INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT STIMULOTON® (STIMULOTON®)

Composition:

Active ingredient: sertraline;

1 tablet contains 100 mg of sertraline (as 111.9 mg of sertraline hydrochloride);

Excipients: magnesium stearate, hydroxypropylcellulose, sodium starch glycolate (type A), calcium hydrogen phosphate, microcrystalline cellulose, hypromellose, macrogol 6000, titanium dioxide (E 171).

Pharmaceutical form: Film-coated tablets.

Main physicochemical properties: white or almost white, oval-shaped, biconvex film-coated tablets with a stylized engraving "E 272" on one side and a score line on the other side, odorless.

Pharmacotherapeutic group: Antidepressants. Selective serotonin reuptake inhibitors. ATC code: N06AB06.

Pharmacological Properties

Pharmacodynamics

Sertraline is a potent and specific inhibitor of neuronal serotonin (5-HT) reuptake in vitro, which in animals leads to potentiation of 5-HT effects. Sertraline has only very weak effects on neuronal reuptake of norepinephrine and dopamine. At clinical doses, sertraline blocks serotonin uptake in human platelets. The drug does not exhibit stimulant, sedative, anticholinergic, or cardiotoxic effects in animal experiments. In controlled studies involving healthy volunteers, sertraline did not demonstrate sedative effects and did not affect psychomotor functions. Since sertraline selectively inhibits the reuptake of 5-HT, it does not stimulate catecholaminergic activity. The drug has no affinity for muscarinic (cholinergic), serotonergic, dopaminergic, adrenergic, histaminergic, GABA, or benzodiazepine receptors. Long-term administration of sertraline in animals leads to decreased activity of brain norepinephrine receptors, a phenomenon also observed with other clinically effective antidepressants and anti-obsessive agents.

Sertraline does not cause drug dependence. In a placebo-controlled, double-blind, randomized study comparing the abuse potential of sertraline, alprazolam, and d-amphetamine in humans, sertraline did not produce positive subjective effects indicative of abuse potential. In contrast, study participants receiving either alprazolam or d-amphetamine showed statistically significantly higher scores for abuse liability, euphoria, and potential for drug dependence compared to those receiving placebo. Sertraline does not produce the stimulant effect or anxiety typical of d-amphetamine, nor the sedative effects and psychomotor impairments characteristic of alprazolam.

Pharmacokinetics

Absorption. The pharmacokinetics of sertraline in the dose range of 50 to 200 mg is dose-dependent. During 14 days of sertraline administration at doses of 50–200 mg (orally, once daily), peak plasma concentrations of sertraline are reached within 4.5–8.4 hours after daily dosing. Food does not significantly alter the bioavailability of sertraline tablets.

Distribution. Approximately 98% of circulating sertraline is protein-bound in plasma.

Biotransformation. Sertraline undergoes extensive presystemic metabolism ("first-pass effect") in the liver.

Elimination. The mean elimination half-life of sertraline is approximately 26 hours (ranging from 22 to 36 hours). Consistent with this terminal half-life, drug accumulation (with approximately doubling of levels) occurs at steady-state concentrations, which are achieved after once-daily dosing for 1 week. The elimination half-life of N-desmethylsertraline is 62–104 hours. Sertraline and N-desmethylsertraline are extensively metabolized in the human body, and their final metabolites are excreted in feces and urine in equal amounts. Only a very small fraction (< 0.2%) of sertraline is excreted unchanged in urine.

Linearity/Non-linearity. The pharmacokinetics of sertraline in the dose range of 50 to 200 mg is dose-dependent.

Pharmacokinetics in Specific Patient Populations

Children with Obsessive-Compulsive Disorder (OCD). The pharmacokinetics of sertraline were studied in 29 children aged 6–12 years and in 32 adolescents aged 13–17 years. The dose was gradually increased by titration up to a daily dose of 200 mg over 32 days, starting from either 25 mg or 50 mg with gradual increments. Tolerability was similar at doses of 25 mg and 50 mg. At steady state with a 200 mg dose, plasma concentrations of sertraline in children aged 6–12 years were approximately 35% higher than in adolescents aged 13–17 years and 21% higher than in the reference group of adults. No significant differences in clearance were observed between boys and girls. Therefore, for pediatric use, particularly in children with low body weight, a low initial dose is recommended, with dose increases during titration in 25 mg increments. Adolescents may be given the same doses as adults.

Adolescents and Elderly Patients. The pharmacokinetic profile of sertraline in adolescents and elderly individuals does not significantly differ from that in adults aged 18–65 years.

Hepatic Impairment. In patients with liver impairment, the elimination half-life of sertraline is prolonged and the area under the pharmacokinetic curve (AUC) increases threefold (see sections "Dosage and Administration" and "Special Precautions").

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

Clinical characteristics.

Indications.

Sertraline is indicated for the treatment of the following disorders:

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

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Concomitant use of sertraline with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of developing serotonin syndrome, which may manifest as agitation, tremor, and hyperthermia. Sertraline therapy must not be initiated within at least 14 days after discontinuation of irreversible MAOI treatment. Sertraline must be discontinued at least 7 days prior to starting therapy with an irreversible MAOI.

