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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Sertraline 50 mg Tablets.

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each tablet contains 50 mg sertraline (as hydrochloride).

For a full list of excipients, see Section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

White capsular shaped tablet with a breakline and ‘SRN 50’ embossed on one side and ‘NEO’ embossed on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Sertraline is indicated for the treatment of symptoms of depressive illness, including accompanying symptoms of anxiety. Following satisfactory response, continuation with sertraline therapy is effective in preventing relapse of the initial episode of depression or recurrence of further depressive episodes, including accompanying symptoms of anxiety.

Sertraline is also indicated for the treatment of obsessive compulsive disorder (OCD). Following initial response, sertraline has been associated with sustained efficacy, safety and tolerability in up to two years treatment of OCD.

Sertraline is also indicated for the treatment of paediatric patients with OCD.

Clinical trials in PTSD demonstrated efficacy in female patients but no evidence of efficacy was seen in males. Treatment with sertraline cannot normally therefore be recommended for male patients with PTSD. A therapeutic trial in males might on occasion be justified, but treatment should subsequently be withdrawn unless there is clear evidence of therapeutic benefit.

Sertraline is not indicated for use in children and adolescents under the age of 18 years with Major Depressive Disorder. In particular, controlled clinical studies have failed to demonstrate efficacy and do not support the use of sertraline in the treatment of children and adolescents with Major Depressive Disorder (See sections 4.3, Contra-indications and 4.8, Undesirable effects).

4.2 Posology and method of administration

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). For oral administration.

Sertraline should be given as a single daily dose. Sertraline tablets can be administered with or without food.

Adults

Depression (including accompanying symptoms of anxiety): The starting dose is 50 mg daily and the usual antidepressant dose is 50 mg daily. In some patients, doses higher than 50 mg may be required.

Obsessive Compulsive Disorder: The starting dose is 50mg daily, and the therapeutic dose range is 50-200 mg daily.

Post-Traumatic Stress Disorder: Treatment for PTSD should be initiated at 25 mg/day. After one week, the dose should be increased to 50 mg once daily. PTSD is a heterogeneous illness and some patient groups fulfilling the criteria for PTSD do not appear to be responsive to treatment with sertraline. Dosing should be reviewed

periodically by the prescribing physician to determine response to therapy and treatment should be withdrawn if there is no clear evidence of efficacy.

Depression (including accompanying symptoms of anxiety), OCD and PTSD: In some patients doses higher than 50 mg daily may be required. In patients with incomplete response but good toleration at lower doses, dosage adjustments should be made in 50 mg increments over a period of weeks to a maximum of 200 mg daily.

Once optimal therapeutic response is achieved the dose should be reduced, depending on therapeutic response, to the lowest effective level. Dosage during prolonged maintenance therapy should be kept at the lowest effective level, with subsequent adjustments depending on therapeutic response. The onset of therapeutic effect may be seen within 7 days, although 2-4 weeks (and even longer in OCD) are usually necessary for full activity. A longer treatment period, even

beyond 12 weeks in some cases, may be required in the case of a therapeutic trial in PTSD.

Use in children aged 6-17years: Treatment should only be initiated by specialists. The safety and efficacy of sertraline has been established in paediatric OCD patients (aged 6-17). The administration of sertraline to paediatric OCD patients (aged 13-17) should commence at 50 mg/day.

Therapy for paediatric OCD patients

(aged 6-12) should commence at 25 mg/day increasing to 50mg/day after 1 week. Subsequent doses may be increased in case of lack of response in 50 mg/day increments up to 200 mg/day as needed. However, the generally lower body weights of children compared to adults should be taken into consideration in advancing the dose from 50 mg, in order to avoid excessive dosing. Given the 24 hour elimination half-life of sertraline, dose changes should not occur at intervals of less than 1 week.

The efficacy and safety of sertraline in children and adolescents under the age of

18 years with Major Depressive Disorder have not been established.

Controlled clinical studies failed to demonstrate efficacy and do not support the use of sertraline in the treatment of children and adolescents with Major Depressive Disorder (see sections 4.3 and 4.8).

