Zotral

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Zotral, 00 mg, coated tablets 1

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each coated tablet contains sertraline hydrochloride equivalent to 100 mg
of sertraline.
Excipient with known effect: monohydrate lactose.
Each coated tablet contains 159.3 mg of monohydrate lactose.
For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Film-coated tablet.
White, film-coated, round, biconvex tablets, 0.39 inches in diameter, with a score line on one side and an embossed letter C on the other. The tablet can be divided into equal doses.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Sertraline is indicated for the treatment of:

• Major depressive episodes. Prevention of relapse of major depressive episodes.
• Panic disorder with or without agoraphobia.
• Obsessive-compulsive disorder (OCD) in adults and pediatric patients aged 6–17 years.
• Social anxiety disorder.
• Post-traumatic stress disorder (PTSD).

4.2 Dosage and Administration

Sertraline should be administered once daily, in the morning or evening.
Sertraline tablets may be taken with or without food.

Initiation of treatment
Depression and OCD
Treatment with sertraline should be initiated at a dose of 50 mg once daily.
Panic disorder, PTSD, and social anxiety disorder
Treatment should be initiated at a dose of 25 mg once daily. After one week, the dose should be increased to 50 mg once daily. This dosing regimen reduces the frequency of adverse reactions typical of the initial phase of treatment for anxiety disorders with panic attacks.

Dose escalation
Depression, OCD, panic disorder, social anxiety disorder, and PTSD
Patients who do not respond to a dose of 50 mg may require dose escalation. Dose adjustments should be made at intervals of at least one week, increasing by 50 mg at each adjustment, up to a maximum dose of 200 mg once daily. Considering the elimination half-life of sertraline (approximately 24 hours), dosage adjustments should not be made more frequently than once per week.
Therapeutic effects may begin within 7 days; however, achieving full effect usually requires more time (particularly in the case of OCD).

Maintenance treatment
During long-term maintenance treatment, the dosage should be maintained at the lowest level that provides therapeutic benefit, and then adjusted as needed.
Depression
Long-term treatment may also be necessary to prevent recurrence of major depressive episodes. In most cases, the recommended dose is the same as that used during the current episode. Patients with depression should be treated for a sufficient duration, at least 6 months, to ensure that symptoms have resolved.
Panic disorder and OCD
In panic disorder and OCD, the need for continued treatment should be regularly assessed, as the ability to prevent relapse in these disorders has not been established.

Paediatric patients
Use in children and adolescents with OCD
Age 13–17 years: initial dose of 50 mg once daily.
Age 6–12 years: initial dose of 25 mg once daily. After one week, the dose may be increased to 50 mg once daily.
If the expected effect is not achieved with a dose of 50 mg once daily, further dose increases may be considered over several weeks, depending on individual needs. The maximum dose is 200 mg once daily.
When increasing the daily dose above 50 mg, the lower body weight of children compared to adults should be taken into account. Dosage adjustments should not be made more frequently than once per week.
The efficacy of sertraline in treating major depression in children has not been demonstrated.
There are no available data on the use of sertraline in children below 6 years of age (see section 4.4).

Use in elderly patients
Sertraline should be used with caution in elderly patients, as they may be at increased risk of hyponatraemia (see section 4.4).

Use in patients with hepatic impairment
Sertraline should be used with caution in patients with hepatic impairment. Lower doses or reduced dosing frequency should be considered (see section 4.4). Due to lack of adequate clinical data, sertraline should not be used in patients with severe hepatic impairment (see section 4.4).

Use in patients with renal impairment
Dosage adjustment is not required in patients with renal impairment (see section 4.4).

Symptoms of discontinuation following cessation of sertraline treatment
Abrupt discontinuation should be avoided. When stopping sertraline treatment, the dose should be gradually reduced over a period of at least one to two weeks to minimize the risk of discontinuation symptoms (see sections 4.4 and 4.8). If discontinuation symptoms occur during dose reduction or after treatment cessation, consideration should be given to resuming the previously recommended dose. The physician may then continue tapering the dose, but in a gradual manner.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Concomitant use of irreversible monoamine oxidase inhibitors (MAO inhibitors) is contraindicated due to the risk of serotonin syndrome, which may present with symptoms such as psychomotor agitation, muscle tremor, and hyperthermia.
Sertraline should not be initiated within at least 14 days after discontinuation of treatment with an irreversible MAO inhibitor.
Sertraline must be discontinued at least 7 days prior to starting treatment with an irreversible MAO inhibitor (see section 4.5).
Concomitant use of pimozide is contraindicated (see section 4.5).

4.4 Special warnings and precautions for use

Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS)
Potentially life-threatening syndromes such as serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS) have been reported in patients taking SSRIs, including patients treated with sertraline. The risk of developing SS or NMS increases when serotonergic drugs (including triptans) are used concomitantly with drugs that impair serotonin metabolism (including MAO inhibitors), antipsychotics and other dopamine antagonists, as well as opioids. Patients should be monitored for symptoms of serotonin syndrome or NMS (see section 4.3).