Concomitant use of sertraline and pimozide is contraindicated (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations

Irreversible monoamine oxidase inhibitors (MAOIs) (e.g., selegiline)

The use of sertraline together with irreversible MAOIs such as selegiline is contraindicated. Sertraline must not be administered within at least 14 days after discontinuation of irreversible MAOI therapy. Sertraline must be discontinued at least 7 days before initiating therapy with an irreversible MAOI (see section "Contraindications").

Reversible selective MAO-A inhibitors (moclobemide)

Due to the risk of serotonin syndrome, sertraline should not be used in combination with reversible selective MAO inhibitors such as moclobemide. After discontinuation of reversible MAO inhibitors, the interval before starting sertraline therapy may be shorter than 14 days. It is recommended to discontinue sertraline at least 7 days before initiating therapy with a reversible MAOI (see section "Contraindications").

Reversible non-selective MAO inhibitors (linezolid)

The antibiotic linezolid is a weak, reversible non-selective MAOI and should not be used in patients taking sertraline (see section "Contraindications").

Severe adverse reactions have been reported in patients who recently discontinued MAOI therapy and started taking sertraline, or who discontinued sertraline shortly before starting MAOI therapy (e.g., methylene blue), or who discontinued sertraline shortly before initiating MAOI therapy. These reactions included tremor, myoclonus, excessive sweating, nausea, vomiting, flushing, dizziness, and hyperthermia with symptoms resembling neuroleptic malignant syndrome, seizures, and fatal outcomes.

Pimozide

In a study with a single low dose of pimozide (2 mg), an increase in pimozide levels by approximately 35% was observed. This increase in levels was not accompanied by any changes in ECG parameters. Although the mechanism of this interaction is unknown, concomitant use of sertraline and pimozide is contraindicated due to the narrow therapeutic range of pimozide (see section "Contraindications").

Not recommended for concomitant use with sertraline

Central nervous system depressants and alcohol

Concomitant administration of sertraline at a dose of 200 mg/day did not potentiate the effects of alcohol, carbamazepine, haloperidol, or phenytoin on cognitive and psychomotor functions in healthy study participants; however, concomitant use of sertraline with alcohol is not recommended.

Other serotonergic medicinal products (see section "Special precautions for use").

Caution is required when co-prescribing sertraline with fentanyl (used primarily during general anesthesia and in chronic pain therapy), other serotonergic agents (including other serotonergic antidepressants, amphetamines, and triptans), and other opioid agents.

Combinations requiring special caution

Medicinal products that prolong the QT interval

The risk of QTc interval prolongation and/or ventricular arrhythmias (e.g., torsades de pointes) increases when sertraline is used concomitantly with other agents that prolong the QTc interval (e.g., certain antipsychotics and antibiotics) (see sections "Special precautions for use" and "Pharmacodynamics").

Lithium

In a placebo-controlled study involving healthy volunteers, concomitant administration of sertraline and lithium did not significantly alter the pharmacokinetics of lithium but resulted in increased tremor compared to placebo, indicating a possible pharmacodynamic interaction. Appropriate monitoring is required when sertraline and lithium are used concomitantly.

Phenytoin

Results from a placebo-controlled study in healthy volunteers indicate that prolonged administration of sertraline at a dose of 200 mg/day does not lead to clinically significant inhibition of phenytoin metabolism. However, case reports suggest high phenytoin exposure in patients taking sertraline; monitoring of plasma phenytoin concentrations is recommended during the initial phase of sertraline therapy, with appropriate dose adjustments of phenytoin. Additionally, concomitant use of sertraline with phenytoin may lead to decreased plasma concentrations of sertraline.

Triptans

During post-marketing surveillance, isolated reports have been received of weakness, hyperreflexia, incoordination, confusion, anxiety, and agitation when sertraline was used concomitantly with sumatriptan. Serotonin syndrome symptoms may also develop when other drugs of this class (triptans) are used. If concomitant treatment with sertraline and triptans is clinically necessary, appropriate patient monitoring should be ensured (see section "Special precautions for use").

Warfarin

Concomitant use of sertraline at a dose of 200 mg/day and warfarin resulted in a small but statistically significant increase in prothrombin time, which may in rare cases lead to disturbances in the international normalized ratio (INR). Therefore, prothrombin time should be carefully monitored at the beginning of sertraline therapy and upon its discontinuation.

Interaction with digoxin, atenolol, cimetidine

Concomitant use with cimetidine led to a significant reduction in sertraline clearance. The clinical significance of these changes is not fully established. Sertraline does not affect the beta-blocking properties of atenolol. No interaction was observed when sertraline at a dose of 200 mg/day was administered concomitantly with digoxin.

Medicinal products affecting platelet function

The risk of bleeding is increased when selective serotonin reuptake inhibitors (SSRIs), including sertraline, are used concomitantly with medicinal products affecting platelet function (e.g., non-steroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, and ticlopidine), or with other medicinal products that increase the risk of bleeding (see section "Special precautions for use").

A possible reduction in plasma levels of sertraline under the influence of other CYP3A4 enzyme inducers, including phenobarbital, carbamazepine, St. John's wort, and rifampicin, cannot be excluded.

Neuromuscular blocking agents

SSRIs may reduce cholinesterase activity in plasma, leading to prolonged neuromuscular blockade by mivacurium or other neuromuscular blocking agents.

