Sertraline 50mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Sertraline 50mg Film-Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 50mg of sertraline (as hydrochloride).
For excipients see 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet
Sertraline 50mg Tablets are white film-coated oblong, biconvex tablets, scored on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Sertraline is indicated for the treatment of:
Major depressive episodes. Prevention of recurrence of major depressive episodes.
Panic disorder, with or without agoraphobia.
Obsessive compulsive disorder (OCD) in adults and paediatric patients aged 617 years.
Social anxiety disorder.
Post-traumatic stress disorder (PTSD).
4.2 Posology and method of administration
Sertraline should be given as a single daily dose. Sertraline 50mg 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. 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should be reviewed periodically by the prescribing physician to determine response to therapy and treatment should be withdrawn if there is no clear evidence of efficacy.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 seven days, although two to four 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 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 one 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, Contra-Indications and 4.8, Undesirable effects).
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 also 'Pharmacological Properties'.
Use in the elderly: No special precautions are required. The usual adult dose is recommended. Several hundred elderly patients have participated in clinical studies with sertraline. The pattern and incidence of adverse reactions in the elderly is similar to that in younger patients.
Sertraline 50mg Tablets are for oral administration only.
Withdrawal symptoms seen on discontinuation of SSRI: Abrupt discontinuation should be avoided. When stopping treatment with SSRIs 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 section 4.4 Special Warnings and Special Precautions for Use and section 4.8 Undesirable Effects). 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.
Some cases presented with features resembling serotonin syndrome.
Symptoms of a drug interaction with a MAOI include: tremor, 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 and at least one day after discontinuing treatment with the reversible MAOI (RIMA), moclobemide. Sertraline must be discontinued for at least 7 days before starting treatment with an irreversible MAOI or RIMA.
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, diaphoresis, nausea, vomiting, flushing, dizziness, features resembling neuroleptic malignant syndrome, seizures, and death.
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.
Concomitant use in patients taking pimozide is contra-indicated (see Section 4.5 - Interaction with other medicinal products and other forms of interaction.
Sertraline should not be used in children and adolescents under the age of 18 years with Major Depressive Disorder (See section 4.8, Undesirable effects) but are used to treat obsessive compulsive disorder (OCD) in children of six years and over (See Section 4.2. Posology and method of administration).
4.4. Special warnings and precautions for use
Monoamine oxidase inhibitors: See Section 4.3 Contra-indications.
Use in patients with renal or hepatic impairment: As with many other medications, sertraline should be used with caution in patients with renal and hepatic impairment (see Section 4.3 Contra-indications).
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 20-50ml/min) or severe renal impairment (creatinine clearance <20ml/min), single dose pharmacokinetic parameters were not significantly different compared with controls. 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.
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.
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 need 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 should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. Sertraline 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 and ECT, caution is advisable.
Serotonin syndrome and neuroleptic malignant syndrome: 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 (see section 4.3 -Contraindications).
Switching from SSRIs, antidepressants or anti-obsessional drugs to sertraline. There is limited controlled experience regarding the optimal timing of switching from SSRIs, antidepressants or anti-obsessional drugs to sertraline. Care and prudent medical judgement should be exercised when switching, particularly from long acting agents such as fluoxetine.
Mania: sertraline should be used with caution in patients with a history of mania/hypomania. Close surveillance by the physician is required in patients taking sertraline with history of mania/hypomania. Manic/hypomanic symptoms have been reported in patients treated with sertraline. Sertraline should be discontinued in any patient entering a manic phase.
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 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 the appearance of suicidal symptoms. In addition, long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking.
Haemorrhage: There have been reports of cutaneous bleeding abnormalities such as ecchymoses and purpura 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 antiinflammatory drugs (NSAIDs)) as well as in patients with a history of bleeding disorders. Haemorrhagic events such as gastrointestinal or gynaecological bleeding have been reported.
Caution in patients taking anticoagulants.
