Sertaline-darnitsya
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SERTRALINE-DARNYTSIA (SERTRALINE – DARNYTSIA)
Composition:
Active substance: sertraline;
One film-coated tablet contains sertraline 50 mg, in the form of sertraline hydrochloride 55.950 mg;
Excipients: microcrystalline cellulose, lactose, copovidone, sodium croscarmellose, magnesium stearate, colloidal anhydrous silicon dioxide, Opadry White film coating.
Pharmaceutical form.
Main physicochemical properties: film-coated tablets, capsule-shaped, white to almost white, with a score on one side and the mark "50" on the other side.
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 leads to potentiation of 5-HT effects. Sertraline has only very weak effects on the processes of 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 produce sedative effects and did not affect psychomotor functions. Due to its selective inhibition of 5-HT reuptake, sertraline does not increase catecholaminergic activity. The drug has no affinity for muscarinic (cholinergic), serotonergic, dopaminergic, adrenergic, histaminergic, GABA, or benzodiazepine receptors. Prolonged 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-obsessional agents.
Sertraline does not cause drug abuse potential. 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 who received either alprazolam or d-amphetamine showed significantly higher scores for abuse liability, euphoria, and potential for drug dependence compared to those receiving placebo. Sertraline did not produce the stimulant effect or anxiety sensations associated with d-amphetamine, nor the sedative effect or psychomotor impairment associated with alprazolam. Sertraline did not serve as a positive reinforcer in rhesus monkeys trained to self-administer cocaine, nor did it substitute as a discriminative stimulus for 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 by the end of an initial 8-week open-label phase of sertraline treatment at doses of 50–200 mg per day. These patients (n=295) were randomized to either continue sertraline at 50–200 mg per 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 per 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).
Pooled data from a total number of patients with PTSD participating in 3 studies indicate a lower response rate among men compared to women. In two clinical studies with a positive overall outcome, the percentage of patients responding to treatment among women and men in the sertraline groups was similar compared to placebo (women: 57.2% vs. 34.5%; men: 53.9% vs. 38.2%). The number of men and women among patients in the pooled study population was 184 and 430, respectively. Results were more consistent in women, while men had other baseline variables (e.g., higher substance abuse, longer duration of illness, cause of trauma, etc.) that 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 per day, twice the maximum recommended daily dose), the upper limit of the two-sided 90% CI for the time-matched mean difference in QTcF between sertraline and placebo, derived by least squares method (11.666 ms), exceeded the predefined threshold of 10 ms at the 4-hour time point after drug administration. 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) was exceeded by at least 2.6-fold compared to the mean maximum concentration Cmax (86 ng/mL) after administration of the highest recommended sertraline dose (200 mg/day) (see sections "Special precautions", "Interaction with other medicinal products and other forms of interaction", "Overdose", and "Adverse reactions").
Obsessive-compulsive disorder (OCD) in pediatric patients.
The safety and efficacy of sertraline (50–200 mg per day) were evaluated in the treatment of children (6–12 years) and adolescents (13–17 years) without depression, treated as outpatients for 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 Global Obsessive-Compulsive Scale (NIMH) (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 in the placebo group were 22.25 ± 6.15 and -3.4 ± 0.82, respectively, 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 post-hoc analysis, the percentage of patients who responded to treatment, defined as patients with a 25% or greater reduction in CY-BOCS score from baseline to endpoint (primary efficacy parameter), was 53% in the sertraline group compared to 37% in the placebo group (p=0.03).
Data on long-term clinical studies evaluating the efficacy of sertraline 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 in 941 patients aged 6 to 16 years to evaluate the long-term safety of sertraline therapy (with and without psychotherapy) compared to psychotherapy alone, with respect to cognitive, emotional, physical, and pubertal development, over a period of up to 3 years. This study was conducted under real-world clinical practice conditions in children and adolescents with a primary diagnosis of obsessive-compulsive disorder, depression, or other anxiety disorders, and assessed cognition (evaluated by the Trails B test and BRIEF index), behavioral/emotional regulation (evaluated by the BRIEF behavioral regulation index), and physical/pubertal maturation (evaluated by standard height/weight/body mass index (BMI) and Tanner stage). Sertraline is approved for use in pediatric practice only for 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 results were consistent with normal development. No statistically significant deviations from baseline were observed except for body weight. In comparative analyses, statistically significant results were observed for body weight, but the magnitude of change was small.