Switching from selective serotonin reuptake inhibitors (SSRIs), antidepressants or anti-obsessional drugs
There is limited experience from controlled studies regarding the optimal switching time from SSRIs, antidepressants or anti-obsessional drugs to sertraline. Caution and careful clinical judgment are required during such switches, especially when switching from long-acting agents such as fluoxetine.

Other serotonergic drugs, e.g. tryptophan, fenfluramine and 5-HT agonists
Sertraline should be used cautiously with other drugs that enhance serotonergic neurotransmission, such as tryptophan, fenfluramine or 5-HT agonists, or herbal products containing St. John’s wort (Hypericum perforatum), and such combinations should be avoided if possible due to the risk of pharmacodynamic interactions.

Activation of hypomania or mania
Manic and/or hypomanic episodes have been observed in a small proportion of patients treated with marketed antidepressants and anti-obsessional drugs, including sertraline. Therefore, sertraline should be used with caution in patients with a history of manic or hypomanic episodes. Close physician monitoring is necessary. Sertraline should be discontinued in any patient entering a manic phase.

Schizophrenia
In patients with schizophrenia, worsening of psychotic symptoms may occur.

Seizures
Seizures may occur in patients treated with sertraline. Sertraline should be avoided in patients with unstable epilepsy, and patients with controlled epilepsy should be closely monitored. Sertraline should be discontinued in any patient who develops seizures.

Suicide, suicidal thoughts or clinical worsening of illness
Depression is associated with an increased risk of suicidal thoughts, self-harm and suicide. This risk persists until full remission occurs. Since improvement may not occur within the first few weeks of treatment or longer, patients should be closely monitored until improvement occurs. Clinical experience indicates that the risk of suicide may increase during the early stages of recovery.

Other psychiatric disorders for which sertraline is prescribed may also be associated with an increased risk of suicidal behaviour. Furthermore, these disorders may coexist with major depressive disorders. Therefore, the same precautions should be taken for patients treated for other psychiatric disorders as for those with major depressive disorders.

Patients with a history of suicidal behaviour or those exhibiting significant suicidal ideation prior to treatment initiation belong to a high-risk group for suicidal thoughts or attempts and should be closely monitored during treatment.

A meta-analysis of placebo-controlled clinical trials of antidepressants in adult psychiatric patients showed an increased (compared to placebo) risk of suicidal behaviour in patients under 25 years of age treated with antidepressants.

During treatment, especially at the beginning of therapy and when dose adjustments are made, patients should be closely monitored, particularly those at increased risk. Patients (and their caregivers) should be advised to watch for any signs of clinical worsening, suicidal thoughts or behaviour, or unusual changes in behaviour, and to seek immediate medical attention if such symptoms occur.

Use in children and adolescents under 18 years of age
Sertraline should not be used in the treatment of children and adolescents under 18 years of age, except for patients with obsessive-compulsive disorder aged 6–17 years. In clinical trials, suicidal behaviour (suicidal thoughts and attempts) and hostility (particularly aggression, oppositional behaviour and anger) were observed more frequently in children and adolescents treated with antidepressants than in the placebo group. If treatment is initiated due to clinical need, patients should be carefully monitored for emergence of suicidal symptoms. Additionally, there are no long-term safety data on growth, maturation, cognitive development and behavioural development in children and adolescents. The health status of children receiving long-term treatment should be regularly monitored by a physician to detect abnormalities in these systems.

Abnormal bleeding/haemorrhage
Reports of abnormal skin bleeding such as petechiae and purpura, as well as other haemorrhagic events such as gastrointestinal or gynaecological bleeding, have been reported during SSRI use. Caution is advised in patients taking SSRIs, particularly when used concomitantly with drugs known to impair platelet function (e.g. anticoagulants, atypical antipsychotics and phenothiazine derivatives, most tricyclic antidepressants, acetylsalicylic acid and non-steroidal anti-inflammatory drugs (NSAIDs)), as well as in patients with a history of bleeding disorders (see section 4.5). SSRIs and SNRIs may increase the risk of postpartum haemorrhage (see sections 4.6 and 4.8).

Hyponatraemia
Hyponatraemia may occur during treatment with SSRIs or SNRIs, including sertraline. In many cases, hyponatraemia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases of serum sodium concentration below 110 mmol/l have been reported. The risk of hyponatraemia during treatment with SSRIs or SNRIs may be greater in elderly patients. Patients taking diuretics or otherwise predisposed to reduced plasma volume may also be at increased risk (see subsection: Use in elderly patients). In patients with symptomatic hyponatraemia, discontinuation of sertraline and initiation of appropriate medical management should be considered. Symptoms of hyponatraemia include headache, difficulty concentrating, memory disturbances, confusion, weakness and imbalance, which may lead to falls. Objective and subjective symptoms associated with more severe and/or acute cases include hallucinations, syncope, seizures, coma, respiratory arrest and death.

