Sertraline Sandoz

Sertraline hydrochloride.

Sertraline Sandoz 50 mg: One film-coated tablet contains 50 mg sertraline as sertraline hydrochloride.
Excipients/Inactive Ingredients: Tablet core: Microcrystalline cellulose, Calcium hydrogen phosphate dehydrate, Hydroxypropylcellulose, Sodium starch glycolate (type A), Magnesium stearate.
Film-coating: Hypromellose, Talc, Titanium dioxide (E 171).

Pharmacotherapeutic group: Antidepressant, selective serotonin re-uptake inhibitor. ATC Code: N06A B06.
PHARMACOLOGY: Pharmacodynamics: Sertraline has proven in vitro to be a potent specific neuronal serotonin (5-HT) re-uptake inhibitor which led to increased effects of 5-HT in the animal trial. Sertraline has only poor effects on the neuronal re-uptake of noradrenaline and dopamine. In clinical doses, sertraline blocks the re-uptake of serotonin in human platelets. Sertraline has no stimulating, sedative or anticholinergic activity and is not cardiotoxic in the animal trial. In controlled studies with healthy volunteers, sertraline had no sedative effect and did not affect the psychomotor behaviour. In accordance with the selective inhibition of the 5-HT re-uptake, sertraline does not intensify the catecholaminergic activity. Sertraline has no affinity for muscarinergic (cholinergic), serotonergic, dopaminergic, adrenergic, histaminergic, GABAergic or benzodiazepinergic receptors. Chronic administration of sertraline in animals resulted in down-regulation of noradrenergic receptors of the brain. This was also seen after use of other clinically effective antidepressants.
No physical or mental dependence on sertraline was seen.
Pharmacokinetics: Absorption: After 14 days at a daily oral dose of 50-200 mg, peak plasma concentrations of sertraline will occur 4.5 - 8.4 hours after the daily administration in humans. On the basis of recovery rates in urine and faeces, it can be estimated that absorption after oral administration is at least 70%. Bioavailability is reduced by the first pass effect. Taking of food does not significantly change the bioavailability of sertraline tablets.
Distribution: Approx. 98% of the circulating active substance is bound to plasma proteins. Data from animal studies indicate a large distribution volume of sertraline. Steady-state concentrations are achieved after approx. 1 week with administration once daily.
Metabolism: Sertraline has marked first-pass hepatic metabolism. The main metabolite in plasma, N-desmethyl sertraline is significantly less active than sertraline (approximately 20 fold) in vitro and there are no signs of activity in vivo. The half-life of N-desmethyl sertraline ranges between 62-104 hours. Both sertraline and N-desmethyl sertraline are metabolised to a great extent, and the resulting metabolites are excreted in faeces and urine in equal amounts. Only a small amount of unchanged sertraline (less than 0.2%) is excreted in the urine. It has been demonstrated in in vitro investigations that the metabolism of sertraline is mainly mediated by the CYP 3A4 enzyme, with only limited involvement of CYP 2D6. At the standard dose of 50 mg, sertraline has only limited effects on the CYP 2D6- and CYP 3A4-mediated metabolism of other substances.
Elimination: The mean half-life of sertraline is approx. 26 hours (22-36 hours). In accordance with this, there is an about 2-fold accumulation up to the steady-state concentrations which are reached after a daily dose for one week. The pharmacokinetics of sertraline are proportional to the dose in the range from 50-200 mg.
Special patient groups: Elderly patients: The pharmacokinetic profile in elderly patients does not significantly differ from that of adults between 18 and 65 years of age.
Impaired organ function: Following multiple dosage, the pharmacokinetics of sertraline are unchanged in patients with moderately to severely impaired renal function (creatinine clearance 10-29 ml/min). In patients with impaired hepatic function, the half-life of sertraline is prolonged and the AUC increased by the 3-fold.
Toxicology: Preclinical safety data: Conventional studies of sertraline did not demonstrate mutagenicity nor carcinogenicity. No teratogenic effects have been observed in studies of reproductive toxicity in rats and rabbits. At 2.5 to 10-fold higher dosages in comparison with the maximum therapeutic dose in humans, however, ossification was delayed in foetal rats and rabbits. Administration of sertraline during the last trimenon of gestation until the end of lactation, at a dosage exceeding the 5-fold of the maximum therapeutic dose in humans, led to an increased number of stillbirths as well as to a decreased survival rate and reduced bodyweight of descendants. It has been demonstrated that intrauterine exposure results in a lower survival rate of descendants.