Psychomotor restlessness: The use of SSRIs has been associated with the development of psychomotor restlessness, which clinically may be very similar to 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 and it may be necessary to review the use of SSRIs.
Schizophrenia: Psychotic symptoms might become aggravated in schizophrenic patients.
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. 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.
Use in the elderly: Several hundred elderly patients have participated in clinical studies with sertraline. The pattern and incidence of adverse reactions in the elderly is similar to that in younger patients.
Use in Children: More than 250 paediatric OCD patients have been exposed to sertraline in completed and ongoing studies. The safety profile of sertraline in these paediatric studies is comparable to that observed in the adult OCD studies. The efficacy of sertraline 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 six have not been established. Physicians should monitor paediatric patients on long term treatment for abnormalities in body systems concerned with growth, maturation, cognitive and behavioural development.
There is limited knowledge with respect to an effect on sexual development in children.
Sodium content: Sertraline 50mg Tablets contain approximately 0.3mg of sodium per tablet. To be taken into consideration by patients on a controlled sodium diet.
Withdrawal symptoms seen on discontinuation of SSRI treatment:
Withdrawal symptoms when treatment is discontinued are common, particularly if discontinuation is abrupt (see section 4.8 Undesirable effects).
In clinical trials adverse events seen on treatment discontinuation occurred in approximately 20% of patients treated with SSRIs. 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 two weeks, though in some individuals they may be prolonged (two to three months or more). It is therefore advised that SSRIs should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see "Withdrawal Symptoms Seen on Discontinuation of SSRIs",
Section 4.2 Posology and Method of Administration).
4.5. Interaction with other medicinal products and other forms of interaction
Monoamine oxidase inhibitors:
Irreversible MAOIs (e.g. selegiline) Sertraline must not be used in combination with irreversible MAOIs such as selegiline. Sertraline must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI. Sertraline must be discontinued for at least 7 days before starting treatment with an irreversible MAOI.
Reversible, selective MAOIs (e.g. moclobemide) - Due to the risk of serotonin syndrome, the combination of sertraline with a reversible, selective MAOI (RIMA) such as moclobemide should not be given. Following treatment with a RIMA, at least one day must elapse before starting treatment with sertraline. It is recommended that sertraline should be discontinued for at least 7 days before starting treatment with a RIMA.
Reversible, non-selective MAOI (e.g. linezolid) - The antibiotic linezolid is a weak, reversible, non-selective MAOI and should not be given to patients treated with sertraline.’
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.
Centrally active medication: Caution is advised if sertraline 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. There is variability among the SSRIs in the extent to which they inhibit the activity of CYP2D6. The clinical significance of this depends on the extent of inhibition and the therapeutic index of the co-administered drug. In formal interaction studies, chronic dosing with sertraline 50mg daily showed minimal elevation (mean 23-37%) of steady state plasma desipramine levels (a marker of CYP2D6 isoenzyme activity).
Pimozide: Increased pimozide levels have been demonstrated in a study of a single low dose of pimozide (2mg) with sertraline coadministration. These increased levels were not associated with any changes in ECG. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide, concomitant use of pimozide and sertraline is contra-indicated.
Alcohol: In 11 healthy subjects administered sertraline (200mg daily) for nine 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.
Lithium and tryptophan: In placebo-controlled trials in normal volunteers, the co-administration of sertraline and lithium did not significantly alter lithium pharmacokinetics. Co-administration of sertraline with lithium did result in an increase in tremor relative to placebo, indicating a possible pharmacodynamic interaction. 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. Patients coadministered sertraline with lithium should be appropriately monitored.
Serotonergic drugs: There is limited controlled experience regarding the optimal timing of switching from other antidepressant or antiobsessional drugs to sertraline. Care and prudent medical judgement 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, or fenfluramine, should not be used concomitantly with sertraline, due to a possible enhancement of 5-HT associated effects.
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 triptans. If concomitant treatment with sertraline and triptans is clinically warranted, appropriate observation of the patient is advised.
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 Section 4.4 Special warnings and precautions for use (Haemorrhage)'. 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.’