Children aged less than six years: Sertraline is not recommended in children under six years of age since safety and efficacy have not been established (see ' section 4.4).

Use in the elderly:

Elderly should be dosed carefully, as elderly may be more at risk for hyponatraemia (see section 4.4).

Use in hepatic insufficiency

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).

Use in renal insufficiency

No dosage adjustment is necessary in patients with renal insufficiency (see section 4.4).

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.

4.3. Contraindications

Sertraline is contra-indicated in patients with a known hypersensitivity to sertraline or any of the excipients.

Monoamine oxidase inhibitors: Cases of serious and sometimes fatal reactions have been reported in patients receiving an SSRI in combination with a monoamine oxidase inhibitor (MAOI), including the selective MAOI selegiline and the reversible MAOI (RIMA) moclobemide and in patients who have recently discontinued an SSRI and have been started on a MAOI.

Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome.

Some cases presented with features resembling serotonin syndrome.

Symptoms of

a drug interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes that include confusion, irritability and extreme agitation progressing to delirium and coma.

Sertraline should not be used in combination with a MAOI. Sertraline may be started 14 days after discontinuing treatment with an irreversible MAOI. Following treatment with a reversible MAO-inhibitor, a shorter withdrawal period than 14 days may be used before initiation of sertraline treatment. At least 7 days should elapse after discontinuing sertraline treatment before starting a MAOI or RIMA (see section 4.5).

Use in hepatic impairment: There is insufficient clinical experience in patients with significant hepatic dysfunction and accordingly sertraline should not be used in such patients (see section 4.4).

Concomitant use in patients taking pimozide is contra-indicated (see section 4.5).

Sertraline should not be used in children and adolescents under the age of 18 years

with Major Depressive Disorder (see section 4.8).

4.4. Special warning and precautions for use

The following special warnings and precautions apply to the therapeutic class of SSRIs (Selective Serotonin Re-uptake Inhibitors).

Paradoxical anxiety:

Some patients with panic disorder may experience increased anxiety symptoms at

the beginning of treatment with antidepressants. This paradoxical reaction usually subsides within two weeks during continued treatment. A low starting dose is advised to reduce the likelihood of an anxiogenic effect (see section 4.2).

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 serotonergic drugs (including triptans), with drugs which impair metabolism of serotonin (including MAOIs), antipsychotics and other dopamine antagonists. Patients should be monitored for the emergence of signs and symptoms of SS or NMS syndrome (see section 4.3).

Caution is advisable if sertraline is used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol and tryptophan. In rare cases, serotonin syndrome has been reported in patients    using SSRIs concomitantly with serotonergic medicinal

products. A combination of symptoms, such as agitation, tremor, myoclonus and hyperthermia may indicate the development of this condition. If this occurs treatment with the SSRI and the serotonergic medicinal product should be discontinued immediately and symptomatic treatment initiated.

Switching from Selective Serotonin Reuptake Inhibitors (SSRIs), antidepressants or antiobsessional drugs

There is limited controlled experience regarding the optimal timing of switching from SSRIs, antidepressants or antiobsessional drugs to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents such as fluoxetine.

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.

Until further data are available, serotonergic drugs, such as tramadol, sumatriptan or fenfluramine, should not be used concomitantly with sertraline, due to a possible enhancement of 5-HT associated effects.

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 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.

Use in children and adolescents under 18 years of age 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, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking. Physicians must monitor paediatric patients on long term treatment for abnormalities in these body systems.

Abnormal bleeding/Haemorrhage

There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura and other hemorrhagic events such as gastrointestinal or gynaecological bleeding, with SSRIs. 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 antiinflammatory 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 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 (AUC_0-24 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 section 4.4).

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.

4.5. Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors Irreversible MAOIs (e.g. selegiline)

Sertraline should not be used in combination with a MAOI. Sertraline may be started 14 days after discontinuing treatment with an irreversible MAOI. At least 7 days should elapse after discontinuing sertraline treatment before starting a Irreversible MAOI (see section 4.3).