Withdrawal symptoms observed after discontinuation of sertraline treatment
Withdrawal symptoms following discontinuation of treatment are common, particularly with abrupt discontinuation (see section 4.8). In clinical trials among patients treated with sertraline, the frequency of reported reactions related to drug discontinuation was 23% in those discontinuing sertraline compared to 12% in those continuing sertraline treatment.

The risk of withdrawal symptoms may depend on several factors, including duration of treatment and dose, as well as the speed of dose reduction. Most commonly reported reactions include dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor and headache. These symptoms are usually mild or moderate in severity; however, in some patients they may be severe. They typically occur within the first few days after discontinuation of treatment, although very rare reports describe such symptoms in patients who inadvertently missed a dose. These symptoms are usually self-limiting and generally resolve within 2 weeks, although in some individuals they may persist longer (2–3 months or more). Therefore, gradual tapering of the sertraline dose over a period of several weeks or months is recommended when discontinuing treatment, depending on patient needs (see section 4.2).

Akathisia/psychomotor agitation
Sertraline use may be associated with akathisia, characterised by a subjectively unpleasant or distressing inner restlessness and an urge to move, often accompanied by an inability to sit or stand still. This disorder most commonly occurs during the first few weeks of treatment. Increasing the dose in patients experiencing these symptoms may be harmful.

Hepatic impairment
Sertraline is extensively metabolized by the liver. A multiple-dose pharmacokinetic study in patients with mild, stable liver cirrhosis showed prolonged elimination half-life and approximately threefold higher AUC and C_max values compared to healthy individuals. No significant differences in plasma protein binding were observed between the two groups. Caution should be exercised when administering sertraline to patients with liver disease. In patients with hepatic impairment, consideration should be given to reducing the dose or decreasing the frequency of administration. Sertraline should not be used in patients with severe hepatic impairment (see section 4.2).

Renal impairment
Sertraline is extensively metabolized, and renal excretion of unchanged drug is a minor elimination pathway. In studies involving patients with mild or 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 or C_max) did not differ significantly from those in control subjects. Dose adjustment of sertraline is not required according to the degree of renal impairment.

Use in elderly patients
Over 700 elderly patients (>65 years) participated in clinical trials. The pattern and frequency of adverse reactions in elderly patients were similar to those in younger patients. However, SSRIs and SNRIs, including sertraline, may be associated with clinically significant hyponatraemia in elderly patients, who may be more susceptible to this adverse event (see subsection: Hyponatraemia in section 4.4).

Diabetes
In diabetic patients, treatment with SSRIs may alter glycaemic control, and adjustment of insulin and/or oral antidiabetic drug dosage may be necessary.

Electroconvulsive therapy (ECT)
No clinical studies have been conducted to determine the risks or benefits of concomitant use of ECT and sertraline.

Grapefruit juice
Concomitant use of sertraline with grapefruit juice is not recommended (see section 4.5).

Abnormalities in urine screening tests
False-positive results in immunological screening tests for urinary benzodiazepines have been reported in patients taking sertraline, due to the lack of specificity of screening tests. False-positive results may persist for several days after discontinuation of sertraline. Confirmatory tests such as gas chromatography and/or mass spectrometry can differentiate sertraline from benzodiazepines.

Narrow-angle glaucoma
SSRI medicinal products, including sertraline, may affect pupil size by causing pupillary dilation. Pupillary dilation may lead to angle closure, resulting in increased intraocular pressure and development of acute angle-closure glaucoma, particularly in patients with predisposing factors. Caution should be exercised when using sertraline in patients with narrow-angle glaucoma or a history of glaucoma.

Sexual dysfunction
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section 4.8). Cases of persistent sexual dysfunction, in which symptoms persisted after discontinuation of SSRIs or SNRIs, have been reported.

Lactose
This medicinal product should not be used in patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Sodium
This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e. the product is considered "sodium-free".

