STIMULOTON®

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

Composition:

active substance: sertraline;

1 tablet contains 50 mg of sertraline (as 55.95 mg sertraline hydrochloride);

excipients: magnesium stearate, hydroxypropylcellulose, sodium starch glycolate (type A), calcium hydrogen phosphate dihydrate, microcrystalline cellulose;

coating: hypromellose, macrogol 6000, titanium dioxide (E 171).

Medicinal form. Film-coated tablets.

Main physicochemical properties: white or almost white, oval-shaped, biconvex, film-coated tablets with a stylized engraving "E 271" 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.

Mechanism of action

Sertraline is a potent and specific inhibitor of neuronal serotonin (5-HT) reuptake in vitro, which in animal systems enhances the effects of 5-HT. Sertraline has only very weak effects on the neuronal reuptake of norepinephrine and dopamine. At clinical doses, sertraline blocks serotonin uptake into 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 impair psychomotor functions. Since sertraline selectively inhibits 5-HT reuptake, it does not increase catecholaminergic activity. The agent has no affinity for muscarinic (cholinergic), serotonergic, dopaminergic, adrenergic, histaminergic, GABA, or benzodiazepine receptors. Chronic administration of sertraline in animals was associated with a reduction in the number of brain norepinephrine receptors, a phenomenon also observed with other clinically effective antidepressants and anti-obsessive agents.

Sertraline does not cause medication abuse. 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, participants receiving either alprazolam or d-amphetamine showed significantly higher scores for abuse liability, euphoria, and potential for medication dependence compared to those receiving placebo. Sertraline did not produce the stimulant effects or anxiety associated with d-amphetamine, nor the sedative effects or psychomotor impairments associated with alprazolam. Sertraline did not produce a positive reinforcing stimulus in rhesus monkeys trained to self-administer cocaine and was not a substitute for the discriminative stimulus of either d-amphetamine or pentobarbital in rhesus monkeys.

Clinical efficacy and safety

Major depressive disorder. Studies were conducted in outpatients with depression who responded to therapy during an initial 8-week open-label phase of sertraline treatment at doses of 50–200 mg/day. These patients (n = 295) were randomized to either continue sertraline at 50–200 mg/day or switch to placebo for 44 weeks in a double-blind study. The relapse rate in the group receiving sertraline was statistically significantly lower compared to the placebo group. The mean dose among participants who completed the study was 70 mg/day. The percentage of patients who responded to treatment (defined as those without relapse) in the sertraline and placebo groups was 83.4% and 60.8%, respectively.

Post-traumatic stress disorder (PTSD). Combined data from a total number of PTSD patients participating in 3 studies indicate a lower response rate in men compared to women. In two clinical studies with a positive overall outcome, the percentage of patients who responded to treatment was similar between women and men in the sertraline groups compared to placebo (women: 57.2% vs. 34.5%; men: 53.9% vs. 38.2%). The number of men and women was 184 and 430, respectively. Results were more consistent in women, while men had more baseline variability (e.g., higher substance abuse, longer duration of illness, trauma etiology, etc.), which correlated with lower drug efficacy.

Cardiac electrophysiology / In a thorough QTc interval study at steady state under supratherapeutic exposures in healthy volunteers (receiving a dose of 400 mg/day, twice the maximum recommended daily dose), the upper limit of the two-sided 90% CI [confidence interval] for the time-matched mean difference in QTcF between sertraline and placebo, derived by least squares, (11.666 ms) exceeded the predefined threshold of 10 ms at the 4-hour post-dose time point. Exposure-response analysis indicated a weak positive relationship between QTcF and plasma sertraline concentration [0.036 ms/(ng/mL); p < 0.0001]. Based on the exposure-response model, the threshold for clinically significant QTcF prolongation (i.e., >10 ms for the predicted 90% CI) increased by at least 2.6-fold compared to that at the mean Cmax (86 ng/mL) after administration of the highest recommended dose of sertraline (200 mg/day) (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", and "Overdose").

