initiated at 25 mg/day. After one week, the dose should
be increased to 50 mg once daily. This dosage regimen has been shown to
reduce the frequency of early treatment emergent side effects characteristic
of panic disorder.
Titration
 Depression, OCD, Panic Disorder, Social Anxiety Disorder and
PTSD
Patients not responding to a 50 mg dose may benefit from dose increases.
Dose changes should be made in steps of 50 mg at intervals of at least one
week, up to a maximum of 200 mg/day. Changes in dose should not be
made more frequently than once per week given the 24-hour elimination
half life of Sertraline.
The onset of therapeutic effect may be seen within 7 days. However,
longer periods are usually necessary to demonstrate therapeutic response,
especially in OCD.
Maintenance
Dosage during long-term therapy should be kept at the lowest effective
level, with subsequent adjustment depending on therapeutic response.
SPC SETRAL 50 mg Film Coated Tablets
 Depression
Longer-term treatment may also be appropriate for prevention of
recurrence of major depressive episodes (MDE). In most of the cases, the
recommended dose in prevention of recurrence of MDE is the same as the
one used during current episode. Patients with depression should be treated
for a sufficient period of time of at least 6 months to ensure they are free
from symptoms.
 Panic disorder and OCD
Continued treatment in panic disorder and OCD should be evaluated
regularly, as relapse prevention has not been shown for these disorders.
Elderly patients
Elderly should be dosed carefully, as elderly may be more at risk for
hyponatraemia (see section 4.4).
Patients with hepatic impairment
The use of Sertraline in patients with hepatic disease should be approached
with caution. A lower or less frequent dose should be used in patients with
hepatic impairment (see section 4.4). Sertraline should not be used in cases
of severe hepatic impairment as no clinical data are available (see section
4.4)
Patients with renal impairment
No dosage adjustment is necessary in patients with renal impairment (see
section 4.4).
Paediatric population
Children and adolescents with obsessive compulsive disorder
 Age 13-17 years: Initially 50 mg once daily.
 Age 6-12 years: Initially 25 mg once daily. The dosage may be
increased to 50 mg once daily after one week.
Subsequent doses may be increased in case of less than desired response in
50 mg increments over a period of some weeks, as needed. The maximum
dosage is 200 mg daily. However, the generally lower body weights of
children compared to those of adults should be taken into consideration
when increasing the dose from 50 mg. Dose changes should not occur at
intervals of less than one week.
Efficacy is not shown in paediatric major depressive disorder.
No data is available for children under 6 years of age (see also section 4.4).
Method of administration
Sertraline should be administered once daily, either in the morning or
evening.
Sertraline tablet can be administered with or without food.
SPC SETRAL 50 mg Film Coated Tablets
Withdrawal symptoms seen on discontinuation of Sertraline
Abrupt discontinuation should be avoided. When stopping treatment with
Sertraline the dose should be gradually reduced over a period of at least
one to two weeks in order to reduce the risk of withdrawal reactions (see
sections 4.4 and 4.8). If intolerable symptoms occur following a decrease
in the dose or upon discontinuation of treatment, then resuming the
previously prescribed dose may be considered. Subsequently, the
physician may continue decreasing the dose, but at a more gradual rate.

Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome
(NMS)
The development of potentially life-threatening syndromes like
serotonin syndrome (SS) or Neuroleptic Malignant Syndrome (NMS)
has been reported with SSRIs, including treatment with sertraline. The
risk of SS or NMS with SSRIs is increased with concomitant use of
other serotonergic drugs (including other serotonergic antidepressants,
amphetamines, triptans), with drugs which impair metabolism of
serotonin (including MAOIs e.g. methylene blue), antipsychotics and
other dopamine antagonists, and with opiate drugs. Patients should be
monitored for the emergence of signs and symptoms of SS or NMS
syndrome (see section 4.3).
 Switching from Selective Serotonin Reuptake Inhibitors (SSRIs),
antidepressants or anti-obsessional drugs
There is limited controlled experience regarding the optimal timing of
switching from SSRIs, antidepressants or anti-obsessional drugs to
Sertraline. Care and prudent medical judgment should be exercised
when switching, particularly from long-acting agents such as
fluoxetine.
SPC SETRAL 50 mg Film Coated Tablets
 Other serotonergic drugs e.g. tryptophan, fenfluramine and 5-HT
agonists
Co-administration of Sertraline with other drugs which enhance the
effects of serotonergic neurotransmission such as tryptophan or
fenfluramine or 5-HT agonists, or the herbal medicine, St John's Wort
(hypericum perforatum), should be undertaken with caution and
avoided whenever possible due to the potential for a pharmacodynamic
interaction.
 QTc Prolongation/Torsade de Pointes (TdP)
Cases of QTc prolongation and TdP have been reported during postmarketing
use of sertraline. The majority of reports occurred in patients
with other risk factors for QTc prolongation/TdP. Effect on QTc
prolongation was confirmed in a thorough QTc study in healthy
volunteers, with a statistically significant positive exposure response
relationship. Therefore, sertraline should be used with caution in
patients with additional risk factors for QTc prolongation such as
cardiac disease, hypokalaemia or hypomagnesemia, familial history of
QTc prolongation, bradycardia and concomitant use of medications
which prolong QTc interval (see sections 4.5 and 5.1).
 Activation of hypomania or mania
Manic/hypomanic symptoms have been reported to emerge in a small
proportion of patients treated with marketed antidepressant and antiobsessional
drugs, including Sertraline. Therefore, Sertraline should be
used with caution in patients with a history of mania/hypomania. Close
surveillance by the physician is required. Sertraline should be
discontinued in any patient entering a manic phase.
 Schizophrenia
Psychotic symptoms might become aggravated in schizophrenic
patients.
 Seizures
Seizures may occur with Sertraline therapy: Sertraline should be
avoided in patients with unstable epilepsy and patients with controlled
epilepsy should be carefully monitored. Sertraline should be
discontinued in any patient who develops seizures.