Treatment of major depressive episodes; Treatment of obsessive-compulsive disorder (OCD); Treatment of panic disorder; Treatment of post-traumatic stress disorder (PTSD); Treatment of social phobia; Treatment of obsessive-compulsive disorder (OCD) in children and adolescents (6-17 years of age).

Treatment of major depressive episodes: The usual daily dose is 50 mg. If dose increments are required, these should be made in steps of 50 mg at minimum intervals of 1 week. Dose changes should not be performed more than once per week due to elimination half-life of sertraline of 24 hours. The maximum daily dose is 200 mg.
Treatment of obsessive-compulsive disorder (OCD): Initially 50 mg once daily. If dose increments are required, these should be made in steps of 50 mg at minimum intervals of 1 week. Dose changes should not be performed more than once per week due to elimination half-life of sertraline of 24 hours. The maximum daily dose is 200 mg.
Treatment of panic disorder, treatment of post-traumatic stress disorder (PTSD) and treatment of social phobia: Initially 25 mg once daily. Increase the dose to 50 mg once daily after 1 week. If dose increments are required, these should be made in steps of 50 mg at minimum intervals of not less than one week. Dose changes should not be performed more than once per week due to elimination half-life of sertraline of 24 hours. The maximum daily dose is 200 mg.
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 (see Precautions).
During long-term therapy the aim is to administer the lowest possible dosage which provides adequate therapeutic efficacy.
Treatment of obsessive-compulsive disorder (OCD) in children and adolescents (6 -17 years of age): Initially 50 mg as a single daily dose (aged 13 - 17).
Initially 25 mg as a single daily dose (aged 6 - 12). The dosage may be increased to 50 mg once daily after one week.
The maximum dose in adolescents under 18 years of age is 200 mg daily. However, lower doses should be considered in patients with low body weight to avoid elevated plasma levels. The diagnosis should be verified by a specialist in child or adolescent psychiatry.
Elderly: As the elimination half-life may be prolonged in elderly patients, it should be advised that the dosage should be as low as possible in the elderly.
Patients with impaired hepatic function: In patients with impaired hepatic function sertraline tablets should be used with caution. Although it is not clear if dosage adjustments are necessary in case of impaired hepatic function, it is recommended that the dose is reduced or the interval between the dosage prolonged. Sertraline should not be used in case of severe hepatic impairment as no clinical data are available.
Patients with impaired renal function: Dose adjustment is not necessary (see Precautions).
Method and duration of administration: Sertraline tablets should be taken as a single daily dose either in the morning or in the evening. Tablets can be taken with or without food, with a sufficient amount of liquid.
The onset of antidepressant effect may occur within 7 days, however, the maximum effect is generally reached after 2-4 weeks of treatment. It is advisable that the patients are informed of this.
The duration of treatment depends upon the nature and severity of the disorder. After remission of the symptoms of depression, patients should be treated for a sufficient period of at least 6 months to ensure that they are free from symptoms.
Withdrawal symptoms seen on discontinuation of SSRI: 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 Precautions and Adverse Reactions). 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.

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

Hypersensitivity to the active substance or to any of the excipients.
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 MAOI (see Interactions).
Concomitant intake of pimozide is contraindicated (see Interactions).