Obsessive-compulsive disorder in pediatric patients. The safety and efficacy of sertraline (50–200 mg/day) were evaluated in the treatment of children (6–12 years) and adolescents (13–17 years) without depression who were receiving outpatient treatment for obsessive-compulsive disorder (OCD). After a 1-week initial period of single-blind placebo administration, patients were randomized to receive either sertraline or placebo for 12 weeks with flexible dosing. Children (6–12 years) initiated treatment at a dose of 25 mg. Patients randomized to the sertraline group showed significantly greater improvement compared to those receiving placebo, as assessed by the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (p = 0.005), the National Institute of Mental Health (NIMH) Global Obsessive Compulsive Scale (p = 0.019), and the Clinical Global Impression-Improvement scale (p = 0.002). Additionally, patients in the sertraline group showed a trend toward greater improvement on the Clinical Global Impression-Severity scale compared to the placebo group (p = 0.089). Baseline mean CY-BOCS score and mean change in score from baseline were 22.25 ± 6.15 and –3.4 ± 0.82, respectively, in the placebo group, while in the sertraline group, baseline mean score and mean change from baseline were 23.36 ± 4.56 and –6.8 ± 0.87, respectively. In a retrospective analysis, the percentage of patients who responded to treatment—defined as those with at least a 25% reduction in CY-BOCS score (primary efficacy endpoint) from baseline to endpoint—was 53% in the sertraline group compared to 37% in the placebo group (p = 0.03).

Data on long-term clinical studies of efficacy in pediatric patients are lacking.

Children. Data on the use of sertraline in children under 6 years of age are lacking.

Post-marketing safety study SPRITES. An observational post-marketing study was conducted involving 941 patients aged 6 to 16 years, evaluating the long-term safety of sertraline therapy (with and without psychotherapy) compared to psychotherapy alone, with follow-up up to 3 years, regarding cognitive, emotional, physical, and pubertal development. This study was conducted under real-world clinical practice conditions in children and adolescents with primary diagnoses of OCD, depression, or other anxiety disorders, assessing cognition (evaluated by the "Trails B" test and the "BRIEF" index), behavioral/emotional regulation (evaluated by the "BRIEF" behavioral regulation index), and physical/pubertal development (evaluated by standardized indices of "height/weight/body mass index (BMI)" and Tanner stage). Sertraline is approved for pediatric use only in patients aged 6 years and older with OCD (see section "Indications"). Standardization of each primary outcome measure based on age- and sex-specific norms showed that overall outcomes were consistent with normal development. No statistically significant deviations from baseline were observed except for body weight. Comparative analyses showed statistically significant results for body weight, although the magnitude of change was minimal.

Pharmacokinetics.

Absorption. After 14 days of sertraline administration at doses of 50–200 mg (orally, once daily) in humans, peak plasma concentration of sertraline is reached within 4.5–8.4 hours after administration. 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.

Based on clinical and in vitro studies, sertraline is metabolized via multiple pathways, including the involvement of CYP3A4, CYP2C19, and CYP2B6 enzymes (see section "Interaction with other medicinal products and other forms of interaction"). Sertraline and its major metabolite, desmethylsertraline, are also substrates of P-glycoprotein in vitro.

Elimination. The mean elimination half-life of sertraline is approximately 26 hours (ranging from 22 to 36 hours). Based on the terminal half-life, drug accumulation (approximately doubling of plasma levels) occurs until steady-state concentrations are reached after about 1 week of once-daily dosing. The elimination half-life of N-desmethylsertraline is 62–104 hours. Sertraline and N-desmethylsertraline are extensively metabolized in humans, with final metabolites excreted in equal amounts in feces and urine. 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 50–200 mg is dose-dependent.

Pharmacokinetics in specific patient populations

Children with OCD. The pharmacokinetics of sertraline were studied in 29 children aged 6–12 years and 32 adolescents aged 13–17 years. In these patients, 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 sertraline concentrations in children aged 6–12 years were approximately 35% higher than in those aged 13–17 years and 21% higher than in the reference adult group. No significant differences in clearance were observed between boys and girls. Therefore, for pediatric use, especially in children with low body weight, a low initial dose and gradual dose titration in 25 mg increments are recommended. Adolescents may receive the same doses as adults.

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

Hepatic impairment. In patients with liver damage, the elimination half-life of sertraline is prolonged and the area under the pharmacokinetic curve (AUC) is increased threefold (see sections "Dosage and administration" and "Special precautions").

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

Pharmacogenomics. In individuals with slow CYP2C19 metabolism, plasma sertraline levels were approximately 50% higher compared to those with rapid CYP2C19 metabolism. The clinical significance of this finding is not fully established; therefore, dose titration based on individual clinical response is recommended.