4.5 Interactions with other medicinal products and other forms of interaction

Contraindicated
Monoamine oxidase inhibitors (MAO inhibitors)
Irreversible MAO inhibitors (e.g. selegiline)
Sertraline must not be used in combination with irreversible MAO inhibitors such as selegiline. Sertraline should not be started within at least 14 days of discontinuing treatment with an irreversible MAO inhibitor. Sertraline should be discontinued for at least 7 days before starting treatment with an irreversible MAO inhibitor (see section 4.3).
Reversible, selective MAO-A inhibitor (moclobemide)
Due to the risk of serotonin syndrome, sertraline should not be used concomitantly with a reversible, selective MAO inhibitor such as moclobemide. After discontinuation of treatment with a reversible MAO inhibitor, a shorter washout period than 14 days may be considered before starting sertraline. However, sertraline should be discontinued for at least 7 days before starting treatment with a reversible MAO inhibitor (see section 4.3).
Reversible, non-selective MAO inhibitor (linezolid)
The antibiotic linezolid is a weak, reversible, and non-selective MAO inhibitor. It should not be administered to patients receiving sertraline (see section 4.3).
Severe adverse reactions have been reported in patients who had recently discontinued MAO inhibitor treatment before starting sertraline, or who had discontinued sertraline shortly before receiving an MAO inhibitor. These reactions included muscle tremor, myoclonus, profuse sweating, nausea, vomiting, flushing, dizziness, hyperthermia with features resembling neuroleptic malignant syndrome, seizures, and death.
Pimozide
In a study using a low single dose of pimozide (2 mg) administered concomitantly with sertraline, an increase in pimozide plasma concentration by approximately 35% was observed. This was not associated with any ECG changes. Since the mechanism of this interaction is unknown and due to the narrow therapeutic index of pimozide, concomitant use of sertraline and pimozide is contraindicated (see section 4.3).

Concomitant use with sertraline is not recommended
CNS depressants, alcohol
Administration of sertraline at a dose of 200 mg daily to healthy volunteers did not potentiate the effects of alcohol, carbamazepine, haloperidol, or phenytoin on cognitive and psychomotor performance. However, alcohol consumption is not recommended during treatment with sertraline.
Other serotonergic drugs
See section 4.4.
Caution is advised when using fentanyl (in general anaesthesia or in chronic pain treatment) or other opioids.

Special warnings
Lithium
Results from a placebo-controlled study in healthy volunteers indicate that concomitant administration of sertraline and lithium does not alter the pharmacokinetics of lithium but increases tremor (compared to placebo), suggesting a possible pharmacodynamic interaction. Appropriate monitoring of patients is recommended when sertraline and lithium are used together.
Phenytoin
A placebo-controlled study in healthy volunteers indicates that long-term administration of sertraline at a dose of 200 mg daily does not cause clinically significant inhibition of phenytoin metabolism. However, since there have been reports of marked effects on phenytoin levels in patients receiving sertraline, monitoring of phenytoin plasma concentrations is recommended at the initiation of sertraline therapy to allow appropriate dose adjustment. Additionally, concomitant use of phenytoin may reduce sertraline plasma concentrations. Other CYP3A4 inducers such as phenobarbital, carbamazepine, St John’s wort, and rifampicin may also reduce sertraline plasma concentrations.
Triptans
In the post-marketing period, rare cases of weakness, excessive motor response, lack of coordination, disorientation, anxiety, and agitation have been reported during concomitant use of sertraline and sumatriptan. Symptoms of serotonin syndrome may also occur with other drugs of the same class (triptans).
If concomitant use of sertraline and triptans is clinically justified, patient observation is recommended (see section 4.4).
Warfarin
Concomitant administration of sertraline at a dose of 200 mg daily and warfarin resulted in a small but statistically significant prolongation of prothrombin time, which in rare cases may alter INR values. Therefore, prothrombin time should be monitored before starting and after discontinuing sertraline treatment.
Interactions with other drugs, digoxin, atenolol, cimetidine
Concomitant administration of cimetidine caused a significant decrease in sertraline clearance. The clinical significance of this change is unknown. Sertraline does not affect the ability of atenolol to block beta-adrenergic receptors. No interaction was observed between sertraline administered at a dose of 200 mg daily and digoxin.
Drugs affecting platelet function
When drugs affecting platelet function (e.g. NSAIDs, acetylsalicylic acid, and ticlopidine) or other drugs that may increase the risk of bleeding are used concomitantly with SSRIs, including sertraline, the risk of bleeding may be increased (see section 4.4).
Drugs metabolized by cytochrome P450
Sertraline may act as a mild or moderate inhibitor of cytochrome CYP2D6.
Interaction studies conducted during long-term administration of sertraline at a dose of 50 mg daily showed a moderate increase (on average by 23–37%) in steady-state plasma levels of desipramine (a marker of CYP2D6 enzyme activity). Clinically significant interactions may occur with other substrates of CYP2D6 with a narrow therapeutic index, such as Class 1C antiarrhythmics (e.g. propafenone and flecainide), tricyclic antidepressants, and typical antipsychotics, especially when higher doses of sertraline are used.
Sertraline does not inhibit the activity of CYP3A4, CYP2C9, CYP2C19, or CYP1A2 enzymes to a clinically significant extent. This has been confirmed in in vivo interaction studies using substrates of CYP3A4 (endogenous cortisol, carbamazepine, terfenadine, alprazolam), CYP2C19 (diazepam), and CYP2C9 (tolbutamide, glibenclamide, and phenytoin).
In vitro studies have shown that sertraline does not inhibit or only slightly inhibits the activity of the CYP1A2 enzyme.
Consumption of three glasses of grapefruit juice daily increased plasma sertraline concentrations by approximately 100% in a crossover study involving eight healthy Japanese volunteers. Therefore, grapefruit juice should be avoided during sertraline treatment (see section 4.4).
Based on interaction studies with grapefruit juice, concomitant administration of sertraline and strong CYP3A4 inhibitors such as protease inhibitors, ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, and nefazodone may lead to even greater exposure to sertraline. This also applies to moderate CYP3A4 inhibitors such as aprepitant, erythromycin, fluconazole, verapamil, and diltiazem. The use of CYP3A4 inhibitors should be avoided during sertraline treatment.
Plasma sertraline concentrations are increased by approximately 50% in individuals who are poor metabolizers via CYP2C19 compared to those who are rapid metabolizers (see section 5.2). Interactions with strong CYP2C19 inhibitors such as omeprazole, lansoprazole, pantoprazole, rabeprazole, fluoxetine, and fluvoxamine cannot be excluded.
Metamizole
Concomitant administration of sertraline with metamizole, which is an inducer of metabolizing enzymes including CYP2B6 and CYP3A4, may result in decreased plasma concentrations of sertraline, potentially reducing its clinical efficacy. Therefore, caution is recommended when using metamizole and sertraline concomitantly. If necessary, clinical response and/or drug concentration should be monitored.

