This information is intended for use by health professionals

1. Name of the medicinal product

Sertraline 50 mg Tablets

2. Qualitative and quantitative composition

Each tablet contains Sertraline hydrochloride equivalent to 50 mg Sertraline.

For Full list of excipients, see section 6.1

3. Pharmaceutical form

Film-coated tablet

50mg are blue coloured, capsule shaped, biconvex, film coated tablets debossed with 'SER' on one side and '5' and '0' on either side of the breakline on the other side.

Sertraline 50 mg Tablets are designed with breakline; this breakline is only to facilitate breaking for ease of swallowing and not to divide it into equal doses.

4. Clinical particulars
4.1 Therapeutic indications

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

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

Sertraline Tablets 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 Tablets 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 A therapeutic trial in males might on occasion be justified, but treatment should subsequently be withdrawn unless there is clear evidence of therapeutic benefit.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 Tablets is not indicated for use in children and adolescents under the age of 18 years with Major Depressive Disorder.

In particular, controlled clinical studies failed to demonstrate efficacy and do not support the use of Sertraline Tablets 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

Sertraline Tablets 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 50mg daily and the usual antidepressant dose is 50mg daily. In some patients, doses higher than 50mg may be required.

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

Post-Traumatic Stress Disorder: Treatment for PTSD should be initiated at 25mg/day. After one week, the dose should be increased to 50mg 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 Tablets. 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 50mg daily may be required. In patients with incomplete response but good toleration at lower doses, dosage adjustments should be made in 50mg increments over a period of weeks to a maximum of 200mg 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 6-17 years Treatment should only be initiated by specialists. The safety and efficacy of Sertraline Tablets has been established in paediatric OCD patients (aged 6-17). The administration of Sertraline Tablets to paediatric OCD patients (aged 13-17) should commence at 50 mg/day. Therapy for paediatric OCD patients (aged 6-12) should commence at 25mg/day increasing to 50mg/day after 1 week. Subsequent doses may be increased in case of lack of response in 50mg/day increments up to 200mg/day as needed.

However, the generally lower body weights of children compared to adults should be taken into consideration in advancing the dose from 50mg, 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 Tablets 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 Tablets in the treatment of children and adolescents with Major Depressive Disorder (See sections 4.3, Contra-Indications and 4.8, Undesirable effects).

Children aged less than six years Sertraline Tablets is not recommended in children under six years of age since safety and efficacy have not been established. See also 'Pharmacological Properties'.

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.

Sertraline Tablets are for oral administration only.

4.3 Contraindications

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

Monoamine oxidase inhibitors:

Concomitant treatment with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with symptoms such as agitation, tremor and hyperthermia. 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 or reversible MAOI (see section 4.5).

Use in hepatic impairment: There is insufficient clinical experience in patients with significant hepatic dysfunction and accordingly Sertraline Tablets should not be used in such patients.

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

Sertraline Tablets should not be used in children and adolescents under the age of 18 years with Major Depressive Disorder. (See section 4.8, Undesirable effects).

4.4 Special warnings and precautions for use

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 – Contraindications).

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.

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.

Monoamine oxidase inhibitors See 'Contra-indications' and 'interactions'.

Renal Impairment

Since sertraline is extensively metabolised, excretion of unchanged drug in urine is a minor route of elimination. In patients with mild to moderate renal impairment (creatinine clearance 30-60ml/min) or moderate to severe renal impairment (creatinine clearance 10-29ml/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. However, steady state pharmacokinetics of sertraline have not been adequately studied in this patient population and caution is advised when treating patients with renal impairment.

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 with 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 should be approached with caution. A lower or less frequent dose should be used in patients with hepatic impairment. Sertraline should not be used in patients with severe hepatic impairment (see section 4.2).

Diabetes In patients with diabetes, treatment with an SSRI may alter glycaemic control, possibly due to improvement of depressive symptoms. Insulin and/or oral hypoglycaemic dosage may be needed to be adjusted.