Serotonin Syndrome (SS) or Neuroleptic Malignant Syndrome (NMS): The development of potentially life-threatening syndromes like serotonin syndrome (SS) or Neuroleptic Malignant Syndrome (NMS) has been reported with SSRIs, including treatment with sertraline. The risk of SS or NMS with SSRIs is increased with concomitant use of other serotonergic medicinal products (including other serotonergic antidepressants, amphetamines, triptans), with medicinal products which impair metabolism of serotonin (including MAOIs e.g. methylene blue), antipsychotics and other dopamine antagonists, and with opiate medicinal products. Patients should be monitored for the emergence of signs and symptoms of SS or NMS syndrome (see Contraindications).
Switching from Selective Serotonin Reuptake Inhibitors (SSRIs), antidepressants or antiobsessional medicinal products: There is limited controlled experience regarding the optimal timing of switching from SSRIs, antidepressants or antiobsessional medicinal products to sertraline. Care and prudent medical judgment should be exercised when switching, particularly from long-acting agents such as fluoxetine.
Other serotonergic medicinal products e.g. tryptophan, fenfluramine and 5-HT agonists: Co-administration of sertraline with other active substances which enhance the effects of serotonergic neurotransmission such as amphetamines, tryptophan or fenfluramine or 5-HT agonists, or the herbal medicine, St John's Wort (Hypericum perforatum), should be undertaken with caution and avoided whenever possible due to the potential for a pharmacodynamic interaction.
QTc Prolongation/Torsade de Pointes (TdP): Cases of QTc prolongation and TdP have been reported during post-marketing use of sertraline. The majority of reports occurred in patients with other risk factors for QTc prolongation/TdP. Effect on QTc prolongation was confirmed in a thorough QTc study in healthy volunteers, with a statistically significant positive exposure-response relationship.
Therefore sertraline should be used with caution in patients with additional risk factors for QTc prolongation such as cardiac disease, hypokalaemia or hypomagnesaemia, familial history of QTc prolongation, bradycardia and concomitant use of medicinal products which prolong QTc interval (see Interactions).
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 medicinal products, 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 medicinal products 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 medicinal product 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 behavior or thoughts and unusual changes in behavior and to seek medical advice immediately if these symptoms present.
Abnormal bleeding/haemorrhage: There have been reports of bleeding abnormalities with SSRIs including cutaneous bleeding (ecchymoses and purpura) and other haemorrhagic events such as gastrointestinal or gynaecological bleeding, including fatal haemorrhages.
SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see Use in Pregnancy & Lactation and Adverse Reactions).
Caution is advised in patients taking SSRIs, particularly in concomitant use with medicinal products known to affect platelet function (e.g. anticoagulants, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAIDs)) as well as in patients with a history of bleeding disorders (see Interactions).
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 the elderly as follows). 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 Adverse Reactions). 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 Dosage & Administration).
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 C_max 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 Dosage & Administration).
Renal impairment: Sertraline is extensively metabolised, and excretion of unchanged substance 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 C_max) were not significantly different compared with controls. Sertraline dosing does not have to be adjusted based on the degree of renal impairment.
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 (ECT): 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 Interactions).
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.
Sexual dysfunction: Selective serotonin reuptake inhibitors (SSRIs)/serotonin norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see Adverse Reactions). There have been reports of long-lasting sexual dysfunction where the symptoms have continued despite discontinuation of SSRIs/SNRI.
Effects on ability to drive and use machines: Clinical pharmacology studies have shown that sertraline has no effect on psychomotor performance. However, as psychotropic medicinal products may impair the mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery, the patient should be cautioned accordingly.
Use in Children: Sertraline should not be used in the treatment of children and adolescents under the age of 18 years, except for patients with obsessive compulsive disorder aged 6-17 years old. Suicide-related behaviours (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials among children and adolescents treated with antidepressants compared to those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken; the patient should be carefully monitored for appearance of suicidal symptoms.
In addition, only limited clinical evidence is available concerning, long-term safety data in children and adolescents including effects on growth, sexual maturation and cognitive and behavioural developments.
A few cases of retarded growth and delayed puberty have been reported post-marketing. The clinical relevance and causality are yet unclear.
Physicians must monitor paediatric patients on long term treatment for abnormalities in growth and development.
Use in the elderly: Over 700 elderly patients (> 65 years) have participated in clinical studies. The pattern and incidence of adverse reactions in the elderly was similar to that in younger patients.
SSRIs or SNRIs including sertraline have however been associated with cases of clinically significant hyponatraemia in elderly patients, who may be at greater risk for this adverse event (see Hyponatraemia as previously mentioned).