Drugs Metabolised by cytochrome P450: Clinically significant interactions may occur with substrates having a narrow therapeutic index such as the class I antiarrhythmics propafenone and flecainide, tricyclic antidepressants and typical antipsychotics, especially at higher sertraline dose levels
Other drug interactions: 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. Coadministration of sertraline (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 had no effect on the beta-adrenergic blocking ability of atenolol. No interaction with sertraline (200mg daily) was observed with glibenclamide or digoxin.
Co-administration of sertraline (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 therapy is initiated or stopped.
Sertraline (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: 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. Maternal use of SSRIs has been associated with increased risk of persistent pulmonary hypertension of the newborn and may result in neonatal complications including CNS toxicity, withdrawal syndrome and neonatal serotonin toxicity. As with all drugs sertraline should only be used in pregnancy if the potential benefits of treatment to the mother outweigh the possible risks to the developing foetus.
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.
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.
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 the majority of instances the complications begin immediately or soon (<24 hours) after delivery
Lactation: Sertraline is known to be excreted in breast milk. Its effects on the nursing infant have not yet been established. If treatment with sertraline is considered necessary, discontinuation of breast-feeding should be considered. 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 the benefit outweighs the risk.
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
Undesirable effects may be dose dependent and transient in nature or decrease in severity/frequency with continued treatment.
Side-effects which occurred significantly more frequently with sertraline than placebo in multiple dose studies were: nausea, diarrhoea/loose stools, anorexia, dyspepsia, tremor, dizziness, insomnia, somnolence, increased sweating, dry mouth and sexual dysfunction (principally ejaculatory delay in males).
The side-effect profile commonly observed in double-blind, placebo-controlled studies in patients with OCD and PTSD was similar to that observed in patients with depression.
Post-marketing spontaneous reports include the following:
Neoplasms benign, malignant and unspecified (including cysts and polyps):
neoplasms
Blood and lymphatic system disorders: There have been rare reports of altered platelet function and/or abnormal clinical laboratory results in patients taking sertraline. While there have been reports of thrombocytopenia, abnormal bleeding, gastrointestinal bleeding, gynaecological bleeding, leucopenia or purpura in several patients taking sertraline, it is unclear whether sertraline had a causative role. See also Section 4.4 'Special warnings and precautions for use'. SSRIs can also cause difficulties in controlling blood sugar levels.
Immune system disorder: Angiodema, anaphylactoid reactions
Endocrine disorders: hypothyroidism
Metabolism and nutrition disorder: Anorexia. Rare cases of hyponatremia have been reported and appeared to be reversible when sertraline was discontinued. Some cases were possibly due to the syndrome of inappropriate antidiuretic hormone secretion. The majority of reports were associated with older patients, and patients taking diuretics or other medications. Increased appetite and hypoglycaemia have also been reported.
Psychiatric disorders: nightmare, decreased libido, bruxism, euphoric mood, apathy, abnormal thinking, depressive symptoms, hallucinations, aggressive reaction, agitation, anxiety, psychosis, depersonalisation, nervousness, panic reaction drug dependence,and paranoia. Psychomotor restlessness/akathisia (see section 4.4 Special Warnings and Precautions for Use).
There have also been reports of manic reaction, although this phenomenon may be part of the underlying disease.
Cases of suicidal ideation and suicidal behaviours have been reported during sertraline therapy or early after treatment discontinuation (see section 4.4).
Nervous system disorders: Amnesia, headache, drowsiness, coma, hypertonia, dysgeusia, disturbance in attention, abnormal coordination, speech disorder, migraine, dyskinesia, movement disorders, paraesthesia, hypoaesthesia, extrapyramidal effects, syncope and signs and symptoms associated with serotonin syndrome which include fever, rigidity, confusion, agitation, diaphoresis, tachycardia, hypertension and diarrhoea.
Convulsions (Seizures): Sertraline should be discontinued in any patient who develops seizures (See Section 4.4 Special warnings and precautions for use').