Seizures Seizures are a potential risk with antidepressant or antiobsessional drugs. The drug should be discontinued in any patient who develops seizures. Sertraline Tablets should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Sertraline Tablets should be discontinued if there is an increase in seizure frequency.

Electroconvulsive therapy (ECT) Since there is little clinical experience of concurrent administration of Sertraline Tablets and ECT, caution is advisable.

Grapefruit juice The administration of sertraline with grapefruit juice is not recommended (see section 4.5)

Suicide/suicidal thoughts 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 Tablets 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.

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. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, aspirin and non-steroidal anti-inflammatory drugs (NSAIDs) and anticoagulants) as well as in patients with a history of bleeding disorders (see section 4.5).

Use in the elderly Over 700 elderly patients (>65 years) have participated in clinical studies with Sertraline Tablets. The pattern and incidence of adverse reactions in the elderly is similar to that in younger patients.

SSRI's or SNRIs including sertraline have however been associated with cases of clinically significant hyponatreamia in elderly patients, who may be at greater risk for this adverse event (see Hyponatreamia in section 4.4).

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.

More than 250 paediatric OCD patients have been exposed to Sertraline Tablets in completed and ongoing studies. The safety profile of Sertraline Tablets in these paediatric studies is comparable to that observed in the adult OCD studies. The efficacy of Sertraline Tablets in paediatric patients with depression or panic disorder has not been demonstrated in controlled trials. Safety and effectiveness in paediatric patients below the age of 6 have not been established.

There is limited knowledge with respect to an effect on sexual development in children.

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.

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 See 'Contra-indications'.

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)

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, fluctuations of vital signs and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.

Centrally active medication Caution is advised if Sertraline Tablets is administered with other centrally active medication. In particular, SSRIs have the potential to interact with tricyclic antidepressants leading to an increase in plasma levels of the tricyclic antidepressant. A possible mechanism for this interaction is the inhibitory effect of SSRIs on the CYP2D6 isoenzyme.

Pimozide– Increased pimozide levels of approximately 35% have been demonstrated in a study of a single low dose pimozide (2mg) with sertraline co administration. 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 pimozide and sertraline is contra-indicated (see section 4.3).

CNS depressants and Alcohol The co-administration of sertraline 200mg daily did not potentiate the effects of alcohol, carbamazapine, haloperidol, or phenytoin on cognitive and psychomotor performance in healthy subjects; however, the concomitant use of Sertraline Tablets 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 placebo-controlled trials in normal volunteers, the co-administration of Sertraline Tablets and lithium did not significantly alter lithium pharmacokinetics.

Co-administration of Sertraline Tablets with lithium 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.

There have been other reports of enhanced effects when SSRIs have been given with lithium or tryptophan and therefore the concomitant use of SSRIs with these drugs should be undertaken with caution.

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.

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). There is variability among the SSRIs in the extent to which they inhibit the activity of CYP2D6. 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.

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.

Serotonergic drugs There is limited controlled experience regarding the optimal timing of switching from other antidepressant or anti-obsessional drugs to Sertraline Tablets. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents. The duration of washout period which should intervene before switching from one selective serotonin reuptake inhibitor (SSRI) to another has not been established.

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

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.

Drugs that affect platelet function, such as NSAIDs See 'Special warnings and special precautions for use (Haemorrhage)'.

Other drug interactions Since Sertraline Tablets is bound to plasma proteins, the potential of Sertraline Tablets to interact with other plasma protein bound drugs should be borne in mind.

Formal drug interaction studies have been performed with Sertraline Tablets. Co-administration of Sertraline Tablets (200mg 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 Tablets had no effect on the beta-adrenergic blocking ability of atenolol. No interaction with Sertraline Tablets (200mg daily) was observed with glibenclamide or digoxin.

Co-administration of Sertraline Tablets (200mg daily) with warfarin resulted in a small but statistically significant increase in prothrombin time, the clinical significance of which is unknown. Accordingly, prothrombin time should be carefully monitored when Sertraline Tablets therapy is initiated or stopped.