Reversible, selective MAO-A inhibitor (moclobemide)

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 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. (see section 4.3).

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.

In 11 healthy subjects administered sertraline (200mg daily) for 9 days, there was no adverse effect on cognitive or psychomotor performance relative to placebo, following a single dose of 500mg/kg alcohol. However, the concomitant use of sertraline and alcohol in depressed patients 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.

Special Precautions

Lithium

In a placebo-controlled trial in normal volunteers, the co-administration 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 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.

Since sertraline is bound to plasma proteins, the potential of sertraline to interact with other plasma protein bound drugs should be borne in mind.

Formal drug interaction studies have been performed with sertraline. Co-administration of sertraline (200 mg daily) with diazepam or tolbutamide resulted in small, statistically significant changes in some pharmacokinetic parameters. 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 with sertraline (200mg daily) was observed with glibenclamide or digoxin.

Sertraline (200mg daily), did not potentiate the effects of carbamazepine, haloperidol or phenytoin on cognitive and psychomotor performance in healthy subjects.

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).

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 withsertraline (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.

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.

St John's Wort: Concomitant use of the herbal remedy St John's wort (Hypericum perforatum) in patients receiving SSRIs should be avoided since there is a possibility of serotonergic potentiation.

4.6. Fertility, Pregnancy and Lactation

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.

Lactation:

Published data concerning sertraline levels in breast milk show that small quantities of sertraline and its metabolite N-desmethylsertraline are excreted in milk. Generally neglible 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:

Animal data did not show an effect of sertraline on fertility parameters (see section 5.3.).

Human case reports with some SSRIs have shown that an effect on sperm quality is reversible.

Impact on human fertility has not been observed so far.

4.7 Effects on ability to drive and use machines

Clinical pharmacology studies have shown that sertraline has no effect on psychomotor performance. However, since antidepressant or antiobsessional drugs may impair the abilities required to perform potentially hazardous tasks such as driving a car or operating machinery, the patient should be cautioned accordingly. Sertraline should not be administered with benzodiazepines or other

tranquillizers in patients who drive or operate machinery

4.8. Undesirable effects

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 (frequency not known).

Very	Common	Uncommon	Rare	Very	Frequency not
Common	(* 1/100 to	(* 1/1000 to	(* 1/10000 to	rare	Known
(*1/10)	<1/10)	<1/100)	<1/1000)	(<1/1000 0)
Infections and Infestations
	Pharyngitis	Upper	Diverticulitis,
		Respiratory	Gastroenteritis, Otitis
		Tract Infection, Rhinitis	Media
Neoplasms benign, malignant (including cysts and polyps)
			Neoplasmf
Blood and lymphatic system disorders
			Lymphadenopathy		Leucopenia, Thrombocytopenia
Immune system disorders
					Anaphylactoid Reaction, Allergic Reaction, Allergy
Endocrine disorders
					Hyper- prolactinaemia, Hypothyroidism and syndrome of inappropriate ADH

					secretion
Metabolism and Nutrition Disorders
	Anorexia, Increased Appetite*		Hyper- cholesterolaemia, Hypoglycaemia		Hyponatremia, Diabetes Mellitus, Hyperglycaemia
Psychiatric Disorders
Insomnia (19%)	Depression*, Depersonal isation, Nightmare, Anxiety*, Agitation*, Nervousness, Libido Decreased*, Bruxism	Hallucination* , Euphoric Mood*, Apathy, Thinking Abnormal	Conversion Disorder, Drug Dependence, Psychotic disorder*, Aggression*, Paranoia, Suicidal Ideation/behaviour* * *, Sleep Walking, Premature Ejaculation		Paroniria,
Nervous System Disorders
Dizziness (11%), Somnolen ce (13%), Headache (21%)*	Paraesthesia*, Tremor, Hypertonia, Dysgeusia, Disturbance in Attention,	Convulsion*, Muscle Contractions Involuntary*, Coordination Abnormal, Hyperkinesia, Amnesia, Hypoaesthesia *, Speech Disorder, Dizziness Postural, Migraine*	Coma*, Choreoathetosis, Dyskinesia, Hyperaesthesia, Sensory Disturbance		Movement Disorders (including extrapyramidal symptoms such as hyperkinesia, hypertonia, dystonia, teeth grinding or gait abnormalities), Syncope. 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. Akathisia and