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 listed in the section "Composition".

Concomitant use of sertraline with irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome, which may present with symptoms such as agitation, tremor, and hyperthermia. Sertraline therapy must not be initiated earlier than 14 days after discontinuation of treatment with an irreversible MAOI. Sertraline administration should 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

Monoamine oxidase inhibitors (MAOIs)

Irreversible MAOIs (e.g., selegiline). Concomitant use of sertraline with irreversible MAOIs such as selegiline is contraindicated. Sertraline therapy may be initiated no earlier than 14 days after discontinuation of irreversible MAOI treatment. Sertraline administration should be discontinued at least 7 days before starting therapy with an irreversible MAOI (see section "Contraindications").

Reversible selective MAO-A inhibitor (moclobemide). Due to the risk of serotonin syndrome, sertraline should not be used in combination with reversible selective MAOIs such as moclobemide. After discontinuation of a reversible MAOI, 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 MAOIs (linezolid). The antibiotic linezolid is a weak, non-selective reversible MAOI and should not be administered to patients receiving sertraline (see section "Contraindications").

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

Pimozide

In a study with single low-dose administration of pimozide (2 mg), an increase in pimozide levels of approximately 35% was observed. This elevation in levels was not associated with 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 index of pimozide (see section "Contraindications").

Concomitant use with sertraline is not recommended

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").

Sertraline should be used with caution when co-administered with opioids (such as fentanyl, primarily used during general anesthesia and in chronic pain therapy) and other serotonergic agents (including other serotonergic antidepressants, amphetamines, and triptans).

Special precautions for use

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 medicinal products 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 patient monitoring is recommended 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 cause clinically significant inhibition of phenytoin metabolism. However, case reports suggest elevated phenytoin exposure in patients receiving 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. A reduction in sertraline plasma levels under the influence of other CYP3A4 enzyme inducers such as phenobarbital, carbamazepine, St. John’s wort, and rifampicin cannot be excluded.

Triptans

During post-marketing surveillance, isolated reports have been received of cases of weakness, hyperreflexia, incoordination, confusion, anxiety, and agitation following concomitant use of sertraline and sumatriptan. Serotonin syndrome symptoms may also develop with other drugs in this class (triptans). If concomitant treatment with sertraline and triptans is clinically necessary, appropriate patient monitoring is recommended (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 other medicinal products, digoxin, atenolol, cimetidine

Concomitant use with cimetidine led to a significant reduction in sertraline clearance. The clinical significance of these changes is not established. Sertraline did 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., nonsteroidal anti-inflammatory drugs (NSAIDs), acetylsalicylic acid, and ticlopidine) or other medicinal products that increase the risk of bleeding (see section "Special precautions for use").

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 by 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 resulted in a moderate increase (on average by 23–37%) in steady-state plasma concentrations of desipramine (a marker of CYP2D6 activity). Clinically significant interactions may occur with other CYP2D6 substrates that have narrow therapeutic ranges, such as class 1C antiarrhythmics (particularly propafenone and flecainide), tricyclic antidepressants, and typical antipsychotics, especially 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 substrates of CYP3A4 (endogenous cortisol, carbamazepine, terfenadine, alprazolam), CYP2C19 (diazepam), and CYP2C9 (tolbutamide, glimepiride, and phenytoin). In vitro study results indicate that sertraline has very low or no inhibitory potential towards CYP1A2.

Daily consumption of three glasses of grapefruit juice increased plasma levels of sertraline by nearly 100% in a crossover study involving 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 potentially even greater increase in sertraline exposure cannot be excluded when sertraline is used concomitantly with potent inhibitors of the CYP3A4 enzyme, such as protease inhibitors, ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, and nefazodone. This also applies to moderate CYP3A4 inhibitors such as 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 approximately 50% compared to individuals with rapid CYP2C19 metabolism (see section "Pharmacokinetics"). Drug interactions with potent inhibitors of CYP2C19, such as omeprazole, lanzoprazole, pantoprazole, rabeprazole, fluoxetine, and fluvoxamine, cannot be excluded.

Special precautions for use.