Pharmacokinetics.
Absorption.
Following 14-day administration of sertraline at doses of 50–200 mg (orally, once daily) in humans, 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.
Biological transformation.
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 those involving 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 (range 22–36 hours). Due to the terminal elimination half-life, drug accumulation (approximately doubling of plasma levels) occurs until steady-state concentration is reached, which occurs after 1 week of once-daily administration. The elimination half-life of N-desmethylsertraline is 62–104 hours. Sertraline and N-desmethylsertraline are extensively metabolized in humans, with their final metabolites 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 mg to 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 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 200 mg daily dosing, 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 significantly differ from that in adults aged 18–65 years.
Hepatic impairment.
In patients with hepatic impairment, the elimination half-life of sertraline is prolonged and the area under the plasma concentration-time curve (AUC) is increased threefold (see sections "Special precautions" and "Dosage and administration").
Renal impairment.
In patients with moderate or severe renal impairment, no significant accumulation of sertraline was observed.
Pharmacogenomics.
In individuals with poor 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 should be based on individual clinical response.
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 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 treatment with an irreversible MAOI. 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
Monoamine oxidase inhibitors (MAOIs)
Irreversible MAO inhibitors (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 must be discontinued at least 7 days before starting therapy with irreversible MAOIs (see section "Contraindications").
Selective reversible MAO-A inhibitor (moclobemide)
Due to the risk of serotonin syndrome, sertraline should not be used in combination with selective reversible MAO inhibitors such as moclobemide. After discontinuation of a reversible MAO inhibitor, the waiting period before initiating sertraline therapy may be shorter than 14 days. It is recommended to discontinue sertraline at least 7 days before starting therapy with a reversible MAOI (see section "Contraindications").
Non-selective reversible MAO inhibitors (linezolid)
The antibiotic linezolid is a weak, non-selective reversible MAO inhibitor 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 (e.g., methylene blue) and started sertraline, 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 single low-dose administration of pimozide (2 mg), an increase in pimozide levels by approximately 35% was observed. This increase 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 not recommended
Central nervous system (CNS) depressants, alcohol
Concomitant administration of sertraline at a dose of 200 mg daily 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 for chronic pain management) and other serotonergic agents (including other serotonergic antidepressants, amphetamines, and triptans).
Special precautions for use
QT-prolonging medicinal products
The risk of QTc interval prolongation and/or ventricular arrhythmias (e.g., torsades de pointes) may be increased when sertraline is used concomitantly with other medicinal products that prolong the QTc interval (e.g., certain antipsychotics and antibiotics) (see sections "Pharmacodynamics" and "Special precautions for use").
Lithium
In a placebo-controlled study in healthy volunteers, concomitant administration of sertraline and lithium did not significantly alter the pharmacokinetics of lithium but resulted in increased tremor compared to placebo, suggesting a possible pharmacodynamic interaction. Appropriate monitoring of patients is recommended when sertraline and lithium are used concomitantly.
Phenytoin
Results from a placebo-controlled study in healthy volunteers indicate that long-term administration of sertraline at a dose of 200 mg daily does not lead to clinically significant inhibition of phenytoin metabolism. However, case reports suggest increased phenytoin exposure in patients taking sertraline; monitoring of plasma phenytoin concentrations is recommended during the initial phase of sertraline therapy, with appropriate dose adjustment 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 the post-marketing surveillance period, 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 occur with other drugs of 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 daily and warfarin resulted in a slight 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 treatment 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 daily was co-administered with digoxin.
MEDICINAL PRODUCTS AFFECTING PLATELET FUNCTION
The risk of bleeding may be 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 may 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. Long-term administration of sertraline at a dose of 50 mg daily led to a moderate increase (on average by 23–37%) in the steady-state plasma concentration of desipramine (a marker of CYP2D6 activity). Clinically significant interactions may occur with other CYP2D6 substrates that have a narrow therapeutic range, 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, 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 sertraline levels by nearly 100% in a crossover study in 8 healthy Japanese volunteers. Therefore, grapefruit juice consumption should be avoided during sertraline treatment (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 strong 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 strong 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"). A drug interaction with strong CYP2C19 inhibitors such as omeprazole, lansoprazole, 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), drugs that impair serotonin metabolism (including MAO inhibitors, such as methylene blue), antipsychotics and other dopamine antagonists, and opioids. Patients should be monitored for the emergence of 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 treatment changes, particularly when switching from long-acting agents such as fluoxetine.