					psychomotor restlessness (see section 4.4). Cerebrovascular Spasm (including reversible cerebral vasconstriction syndrome and call-fleming syndrome).
Eye Disorders
	Visual Disturbance		Glaucoma, Lacrimal Disorder, Scotoma, Diplopia, Photophobia, Hyphaema, Mydriasis*		Vision Abnormal, Pupils Unequal
Ear and Labyrinth Disorders
	Tinnitus*	Ear Pain
Cardiac Disorders
	Palpitations*	Tachycardia	Myocardial Infarction, Bradycardia, Cardiac Disorder
Vascular Disorders
	Hot flush*	Hypertension* , Flushing	Peripheral Ischaemia		Abnormal Bleeding (such as epistaxis, gastrointestinal bleeding or haematuria)
Respiratory, Thoracic, and Mediastinal Disorders
	Yawning*	Bronchospasm *, Dyspnoea, Epistaxis	Laryngospasm, Hyperventilation, Hypoventilation, Stridor, Dysphonia, Hiccups		Interstitial Lung Disease
Gastrointestinal Disorders
Diarrhoea (18%), Nausea (24%), Dry Mouth (14%)	Abdominal Pain* Vomiting*, Constipation* Dyspepsia, Flatulence	Oesophagitis, Dysphagia, Haemorrhoids, Salivary Hypersecretio n, Tongue Disorder, Eructation	Melaena, Haematochezia, Stomatitis, Tongue ulceration, Tooth Disorder, Glossitis, Mouth Ulceration		Pancreatitis

Hepatobiliary Disorders
			Hepatic Function Abnormal		Serious liver events (including hepatitis, jaundice and liver failure)
Skin and Subcutaneous Tissue Disorders
	Rash*, Hyperhidrosis	Periorbital Oedema*, Purpura*, Alopecia*, Cold Sweat, Dry skin, Urticaria*	Dermatitis, Dermatitis Bullous, Rash Follicular, Hair Texture Abnormal, Skin Odour Abnormal		Rare reports of severe cutaneous adverse reactions (SCAR): e.g. Stevens-Johnson syndrome and epidermal necrolysis, Angioedema, Face Oedema, Photosensitivity, Skin Reaction, Pruritus
Musculoskeletal and Connective Tissue Disorders
	Myalgia	Osteoarthritis, Muscular Weakness, Back Pain, Muscle Twitching	Bone Disorder		Arthralgia, Muscle Cramps
Renal and Urinary Disorders
		Nocturia, Urinary Retention*, Polyuria, Pollakiuria, Micturition disorder	Oliguria, Urinary Incontinence*, Urinary Hesitation
Reproductive System and Breast Disorders**
Ejaculatio n Failure (14%)	Sexual Dysfunction, Erectile Dysfunction	Vaginal Haemorrhage, Female Sexual Dysfunction	Menorrhagia, Atrophic Vulvovaginitis, Balanoposthitis, Genital Discharge, Priapism*, Galactorrhoea*		Gynaecomastia, Menstrual Irregularities
General Disorders and Administration Site Conditions
Fatigue (10%)*	Chest Pain*	Malaise*, Chills, Pyrexia*, Asthenia*, Thirst	Hernia, , Drug Tolerance Decreased, Gait Disturbance		Oedema Peripheral

		Weight Decreased*, Weight Increased*	Alanine Aminotransferase Increased*, Aspartate Aminotransferase Increased*, Semen Abnormal		Abnormal Clinical Laboratory Results, Altered Platelet Function, Increased Serum Cholesterol
Injury and poisoning
			Injury
Surgical and medical procedures
			Vasodilation Procedure

If adverse experience occurred in depression, OCD, panic disorder, PTSD and social anxiety disorder, body term reclassified by depression studies body term.