Medicinal products metabolized via cytochrome P450

Sertraline may act as a weak or moderate inhibitor of the CYP2D6 isoenzyme. Prolonged administration of sertraline at a dose of 50 mg/day led to a moderate increase (on average by 23–37%) in steady-state plasma concentrations of desipramine (a marker of CYP2D6 isoenzyme activity). Clinically significant interactions may occur with other CYP2D6 substrates that have narrow therapeutic ranges, such as class 1C antiarrhythmics (e.g., propafenone and flecainide), tricyclic antidepressants, and typical antipsychotics, particularly when sertraline is used at higher doses.

Sertraline is not a clinically significant inhibitor of the CYP3A4, CYP2C9, CYP2C19, or CYP1A2 isoenzymes. This is supported by results from in vivo drug interaction studies using CYP3A4 substrates (endogenous cortisol, carbamazepine, terfenadine, alprazolam), CYP2C19 substrate (diazepam), and CYP2C9 substrates (tolbutamide, glipizide, and phenytoin). In vitro study results indicate that sertraline has very low or no potential to inhibit CYP1A2.

Daily consumption of three glasses of grapefruit juice increased plasma levels of sertraline by nearly 100% in a crossover study in 8 healthy Japanese subjects. Therefore, grapefruit juice should be avoided during sertraline therapy (see section "Special precautions for use").

Based on the results of the grapefruit juice interaction study, a significantly greater increase in sertraline exposure cannot be excluded when sertraline is used concomitantly with potent CYP3A4 enzyme inhibitors, including protease inhibitors, ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, and nefazodone. This also applies to moderate CYP3A4 inhibitors: aprepitant, erythromycin, fluconazole, verapamil, and diltiazem. The use of potent CYP3A4 inhibitors should be avoided during sertraline therapy.

In individuals with slow CYP2C19 metabolism, plasma levels of sertraline are increased by 50% compared to individuals with rapid CYP2C19 metabolism (see section "Pharmacokinetics"). A drug interaction with potent CYP2C19 inhibitors such as omeprazole, lansoprazole, pantoprazole, rabeprazole, fluoxetine, and fluvoxamine cannot be excluded.

Special precautions for use.

Symptoms such as restlessness, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, psychomotor agitation, hypomania, and mania have been observed in adults and children treated with antidepressants. These symptoms may precede the emergence of suicidal ideation. Consideration should be given to changing the therapeutic regimen or discontinuing the medication if depressive symptoms worsen, suicidal ideation emerges, or symptoms of worsening suicidality occur. If a decision is made to discontinue treatment, the drug should be tapered as rapidly as possible, but it should be remembered that abrupt discontinuation may be associated with withdrawal syndrome. Before initiating treatment, patients should be evaluated to determine the risk of developing bipolar disorder. A thorough psychiatric history, including family history of suicide, bipolar disorders, and depression, should be obtained. Stimuloton® is not intended for the treatment of bipolar depression.

Serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS)

Life-threatening syndromes such as serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS) have been reported with the use of SSRIs, including sertraline therapy. The risk of developing SS or NMS with SSRIs increases when serotonergic agents (including triptans, amphetamines, and fentanyl) are used concomitantly with agents that impair serotonin metabolism (including MAOIs, such as methylene blue), antipsychotics, other dopamine antagonists, and opioids. Serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic dysfunction (tachycardia, blood pressure fluctuations, hyperthermia), neuromuscular abnormalities (hyperreflexia, incoordination), reproductive system disturbances (erectile dysfunction), and/or gastrointestinal symptoms (nausea, vomiting, diarrhea). Some manifestations of serotonin syndrome, including hyperthermia, muscle rigidity, autonomic instability, and mental status changes, resemble those of neuroleptic malignant syndrome. Patients should be monitored for signs and symptoms of SS or NMS (see section "Contraindications").

Switching from SSRIs, antidepressants, or anti-obsessive agents

Data from controlled studies regarding the optimal timing for switching from SSRIs, antidepressants, or anti-obsessive agents to sertraline are limited. Caution should be exercised when making such treatment changes, particularly when switching to sertraline from long-acting agents such as fluoxetine.

Other serotonergic agents, e.g., tryptophan, fenfluramine, and 5-HT agonists

Concomitant use of sertraline with other agents that enhance serotonergic neurotransmission, including amphetamines, tryptophan, fenfluramine, fentanyl, 5-HT agonists, or herbal products containing St. John's wort (Hypericum perforatum), should be done with caution, and such combination therapy should be avoided (due to possible pharmacodynamic interactions).

QTc interval prolongation / torsades de pointes ventricular tachycardia

Cases of QTc interval prolongation and torsades de pointes ventricular tachycardia have been reported during post-marketing use of sertraline. Most cases occurred in patients with other risk factors for QTc interval prolongation/torsades de pointes. The effect on QTc interval prolongation was confirmed in a QTc study in healthy volunteers, showing a statistically significant positive concentration-response relationship. Therefore, sertraline should be used with caution in patients with additional risk factors for QTc interval prolongation, such as cardiac disease, hypokalemia or hypomagnesemia, family history of QTc prolongation, bradycardia, or concomitant use of drugs that prolong the QTc interval (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

Exacerbation of hypomania or mania

Exacerbation of manic/hypomanic symptoms has been reported in a small percentage of patients receiving approved antidepressants and anti-obsessive agents, including sertraline. Therefore, sertraline should be used with caution in patients with a history of mania/hypomania. Close physician monitoring is required. If signs of a manic episode occur, sertraline should be discontinued.