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 PHARMACOLOGY: Toxicology: Preclinical safety data under Actions).
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.
Observational data indicate an increased risk (less than 2-fold) of postpartum haemorrhage following SSRI/SNRI exposure within the month prior to birth (see Precautions and Adverse Reactions).
Breast feeding: Published data concerning sertraline levels in breast milk show that small quantities of sertraline and its metabolite N-desmethylsertraline are excreted in milk. Generally negligible to undetectable levels were found in infant serum, with one exception of an infant with serum levels about 50% of the maternal level (but without a noticeable health effect in this infant). To date, no adverse effects on the health of infants nursed by mothers using sertraline have been reported, but a risk cannot be excluded. Use in nursing mothers is not recommended unless, in the judgment of the physician, the benefit outweighs the risk.
Fertility: Animal data did not show an effect of sertraline on fertility parameters (see PHARMACOLOGY: Toxicology: Preclinical safety data under Actions).
Human case reports with some SSRI's have shown that an effect on sperm quality is reversible.
Impact on human fertility has not been observed so far.

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.
Adverse reactions listed as follows were observed from post-marketing 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 as follows may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy.
Adverse reactions: Frequency of adverse reactions observed from placebo-controlled clinical trials in depression, OCD, panic disorder, PTSD and social anxiety disorder. Pooled analysis and post marketing experience.
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); Not known (frequency cannot be estimated from the available data).
Infections and infestations: Common: Upper respiratory tract infection, pharyngitis, rhinitis.
Uncommon: Gastroenteritis, otitis media.
Rare: Diverticulitis^§.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Uncommon: Neoplasm.
Blood and lymphatic system disorders: Rare: Lymphadenopathy, thrombocytopenia^*§, leukopenia^*§.
Immune system disorders: Uncommon: Hypersensitivity^*, seasonal allergy^*.
Rare: Anaphylactoid reaction^*.
Endocrine disorders: Uncommon: Hypothyroidism^*.
Rare: Hyperprolactinaemia^*§, inappropriate antidiuretic hormone secretion^*§.
Metabolism and nutrition disorders: Common: Decreased appetite, increased appetite^*.
Rare: Hypercholesterolaemia, diabetes mellitus^*, hypoglycaemia^*, hyperglycaemia^*§, hyponatraemia^*§.
Psychiatric disorders: Very common: Insomnia.
Common: Anxiety^*, depression^*, agitation^*, libido decreased^*, nervousness, depersonalisation, nightmare, bruxism^*.
Uncommon: Suicidal ideation/behaviour, psychotic disorder*, thinking abnormal, apathy, hallucination^*, aggression^*, euphoric mood^*, paranoia.
Rare: Conversion disorder^*§, paroniria^*§, drug dependence, sleep walking, premature ejaculation.
Nervous system disorders: Very common: Dizziness, headache^*, somnolence.
Common: Tremor, movement disorders (including extrapyramidal symptoms such as hyperkinesia, hypertonia, dystonia, teeth grinding or gait abnormalities), paraesthesia^*, hypertonia^*, disturbance in attention, dysgeusia.
Uncommon: Amnesia, hypoaesthesia^*, muscle contractions involuntary^*, syncope^*, hyperkinesia^*, migraine^*, convulsion^*, dizziness postural, coordination abnormal, speech disorder.
Rare: Coma^*, akathisia (see Precautions), dyskinesia, hyperaesthesia, cerebrovascular spasm (including reversible cerebral vasoconstriction syndrome and call-fleming syndrome)^*§, psychomotor restlessness^*§ (see Precautions), sensory disturbance, choreoathetosis^§, also reported were signs and symptoms associated with serotonin syndrome^* or neuroleptic malignant syndrome: in some cases associated with concomitant use of serotonergic medicinal products that included agitation, confusion, diaphoresis, diarrhoea, fever, hypertension, rigidity and tachycardia^§.