 Suicide/suicidal thoughts/suicide attempts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts,
self harm and suicide (suicide-related events). This risk persists until
significant remission occurs. As improvement may not occur during
the first few weeks or more of treatment, patients should be closely
SPC SETRAL 50 mg Film Coated Tablets
monitored until such improvement occurs. It is general clinical
experience that the risk of suicide may increase in the early stages of
recovery.
Other psychiatric conditions, for which Sertraline is prescribed, can
also be associated with an increased risk of suicide-related events. In
addition, these conditions may be co-morbid with major depressive
disorder. The same precautions observed when treating patients with
major depressive disorder should therefore be observed when treating
patients with other psychiatric disorders.
Patients with a history of suicide-related events, or those exhibiting a
significant degree of suicidal ideation prior to commencement of
treatment are known to be at greater risk of suicidal thoughts or suicide
attempts, and should receive careful monitoring during treatment. A
meta-analysis of placebo-controlled clinical trials of antidepressant
drugs in adult patients with psychiatric disorders showed an increased
risk of suicidal behaviour with antidepressants compared to placebo in
patients less than 25 years old.
Close supervision of patients and in particular those at high risk should
accompany drug therapy especially in early treatment and following
dose changes. Patients (and caregivers of patients) should be alerted
about the need to monitor for any clinical worsening, suicidal
behaviour or thoughts and unusual changes in behaviour and to seek
medical advice immediately if these symptoms present.
 Paediatrec population
Sertraline should not be used in the treatment of children and
adolescents under the age of 18 years, except for patients with
obsessive compulsive disorder aged 6-17 years old. Suicide-related
behaviours (suicide attempt and suicidal thoughts), and hostility
(predominantly aggression, oppositional behaviour and anger) were
more frequently observed in clinical trials among children and
adolescents treated with antidepressants compared to those treated with
placebo. If, based on clinical need, a decision to treat is nevertheless
taken; the patient should be carefully monitored for appearance of
suicidal symptoms. In addition only limited clinical evidence is
available concerning, long-term safety data in children and adolescents
including effects on growth, sexual maturation and cognitive and
behavioural developments. A few cases of retarded growth and delayed
puberty have been reported post-marketing. The clinical relevance and
causality are yet unclear (see section 5.3 for corresponding preclinical
safety data). Physicians must monitor paediatric patients on long term
treatment for abnormalities in growth and development.
 Abnormal bleeding/Haemorrhage
There have been reports of bleeding abnormalities with SSRIs
including cutaneous bleeding (ecchymoses and purpura) and other
SPC SETRAL 50 mg Film Coated Tablets
haemorrhagic events such as gastrointestinal or gynaecological
bleeding, including fatal haemorrhages. Caution is advised in patients
taking SSRIs, particularly in concomitant use with drugs known to
affect platelet function (e.g. anticoagulants, atypical antipsychotics and
phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and
non-steroidal anti-inflammatory drugs (NSAIDs)) as well as in patients
with a history of bleeding disorders (see section 4.5).
 Hyponatraemia
Hyponatraemia may occur as a result of treatment with SSRIs or
SNRIs including Sertraline. In many cases, hyponatraemia appears to
be the result of a syndrome of inappropriate antidiuretic hormone
secretion (SIADH). Cases of serum sodium levels lower than 110
mmol/l have been reported.
Elderly patients may be at greater risk of developing hyponatraemia
with SSRIs and SNRIs. Also patients taking diuretics or who are
otherwise volume-depleted may be at greater risk (see Use in elderly).
Discontinuation of Sertraline should be considered in patients with
symptomatic hyponatraemia and appropriate medical intervention
should be instituted. Signs and symptoms of hyponatraemia include
headache, difficulty concentrating, memory impairment, confusion,
weakness and unsteadiness which may lead to falls. Signs and
symptoms associated with more severe and/or acute cases have
included hallucination, syncope, seizure, coma, respiratory arrest, and
death.
 Withdrawal symptoms seen on discontinuation of Sertraline
treatment
Withdrawal symptoms when treatment is discontinued are common,
particularly if discontinuation is abrupt (see section 4.8). In clinical
trials, among patients treated with Sertraline, the incidence of reported
withdrawal reactions was 23% in those discontinuing Sertraline
compared to 12% in those who continued to receive Sertraline
treatment.
The risk of withdrawal symptoms may be dependent on several factors
including the duration and dose of therapy and the rate of dose
reduction. Dizziness, sensory disturbances (including paraesthesia),
sleep disturbances (including insomnia and intense dreams), agitation
or anxiety, nausea and/or vomiting, tremor and headache are the most
commonly reported reactions. Generally these symptoms are mild to
moderate; however, in some patients they may be severe in intensity.
They usually occur within the first few days of discontinuing
treatment, but there have been very rare reports of such symptoms in
patients who have inadvertently missed a dose. Generally these
symptoms are self-limiting and usually resolve within 2 weeks, though
in some individuals they may be prolonged (2-3 months or more). It is
therefore advised that Sertraline should be gradually tapered when
SPC SETRAL 50 mg Film Coated Tablets
discontinuing treatment over a period of several weeks or months,
according to the patient's needs (see section 4.2).
 Akathisia/psychomotor restlessness
The use of Sertraline has been associated with the development of
akathisia, characterised by a subjectively unpleasant or distressing
restlessness and need to move often accompanied by an inability to sit
or stand still. This is most likely to occur within the first few weeks of
treatment. In patients who develop these symptoms, increasing the
dose may be detrimental.
 Hepatic impairment
Sertraline is extensively metabolised by the liver. A multiple dose
pharmacokinetic study in subjects with mild, stable cirrhosis
demonstrated a prolonged elimination half life and approximately
three-fold greater AUC and Cmax in comparison to normal subjects.