Schizophrenia

Psychotic symptoms may be exacerbated in patients with schizophrenia during treatment with the drug.

Seizures

Seizures may occur during sertraline therapy: sertraline should not be prescribed to patients with unstable epilepsy; in patients with controlled epilepsy, sertraline use requires careful monitoring. The drug should be discontinued in patients who experience seizures.

Suicidality / suicidal thoughts / suicide attempts or clinical worsening

Patients with depression have an increased risk of suicidal thoughts, self-harm, and suicide attempts (suicidal behaviors and manifestations). This risk persists until significant remission occurs. Since improvement in patients may take several weeks or longer, patients should be closely monitored until such improvement occurs. Clinical experience generally indicates that the risk of suicide may increase during the early stages of recovery.

Other psychiatric disorders for which sertraline is indicated may also be associated with an increased risk of suicidal behaviors and manifestations. Additionally, these disorders may coexist with major depressive disorder. Thus, the warnings regarding treatment of patients with major depressive disorder also apply to treatment of patients with other psychiatric disorders.

Patients with a history of suicidal behaviors or manifestations and patients who have pronounced suicidal ideation prior to the start of therapy have a higher risk of developing suicidal thoughts or suicide attempts during treatment and therefore require close monitoring during treatment. A meta-analysis of data from placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressant use in patients under 25 years of age compared to placebo.

Careful monitoring of patients at high risk of developing suicidality is indicated during treatment with this medicinal product, especially at the beginning of therapy and after any dosage adjustments. Patients (and caregivers) should be advised to monitor for any clinical worsening, emergence of suicidal behavior or suicidal thoughts, or any unusual changes in behavior, and to seek immediate medical attention if these symptoms occur.

Use in children

Stimuloton® should not be used for the treatment of children and adolescents, except for patients aged 6–17 years with obsessive-compulsive disorder. In clinical trials, children receiving antidepressants showed a higher incidence of suicidal behavior (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behavior, and anger) compared to patients receiving placebo. If, based on clinical need, a decision is made to prescribe this drug, careful monitoring for signs of suicidal symptoms is required. Additionally, only limited clinical data are available regarding the long-term safety of the drug in children and adolescents, including its impact on growth, sexual maturation, and cognitive and behavioral development. During the post-marketing period, several cases of delayed growth and delayed sexual maturation have been reported. The clinical significance and causal relationship remain unclear. In long-term therapy of pediatric patients, physicians should monitor for deviations from normal development.

Abnormal bleeding/bleeding events

Pathological hemorrhagic events, including skin hemorrhages (ecchymoses and purpura), and other hemorrhagic events such as gastrointestinal or gynecological bleeding, including fatal bleeding, have been reported with the use of SSRIs. Caution is recommended when using SSRIs, especially when used concomitantly with medicinal products affecting platelet function (e.g., anticoagulants, atypical antipsychotics, phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, and NSAIDs), and in patients with a history of hemorrhagic disorders (see section "Interaction with other medicinal products and other forms of interaction").

Grapefruit juice

Concomitant use of sertraline with grapefruit juice is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with urine screening tests

False-positive results in immunoassay screening tests for benzodiazepine metabolites in urine have been reported in patients taking sertraline. False-positive results are due to the low specificity of the laboratory test and may occur for several days after discontinuation of sertraline. Sertraline can be differentiated from benzodiazepine derivatives in urine by confirmatory tests such as gas chromatography/mass spectrometry.

Closed-angle glaucoma

SSRI-class drugs, including sertraline, may affect pupil size, leading to mydriasis. This effect may result in narrowing of the eye angle, increased intraocular pressure, and development of closed-angle glaucoma, particularly in predisposed patients. Sertraline should be used with caution in patients with a history of closed-angle glaucoma.

Hyponatremia

Hyponatremia may develop during therapy with SSRIs or SNRIs, including sertraline. In many cases, hyponatremia is due to the syndrome of inappropriate antidiuretic hormone secretion. Serum sodium levels below 110 mmol/L have been reported. Elderly patients have a higher risk of developing hyponatremia when treated with SSRIs and SNRIs. The risk of this complication is also increased in patients taking diuretics and in patients with hypovolemia of any origin (see section "Use in elderly patients"). In cases of symptomatic hyponatremia, discontinuation of sertraline therapy should be considered, and appropriate measures taken. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and loss of physical balance, which may lead to falls. Signs and symptoms associated with more severe and/or acute episodes of hyponatremia include hallucinations, syncope, seizures, coma, respiratory arrest, and fatal outcome.

Withdrawal symptoms observed upon discontinuation of sertraline therapy

Withdrawal symptoms are a common occurrence when stopping treatment with the drug, especially in cases of abrupt discontinuation (see section "Adverse reactions"). Clinical trial data show that the incidence of withdrawal reactions in patients who discontinued sertraline was 23%, compared to 12% in patients who continued sertraline therapy.