Other serotonergic agents, e.g., tryptophan, fenfluramine, and 5-HT agonists
Concomitant use of sertraline with other medicinal products that enhance serotonergic neurotransmission, such as amphetamines, tryptophan, fenfluramine, 5-HT agonists, herbal preparations, or St. John’s wort (Hypericum perforatum), should be undertaken with caution, and such combination therapy should be avoided if possible (due to potential pharmacodynamic interactions).
QTc interval prolongation/ventricular tachycardia of the "torsades de pointes" type
Cases of QTc interval prolongation and ventricular tachycardia of the "torsades de pointes" type have been reported during the post-marketing use of sertraline. Most cases occurred in patients with other risk factors for QTc prolongation/ventricular tachycardia of the "torsades de pointes" type. 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, or concomitant use of medicinal products that prolong the QTc interval (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").
Exacerbation of hypomania or mania
Cases of mania/hypomania 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 physician monitoring 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 sertraline therapy: sertraline should not be prescribed to patients with unstable epilepsy; in patients with controlled epilepsy, sertraline use requires close monitoring. The drug should be discontinued in patients who experience seizures.
Suicide/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 occurs. Since improvement in patients may not occur during the first few weeks or longer periods of therapy, 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 necessary when treating patients with other psychiatric disorders.
Patients with a history of suicidal behaviors or manifestations, or patients who exhibit pronounced suicidal ideation prior to the start of therapy, are at higher risk of developing suicidal thoughts or suicide attempts and should therefore be closely monitored 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.
Close monitoring of patients, particularly those at high risk of suicidality, is essential, especially at the beginning of therapy and after any dosage adjustments. Patients (and caregivers) should be advised to monitor for any signs of 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
Sertraline should not be used to treat children and adolescents, except for patients aged 6–17 years with obsessive-compulsive disorder. In clinical trials involving children and adolescents receiving antidepressants, suicidal behavior (suicide attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behavior, and anger) were observed more frequently compared to patients receiving placebo. If, based on clinical need, a decision is made to prescribe this medication, close 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 to 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. Additionally, there is limited clinical evidence on the long-term safety of the drug in children and adolescents, including its impact on growth, sexual maturation, and cognitive and behavioral development. In the post-marketing period, several cases of delayed growth and delayed sexual maturation have been reported. The clinical significance and causal relationship have not yet been established. Physicians should monitor for deviations from normal growth and development in children undergoing long-term therapy.
Abnormal bleeding/hemorrhage
Cases of 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 SSRIs. SSRIs/SNRIs (serotonin-norepinephrine reuptake inhibitors) may increase the risk of postpartum hemorrhage (see sections "Use during pregnancy or breastfeeding" and "Adverse reactions"). Caution is recommended when using SSRIs in patients, especially when used concomitantly with medicinal products known to affect platelet function (e.g., anticoagulants, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, and NSAIDs), as well as in patients with a history of hemorrhagic disorders (see section "Interaction with other medicinal products and other forms of interaction").
Hyponatremia
Hyponatremia may develop during treatment with SSRIs or SNRIs, including sertraline. In many cases, hyponatremia is due to the syndrome of inappropriate antidiuretic hormone secretion. Cases of serum sodium levels below 110 mmol/L have been reported.
Elderly patients may be at increased risk of developing hyponatremia when treated with SSRIs or SNRIs. The risk of this complication may also be increased in patients taking diuretics or in patients with hypovolemia of any origin (see information on use in elderly patients in sections "Method of administration and dosage" and "Adverse reactions"). In patients with symptomatic hyponatremia, discontinuation of sertraline therapy and implementation of appropriate medical interventions should be considered. 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 outcomes.
Withdrawal symptoms observed upon discontinuation of sertraline therapy
Withdrawal symptoms are common upon discontinuation of the drug, particularly 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, although in very rare cases, such symptoms have been observed in patients who inadvertently 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 therapy over a period of several weeks or months, depending on patient needs (see section "Method of administration and dosage").
Akathisia/psychomotor agitation
Sertraline use is associated with the development of akathisia, characterized by subjectively unpleasant or irresistible restlessness and a need 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 therapy. Increasing the dose in patients who develop these symptoms may be harmful.