There were no significant differences in plasma protein binding
observed between the two groups. The use of Sertraline in patients
with hepatic disease must be approached with caution. If Sertraline is
administered to patients with hepatic impairment, a lower or less
frequent dose should be considered. Sertraline should not be used in
patients with severe hepatic impairment (see section 4.2).
 Renal impairment
Sertraline is extensively metabolised, and excretion of unchanged drug
in urine is a minor route of elimination. In studies of patients with mild
to moderate renal impairment (creatinine clearance 30-60 ml/min) or
moderate to severe renal impairment (creatinine clearance 10-29
ml/min), multiple-dose pharmacokinetic parameters (AUC0-24 or
Cmax) were not significantly different compared with controls.
Sertraline dosing does not have to be adjusted based on the degree of
renal impairment.
 Use in elderly
Over 700 elderly patients (>65 years) have participated in clinical
studies. The pattern and incidence of adverse reactions in the elderly
was similar to that in younger patients.
SSRIs or SNRIs including Sertraline have however been associated
with cases of clinically significant hyponatraemia in elderly patients,
who may be at greater risk for this adverse event (see Hyponatraemia
in section 4.4).
SPC SETRAL 50 mg Film Coated Tablets
 Diabetes
In patients with diabetes, treatment with an SSRI may alter glycaemic
control. Insulin and/or oral hypoglycaemic dosage may need to be
adjusted.
 Electroconvulsive therapy
There are no clinical studies establishing the risks or benefits of the
combined use of ECT and Sertraline.
 Grapefruit juice
The administration of Sertraline with grapefruit juice is not
recommended (see section 4.5).
 Interference with urine screening tests
False-positive urine immunoassay screening tests for benzodiazepines
have been reported in patients taking Sertraline. This is due to lack of
specificity of the screening tests. False-positive test results may be
expected for several days following discontinuation of Sertraline
therapy. Confirmatory tests, such as gas chromatography/mass
spectrometry, will distinguish Sertraline from benzodiazepines.
 Angle-Closure Glaucoma
SSRIs including Sertraline may have an effect on pupil size resulting in
mydriasis. This mydriatic effect has the potential to narrow the eye
angle resulting in increased intraocular pressure and angle-closure
glaucoma, especially in patients pre-disposed. Sertraline should
therefore be used with caution in patients with angle-closure glaucoma
or history of glaucoma.
- SSRIs/ SNRIs may increase the risk of postpartum hemorrhage.

Contraindicated
Monoamine Oxidase Inhibitors
Irreversible MAOIs (e.g. selegiline)
Sertraline must not be used in combination with irreversible MAOIs
such as selegiline. Sertraline must not be initiated for at least 14 days
after discontinuation of treatment with an irreversible MAOI.
Sertraline must be discontinued for at least 7 days before starting
treatment with an irreversible MAOI (see section 4.3).
Reversible, selective MAO-A inhibitor (moclobemide)
SPC SETRAL 50 mg Film Coated Tablets
Due to the risk of serotonin syndrome, the combination of Sertraline
with a reversible and selective MAOI, such as moclobemide, should
not be given. Following treatment with a reversible MAO-inhibitor, a
shorter withdrawal period than 14 days may be used before initiation of
Sertraline treatment. It is recommended that Sertraline should be
discontinued for at least 7 days before starting treatment with a
reversible MAOI (see section 4.3).
Reversible, non-selective MAOI (linezolid)
The antibiotic linezolid is a weak reversible and non-selective MAOI
and should not be given to patients treated with Sertraline (see section
4.3).
Severe adverse reactions have been reported in patients who have
recently been discontinued from an MAOI (e.g. methylene blue) and
started on Sertraline or have recently had Sertraline therapy
discontinued prior to initiation of an MAOI. These reactions have
included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing,
dizziness, and hyperthermia with features resembling neuroleptic
malignant syndrome, seizures, and death.
Pimozide
Increased pimozide levels of approximately 35% have been
demonstrated in a study of a single low dose pimozide (2 mg). These
increased levels were not associated with any changes in EKG. While
the mechanism of this interaction is unknown, due to the narrow
therapeutic index of pimozide, concomitant administration of
Sertraline and pimozide is contraindicated (see section 4.3).
Co-administration with Sertraline is not recommended
CNS depressants and alcohol
The co-administration of Sertraline 200 mg daily did not potentiate the
effects of alcohol, carbamazepine, haloperidol, or phenytoin on
cognitive and psychomotor performance in healthy subjects; however,
the concomitant use of Sertraline and alcohol is not recommended.
Other serotonergic drugs
See section 4.4.
Caution is also advised with fentanyl (used in general anaesthesia or in
the treatment of chronic pain), other serotonergic drugs (including
other serotonergic antidepressants, amphetamines, triptans), and with
other opiate drugs.
Special Precautions
Drugs that Prolong the QT Interval
SPC SETRAL 50 mg Film Coated Tablets
The risk of QTc prolongation and/or ventricular arrhythmias (e.g. TdP)
may be increased with concomitant use of other drugs which prolong the
QTc interval (e.g. some antipsychotics and antibiotics) (see section 4.4).
Lithium
In a placebo-controlled trial in normal volunteers, the coadministration
of Sertraline with lithium did not significantly alter
lithium pharmacokinetics, but did result in an increase in tremor
relative to placebo, indicating a possible pharmacodynamic interaction.
When co-administering Sertraline with lithium, patients should be
appropriately monitored.
Phenytoin
A placebo-controlled trial in normal volunteers suggests that chronic
administration of Sertraline 200 mg/day does not produce clinically
important inhibition of phenytoin metabolism. Nonetheless, as some
case reports have emerged of high phenytoin exposure in patients using
Sertraline, it is recommended that plasma phenytoin concentrations be
monitored following initiation of Sertraline therapy, with appropriate
adjustments to the phenytoin dose. In addition, co-administration of
phenytoin may cause a reduction of Sertraline plasma levels. It cannot
be excluded that other CYP3A4 inducers, e.g. phenobarbital,
carbamazepine, St John's Wort, rifampicin may cause a reduction of
Sertraline plasma levels.