Eye disorders: Common: Visual disturbance^*.
Uncommon: Mydriasis^*.
Rare: Scotoma, glaucoma, diplopia, photophobia, hyphaema^*§, pupils unequal^*§, vision abnormal^§, lacrimal disorder.
Not known: Maculopathy, blindness.
Ear and labyrinth disorders: Common: Tinnitus^*.
Uncommon: Ear pain.
Cardiac disorders: Common: Palpitations^*.
Uncommon: Tachycardia^*, cardiac disorder.
Rare: Myocardial infarction^*§, Torsade de Pointes^*§ (see Precautions and Interactions), bradycardia, QTc prolongation^* (see Precautions and Interactions).
Vascular disorders: Common: Hot flush^*.
Uncommon: Abnormal bleeding (such as gastrointestinal bleeding)^*, hypertension^*, flushing, haematuria^*.
Rare: Peripheral ischaemia.
Respiratory, thoracic, and mediastinal disorders: Common: Yawning^*.
Uncommon: Dyspnoea, epistaxis^*, bronchospasm^*.
Rare: Hyperventilation, interstitial lung disease^*§, laryngospasm, dysphonia, stridor^*§, hypoventilation, hiccups.
Gastrointestinal disorders: Very common: Nausea, diarrhoea, dry mouth.
Common: Dyspepsia, constipation^*, abdominal pain^*, vomiting^*, flatulence.
Uncommon: Melaena, tooth disorder, oesophagitis, glossitis, haemorrhoids, salivary hypersecretion, dysphagia, eructation, tongue disorder.
Rare: Mouth ulceration, pancreatitis^*§, haematochezia, tongue ulceration, stomatitis.
Not known: Colitis microscopic.
Hepatobiliary disorders: Rare: Hepatic function abnormal, serious liver events (including hepatitis, jaundice and hepatic failure).
Skin and subcutaneous tissue disorders: Common: Hyperhidrosis, rash^*.
Uncommon: Periorbital oedema^*, urticaria^*, alopecia^*, pruritus^*, purpura^*, dermatitis, dry skin, face oedema, cold sweat.
Rare: Rare reports of severe cutaneous adverse reactions (SCAR): e.g. Stevens-Johnson syndrome^* and epidermal necrolysis^*§, skin reaction^*§, photosensitivity^§, angioedema, hair texture abnormal, skin odour abnormal, dermatitis bullous, rash follicular.
Musculoskeletal and connective tissue disorders: Common: Back pain, arthralgia^*, myalgia.
Uncommon: Osteoarthritis, muscle twitching, muscle cramps^*, muscular weakness.
Rare: Rhabdomyolysis^*§, bone disorder.
Not known: Trismus^*.
Renal and urinary disorders: Uncommon: Pollakiuria, micturition disorder, urinary retention, urinary incontinence^*, polyuria, nocturia.
Rare: Urinary hesititation^*, oliguria.
Reproductive system and breast disorders: Very common: Ejaculation failure.
Common: Menstruation irregular^*, erectile dysfunction.
Uncommon: Sexual dysfunction, menorrhagia, vaginal haemorrhage, female sexual dysfunction.
Rare: Galactorrhoea^*, atrophic vulvovaginitis, genital discharge, balanoposthitis^*§, gynaecomastia^*, priapism^*.
Not known: Postpartum haemorrhage^**.
General disorders and administration site conditions: Very common: Fatigue^*.
Common: Malaise^*, chest pain^*, asthenia^*, pyrexia^*.
Uncommon: Oedema peripheral^*, chills, gait disturbance^*, thirst.
Rare: Hernia, drug tolerance decreased.
Investigations: Common: Weight increased^*.
Uncommon: Alanine aminotransferase increased^*, aspartate aminotransferase increased^*, weight decreased^*.
Not known: Blood cholesterol increased^*, abnormal clinical laboratory results, semen abnormal, altered platelet function^*§.
Injury, poisoning and procedural complications: Common: Injury.
Surgical and medical procedures: Rare: Vasodilation procedure.
^*ADR identified post-marketing.
^§ADR frequency represented by the estimated upper limit of the 95% confidence interval using "The Rule of 3".
^**This event has been reported for the therapeutic class of SSRIs/SNRIs (see Precautions and Use in Pregnancy & Lactation).
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 Dosage & Administration and Precautions).
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 Precautions).
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: Headache (22%), insomnia (21%), diarrhoea (11%) and nausea (15%).
Common: 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: ECG QT prolonged (see Precautions and Interactions), 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.
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.