4.6 Fertility, pregnancy and lactation

Pregnancy
There are no adequately controlled studies on the use of the medicinal product in pregnant women.
However, experimental studies have not shown congenital malformations caused by sertraline.
Animal studies have shown an effect of the drug on fertility, probably due to the pharmacodynamic toxicity of the substance on the mother, as well as direct pharmacodynamic effects on the foetus (see section 5.3).
Observational data indicate an increased (less than two-fold) risk of postpartum haemorrhage following exposure to SSRIs or SNRIs within one month before delivery (see sections 4.6 and 4.8).
It has been observed that the use of sertraline during pregnancy may lead to symptoms consistent with withdrawal symptoms in some newborns whose mothers were treated with sertraline. This phenomenon has also been observed with other antidepressant drugs of the SSRI class. Sertraline is not recommended during pregnancy unless the clinical condition of the woman justifies such use and the potential benefits of treatment outweigh the possible risks.
If the mother continues to take sertraline during late pregnancy, especially in the third trimester, the newborn should be monitored. After maternal use of sertraline during late pregnancy, the following symptoms may occur in the newborn: respiratory distress, cyanosis, apnoea, convulsions, temperature fluctuations, feeding difficulties, vomiting, hypoglycaemia, increased muscle tone, decreased muscle tone, hyperreflexia, muscle tremors, muscle spasms, irritability, somnolence, persistent crying, drowsiness and sleep disturbances. These symptoms may result either from serotonergic effects or from the occurrence of withdrawal symptoms. In most cases, complications occur immediately or shortly after birth (within less than 24 hours).
Epidemiological data suggest that the use of serotonin reuptake inhibitors in pregnant women, especially during the third trimester, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Five such cases have been observed per 1000 pregnant women. In the general population, 1 to 2 cases of persistent pulmonary hypertension in the newborn per 1000 pregnant women are reported.

Breast-feeding
Published data on sertraline concentrations in breast milk indicate that small amounts of sertraline and its metabolite N-desmethylsertraline are excreted into milk. In breastfed infants, serum concentrations of the drug are generally very low or undetectable, with a single exception of an infant with sertraline concentration corresponding to about 50% of the maternal level (however, without any observable effect on the infant's health).
To date, no adverse effects have been reported in breastfed infants of mothers taking sertraline, but the risk of such effects cannot be excluded.
The use of the drug is not recommended in breastfeeding mothers unless, in the physician's opinion, the benefits associated with its use outweigh the risks.

Effect on fertility
Animal studies have not shown any effect of sertraline on fertility parameters (see section 5.3).
Case reports on the use of certain SSRIs in humans suggest that effects on semen quality are transient.
No effect on fertility has been observed in humans.

4.7 Effects on ability to drive and use machines

Clinical pharmacological studies have shown that sertraline does not impair
psychomotor performance. However, antidepressant medications may impair mental or physical functions
required for the successful performance of potentially hazardous tasks, such as driving a car or operating machinery, and patients should be warned accordingly.