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

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 Tablets 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 Tablets 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

(≥1/10)

Common

(≥1/100 to <1/10)

Uncommon

(≥1/1000 to <1/100)

Rare

(≥1/10000 to <1/1000)

Very rare

(<1/10000)

Frequency not Known

Infections and Infestations

Pharyngitis

Upper Respiratory Tract Infection, Rhinitis

Diverticulitis, Gastroenteritis, Otitis Media

Neoplasms benign, malignant (including cysts and polyps)

Neoplasm†

Blood and lymphatic system disorders

Lymphadenopathy

Leucopenia, Thrombocytopenia

Immune system disorders

Anaphylactoid Reaction, Allergic Reaction, Allergy

Endocrine disorders

Hyperprolactinaemia, Hypothyroidism and syndrome of inappropriate ADH secretion

Metabolism and Nutrition Disorders

Anorexia, Increased Appetite*

Hypercholesterolaemia, Hypoglycaemia

Hyponatremia, Diabetes Mellitus, Hyperglycaemia

Psychiatric Disorders

Insomnia (19%)

Depression*, Depersonalisation, 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%), Somnolence (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 pyschomotor 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 Hypersecretion, 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, Urticuria*

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, Pollakiura, Micturition disorder

Oliguria, Urinary Incontinence*, Urinary Hesitation

Reproductive System and Breast Disorders**

Ejaculation Failure (14%)

Sexual Dysfunction, Erectile Dysfunction

Vaginal Haemorrhage, Female Sexual Dysfunction

Menorrhagia, Atrophic Vulvuvaginitis, 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

Investigations

Weight Decreased*, Weight Increased*

Alanine Aminotransferarase 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.

One case of neoplasm was reported in one patient receiving sertraline compared with no cases in the placebo arm.

* these adverse reactions also occurred in postmarketing experience

** the denominator uses the number of patients in that sex group-combined: sertraline (1118 males, 1424 females) placebo (926 males, 1219 females)

For OCD, short term, 1-12 week studies only

*** Cases of suicidal ideation and suicidal behaviours have been reported during sertraline therapy or early after treatment discontinuation (see section 4.4).

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):

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.

4.9 Overdose

On the evidence available, Sertraline Tablets has a wide margin of safety in overdose. Overdoses of Sertraline Tablets alone of up to 13.5g have been reported. Deaths involving overdoses of Sertraline Tablets 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 Tablets. 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

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

Sertraline Tablets has been evaluated in paediatric OCD patients aged 6 to 17 in a 12 week placebo-controlled study. Therapy for paediatric OCD patients (aged 6-12) 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 50-200mg. 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 half-life 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 6-12 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 to younger adults.

Food does not significantly change the bioavailability of Sertraline Tablets 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

Sertraline tablets include the following ingredients:

Tablet cores:

Calcium hydrogen phosphate anhydrous (E 341)

Microcrystalline cellulose (E460)

Hydroxypropylcellulose (E463)

Sodium starch glycolate

Magnesium stearate

Film coating in 50mg:

Opadry blue

Hydroxy Propyl methyl cellulose (E464)

Titanium dioxide (E171)

Macragol

Polysorbate 80 (E433)

FD&C Blue#2/Indigo Carmine Aluminum Lake (E132)

6.2 Incompatibilities

None.

6.3 Shelf life

3 years

6.4 Special precautions for storage

None

6.5 Nature and contents of container

Sertraline 50mg Tablets are available in packs of 7, 10, 14, 15, 20, 28, 30, 50, 56, 60, 84, 90, 98, 100, 200, 250, 300, and 500 tablets packaged in opaque white PVC/PVDC/AL blister strips

* not all pack sizes may be marketed..

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Lupin (Europe) Limited

Victoria Court

Bexton Road

Knutsford

Cheshire WA16 0PF

United Kingdom

8. Marketing authorisation number(s)

Sertraline 50mg Tablets PL 35507/0020

9. Date of first authorisation/renewal of the authorisation

01/09/09

10. Date of revision of the text

March 2013