The risk of developing withdrawal syndrome may depend on several factors, including duration of therapy, dosage, and rate of dose reduction. The 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. Generally, these symptoms are mild to moderate in severity, but in some patients, they may be severe. They usually occur within the first few days after discontinuation of therapy; in very rare cases, such symptoms have been observed in patients who accidentally missed a dose. In most cases, these symptoms resolve spontaneously within 2 weeks, although in some patients they may persist longer (2–3 months or more). Therefore, it is recommended to gradually reduce the dose of sertraline when discontinuing treatment over a period of several weeks or months, depending on patient needs (see section "Dosage and administration").

Akathisia / psychomotor restlessness

Sertraline use has been associated with akathisia, characterized by a subjectively unpleasant or irresistible urge to move, often accompanied by an inability to sit or stand still. The risk of such complications is highest during the first 2 weeks of therapy. For patients who develop these symptoms, increasing the dose may be harmful.

Use in hepatic impairment

Sertraline is extensively metabolized in the liver. Pharmacokinetic studies with multiple dosing showed that patients with stable mild cirrhosis had approximately a threefold increase in half-life, AUC, and Cmax compared to individuals with normal liver function. No significant differences in plasma protein binding of the drug between these two groups were observed. Caution should be exercised when using sertraline in patients with liver disease. When prescribing sertraline to patients with impaired liver function, consideration should be given to reducing the dose or frequency of administration. Sertraline should not be used in patients with severe hepatic impairment (see section "Dosage and administration").

Use in renal impairment

Sertraline is extensively metabolized; unchanged drug excretion in urine is a minor elimination pathway. Pharmacokinetic parameters (AUC0–24 and Cmax) after multiple dosing in patients with mild to moderate (creatinine clearance 30–60 mL/min) or moderate to severe (creatinine clearance 10–29 mL/min) renal impairment did not differ significantly from those in the control group. Dose adjustment based on the degree of renal impairment is not necessary.

Use in elderly patients

Over 700 elderly patients (aged >65 years) participated in clinical trials. The nature and frequency of adverse reactions in elderly patients were similar to those observed in younger patients.

However, the use of SSRIs and SNRIs, including sertraline, has been associated with cases of clinically significant hyponatremia in elderly patients, who may have a higher risk of developing this adverse effect (see "Hyponatremia" in the "Special precautions for use" section).

Diabetes mellitus

New-onset diabetes mellitus has been reported in patients receiving SSRI therapy, including sertraline. Loss of glycemic control, including both hyperglycemia and hypoglycemia, has been reported in patients with and without diabetes mellitus. Therefore, patients should be monitored for signs and symptoms of glucose level changes. Diabetic patients, in particular, should carefully monitor glucose levels, as their insulin and/or other oral hypoglycemic agent dosage may need adjustment.

Electroconvulsive therapy (ECT)

No clinical studies have been conducted to evaluate the risks or benefits of combining ECT and sertraline.

Use during pregnancy or breastfeeding.

Pregnancy

Well-controlled studies of the medicinal product Stimuloton® in pregnant women are lacking. However, a substantial amount of available data does not indicate an increased risk of congenital malformations due to sertraline use. Animal studies have shown effects on reproductive function, likely due to the toxic effect of the drug on the maternal organism caused by its pharmacodynamic action and/or direct pharmacodynamic effects on the fetus.

It has been reported that sertraline use during pregnancy may cause symptoms in some newborns (whose mothers took sertraline) similar to withdrawal reactions. This phenomenon has also been observed with other SSRIs. Stimuloton® is not recommended during pregnancy except when the woman's clinical condition indicates that the expected benefits outweigh the potential risks.

Women of reproductive age taking sertraline should use appropriate contraceptive methods.

Newborns should be monitored if the mother continues sertraline use in late pregnancy, particularly in the third trimester. Newborns exposed to sertraline in late pregnancy may experience symptoms such as respiratory distress syndrome, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, increased neuromuscular excitability, irritability, lethargy/apathy, persistent crying, somnolence, and difficulty sleeping. These symptoms may be due to other serotonergic effects or withdrawal symptoms. In most cases, these complications occur immediately after birth or shortly thereafter (within less than 24 hours).

Epidemiological data suggest that SSRI use during pregnancy, particularly in late pregnancy, increases the risk of persistent pulmonary hypertension in the newborn. The risk during drug exposure is approximately 5 cases per 1000 pregnancies. In the general population, 1–2 cases of persistent pulmonary hypertension in the newborn per 1000 pregnancies are observed.

Observational data indicate an increased risk (almost 2-fold) of postpartum hemorrhage with SSRI/SNRI use within one month before delivery (see section "Adverse reactions").

Breastfeeding

Published data on sertraline levels in breast milk indicate that sertraline and its metabolite N-desmethylsertraline are excreted in small amounts into breast milk. Generally, negligible or undetectable concentrations of the drug were found in infant plasma, except in one case where the drug concentration in infant plasma was approximately 50% of the concentration in maternal plasma (but without any noticeable effect on the infant's health). To date, no adverse effects of the drug on the health of breastfed children have been reported, but such a risk cannot be excluded. The use of the medicinal product Stimuloton® during breastfeeding is not recommended, except when, in the physician's opinion, the benefit of taking the drug outweighs the potential risk.