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

Cases of potentially life-threatening syndromes such as serotonin syndrome (SS) or neuroleptic malignant syndrome (NMS) have been reported during treatment with SSRIs, including sertraline. The risk of developing SS or NMS increases when SSRIs are used concomitantly with other serotonergic agents (including other serotonergic antidepressants, amphetamines, triptans), agents that impair serotonin metabolism (including MAO inhibitors, e.g., methylene blue), antipsychotics, other dopamine antagonists, and opioids. Patients should be monitored for signs and symptoms of SS or NMS (see section "Contraindications").

Switching from SSRIs, antidepressants, or anti-obsessive agents

There are limited data from controlled studies on the optimal timing for switching from SSRIs, antidepressants, or anti-obsessive agents to sertraline. Appropriate medical evaluation should be conducted when making such changes in therapy, especially 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, such as amphetamines, tryptophan, fenfluramine, 5-HT agonists, or herbal preparations (e.g., St. John’s wort, Hypericum perforatum), should be done with caution, and such combination therapy should be avoided due to possible pharmacodynamic interactions.

Prolongation of the QTc interval / torsades de pointes

Post-marketing reports have documented cases of QTc interval prolongation and ventricular tachycardia of the torsades de pointes type, mostly in patients with risk factors. The effect on QTc prolongation has been confirmed in a QTc study in healthy volunteers, showing a statistically significant positive exposure-response relationship. Therefore, sertraline should be used with caution in patients with additional risk factors for QTc prolongation, such as cardiac disease, hypokalemia or hypomagnesemia, family history of QTc prolongation, bradycardia, and 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

Manic/hypomanic symptoms have 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 medical supervision is required. If signs of a manic episode occur, sertraline should be discontinued.

Schizophrenia

Psychotic symptoms may worsen in patients with schizophrenia.

Seizures

Seizures may occur during treatment with sertraline; sertraline should not be prescribed to patients with unstable epilepsy. In patients with controlled epilepsy, sertraline treatment requires careful monitoring. Sertraline should be discontinued in patients who develop seizures.

Suicidality / suicidal thoughts / suicide attempts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide attempts (suicidal behaviors and manifestations). This risk persists until significant remission is achieved. Since improvement may not occur during the first few weeks or longer periods of treatment, patients should remain under close supervision until improvement occurs. Clinical experience generally indicates that the risk of suicide may increase during the early stages of recovery.

Other psychiatric conditions for which sertraline is prescribed may also be associated with an increased risk of suicidal behaviors and manifestations. Additionally, these conditions may coexist with major depressive disorder. Therefore, similar precautionary measures applicable to the treatment of patients with major depressive disorder are also necessary when treating patients with other psychiatric disorders.

It is known that patients with a history of suicidal behaviors or manifestations, or those who exhibit pronounced suicidal ideation prior to the start of treatment, are at higher risk of developing suicidal thoughts or attempts; thus, they 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 antidepressants compared to placebo in patients under 25 years of age.

Patients, particularly those at high risk of suicidality, should be closely observed, 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 thoughts, or any unusual changes in behavior, and to seek immediate medical attention if these symptoms occur.

Use in children

Sertraline should not be used to treat children and adolescents, except for patients aged 6–17 years with obsessive-compulsive disorder. In clinical trials, children and adolescents receiving antidepressants showed higher rates of suicidal behavior (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behavior, and anger) compared to those receiving placebo. If, based on clinical need, a decision is made to prescribe this medication, careful monitoring for signs of suicidal symptoms is required, especially at the beginning of treatment. Long-term safety regarding cognitive, emotional, physical, and pubertal development in children and adolescents aged 6–16 years was evaluated in a long-term observational study lasting up to 3 years (see section "Pharmacological properties"). In the post-marketing period, several cases of delayed growth and delayed sexual maturation have been reported. The clinical significance and causal relationship remain unclear. Physicians should monitor growth and development in children undergoing long-term therapy.

Abnormal bleeding/bleeding events

Cases of pathological hemorrhagic events, including skin hemorrhages (ecchymoses and purpura), gastrointestinal or gynecological bleeding, and even fatal bleeding, have been reported with SSRIs. SSRIs/SNRIs increase the risk of postpartum hemorrhage (see sections "Use during pregnancy or breastfeeding" and "Adverse reactions"). Caution is recommended when using SSRIs, especially in combination 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 bleeding disorders (see section "Interaction with other medicinal products and other forms of interaction").