Contraindicated: Monoamine Oxidase Inhibitors: Irreversible MAOIs (e.g. selegiline): Sertraline must not be used in combination with irreversible. MAOIs such as selegiline. Sertraline must not be initiated for at least 14 days after discontinuation of treatment with an irreversible MAOI. Sertraline must be discontinued for at least 7 days before starting treatment with an irreversible MAOI (see Contraindications).
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 Contraindications).
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 Contraindications).
Severe adverse reactions have been reported in patients who have recently been discontinued from an MAOI (e.g. methylene blue) and started on sertraline, or have recently had sertraline therapy discontinued prior to initiation of an MAOI. These reactions have included tremor, myoclonus, diaphoresis, nausea, vomiting, flushing, dizziness, and hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.
Pimozide: Increased pimozide levels of approximately 35% have been demonstrated in a study of a single low dose pimozide (2 mg). These increased levels were not associated with any changes in EKG. While the mechanism of this interaction is unknown, due to the narrow therapeutic index of pimozide, concomitant administration of sertraline and pimozide is contraindicated (see Contraindications).
Co-administration with sertraline is not recommended: CNS depressants and alcohol: The co-administration of sertraline 200 mg daily did not potentiate the effects of alcohol, carbamazepine, haloperidol, or phenytoin on cognitive and psychomotor performance in healthy subjects; however, the concomitant use of sertraline and alcohol is not recommended.
Other serotonergic medicinal products: See Precautions.
Caution is also advised with fentanyl (used in general anaesthesia or in the treatment of chronic pain), other serotonergic medicinal products (including other serotonergic antidepressants, amphetamines, triptans), and with other opiate medicinal products.
Special precautions: Medicinal products that prolong the QT interval: The risk of QTc prolongation and/or ventricular arrhythmias (e.g. TdP) may be increased with concomitant use of other medicinal products which prolong the QTc interval (e.g. some antipsychotics and antibiotics) (see 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 Precautions).
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.
Medicinal products 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 Precautions).
Neuromuscular blockers: SSRIs may reduce plasma cholinesterase activity resulting in a prolongation of the neuromuscular blocking action of mivacurium or other neuromuscular blockers.
Medicinal products metabolized by cytochrome P450: Sertraline may act as a mild-moderate inhibitor of CYP2D6. Chronic dosing with sertraline 50 mg daily showed moderate elevation (mean 23%-37%) of steady-state desipramine plasma levels (a marker of CYP2D6 isozyme activity). Clinical relevant interactions may occur with other CYP2D6 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 CYP3A4, CYP2C9, CYP2C19, and CYP1A2 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 CYP1A2.
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 Precautions).
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 PHARMACOLOGY: Pharmacokinetics under Actions). Interaction with strong inhibitors of CYP2C19, e.g. omeprazole, lansoprazole, pantoprazole, rabeprazole, fluoxetine, fluvoxamine cannot be excluded.
Co-administration of sertraline with metamizole, which is an inducer of metabolizing enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of sertraline with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and sertraline are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.

Incompatibilities: Not applicable.

This medicinal product does not require any special storage conditions. Do not store above 30°C.

Antidepressants

N06AB06 - sertraline ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.

D