4.8 Undesirable effects

The most common adverse effect is nausea. In the treatment of social anxiety disorder, 14%
of men experienced sexual disorders (inability to ejaculate) compared to 0%
in the placebo group. These adverse effects are dose-dependent and often transient
during continued treatment.
The adverse effect profile commonly observed in placebo-controlled, double-blind studies
involving patients with OCD, panic attacks, PTSD, and social anxiety disorder was similar to that observed in clinical studies of patients with depression.
Table 1 presents adverse effects observed after marketing authorization (frequency unknown) and in placebo-controlled clinical trials (involving a total of 2542 patients treated with sertraline and 2145 individuals receiving placebo), concerning depression, OCD, panic attacks, PTSD, and social anxiety disorder.
Some adverse drug reactions listed in Table 1 may decrease in intensity and frequency during continued treatment and usually do not require discontinuation of the drug.
Table 1: Adverse effects
Frequency of adverse effects observed in placebo-controlled studies on depression, OCD, panic attacks, PTSD, and social anxiety disorder. Combined analysis and post-marketing reports (frequency unknown).

† One case of malignant neoplasm was reported in a patient receiving sertraline,
compared to no such cases in the placebo group.
* these adverse reactions were also reported during post-marketing surveillance
** the numerator indicates the total number of patients in each subgroup categorized by sex:
sertraline (1118 males, 1424 females), placebo (926 males, 1219 females)
For ZO-K – only short-term studies lasting from 1 to 12 weeks.
*** suicidal thoughts and suicidal behaviors have been reported during treatment with sertraline or shortly after discontinuation of this medication (see section 4.4).
**** this event has been reported for the class of SSRIs and SNRIs (see sections 4.4 and 4.6).
Withdrawal symptoms observed after discontinuation of sertraline
Discontinuation of sertraline (especially abrupt discontinuation) frequently leads to withdrawal symptoms. The most commonly reported reactions are: dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, and headache. These symptoms are usually mild to moderate in severity and self-limiting; however, in some patients they may be severe and/or prolonged. Therefore, when treatment with sertraline is no longer required, gradual dose reduction is recommended (see sections 4.2 and 4.4).
Elderly population
SSRIs or SNRIs, including sertraline, may be associated with clinically significant hyponatremia in elderly patients, who may be more susceptible to this adverse event (see section 4.4).
Paediatric patients
In over 600 paediatric patients treated with sertraline, the overall adverse reaction profile was generally similar to that observed in adult studies. In controlled trials (n=281 patients treated with sertraline), the following adverse reactions were observed:
Very common (≥ 1/10): headache (22%), insomnia (21%), diarrhoea (11%), and nausea (15%).
Common (≥ 1/100 to < 1/10): chest pain, mania, fever, vomiting, anorexia, emotional lability, aggression, agitation, nervousness, attention disturbances, dizziness, hyperkinesia, migraine, somnolence, tremor, visual disturbances, dry mouth, dyspepsia, nightmares, fatigue, urinary incontinence, rash, acne, epistaxis, flatulence.
Uncommon (≥ 1/1,000 to < 1/100): QT interval prolongation in ECG, suicide attempts, seizures, extrapyramidal disorders, paresthesia, depression, hallucinations, purpura, hyperventilation, anaemia, liver function abnormalities, increased alanine aminotransferase concentration, cystitis, herpes simplex, otitis externa, ear pain, eye pain, pupillary dilation, malaise, haematuria, pustular rash, rhinitis, injuries, weight loss, muscle cramps, abnormal dreams, apathy, albuminuria, pollakiuria, polyuria, breast pain, menstrual disorders, alopecia, dermatitis, skin disorders, abnormal skin odour, urticaria, bruxism, hot flushes.
Frequency not known: involuntary urination.
Study findings
Epidemiological study results, primarily in patients aged 50 years and older, indicate an increased risk of bone fractures in patients taking serotonin reuptake inhibitors and tricyclic antidepressants. The mechanism of this effect is unknown.
Reporting suspected adverse reactions
After marketing authorization, it is important to report suspected adverse reactions. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Al. Jerozolimskie 181C
02-222 Warsaw
Tel.: + 48 22 49 21 301
Fax: + 48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the responsible entity.