Hyponatremia

Hyponatremia may develop during treatment with SSRIs or serotonin-norepinephrine reuptake inhibitors (SNRIs), including sertraline. In many cases, hyponatremia is due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases of serum sodium levels below 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia when treated with SSRIs and SNRIs. The risk may also be increased in patients taking diuretics or those with hypovolemia of any origin (for use in elderly patients, see sections "Dosage and administration" and "Adverse reactions"). For patients with symptomatic hyponatremia, discontinuation of sertraline therapy and appropriate medical intervention should be considered. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and loss of physical coordination, which may lead to falls. More severe and/or acute episodes may present with hallucinations, syncope, seizures, coma, respiratory arrest, and even death.

Withdrawal symptoms observed upon discontinuation of sertraline

Withdrawal symptoms are common upon discontinuation of the drug, particularly with abrupt cessation (see section "Adverse reactions"). Clinical trial data show that the incidence of withdrawal reactions was 23% in patients who discontinued sertraline compared to 12% in those who continued treatment.

The risk of withdrawal syndrome may depend on several factors, including duration of treatment, dosage, and speed of dose reduction. Most frequently 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 generally mild to moderate in severity, but may be severe in some patients. They usually occur within the first few days after discontinuation, although in very rare cases, such symptoms have been reported in patients who accidentally missed a dose. In most cases, 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 over several weeks or months according to patient needs when discontinuing treatment (see section "Dosage and administration").

Akathisia/psychomotor restlessness

Sertraline use has been associated with akathisia, characterized by a subjective sense of inner restlessness or distress and an urge to move, often accompanied by an inability to sit or stand still. The risk of such complications is highest during the first few weeks of treatment. Increasing the dose in patients who develop these symptoms may be harmful.

Use in hepatic impairment

Sertraline is extensively metabolized in the liver. In a pharmacokinetic study with multiple dosing in patients with stable mild cirrhosis, elimination half-life was prolonged and AUC or Cmax increased approximately threefold compared to individuals with normal hepatic function. No significant differences in plasma protein binding were observed between the two groups. Sertraline should be used with caution in patients with hepatic disease. When prescribing sertraline to patients with impaired liver function, consideration should be given to reducing the dose or dosing frequency. Sertraline should not be used in patients with severe hepatic impairment (see section "Dosage and administration").

Use in renal impairment

Sertraline is extensively metabolized; renal excretion of unchanged drug is a minor elimination pathway. In studies involving patients with mild to moderate (creatinine clearance 30–60 mL/min) or moderate to severe (creatinine clearance 10–29 mL/min) renal impairment, pharmacokinetic parameters (AUC0–24 and Cmax) after multiple dosing showed no statistically significant differences compared to 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, use of SSRIs and SNRIs, including sertraline, has been associated with cases of clinically significant hyponatremia in elderly patients, who are at greater risk of this adverse effect (see "Hyponatremia" in section "Special precautions for use").

Diabetes mellitus

In patients with diabetes mellitus, SSRIs may affect glycemic control. Insulin and/or oral hypoglycemic agent dosing may require adjustment.

Electroconvulsive therapy (ECT)

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

Grapefruit juice

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

Effect on urine screening test results

False-positive results in immunological urine screening tests for benzodiazepines have been reported in patients taking sertraline. These false-positive results are due to the low specificity of the laboratory test and may persist for several days after discontinuation of sertraline. Sertraline can be differentiated from benzodiazepines in urine by confirmatory testing using gas chromatography/mass spectrometry.

Angle-closure glaucoma

SSRI-class drugs, including sertraline, may affect pupil size, causing mydriasis. This effect may lead to narrowing of the anterior chamber angle, resulting in increased intraocular pressure and angle-closure glaucoma, particularly in patients with a predisposition. Therefore, sertraline should be used with caution in patients with angle-closure glaucoma or a history of glaucoma.

Information on excipients

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

Use during pregnancy or breastfeeding.

Pregnancy

Well-controlled studies of the drug in pregnant women have not been conducted. However, substantial data are available showing no evidence of congenital malformations due to sertraline use. Animal studies have shown effects on reproductive function, likely due to the toxic effects of the drug on the maternal organism and/or the fetus.