Triptans
There have been rare post-marketing reports describing patients with
weakness, hyperreflexia, incoordination, confusion, anxiety and
agitation following the use of Sertraline and sumatriptan. Symptoms of
serotonergic syndrome may also occur with other products of the same
class (triptans). If concomitant treatment with Sertraline and triptans is
clinically warranted, appropriate observation of the patient is advised
(see section 4.4).
Warfarin
Co-administration of Sertraline 200 mg daily with warfarin resulted in
a small but statistically significant increase in prothrombin time, which
may in some rare cases unbalance the INR value.
Accordingly, prothrombin time should be carefully monitored when
Sertraline therapy is initiated or stopped.
Other drug interactions, digoxin, atenolol, cimetidine
SPC SETRAL 50 mg Film Coated Tablets
Co-administration with cimetidine caused a substantial decrease in
Sertraline clearance. The clinical significance of these changes is
unknown. Sertraline had no effect on the beta-adrenergic blocking
ability of atenolol. No interaction of Sertraline 200 mg daily was
observed with digoxin.
Drugs affecting platelet function
The risk of bleeding may be increased when medicines acting on
platelet function (e.g. NSAIDs, acetylsalicylic acid and ticlopidine) or
other medicines that might increase bleeding risk are concomitantly
administered with SSRIs, including Sertraline (see section 4.4).
Neuromuscular Blockers
SSRIs may reduce plasma cholinesterase activity resulting in a
prolongation of the neuromuscular blocking action of mivacurium or
other neuromuscular blockers.
Drugs Metabolized by Cytochrome P450
Sertraline may act as a mild-moderate inhibitor of CYP 2D6. Chronic
dosing with Sertraline 50 mg daily showed moderate elevation (mean
23%-37%) of steady-state desipramine plasma levels (a marker of CYP
2D6 isozyme activity). Clinical relevant interactions may occur with
other CYP 2D6 substrates with a narrow therapeutic index like class
1C antiarrhythmics such as propafenone and flecainide, TCAs and
typical antipsychotics, especially at higher Sertraline dose levels.
Sertraline does not act as an inhibitor of CYP 3A4, CYP 2C9, CYP
2C19, and CYP 1A2 to a clinically significant degree. This has been
confirmed by in-vivo interaction studies with CYP3A4 substrates
(endogenous cortisol, carbamazepine, terfenadine, alprazolam),
CYP2C19 substrate diazepam, and CYP2C9 substrates tolbutamide,
glibenclamide and phenytoin. In vitro studies indicate that Sertraline
has little or no potential to inhibit CYP 1A2.
Intake of three glasses of grapefruit juice daily increased the Sertraline
plasma levels by approximately 100% in a cross-over study in eight
Japanese healthy subjects. Therefore, the intake of grapefruit juice
should be avoided during treatment with Sertraline (see section 4.4).
Based on the interaction study with grapefruit juice, it cannot be
excluded that the concomitant administration of Sertraline and potent
CYP3A4 inhibitors, e.g. protease inhibitors, ketoconazole,
itraconazole, posaconazole, voriconazole, clarithromycin,
telithromycin and nefazodone, would result in even larger increases in
exposure of Sertraline. This also concerns moderate CYP3A4
inhibitors, e.g. aprepitant, erythromycin, fluconazole, verapamil and
diltiazem. The intake of potent CYP3A4 inhibitors should be avoided
during treatment with Sertraline.
SPC SETRAL 50 mg Film Coated Tablets
Sertraline plasma levels are enhanced by about 50% in poor
metabolizers of CYP2C19 compared to rapid metabolizers (see section
5.2). Interaction with strong inhibitors of CYP2C19, e.g. omeprazole,
lansoprazole, pantoprazole, rabeprazole, fluoxetine, fluvoxamine
cannot be excluded

Pregnancy
There are no well controlled studies in pregnant women. However, a
substantial amount of data did not reveal evidence of induction of
congenital malformations by Sertraline. Animal studies showed evidence
for effects on reproduction probably due to maternal toxicity caused by
the pharmacodynamic action of the compound and/or direct
pharmacodynamic action of the compound on the foetus (see 5.3).
Use of Sertraline during pregnancy has been reported to cause
symptoms, compatible with withdrawal reactions, in some neonates,
whose mothers had been on Sertraline. This phenomenon has also been
observed with other SSRI antidepressants. Sertraline is not recommended
in pregnancy, unless the clinical condition of the woman is such that the
benefit of the treatment is expected to outweigh the potential risk.
Neonates should be observed if maternal use of Sertraline continues into
the later stages of pregnancy, particularly the third trimester. The
following symptoms may occur in the neonate after maternal Sertraline
use in later stages of pregnancy: respiratory distress, cyanosis, apnoea,
seizures, temperature instability, feeding difficulty, vomiting,
hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness,
irritability, lethargy, constant crying, somnolence and difficulty in
sleeping. These symptoms could be due to either serotonergic effects or
withdrawal symptoms. In a majority of instances the complications begin
immediately or soon (<24 hours) after delivery.
Epidemiological data have suggested that the use of SSRIs in pregnancy,
particular in late pregnancy, may increase the risk of persistent
pulmonary hypertension in the newborn (PPHN). The observed risk was
approximately 5 cases per 1000 pregnancies. In the general population 1
to 2 cases of PPHN per 1000 pregnancies occur.
Breast-feeding
Published data concerning Sertraline levels in breast milk show that
small quantities of Sertraline and its metabolite N-desmethylSertraline
are excreted in milk. Generally negligible to undetectable levels were
found in infant serum, with one exception of an infant with serum levels
about 50% of the maternal level (but without a noticeable health effect in
this infant). To date, no adverse effects on the health of infants nursed by
mothers using Sertraline have been reported, but a risk cannot be
excluded. Use in nursing mothers is not recommended unless, in the
judgment of the physician, the benefit outweighs the risk.