4.9 Overdose

Available data indicate that sertraline has a wide safety margin in overdose.
Overdoses of sertraline alone in doses up to 13.5 g have been reported. Fatalities following
sertraline overdose occurred primarily in combination with other drugs and/or alcohol.
Therefore, aggressive medical management should be initiated in every case of overdose.
Symptoms
Symptoms of overdose include adverse effects of sertraline such as drowsiness, gastrointestinal
disturbances (such as nausea and vomiting), tachycardia, tremors, agitation, and dizziness.
Coma has been reported less frequently.
Treatment
There is no specific antidote for sertraline. Airway patency should be ensured and maintained,
and adequate ventilation and oxygen administration should be provided when necessary.
Activated charcoal, which may be used in combination with a cathartic agent, may be as effective
or more effective than gastric lavage and should be considered in the management of overdose.
Induction of vomiting is not recommended. Cardiac monitoring and observation of vital
physiological parameters are advised, along with general symptomatic and supportive treatment.
Due to the large volume of distribution of sertraline, the effectiveness of forced diuresis, dialysis,
hemoperfusion, and exchange transfusion is unlikely.
Sertraline overdose may prolong the QT interval; therefore, ECG monitoring is recommended in
all cases of sertraline overdose.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective serotonin reuptake inhibitors.
ATC code: N06AB06
Sertraline is a potent and specific inhibitor of neuronal serotonin (5HT) reuptake in vitro and
enhances 5HT-mediated effects in animals. It has only very weak effects on the reuptake of
norepinephrine and dopamine. At therapeutic doses, sertraline inhibits serotonin reuptake in
human platelets. In animal studies, sertraline did not show stimulant, sedative, cholinolytic, or
cardiotoxic effects. In controlled studies in healthy volunteers, sertraline did not cause sedation or
impair psychomotor performance.
As a selective 5HT reuptake inhibitor, sertraline does not affect catecholaminergic neurotransmission.
Sertraline has no affinity for muscarinic (cholinergic), serotonin, dopamine, adrenergic, histamine,
GABA, or benzodiazepine receptors. Long-term administration of sertraline to animals leads to a
reduction in the number and sensitivity of noradrenergic receptors in the brain. A similar effect has
been observed with other antidepressants and drugs used in the treatment of OCD.
Sertraline has not been shown to have abuse potential. In a controlled, double-blind, placebo-
controlled comparative study assessing the abuse liability of sertraline, alprazolam, and d-amphetamine
in humans, sertraline did not produce positive subjective effects indicative of abuse potential. In
contrast, study participants rated both alprazolam and d-amphetamine significantly higher than
placebo in terms of drug liking, euphoria, and potential for abuse. Sertraline did not produce the
stimulation or agitation associated with d-amphetamine, nor did it produce the calming effects and
psychomotor disturbances associated with alprazolam. Sertraline did not produce positive
reinforcement in rhesus monkeys trained to self-administer cocaine, nor did it substitute for either
d-amphetamine or pentobarbital as a discriminative stimulus in rhesus monkeys.

Clinical studies
Major depressive disorder
A study was conducted in outpatients with depression who responded at the end of an initial 8-week open-label phase of sertraline treatment at doses of 50–200 mg/day. These patients (n=295) were randomized to continue double-blind treatment with sertraline 50–200 mg/day or placebo for 44 weeks. Patients receiving sertraline had a statistically significant lower relapse rate compared to those receiving placebo. The mean dose among patients who completed the study was 70 mg/day. The proportion of patients responding to treatment (defined as the proportion of patients who did not experience relapse) in the sertraline and placebo groups was 83.4% and 60.8%, respectively.

Post-traumatic stress disorder (PTSD)
Pooled data from three PTSD studies in the general population indicate a lower response rate in men than in women. In two general population studies with positive outcomes, the proportion of women and men responding to sertraline treatment compared to placebo was similar (women: 57.2% vs. 34.5%; men: 53.9% vs. 38.2%). The number of patients in the pooled general population studies was 184 men and 430 women; therefore, results in women are better substantiated, whereas in men, the influence of other baseline variables (more frequent substance abuse, longer duration of illness, trauma source, etc.) that correlate with reduced drug efficacy is evident.

Pediatric patients with OCD
The safety and efficacy of sertraline (50–200 mg/day) were evaluated in children (6–12 years) and adolescents (13–17 years) without depression, treated as outpatients for obsessive-compulsive disorder (OCD). After a one-week single-blind lead-in phase, patients were randomly assigned to receive either flexible-dose sertraline or placebo for twelve weeks. The initial dose in children (6–12 years) was 25 mg. Patients in the sertraline group showed significantly greater improvement on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (p = 0.005), the NIMH Global Obsessive Compulsive Scale (p = 0.019), and the CGI Improvement scale (p = 0.002) compared to the placebo group. Additionally, a trend toward greater improvement in the sertraline group compared to placebo was observed on the CGI Severity scale (p = 0.089).
On the CY-BOCS scale, mean baseline score and change from baseline in the placebo group were 22.25 ± 6.15 and -3.4 ± 0.82, respectively, while in the sertraline group, mean baseline score and change from baseline were 23.36 ± 4.56 and -6.8 ± 0.87, respectively. In a post hoc analysis, responders, defined as patients with a 25% or greater reduction in CY-BOCS score (the primary efficacy measure) from baseline to the planned endpoint, comprised 53% of the sertraline group compared to 37% in the placebo group (p = 0.03).
There are no data on the safety and efficacy of long-term use of the drug in pediatric patients.
There are no data available for children under 6 years of age.