Fertility

Data from animal studies did not reveal any effect of sertraline on fertility parameters.

Reports from human studies on the use of some SSRIs suggest that effects on sperm quality are reversible. To date, no effect on human fertility has been identified.

Ability to affect reaction speed when driving or operating machinery.

Clinical pharmacological studies indicate no effect of sertraline on psychomotor functions. However, patients should exercise caution, as the drug may impair mental or physical reactions required for performing potentially hazardous tasks such as driving a car or operating machinery.

Method of Administration and Dosage

Stimuloton® should be taken once daily (in the morning or evening). Stimuloton® tablets may be taken independently of food intake.

Initiation of Treatment

Depression and OCD

Treatment with Stimuloton® should be initiated at a dose of 50 mg/day.

Panic Disorders, PTSD, and Social Anxiety Disorder

Treatment should be initiated at a dose of 25 mg/day. After 1 week, the dose should be increased to 50 mg once daily. This dosing regimen has been shown to reduce the frequency of adverse effects characteristic of panic disorders during the initial treatment phase.

Dose Titration

Depression, OCD, Panic Disorders, Social Anxiety Disorder, and PTSD

In patients who do not respond to the 50 mg dose, therapeutic effect may be achieved by increasing the dose. Dose adjustments should not begin earlier than 1 week after starting treatment, increasing gradually by 50 mg at intervals of at least one week. The maximum dose should not exceed 200 mg/day. Dose adjustments should be made no more frequently than once per week, considering the elimination half-life of sertraline, which is 24 hours.

Initial signs of therapeutic effect may be observed within 7 days of treatment. However, achieving a full therapeutic response usually requires a longer period, especially in patients with OCD.

Maintenance Dose

Dosing during long-term therapy should be maintained at the lowest effective level, with subsequent adjustments based on therapeutic response.

Depression

Long-term therapy may also be used to prevent relapse of major depressive episodes (MDE). In most cases, the recommended dose for prevention of MDE relapse is the same as the dose used during treatment of the depressive episode. Patients with depression should continue therapy for a sufficient duration—minimum of 6 months—to ensure complete absence of symptoms.

Panic Disorders and OCD

During long-term therapy in patients with panic disorders and OCD, regular assessment of treatment is required, as efficacy of the drug in preventing relapse has not been demonstrated for these disorders.

Use in Children

Children with Obsessive-Compulsive Disorder (OCD)

Children aged 13–17 years: initial dose is 50 mg once daily.

Children aged 6–12 years: initial dose is 25 mg once daily. After 1 week, the dose may be increased to 50 mg once daily.

If necessary, in cases of insufficient response to 50 mg/day, further dose increases are possible, increasing by 50 mg once daily over several weeks. The maximum dose is up to 200 mg/day.

However, when increasing the dose beyond 50 mg in pediatric patients, the generally lower body weight of children compared to adults should be taken into account. Dose adjustments should not occur more frequently than once per week.

The efficacy of the drug in children with major depressive disorder has not been established.

There are no data on the use of the drug in children under 6 years of age (see section "Special Instructions").

Use in Elderly Patients

The drug should be used with caution in elderly patients, as they have an increased risk of developing hyponatremia (see section "Special Instructions").

Use in Hepatic Impairment

Caution should be exercised when administering sertraline to patients with liver disease. In patients with impaired liver function, the dose or frequency of administration should be reduced. Sertraline should not be used in patients with severe hepatic impairment, as there are no clinical data on the use of the drug in such patients (see section "Special Instructions").

Use in Renal Impairment

Dose adjustment of the drug is not required in patients with impaired renal function (see section "Special Instructions").

Withdrawal Symptoms Observed Upon Discontinuation of Sertraline Therapy

Abrupt discontinuation of the drug should be avoided. When stopping sertraline treatment, the dose should be gradually reduced over at least 1–2 weeks to minimize the risk of withdrawal syndrome (see sections "Special Instructions" and "Adverse Reactions"). If intolerable symptoms occur after dose reduction or discontinuation, resumption of the drug at the previously prescribed dose may be considered. The physician may then continue tapering the dose, but more gradually.

Children.

Stimuloton® should not be used for the treatment of children, except for children aged 6 years and older with obsessive-compulsive disorders (see section "Method of Administration and Dosage").

Overdose.

Toxicity

Sertraline has a safety margin that depends on the patient population and concomitant use of other medicinal products. Fatal outcomes following sertraline overdose have been reported both with sertraline alone (without concomitant drugs) and in combination with other medicinal products and/or alcohol. Therefore, each case of overdose requires intensive therapy.

Symptoms

Symptoms of overdose include serotonin-mediated adverse effects, particularly drowsiness, gastrointestinal disturbances (including nausea and vomiting), tachycardia, tremor, agitation, and dizziness. Coma has been reported less frequently.

Treatment

There are no specific antidotes for sertraline. Airway patency, adequate oxygenation, and ventilation must be ensured and maintained. Administration of activated charcoal, which may be used together with a laxative, may be as effective as gastric lavage and should be considered in the management of overdose. Induced vomiting is not recommended. Continuous cardiac monitoring and observation of other vital signs are recommended, along with symptomatic and supportive therapy. Due to the large volume of distribution of sertraline, interventions such as forced diuresis, dialysis, hemoperfusion, or exchange transfusion are unlikely to be beneficial.