Sertraline use during pregnancy has been reported to cause withdrawal-like symptoms in some newborns (whose mothers took sertraline). This phenomenon has also been observed with other SSRIs. Sertraline is not recommended during pregnancy except when the woman’s clinical condition warrants its use and the expected benefits outweigh the potential risks.

Observational data indicate an increased (approximately twofold) risk of postpartum hemorrhage when SSRIs/SNRIs are used within one month before delivery (see sections "Special precautions for use" and "Adverse reactions").

Newborns should be monitored if the mother continues sertraline use in late pregnancy, especially during the third trimester. Neonates exposed to sertraline in late pregnancy may exhibit the following symptoms: respiratory distress syndrome, cyanosis, apnea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, increased neuromuscular excitability, irritability, lethargy, persistent crying, somnolence, and difficulty sleeping. These symptoms may be due to serotonergic effects or withdrawal. Most 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, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). This syndrome has been observed at a rate of approximately 5 cases per 1000 pregnancies. In the general population, the incidence is 1–2 cases per 1000 pregnancies.

Breastfeeding

Published data on sertraline levels in breast milk indicate that sertraline and its metabolite N-desmethylsertraline are excreted in small amounts. Generally, negligible or undetectable concentrations of the drug have been found in infant plasma, except in one case where the infant’s plasma concentration was approximately 50% of the mother’s (but without any noticeable effect on the infant’s health). No adverse effects on the health of breastfed infants have been reported to date, but this risk cannot be excluded. Use of the drug during breastfeeding is not recommended, except when, in the physician’s opinion, the benefit of treatment outweighs the potential risk.

Fertility

Animal studies did not show any effect of sertraline on fertility parameters.

Reports from studies of some SSRIs suggest that effects on sperm quality in humans are reversible. To date, no effects on human fertility have been identified.

Ability to influence reaction speed when driving or operating machinery.

Clinical pharmacological studies indicate no effect of sertraline on psychomotor function. However, patients should be warned that psychotropic drugs may impair mental or physical abilities required for potentially hazardous tasks such as driving a car or operating machinery.

Dosage and Administration

Route of Administration

Sertraline should be taken once daily (in the morning or in the evening).

Sertraline tablets may be taken independently of food intake.

Initiation of Treatment

Depression and OCD

Treatment with sertraline 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 typical of panic disorders during the initial phase of treatment.

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 dose escalation. Dose adjustments should be made in 50 mg increments up to the maximum dose of 200 mg/day, no more frequently than once weekly, considering sertraline’s elimination half-life of 24 hours.

Initial signs of therapeutic effect may be observed within 7 days of treatment. However, a longer period is usually required to achieve a full therapeutic response, particularly in patients with OCD.

Maintenance Dose

During long-term therapy, dosage 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, at least 6 months, to ensure complete symptom remission.

Panic Disorders and OCD

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

Use in Children

Children and Adolescents with Obsessive-Compulsive Disorder (OCD)

Adolescents 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, further dose increases by 50 mg once weekly may be considered over several weeks. The maximum dose is 200 mg/day.

However, when increasing the dose above 50 mg, the generally lower body weight of children compared to adults should be taken into account. Dose adjustments should not be made more frequently than once weekly.

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

Data on the use of the drug in children under 6 years of age are lacking (see also section "Special Warnings and Precautions for Use").

Use in Elderly Patients

Dosage in elderly patients should be selected with caution, as these patients are at increased risk of developing hyponatremia (see section "Special Warnings and Precautions for Use").

Use in Hepatic Impairment

Caution is advised when administering sertraline to patients with hepatic 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 due to the absence of clinical data on drug use in such patients (see section "Special Warnings and Precautions for Use").

Use in Renal Impairment

Dose adjustment is not required in patients with renal impairment (see section "Special Warnings and Precautions for Use").

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 reactions (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). If intolerable symptoms occur after dose reduction or discontinuation, re-institution of the previously prescribed dose may be considered. Subsequently, the physician may continue to taper the dose more gradually.

Children

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

Overdose

Toxicity

Sertraline has a safety margin that depends on the patient population and/or concomitant use of other medicinal products. Fatal outcomes have been reported following sertraline overdose, both with sertraline alone and in combination with other agents and/or alcohol. Therefore, each case of overdose requires intensive management.

Symptoms

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

Prolongation of the QTc interval / ventricular tachycardia of the torsades de pointes type has also been observed; therefore, ECG monitoring is recommended in all cases of sertraline overdose (see sections "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Pharmacodynamics").