Fertility
SPC SETRAL 50 mg Film Coated Tablets
Animal data did not show an effect of Sertraline on fertility parameters
(see section 5.3.).
Human case reports with some SSRI's have shown that an effect on
sperm quality is reversible.
Impact on human fertility has not been observed so far.
- observational data indicate an increased risk (less than 2- fold) of
postpartum haemorrhage following SSRI/ SNRI exposure within the
month prior to birth.

Clinical pharmacology studies have shown that Sertraline has no effect
on psychomotor performance. However, as psychotropic drugs may
impair the mental or physical abilities required for the performance of
potentially hazardous tasks such as driving a car or operating machinery,
the patient should be cautioned accordingly.
4-8

Nausea is the most common undesirable effect. In the treatment of social
anxiety disorder, sexual dysfunction (ejaculation failure) in men occurred
in 14% for Sertraline vs 0% in placebo. These undesirable effects are
dose dependent and are often transient in nature with continued
treatment.
The undesirable effects profile commonly observed in double-blind,
placebo-controlled studies in patients with OCD, panic disorder, PTSD
and social anxiety disorder was similar to that observed in clinical trials
in patients with depression.
Table 1 displays adverse reactions observed from postmarketing
experience (frequency not known) and placebo-controlled clinical trials
(comprising a total of 2542 patients on Sertraline and 2145 on placebo)
in depression, OCD, panic disorder, PTSD and social anxiety disorder.
Some adverse drug reactions listed in Table 1 may decrease in intensity
and frequency with continued treatment and do not generally lead to
cessation of therapy.
Table 1: Adverse Reactions
Frequency of adverse reactions observed from placebo-controlled
clinical trials in depression, OCD, panic disorder, PTSD and social
anxiety disorder. Pooled analysis and postmarketing experience.
Table 1: Adverse Reactions
Frequency of adverse reactions observed from placebo-controlled clinical trials in depression, OCD, panic disorder,
PTSD and social anxiety disorder. Pooled analysis and post-marketing experience.
System Organ
Class
Very Common
(≥1/10)
Common
(≥1/100 to <1/10)
Uncommon
(≥1/1,000 to
<1/100)
Rare
(≥1/10,000 to <1/1,000)
Frequency
Not Known
(Cannot be
Estimated
From the
Available
SPC SETRAL 50 mg Film Coated Tablets
Data)
Infections and
infestations
upper respiratory
tract
infection, pharyngitis,
rhinitis
gastroenteritis, otitis
media
diverticulitis§
Neoplasms
benign, malignant
and unspecified
(including cysts
and polyps)
neoplasm
Blood and
lymphatic system
disorders
lymphadenopathy,
thrombocytopenia∗§,
leukopenia∗§
Immune system
disorders
hypersensitivity∗,
seasonal allergy∗
anaphylactoid reaction∗
Endocrine
disorders
hypothyroidism∗ hyperprolactinaemia∗§,
inappropriate antidiuretic
hormone secretion∗§
Metabolism and
nutrition disorders
decreased appetite,
increased appetite∗
hypercholesterolaemia,
diabetes mellitus∗,
hypoglycaemia∗,
hyperglycaemia∗§,
hyponatraemia∗§
Psychiatric
disorders
insomnia anxiety*, depression*,
agitation*,
libido decreased*,
nervousness,
depersonalisation,
nightmare, bruxism*
suicidal
ideation/behaviour,
psychotic disorder∗,
thinking abnormal,
apathy,
hallucination*,
aggression*,
euphoric mood*,
paranoia
conversion disorder∗§,
paroniria∗§, drug
dependence, sleep
walking, premature
ejaculation
Nervous system
disorders
dizziness,
headache*, somnolence
tremor, movement
disorders (including
extrapyramidal
symptoms such as
hyperkinesia,
hypertonia, dystonia,
teeth grinding or gait
abnormalities),
paraesthesia*,
hypertonia*,
disturbance in
attention, dysgeusia
amnesia,
hypoaesthesia*,
muscle contractions
involuntary*,
syncope*,
hyperkinesia*,
migraine*,
convulsion*,
dizziness postural,
coordination
abnormal, speech
disorder
coma*, akathisia (see
section 4.4), dyskinesia,
hyperaesthesia,
cerebrovascular spasm
(including reversible
cerebral vasoconstriction
syndrome and Call-
Fleming syndrome)∗§,
psychomotor
restlessness∗§ (see section
4.4), sensory
disturbance,
choreoathetosis§, also
reported were signs and
symptoms associated
with serotonin
syndrome∗ or neuroleptic
malignant syndrome: In
some cases associated
with concomitant use of
serotonergic drugs that
included agitation,
confusion, diaphoresis,
diarrhoea, fever,
hypertension, rigidity
and tachycardia§
SPC SETRAL 50 mg Film Coated Tablets
Eye disorders visual disturbance∗ mydriasis∗ scotoma, glaucoma,
diplopia, photophobia,
hyphaema∗§, pupils
unequal∗§, vision
abnormal§, lacrimal
disorder
maculopathy
Ear and labyrinth
disorders
tinnitus∗ ear pain
Cardiac disorders palpitations∗ tachycardia∗, cardiac
disorder
myocardial infarction∗§,
Torsade de Pointes∗§ (see
sections 4.4, 4.5 and
5.1), bradycardia, QTc
prolongation∗(see
sections 4.4, 4.5 and 5.1)
Vascular disorders hot flush∗ abnormal bleeding
(such as
gastrointestinal
bleeding)∗,
hypertension∗,
flushing,
haematuria∗
peripheral ischaemia
Respiratory,
thoracic and
mediastinal
disorders
yawning∗ dyspnoea,
epistaxis∗,
bronchospasm*
hyperventilation,
interstitial lung disease∗§,
laryngospasm,
dysphonia, stridor∗§,
hypoventilation, hiccups
Gastrointestinal
disorders
nausea, diarrhoea, dry
mouth
dyspepsia,
constipation*,
abdominal pain*,
vomiting*, flatulence
melaena, tooth
disorder,
oesophagitis,
glossitis,
haemorrhoids,
salivary
hypersecretion,
dysphagia,
eructation, tongue
disorder
mouth ulceration,
pancreatitis∗§,
haematochezia, tongue
ulceration, stomatitis
Microscopic
colitis
Hepatobiliary
disorders
hepatic function
abnormal, serious liver
events (including
hepatitis, jaundice and
hepatic failure)
Skin and
subcutaneous
tissue disorders
hyperhidrosis, rash* periorbital oedema*,
urticaria*, alopecia*,
pruritus*, purpura*,
dermatitis, dry skin,
face oedema, cold
sweat
rare reports of severe
cutaneous adverse
reactions (SCAR): e.g.