Sertraline overdose may lead to QT interval prolongation; therefore, ECG monitoring is recommended in all cases of drug overdose.

Adverse Reactions

The most commonly observed adverse effect is nausea. In the treatment of social anxiety disorder with sertraline, sexual dysfunction (ejaculation disorder) occurred in 14% of men compared to 0% of patients receiving placebo. These adverse effects are dose-dependent and often resolve spontaneously with continued therapy.

The adverse effect profile observed in double-blind, placebo-controlled studies involving patients with OCD, panic disorder, PTSD, and social anxiety disorders was similar to that seen in patients with depression participating in clinical trials.

Below are data on adverse reactions observed during post-marketing surveillance (frequency unknown) and in placebo-controlled clinical trials (in which a total of 2542 patients received sertraline and 2145 patients received placebo), involving patients with depression, OCD, panic disorders, PTSD, and social anxiety disorders.

Some of the adverse reactions listed below may decrease in intensity and frequency with prolonged treatment and do not necessarily lead to discontinuation of therapy.

The frequency of adverse reactions is categorized as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

Infections and infestations

Common: pharyngitis; uncommon: upper respiratory tract infections, rhinitis; rare: diverticulitis§, gastroenteritis, otitis media.

Benign and malignant neoplasms (including cysts and polyps)

Rare: neoplasm in one patient receiving sertraline, compared to no cases in the placebo group.

Blood and lymphatic system disorders

Rare: lymphadenopathy*, thrombocytopenia*§, leukopenia*§.

Immune system disorders

Uncommon: hypersensitivity*, seasonal allergy*; rare: anaphylactoid reaction*; frequency not known: allergy.

Endocrine disorders

Uncommon: hypothyroidism*; rare: hyperprolactinemia*, hypothyroidism, syndrome of inappropriate antidiuretic hormone secretion (SIADH)*§.

Metabolism and nutrition disorders

Common: decreased appetite, increased appetite*; rare: diabetes mellitus, hypercholesterolemia, hypoglycemia*, hyponatremia*§, hyperglycemia*§.

Psychiatric disorders

Very common: insomnia (19%); common: depression*, depersonalization, nightmares, anxiety*, agitation*, nervousness, decreased libido*, bruxism*; uncommon: hallucinations*, euphoric mood*, apathy, pathological thinking; uncommon: aggression*; rare: conversion disorder, drug dependence, psychotic disorder*, paranoia, suicidal ideation/suicidal behavior*§ [in patients with OCD during short-term use, in studies lasting 1–12 weeks, cases of suicidal thoughts and suicidal behavior were reported during sertraline therapy or shortly after discontinuation (see section "Special precautions for use")]; rare: conversion disorder*§, paroniria*§, drug dependence, sleepwalking, premature ejaculation.

Nervous system disorders

Very common: dizziness, headache*, somnolence; common: tremor, movement disorders (including extrapyramidal symptoms such as hyperkinesia, hypertonia, dystonia, jaw spasms, or gait disturbances), paresthesia*, hypertonia*, attention disturbances, dysgeusia; uncommon: amnesia, hypoesthesia*, involuntary muscle contractions*, syncope*, hyperkinesia*, migraine*, seizures*, postural dizziness, coordination disturbances, speech disorders; rare: coma*, akathisia (see section "Special precautions for use"), dyskinesia, hyperesthesia, cerebral vasospasm (including transient cerebral vasoconstriction syndrome and Call-Fleming syndrome)*§, psychomotor agitation*§ (see section "Special precautions for use"), sensory disturbances, choreoathetosis§; symptoms associated with serotonin syndrome* or neuroleptic malignant syndrome have also been reported, in some cases associated with concomitant use of serotonergic agents, such as agitation, confusion, diaphoresis, diarrhea, fever, hypertension, rigidity, and tachycardia§.

Eye disorders

Common: visual disturbances*; uncommon: mydriasis*; rare: glaucoma, lacrimation disorders, scotoma, diplopia, photophobia; frequency not known: maculopathy, hyphema*§, visual disorders§, anisocoria§.

Ear and labyrinth disorders

Common: tinnitus*; uncommon: ear pain.

Cardiac disorders

Common: palpitations*; uncommon: tachycardia*, cardiac arrhythmias; rare: myocardial infarction*§, bradycardia, torsades de pointes ventricular tachycardia*§ (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Pharmacodynamics"), bradycardia, QTc interval prolongation* (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Pharmacodynamics").

Vascular disorders

Common: hot flushes*; uncommon: hypertension*, hemorrhagic events (such as epistaxis, gastrointestinal bleeding)*, hyperemia, hematuria*§; rare: peripheral ischemia.

Respiratory, thoracic and mediastinal disorders

Common: yawning*; uncommon: bronchospasm*, dyspnea, epistaxis*; rare: laryngospasm, hyperventilation, hypoventilation, stridor*§, dysphonia, hiccups, interstitial lung disease*§.