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 selflimiting; 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).

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):

Very common (^1/10): Headache (22%), insomnia (21%), diarrhoea (11%) and nausea (15%).

Common (z1/100 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 SSRs and TCAs. The mechanism leading to this risk is unknown.

4.9. Overdose

On the evidence available, sertraline has a wide margin of safety in overdose. Overdoses of sertraline alone of up to 13.5g have been reported. Deaths involving overdoses of sertraline in combination with other drugs and/or alcohol have been reported. Therefore, any overdosage should be 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. Less frequently reported was coma.

Treatment

No specific therapy is recommended and there are no specific antidotes to sertraline. Establish and maintain an airway, ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdose. Cardiac and vital signs monitoring is 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.

Sertraline overdose may prolong the QT-interval, and ECG-monitoring is recommended in all ingestions of sertraline overdoses.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC code: N06A B06 (Selective serotonin reuptake inhibitor).

Sertraline is a potent and specific inhibitor of neuronal serotonin (5-HT) uptake in vitro and in vivo, but is without affinity for muscarinic, serotonergic, dopaminergic, adrenergic, histaminergic, GABA or benzodiazepine receptors.

Sertraline is devoid of stimulant, sedative or anticholinergic activity or cardiotoxicity in animals.

Unlike tricyclic antidepressants, no weight gain is observed with treatment for depression.

Sertraline has not been observed to produce physical or psychological dependence.

Sertraline has been evaluated in paediatric OCD patients aged 6 to 17 in a 12 week placebo-controlled study. Therapy for paediatric OCD patients (aged 612) commenced at 25mg/day increasing to 50mg/day after 1 week. Side-effects which occurred significantly more frequently with sertraline than placebo were: headache, insomnia, agitation [6-12 years]; insomnia, anorexia, tremor [13-17 years].

There is limited evidence of efficacy and safety beyond 12 weeks of treatment.

5.2 Pharmacokinetic properties

Sertraline exhibits dose proportional pharmacokinetics over a range of 50200mg. After oral administration of sertraline in man, peak blood levels occur

at about 4.5 - 8.4 hours. Daily doses of sertraline achieve steady-state after one week. Sertraline has a plasma half-life of approximately 26 hours with a mean half-life for

young and elderly adults ranging from 22-36 hours. Sertraline is approximately 98% bound to plasma proteins. The principal metabolite, N-desmethylsertraline, is inactive in in vivo models of depression and has a halflife of approximately 62-104 hours. Sertraline and N-desmethylsertraline are both extensively metabolised 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.

The pharmacokinetics of sertraline in paediatric OCD patients have been shown to be comparable with adults (although paediatric patients metabolise sertraline with slightly greater efficiency). However, lower doses may be advisable for paediatric patients given their lower body weights (especially 612 years), in order to avoid excessive plasma levels.

A clear relationship between sertraline concentration and the magnitude of therapeutic response has not been established. The pharmacokinetics of sertraline in elderly patients are similar younger adults.

Food does not significantly change the bioavailability of Sertraline tablets.

5.3 Preclinical safety data

Extensive chronic safety evaluation studies in animals show that sertraline is generally well tolerated at doses that are appreciable multiples of those that are clinically effective.

Animal data from rodents and non-rodents does not reveal effects on fertility.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet cores:

Microcrystalline cellulose Maize starch

Sodium starch glycolate (Type A)

Magnesium stearate

Film coating:

-    titanium dioxide (E171)

-    hypromellose

-    macrogol 6000

6.2 Incompatibilities

None.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Calendar packs of 28 tablets. Aluminium/PVC blister strips, 14 tablets/strip, 2 strips in a carton box.

6.6 Special precautions for disposal

No special requirements.

MARKETING AUTHORISATION HOLDER

Cipla (EU) Limited

Hillbrow House

Hillbrow Road

Esher

Surrey

KT10 9NW

8    MARKETING AUTHORISATION NUMBER(S)

PL 36390/0037

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

04/07/2012

10    DATE OF REVISION OF THE TEXT

19/11/2014