Treatment

There are no specific antidotes for sertraline. Maintenance of a patent airway and adequate oxygenation and ventilation should be ensured and supported as needed. In the management of overdose, activated charcoal, which may be used with a laxative, may be as effective as gastric lavage. Induction of emesis is not recommended. Recommended monitoring includes cardiac monitoring (e.g., ECG) and vital signs, along with general symptomatic and supportive therapy. Given the large volume of distribution of sertraline, interventions such as forced diuresis, dialysis, hemoperfusion, or exchange transfusion are unlikely to be beneficial.

Adverse Reactions

The most commonly observed adverse effect is nausea. In the treatment of social anxiety disorder, sexual dysfunction (ejaculation disorder) was reported in 14% of men receiving sertraline 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 trials involving patients with OCD, panic disorders, PTSD, and social anxiety disorders was similar to that observed 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 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 usually do not lead to discontinuation of therapy.

The frequency of adverse reactions observed in placebo-controlled clinical trials in patients with depression, OCD, panic disorders, PTSD, and social anxiety disorders is presented below. Combined data from clinical trials and post-marketing surveillance (frequency unknown) are provided.

Adverse reaction frequency 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: upper respiratory tract infections, pharyngitis, rhinitis
Uncommon: gastroenteritis, otitis media
Rare: diverticulitis§

Benign, malignant and unspecified neoplasms (including cysts and polyps)
Uncommon: neoplasm

Blood and lymphatic system disorders
Rare: lymphadenopathy, thrombocytopenia*§, leukopenia*§

Immune system disorders
Uncommon: hypersensitivity*, seasonal allergy*
Rare: anaphylactoid reaction*

Endocrine disorders
Uncommon: hypothyroidism*
Rare: hyperprolactinemia*§, syndrome of inappropriate antidiuretic hormone secretion*§

Metabolism and nutrition disorders
Common: decreased appetite, increased appetite*
Rare: hypercholesterolemia, diabetes mellitus, hypoglycemia*, hyperglycemia*§, hyponatremia*§

Psychiatric disorders
Very common: insomnia
Common: anxiety*, depression*, agitation*, decreased libido*, restlessness, depersonalization, nightmares, bruxism*
Uncommon: suicidal ideation/suicidal behavior, psychotic disorder*, pathological thinking, apathy, hallucinations*, aggression*, euphoric mood*, paranoia
Rare: conversion disorder*§, paraphrenia*§, 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 disturbance), paresthesia*, hypertonia*, attention disturbance, dysgeusia
Uncommon: amnesia, hypoesthesia*, involuntary muscle contractions*, syncope*, hyperkinesia*, migraine*, seizures*, postural dizziness, coordination disturbance, speech disorder
Rare: coma*, akathisia (see section "Special precautions"), dyskinesia, hyperesthesia, cerebral vasospasm (including transient cerebral vasoconstriction syndrome and Call-Fleming syndrome)*§, psychomotor agitation*§ (see section "Special precautions"), sensory disturbances, choreoathetosis§
Also reported were symptoms associated with serotonin syndrome* or neuroleptic malignant syndrome, in some cases related to concomitant use of serotonergic agents, such as agitation, confusion, diaphoresis, diarrhea, fever, hypertension, rigidity, and tachycardia§

Eye disorders
Common: visual disturbance*
Uncommon: mydriasis*
Rare: scotoma, glaucoma, diplopia, photophobia, hyphema*§, anisocoria*§, visual disorders§, lacrimation disorders
Frequency not known: maculopathy

Ear and labyrinth disorders
Common: tinnitus*
Uncommon: ear pain

Cardiac disorders
Common: palpitations*
Uncommon: tachycardia*, cardiac arrhythmia
Rare: myocardial infarction*§, torsades de pointes ventricular tachycardia*§ (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Pharmacodynamics"), bradycardia, QTc interval prolongation* (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Pharmacodynamics")

Vascular disorders
Common: flushing*
Uncommon: pathological bleeding (e.g., gastrointestinal bleeding)*, hypertension*, hyperemia, hematuria*
Rare: peripheral ischemia

Respiratory, thoracic and mediastinal disorders
Common: yawning*
Uncommon: dyspnea, epistaxis*, bronchospasm*
Rare: hyperventilation, interstitial lung disease*§, laryngospasm, dysphonia, stridor*§, hypoventilation, hiccups