Gastrointestinal disorders

Very common: diarrhea (18%), nausea (24%), dry mouth (14%); common: abdominal pain*, vomiting*, constipation*, dyspepsia, flatulence; uncommon: melena, esophagitis, glossitis, dysphagia, hemorrhoids, hypersalivation, tongue changes, eructation; rare: hematochezia, stomatitis, tongue ulcers, dental disorders, oral mucosal ulcers; pancreatitis*; frequency not known: microscopic colitis.

Hepatobiliary disorders

Rare: hepatic function abnormalities; serious hepatic disorders, including hepatitis, jaundice, and hepatic failure, which rarely may lead to fatal outcomes, fulminant hepatitis, necrotizing hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders

Common: rash*, hyperhidrosis; uncommon: periorbital edema*, purpura*, alopecia*, pruritus*, cold sweat, dry skin, urticaria*, facial swelling; rare: severe skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis*§, dermatitis, bullous dermatitis, vesicular rash, hair texture abnormalities, unusual skin odor, angioneurotic edema, photosensitivity reactions§, skin reactions*§, pruritus.

Musculoskeletal and connective tissue disorders

Common: back pain, myalgia, arthralgia*; uncommon: osteoarthritis, muscle weakness, muscle spasms*; rare: rhabdomyolysis*§, bone disorders; frequency not known: trismus*.

Renal and urinary disorders

Uncommon: nocturia, urinary retention*, urinary incontinence*, polyuria, pollakiuria; rare: micturition disorders*, oliguria, difficulty initiating micturition.

Reproductive system and breast disorders

Very common: ejaculation disorder (14%); common: irregular menstrual cycle, erectile dysfunction; uncommon: vaginal bleeding, sexual dysfunction, menorrhagia, female sexual dysfunction; rare: atrophic vulvovaginitis, balanoposthitis, genital discharge, priapism*, galactorrhea*, gynecomastia; frequency not known: postpartum hemorrhage*.

General disorders

Very common: increased fatigue*; common: malaise*, chest pain*, asthenia*, pyrexia*; uncommon: peripheral edema, malaise*, chills, thirst; rare: hernia, fibrosis, drug intolerance, gait disturbances, unspecified events.

Investigations

Uncommon: weight decrease*, weight increase*; uncommon: increased alanine aminotransferase*, increased aspartate aminotransferase*; rare: increased cholesterol, sperm quality abnormalities; frequency not known: laboratory test abnormalities, platelet function changes, increased serum cholesterol concentration.

Injury, poisoning and procedural complications

Rare: injury.

Surgical and medical procedures

Rare: vasodilation procedure.

If an adverse event was observed in patients with depression, OCD, panic disorder, PTSD, and social anxiety disorder, the terms used to describe adverse events were reclassified according to terms used for patients with depression.

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* Adverse reactions reported during post-marketing surveillance.

§ Frequency of adverse reactions estimated using the upper bound of the 95% confidence interval according to the "rule of three".

Withdrawal symptoms observed upon discontinuation of sertraline therapy

Discontinuation of sertraline therapy (especially abrupt discontinuation) usually leads to withdrawal symptoms. The most commonly reported adverse events include dizziness, sensory disturbances (including paresthesia), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, and headache. These adverse events are generally mild to moderate in severity and resolve spontaneously; however, in some patients, they may be severe and/or prolonged. Therefore, when sertraline therapy is no longer required, gradual discontinuation by stepwise dose reduction is recommended (see sections "Dosage and administration" and "Special precautions for use").

Use in elderly patients

The use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs), including sertraline, has been associated with clinically significant cases of hyponatremia in elderly patients, who are at increased risk of developing this adverse effect (see section "Special precautions for use").

Use in children

In over 600 children treated with sertraline, the overall adverse reaction profile was generally similar to that observed in clinical studies in adult patients. The following adverse reactions were reported in controlled clinical trials (number of patients receiving sertraline: 281).

Very common (≥ 1/10): headache (22%), insomnia (21%), diarrhea (11%), nausea (15%).
Common (≥ 1/100 to < 1/10): chest pain, mania, pyrexia, vomiting, anorexia, affective 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 (≥ 1/1000 to < 1/100): QT interval prolongation on ECG, suicide attempts, seizures, extrapyramidal disorder, paresthesia, depression, hallucinations, purpura, hyperventilation, anemia, hepatic function abnormalities, increased alanine aminotransferase, cystitis, herpes simplex, otitis externa, ear pain, eye pain, mydriasis, malaise, hematuria, pustular rash, rhinitis, injury, weight loss, muscle twitching, unusual dreams, apathy, albuminuria, pollakiuria, polyuria, breast pain, menstrual cycle disturbances, alopecia, dermatitis, skin lesions, unusual skin odor, urticaria, bruxism, hyperemia.
Frequency not known: enuresis.

Effects specific to this class of medicinal products

Epidemiological studies, primarily conducted in patients aged 50 years and older, have shown an increased risk of bone fractures in patients receiving SSRIs and tricyclic antidepressants. The mechanism underlying this increased risk is unknown.

Shelf life: 5 years.

Storage conditions: Store at temperatures not exceeding 25°C, in a place inaccessible to children.

Packaging: 14 film-coated tablets in a blister; 1 or 2 blisters in a cardboard box.

Prescription status: Prescription only.

Manufacturer: EGIS Pharmaceuticals PLC.

Manufacturer's address:
9900 Kőrmeny, Matyas kiraly ut. 65, Hungary.