Stevens-Johnson
syndrome∗ and epidermal
necrolysis∗§, skin
reaction∗§,
photosensitivity§,
angioedema, hair texture
abnormal, skin odour
abnormal, dermatitis
bullous, rash follicular
Musculoskeletal
and connective
tissue disorders
back pain, arthralgia∗,
myalgia
osteoarthritis,
muscle twitching,
muscle cramps∗,
muscular weakness
rhabdomyolysis∗§, bone
disorder
trismus*
Renal and urinary pollakiuria, urinary hesitation*,
SPC SETRAL 50 mg Film Coated Tablets
disorders micturition disorder,
urinary retention,
urinary
incontinence*,
polyuria, nocturia
oliguria
Reproductive
system and breast
disorders
ejaculation failure menstruation
irregular∗, erectile
dysfunction
sexual dysfunction
(see section 4.4),
menorrhagia,
vaginal
haemorrhage,
female sexual
dysfunction (see
section 4.4)
galactorrhoea*, atrophic
vulvovaginitis, genital
discharge,
balanoposthitis∗§,
gynaecomastia∗,
priapism*
Postpartum
hemorrhage *
General disorders
and administration
site conditions
fatigue* malaise*, chest pain*,
asthenia∗, pyrexia∗
oedema peripheral*,
chills, gait
disturbance∗, thirst
hernia, drug tolerance
decreased
Investigations weight increased∗ alanine
aminotransferase
increased*, aspartate
aminotransferase
increased*, weight
decreased*
blood cholesterol
increased∗, abnormal
clinical laboratory
results, semen abnormal,
altered platelet function∗§
Injury, poisoning
and procedural
complications
injury
Surgical and
medical
procedures
vasodilation procedure
∗ ADR identified post-marketing
§ ADR frequency represented by the estimated upper limit of the 95% confidence interval using “The Rule of 3”.
* this event has been reported for the therapeutic class of SSRIs/ SNRIs.
Withdrawal symptoms seen on discontinuation of Sertraline treatment
Discontinuation of Sertraline (particularly when abrupt) commonly leads
to withdrawal symptoms. Dizziness, sensory disturbances (including
paraesthesia), sleep disturbances (including insomnia and intense
dreams), agitation or anxiety, nausea and/or vomiting, tremor and
headache are the most commonly reported. Generally these events are
mild to moderate and are self-limiting; however, in some patients they
may be severe and/or prolonged. It is therefore advised that when
Sertraline treatment is no longer required, gradual discontinuation by
dose tapering should be carried out (see sections 4.2 and 4.4).
Elderly population
SSRIs or SNRIs including Sertraline have been associated with cases of
clinically significant hyponatraemia in elderly patients, who may be at
greater risk for this adverse event (see section 4.4).
Paediatric population
In over 600 paediatric patients treated with Sertraline, the overall profile
of adverse reactions was generally similar to that seen in adult studies.
The following adverse reactions were reported from controlled trials
(n=281 patients treated with Sertraline):
SPC SETRAL 50 mg Film Coated Tablets
Very common (≥1/10): Headache (22%), insomnia (21%), diarrhoea
(11%) and nausea (15%).
Common (≥1/100 to <1/10): Chest pain, mania, pyrexia, vomiting,
anorexia, affect lability, aggression, agitation, nervousness, disturbance
in attention, dizziness, hyperkinesia, migraine, somnolence, tremor,
visual disturbance, dry mouth, dyspepsia, nightmare, fatigue, urinary
incontinence, rash, acne, epistaxis, flatulence.
Uncommon (≥1/1000 to <1/100): ECG QT prolonged, suicide attempt,
convulsion, extrapyramidal disorder, paraesthesia, depression,
hallucination, purpura, hyperventilation, anaemia, hepatic function
abnormal, alanine aminotransferase increased, cystitis, herpes simplex,
otitis externa, ear pain, eye pain, mydriasis, malaise, haematuria, rash
pustular, rhinitis, injury, weight decreased, muscle twitching, abnormal
dreams, apathy, albuminuria, pollakiuria, polyuria, breast pain, menstrual
disorder, alopecia, dermatitis, skin disorder, skin odour abnormal,
urticaria, bruxism, flushing.
Frequency not known: enuresis
Class effects
Epidemiological studies, mainly conducted in patients 50 years of age
and older, show an increased risk of bone fractures in patients receiving
SSRIs and TCAs. The mechanism leading to this risk is unknown.
Saudi Arabia: To report any side effect(s): National Pharmacovigilance Center
(NPC): Fax: +966-11-205-7662, SFDA Call center: 19999, E-mail:
npc.drug@sfda.gov.sa, Website: https://ade.sfda.gov.sa

Toxicity
Sertraline has a margin of safety dependent on patient population and/or
concomitant medication. Deaths have been reported involving overdoses
of Sertraline, alone or in combination with other drugs and/or alcohol.