Gastrointestinal disorders
Very common: nausea, diarrhea, dry mouth
Common: dyspepsia, constipation*, abdominal pain*, vomiting*, flatulence
Uncommon: melena, dental disorders, esophagitis, glossitis, hemorrhoids, hypersalivation, dysphagia, eructation, tongue changes
Rare: oral mucosal ulcers, pancreatitis*§, hematochezia, tongue ulcers, stomatitis
Frequency not known: microscopic colitis*

Hepatobiliary disorders
Rare: hepatic function abnormalities, serious hepatic function abnormalities (including hepatitis, jaundice, and hepatic failure)

Skin and subcutaneous tissue disorders
Common: hyperhidrosis, rash*
Uncommon: periorbital edema*, urticaria*, alopecia*, pruritus*, purpura*, dermatitis, dry skin, facial edema, cold sweat
Rare: severe skin reactions such as Stevens-Johnson syndrome* and toxic epidermal necrolysis*§, skin reaction*§, photosensitivity§, angioedema, pathological changes in hair texture, unusual skin odor, bullous dermatitis, vesicular rash

Musculoskeletal and connective tissue disorders
Common: back pain, arthralgia*, myalgia
Uncommon: osteoarthritis, muscle twitching, muscle spasms*, muscle weakness
Rare: rhabdomyolysis*§, bone injury
Frequency not known: trismus*

Renal and urinary disorders
Uncommon: polyuria, micturition disorder, urinary retention, urinary incontinence*, polyuria, nocturia
Rare: micturition disorder*, oliguria

Reproductive system and breast disorders
Very common: ejaculation disorder
Common: irregular menstrual cycle*, erectile dysfunction
Uncommon: sexual dysfunction, menorrhagia, vaginal bleeding, female sexual dysfunction
Rare: galactorrhea*, atrophic vulvovaginitis, genital discharge, balanoposthitis*§, gynecomastia*, priapism*
Frequency not known: postpartum hemorrhage*†

General disorders
Very common: fatigue*
Common: malaise*, chest pain*, asthenia*, pyrexia*
Uncommon: peripheral edema*, chills, gait disturbance*, thirst
Rare: hernia, drug intolerance

Investigations
Common: weight gain*
Uncommon: increased alanine aminotransferase level*, increased aspartate aminotransferase level*, weight loss*
Rare: increased blood cholesterol level*, abnormal clinical laboratory test results, sperm quality abnormality, platelet function abnormality*§

Injury, poisoning and procedural complications
Common: injury

Surgical and medical procedures
Rare: vasodilation procedure

* Adverse reactions reported during post-marketing surveillance
§ Frequency of adverse reactions estimated using the upper bound of the 95% confidence interval calculated by the "rule of three"
† This adverse reaction was reported for the SSRI/SNRI therapeutic group (see sections "Special precautions" and "Use during pregnancy or breastfeeding")

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 effects 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 effects were generally mild to moderate in severity and resolved 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").

Use in elderly patients

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, in whom the risk of developing this adverse effect may be increased (see section "Special precautions").

Use in children

In over 600 children receiving sertraline, the overall adverse reaction profile was generally similar to that observed in adult clinical trials. In controlled trials, the following adverse reactions were reported (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, restlessness, attention disturbance, dizziness, hyperkinesia, migraine, somnolence, tremor, visual disturbance, dry mouth, dyspepsia, nightmares, fatigue, urinary incontinence, rash, acne, epistaxis, flatulence
Uncommon (≥1/1000 to <1/100): QT interval prolongation on ECG (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", and "Pharmacodynamics"), suicide attempts, seizures, extrapyramidal disorder, paresthesia, depression, hallucinations, purpura, hyperventilation, anemia, hepatic function disorders, 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, polyuria, breast pain, menstrual cycle disturbance, alopecia, dermatitis, skin injury, unusual skin odor, urticaria, bruxism, flushing
Frequency not known: enuresis

Effects typical of 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.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk profile of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life: 5 years

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

Packaging:
10 tablets per blister; 3 blisters per cardboard box.

Prescription status: Prescription only

Manufacturer:
JSC EGIS Pharmaceutical Plant / EGIS Pharmaceuticals PLC

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