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 (see section 4.3 - Contraindications).
Eye disorders: Abnormal vision. mydriasis, diplopia, lacrimal disorder, photophobia, diplopia
Ear disorders: tinnitus, ear pain
Cardiac disorders: myocardial infarction, palpitations, bradycardia, tachycardia
Vascular disorders: Blood pressure disturbances including postural hypotension, hypertension, hot flush, flushing
Respiratory, thoracic and mediastinal disorders: bronchospasm, dyspnoea, epistaxis, and hyperventilation
Gastrointestinal disorders. Vomiting, abdominal pain, constipation, flatulence, dysphagia, salivary hypersecretion, melaena and mouth ulceration
Hepatobiliary disorder: Rarely, pancreatitis and serious liver events (including hepatitis, jaundice and liver failure). Asymptomatic elevations in serum transaminases (SGOT and SGPT) have been reported in association with sertraline administration (0.8 - 1.3%), with an increased risk associated with the 200mg daily dose. The abnormalities usually occurred within the first one to nine weeks of drug treatment and promptly diminished upon drug discontinuation.
Skin and subcutaneous tissue disorders: Rash (including rare reports of erythema multiforme, photosensitivity), Stevens Johnson syndrome, periorbital oedema, dermatitis and dermatitis bullous, toxic epidermal necrolysis and cold sweat, ecchymoses, urticaria, alopecia, and pruritus.
Musculoskeletal and connective tissue disorders: Arthralgia, myalgia, muscular weakness, back pain, muscle twitching, arthritis, bone disorder, and involuntary muscle contractions 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.
Renal & urinary disorders: Urinary retention, pollakiuria and urinary incontinence
Reproductive system and breast disorders: Hyperprolactinemia, galactorrhoea, menstrual irregularities, anorgasmy, erectile dysfunction, vaginal haemorrhage, menorrhagia, priapism, and gynaecomastia
General disorders and administration site conditions: Malaise, yawning fatigue, chest pain, chills, pyrexia, asthenia, thirst, gait disturbance, odema peripheral, and hernia
Investigations: weight loss, increased weight
Paediatric population treated with sertraline: 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.
Withdrawal symptoms seen on discontinuation of SSRI treatment:
Discontinuation of SSRIs (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 reactions. 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 SSRI treatment is no longer required, gradual discontinuation by dose tapering should be carried out (see section 4.2 Posology and Method of Administration and section 4.4 Special Warnings and Special Precautions for use).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9 Overdose
On the evidence available, sertraline has a wide margin of safety in overdose. Overdoses of sertraline alone of up to 8g 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 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.
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.
The induction of emesis is not recommended.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic Group: Selective serotonin reuptake inhibitors ATC Code: N06A B
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, gamma-aminobutyric acid (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.
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.
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.
6.1 List of excipients
Tablet Core
Microcrystalline cellulose Dibasic calcium phosphate dihydrate Hydroxypropylcellulose Sodium starch glycollate Magnesium stearate
Tablet coating
Opadry White YS-1R-7003 - Hydroxypropyl methylcellulose 2910, 3cP
- Hydroxypropyl methylcellulose 2910, 5cP
- Polyethylene glycol 400
- Titanium dioxide
- Polysorbate 80
Opadry Clear YS-1R-7006 - Hydroxypropyl methylcellulose 2910, 5cP
- Polyethylene glycol 400
- Polyethylene glycol 6000
6.2 Incompatibilities
Not applicable
6.3 Shelf life
Two years
6.4 Special precautions for storage
Do not store above 25 °C.
Keep out of the reach and sight of children.
6.5 Nature and contents of container
PVC/PVdC/aluminium foil opaque blister packs containing 7, 14, 28, 30 or 100* tablets.
*Not all pack sizes may be marketed
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Wockhardt UK Ash Road North Wrexham LL13 9UF United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0184
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
28/10/2005 / 10/12/2010
10 DATE OF REVISION OF THE TEXT
01/10/2015