Therefore, any overdosage should be medically treated aggressively.
Symptoms
Symptoms of overdose include serotonin-mediated side effects such as
somnolence, gastrointestinal disturbances (such as nausea and vomiting),
tachycardia, tremor, agitation and dizziness. Coma has been reported
although less frequently.
QTc prolongation/Torsade de Pointes has been reported following
sertraline overdose; therefore, ECG-monitoring is recommended in all
ingestions of sertraline overdoses.
Managment
There are no specific antidotes to Sertraline. It is recommended to
establish and maintain an airway and, if necessary, ensure adequate
oxygenation and ventilation. Activated charcoal, which may be used with
a cathartic, may be as, or more effective than lavage, and should be
SPC SETRAL 50 mg Film Coated Tablets
considered in treating overdose. Induction of emesis is not
recommended. Cardiac (e.g. ECG) and vital sign monitoring is also
recommended, along with general symptomatic and supportive measures.
Due to the large volume of distribution of sertraline, forced diuresis,
dialysis, haemoperfusion and exchange transfusion are unlikely to be of
benefit

Pharmacotherapeutic group: Selective serotonin reuptake inhibitors
(SSRI)
ATC Code: N06 AB06
Mechanism of action
Sertraline is a potent and specific inhibitor of neuronal serotonin (5 HT)
uptake in vitro, which results in the potentiation of the effects of 5-HT in
animals. It has only very weak effects on norepinephrine and dopamine
neuronal reuptake. At clinical doses, Sertraline blocks the uptake of
serotonin into human platelets. It is devoid of stimulant, sedative or
anticholinergic activity or cardiotoxicity in animals. In controlled studies
in normal volunteers, Sertraline did not cause sedation and did not
interfere with psychomotor performance. In accord with its selective
inhibition of 5-HT uptake, Sertraline does not enhance catecholaminergic
activity. Sertraline has no affinity for muscarinic (cholinergic),
serotonergic, dopaminergic, adrenergic, histaminergic, GABA or
benzodiazepine receptors. The chronic administration of Sertraline in
animals was associated with down-regulation of brain norepinephrine
receptors as observed with other clinically effective antidepressants and
antiobsessional drugs.
Sertraline has not demonstrated potential for abuse. In a placebocontrolled,
double-blind randomized study of the comparative abuse
liability of Sertraline, alprazolam and d-amphetamine in humans,
Sertraline did not produce positive subjective effects indicative of abuse
potential. In contrast, subjects rated both alprazolam and d-amphetamine
significantly greater than placebo on measures of drug liking, euphoria
and abuse potential. Sertraline did not produce either the stimulation and
anxiety associated with d-amphetamine or the sedation and psychomotor
impairment associated with alprazolam. Sertraline does not function as a
positive reinforcer in rhesus monkeys trained to self administer cocaine,
nor does it substitute as a discriminative stimulus for either damphetamine
or pentobarbital in rhesus monkeys.
Clinical efficacy and safety
Major Depressive Disorder
A study was conducted which involved depressed outpatients who had
responded by the end of an initial 8-week open treatment phase on
Sertraline 50-200 mg/day. These patients (n=295) were randomized to
SPC SETRAL 50 mg Film Coated Tablets
continuation for 44 weeks on double-blind Sertraline 50-200 mg/day or
placebo. A statistically significantly lower relapse rate was observed for
patients taking Sertraline compared to those on placebo. The mean dose
for completers was 70 mg/day. The % of responders (defined as those
patients that did not relapse) for Sertraline and placebo arms were 83.4%
and 60.8%, respectively.
Post traumatic stress disorder (PTSD)
Combined data from the 3 studies of PTSD in the general population
found a lower response rate in males compared to females. In the two
positive general population trials, the male and female Sertraline vs.
placebo responder rates were similar (females: 57.2% vs 34.5%; males:
53.9% vs 38.2%). The number of male and female patients in the pooled
general population trials was 184 and 430, respectively and hence the
results in females are more robust and males were associated with other
baseline variables (more substance abuse, longer duration, source of
trauma etc) which are correlated with decreased effect.
Cardiac Electrophysiology
In a dedicated thorough QTc study, conducted at steady state at
supratherapeutic exposures in healthy volunteers (treated with 400
mg/day, twice the maximum recommended daily dose), the upper bound
of the 2-sided 90% CI for the time matched Least Square mean
difference of QTcF between sertraline and placebo (11.666 msec) was
greater than the predefined threshold of 10 msec at the 4-hour postdose
time point. Exposure-response analysis indicated a slightly positive
relationship between QTcF and sertraline plasma concentrations [0.036
msec/(ng/mL); p<0.0001].
Based on the exposure response model, the threshold for clinically
significant prolongation of the QTcF (i.e. for predicted 90% CI to exceed
10 msec) is at least 2.6-fold greater than the average Cmax (86 ng/mL)
following the highest recommended dose of sertraline (200 mg/day) (see
sections 4.4, 4.5, 4.8 and 4.9).
Paediatric OCD
The safety and efficacy of Sertraline (50-200 mg/day) was examined in
the treatment of non-depressed children (6-12 years old) and adolescent
(13-17 years old) outpatients with obsessive compulsive disorder (OCD).