5.2 Pharmacokinetic properties

Absorption
Sertraline exhibits dose-proportional pharmacokinetics in the dose range of 50 to 200 mg.
In humans, following oral administration of 50 to 200 mg once daily for 14 days, peak plasma concentrations
of sertraline occurred between 4.5 and 8.4 hours after daily dosing. Food has no significant effect on the bioavailability of sertraline tablets.

Distribution
Approximately 98% of circulating drug is plasma protein bound.

Metabolism
Sertraline undergoes extensive first-pass metabolism in the liver.

Elimination
The mean elimination half-life of sertraline is approximately 26 hours (range 22–36 hours). Consistent
with this terminal elimination half-life, accumulation is approximately twofold, reaching steady-state concentrations after one week of once-daily dosing. The half-life of N-desmethylsertraline ranges from 62 to 104 hours. Both sertraline and N-desmethylsertraline are extensively metabolized in humans, and the resulting metabolites are excreted in equal amounts in faeces and urine. Only a small amount (<0.2%) of unchanged sertraline is excreted in urine.

Pharmacokinetics in special patient populations

Paediatric patients with OCD
The pharmacokinetics of sertraline were studied in a group of 29 children aged 6 to 12 years and 32 adolescents aged 13 to 17 years. Doses were gradually increased to a daily dose of 200 mg over 32 days, either starting with an initial dose of 25 mg and gradually increasing, or starting with an initial dose of 50 mg and gradually increasing. Both dosing regimens with initial doses of 25 mg and 50 mg were equally well tolerated. At a dose of 200 mg, steady-state plasma concentrations of sertraline in children aged 6 to 12 years were approximately 35% higher than in adolescents aged 13 to 17 years, and 21% higher than in the reference group of adult subjects. No significant differences in creatinine clearance were observed between boys and girls. Therefore, in children, especially those with low body weight, it is recommended to use a low initial dose and to increase the dose gradually by 25 mg increments.
In adolescents, the drug should be dosed similarly to adults.

Adolescents and elderly
The pharmacokinetic profile of the drug in adolescents and elderly patients does not differ significantly from that in adults aged 18 to 65 years.

Hepatic impairment
In patients with hepatic impairment, the half-life of sertraline is prolonged and AUC values increase threefold (see sections 4.2 and 4.4).

Renal impairment
In patients with moderate to severe renal impairment, no significant accumulation of sertraline was observed.

5.3 Preclinical safety data

Non-clinical data derived from conventional pharmacological safety studies, repeated-dose toxicity, genotoxicity, potential carcinogenic effects, and toxic effects on fertility and developmental toxicity revealed no special hazard for humans. Studies assessing reproductive toxicity in animals showed no evidence of teratogenicity or adverse effects of the drug on male fertility. Observed fetotoxicity was probably related to the toxic effect of the drug on the mother. Reduced survival and decreased body weight were observed only during the first days after birth. Available data indicate that early postnatal mortality resulted from drug exposure in utero after day 15 of pregnancy.
Developmental delays observed in offspring of females treated with the drug were probably due to the effect of the drug on the mothers, and therefore are not associated with a significantly increased risk in humans.
Studies conducted in rodents and other animals revealed no effect on fertility.
6. PHARMACEUTICAL DATA
6.1 List of excipients
Tablet core:
Monohydrate lactose
Microcrystalline cellulose (Avicel PH 102)
Povidone K30
Sodium carboxymethyl starch
Magnesium stearate
Tablet coating:
Hypromellose 6
Hypromellose 15
Talc
Propylene glycol
Titanium dioxide (E 171).

6.2 Pharmaceutical incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions during storage

No special storage instructions required.

6.5 Type and content of the container

PVC/PVDC/aluminium blisters in cardboard packaging: 7, 14, 15, 20, 28, 30, 50, 60, 98, and 100 film-coated tablets.
Single-dose PVC/PVDC/aluminium blisters in cardboard packaging: 28x1, 30x1, 50x1, 98x1, and 100x1 film-coated tablets.
Round HDPE bottles with snap-fastening closure: 100, 250, and 500 film-coated tablets.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal and preparation of the medicinal product

for use
No special requirements.

7. MARKETING AUTHORISATION HOLDER

MARKETING AUTHORISATION HOLDER
Zakłady Farmaceutyczne POLPHARMA S.A.
ul. Pelplińska 19, 83-200 Starogard Gdański

8. MARKETING AUTHORISATION NUMBER

Authorisation number: 11131

9. DATE OF FIRST AUTHORIZATION AND DATE OF LAST RENEWAL OF THE AUTHORISATION

Date of first authorization: 09.12.2004
Date of last renewal of the authorization: 09.09.2010

10. DATE OF ADOPTION OR PARTIAL MODIFICATION OF THE

PRODUCT CHARACTERISTICS
01.08.2025