After a one week single blind placebo lead-in, patients were randomly
assigned to twelve weeks of flexible dose treatment with either Sertraline
or placebo. Children (6-12 years old) were initially started on a 25 mg
dose. Patients randomized to Sertraline showed significantly greater
improvement than those randomised to placebo on the Children's Yale-
Brown Obsessive Compulsive Scale CY-BOCS (p =0.005) the NIMH
Global Obsessive Compulsive Scale (p=0.019), and the CGI
Improvement (p =0.002) scales. In addition, a trend toward greater
improvement in the Sertraline group than the placebo group was also
observed on the CGI Severity scale (p=0.089). For CY-BOCs the mean
baseline and change from baseline scores for the placebo group was
22.25 ± 6.15 and -3.4 ± 0.82, respectively, while for the Sertraline group,
SPC SETRAL 50 mg Film Coated Tablets
the mean baseline and change from baseline scores were 23.36 ± 4.56
and -6.8 ± 0.87, respectively. In a post-hoc analysis, responders, defined
as patients with a 25% or greater decrease in the CY-BOCs (the primary
efficacy measure) from baseline to endpoint, were 53% of Sertralinetreated
patients compared to 37% of placebo-treated patients (p=0.03).
Long term safety and efficacy data are lacking for this paediatric
population.
Paediatric population
No data is available for children under 6 years of age.

Absorption
In man, following an oral once-daily dosage of 50 to 200 mg for 14 days,
peak plasma concentrations of sertraline occur at 4.5 to 8.4 hours after the
daily administration of the drug. Food does not significantly change the
bioavailability of sertraline tablets.
Distribution
Approximately 98% of the circulating drug is bound to plasma proteins.
Biotransformation
Sertraline undergoes extensive first-pass hepatic metabolism.
Based on clinical and in-vitro data, it can be concluded that Sertraline is
metabolized by multiple pathways including CYP3A4, CYP2C19 (see
section 4.5) and CYP2B6. Sertraline and its major metabolite
desmethylSertraline are also substrate of P-glycoprotein in-vitro.
Elimination
The mean half-life of Sertraline is approximately 26 hours (range 22-36
hours). Consistent with the terminal elimination half-life, there is an
approximately two-fold accumulation up to steady state concentrations,
which are achieved after one week of once-daily dosing. The half-life of NdesmethylSertraline
is in the range of 62 to 104 hours. Sertraline and NdesmethylSertraline
are both extensively metabolized in man and the
resultant metabolites excreted in faeces and urine in equal amounts. Only a
small amount (<0.2%) of unchanged Sertraline is excreted in the urine.
Linearity/non-linearity
Sertraline exhibits dose proportional pharmacokinetics in the range of 50 to
200 mg.
Pharmacokinetics in specific patient groups
Paediatric patients with OCD
SPC SETRAL 50 mg Film Coated Tablets
Pharmacokinetics of Sertraline was studied in 29 paediatric patients aged 6-
12 years old, and 32 adolescent patients aged 13-17 years old. Patients were
gradual uptitrated to a 200 mg daily dose within 32 days, either with 25 mg
starting dose and increment steps, or with 50 mg starting dose or
increments. The 25 mg regimen and the 50 mg regimen were equally
tolerated. In steady state for the 200 mg dose, the Sertraline plasma levels
in the 6-12 year old group were approximately 35% higher compared to the
13-17 year old group, and 21% higher compared to adult reference group.
There were no significant differences between boys and girls regarding
clearance. A low starting dose and titration steps of 25 mg are therefore
recommended for children, especially with low bodyweight. Adolescents
could be dosed like adults.
Adolescents and elderly
The pharmacokinetic profile in adolescents or elderly is not significantly
different from that in adults between 18 and 65 years.
Hepatic impairment
In patients with liver damage, the half life of Sertraline is prolonged and
AUC is increased three fold (see sections 4.2 and 4.4).
Renal impairment
In patients with moderate-severe renal impairment, there was no significant
accumulation of Sertraline.
Pharmacogenomics
Plasma levels of Sertraline were about 50% higher in poor metabolizers of
CYP2C19 versus extensive metabolizers. The clinical meaning is not clear,
and patients need to be titrated based on clinical response.

Preclinical data does not indicate any special hazard for humans based on
conventional studies of safety pharmacology, repeated dose toxicity,
genotoxicity and carcinogenesis. Reproduction toxicity studies in animals
showed no evidence of teratogenicity or adverse effects on male fertility.
Observed foetotoxicity was probably related to maternal toxicity. Postnatal
pup survival and body weight were decreased only during the first days
after birth. Evidence was found that the early postnatal mortality was due to
in-utero exposure after day 15 of pregnancy. Postnatal developmental
delays found in pups from treated dams were probably due to effects on the
dams and therefore not relevant for human risk.
Juvenile animal studies
Animal data from rodents and non-rodents does not reveal effects on
fertility.
A juvenile toxicology study in rats has been conducted in which sertraline
was administered orally to male and female rats on Postnatal Days 21
through 56 (at doses of 10, 40, or 80 mg/kg/day) with a nondosing recovery
phase up to Postnatal Day 196. Delays in sexual maturation occurred in
SPC SETRAL 50 mg Film Coated Tablets
males and females at different dose levels (males at 80 mg/kg and females
at ≥10 mg/kg), but despite this finding there were no sertraline-related
effects on any of the male or female reproductive endpoints that were
assessed. In addition, on Postnatal Days 21 to 56, dehydration,
chromorhinorrhea, and reduced average body weight gain was also
observed. All of the aforementioned effects attributed to the administration
of sertraline were reversed at some point during the nondosing recovery
phase of the study. The clinical relevance of these effects observed in rats
administered sertraline has not been established.
 

Microcrystalline Cellulose 50 micrometer
 Anhydrous Calcium Hydrogen Phosphate
 Sodium Starch Glycolate (Type A)
 Hydroxypropyl Cellulose (Klucel EF)
 Magnesium Stearate
 Hydroxypropyl Methylcellulose Type 2910 (Methocel E5)
 Polyethylene Glycol 400
 Titanium Dioxide
 White Beeswax

Not applicable.

SETRAL 50 Tablets should not be stored at a temperature above 30ºC.

SETRAL 50 Tablets are packed in boxes of 10 Tablets blistered in
PVC/ aluminium foil.
 SETRAL 50 Tablets are packed in boxes of 30 Tablets blistered in
PVC/ aluminium foil.

No special requirements.