Use in hepatic impairment
Sertraline is extensively metabolized in the liver. Pharmacokinetic studies with multiple dosing in patients with stable mild cirrhosis showed a prolonged elimination half-life and approximately a threefold increase in AUC or Cmax compared to individuals with normal hepatic function. No significant differences in plasma protein binding between these two study groups were observed. Caution is advised when prescribing sertraline to patients with liver disease. When prescribing sertraline to patients with hepatic impairment, consideration should be given to reducing the dose or dosing frequency. Sertraline should not be used in patients with severe hepatic impairment (see section "Method of administration and dosage").
Use in renal impairment
Sertraline is extensively metabolized; unchanged drug excretion in urine 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 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 be at increased risk of developing this adverse effect (see "Hyponatremia" in section "Special precautions for use").
Diabetes
In patients with diabetes, SSRIs may affect glycemic control. Dosage adjustments of insulin and/or oral hypoglycemic agents may be required.
Electroconvulsive therapy (ECT)
No clinical studies have been conducted to evaluate the risks or benefits of combining ECT with 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. False-positive results are due to the low specificity of the laboratory test and may persist for several days after discontinuation of sertraline treatment. Sertraline can be differentiated from benzodiazepines 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 cause narrowing of the eye angle, resulting in increased intraocular pressure and development of closed-angle glaucoma, particularly in patients with predisposition. Therefore, sertraline should be used with caution in patients with closed-angle 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.
The medicinal product contains lactose; therefore, it should not be used in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.
Use during pregnancy or breastfeeding.
Pregnancy
There are no well-controlled studies of the drug in pregnant women. However, a substantial amount of data has not shown evidence of congenital malformations due to sertraline use. Animal studies revealed effects on reproductive function, likely due to the toxic effect of the drug on the maternal organism, caused by the pharmacodynamic action of the drug and/or direct pharmacodynamic effects on the fetus.
Use of sertraline during pregnancy has been reported to cause symptoms similar to withdrawal reactions 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 (less than two-fold) risk of postpartum hemorrhage if 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 during 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, syndrome of increased neuromuscular excitability, irritability, lethargy, persistent crying, somnolence, and difficulty sleeping. These symptoms may be due to either 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 the use of SSRIs during pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in newborns. The risk is observed at a frequency of approximately 5 cases per 1000 pregnancies. In the general population, 1–2 cases of persistent pulmonary hypertension in newborns per 1000 pregnancies are observed.
Breastfeeding period.
Published data on sertraline levels in breast milk indicate that sertraline and its metabolite N-desmethylsertraline are excreted into breast milk in small amounts. 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). No adverse effects of the drug on the health of breastfed children 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 taking the drug outweighs the risk.
Fertility.
Animal studies did not reveal any effect of sertraline on fertility parameters.
Reports from human studies on the use of certain 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 be warned that psychotropic drugs may impair mental or physical reactions required for performing potentially hazardous tasks, such as driving a car or operating machinery.
Dosage and Administration
The medicinal product Sertraline-Darnitsia should be taken once daily (in the morning or in the evening). Administration of sertraline tablets is independent of food intake.
Initiation of treatment.
Depression and OCD.
Treatment with sertraline should be initiated at a dose of 50 mg once daily.
Panic disorders, PTSD, and social anxiety disorder.
Treatment should be initiated at a dose of 25 mg once daily. 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 for panic disorders at the initial stage 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 increasing the dose. Dose adjustments should be made in 50 mg increments at intervals of no less than one week, up to a maximum dose of 200 mg once daily. Dose adjustments should not occur 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 preventing 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 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 relapses has not been demonstrated for these disorders.
Use in children.
Children and adolescents with 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 case of insufficient effect, further dose increases are possible, increasing by 50 mg at a time over several weeks. The maximum dose is 200 mg once daily. However, when increasing the dose beyond 50 mg, 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 demonstrated.
Data on the use of the drug in children under 6 years of age are lacking (see also section "Special Instructions").
Use in elderly patients.
Dosage in elderly patients should be carefully selected, as these patients may 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 clinical data on the use of the drug in such patients are lacking (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").
Discontinuation symptoms observed upon stopping sertraline therapy.
Abrupt discontinuation of the drug should be avoided. When stopping sertraline therapy, the dose should be gradually reduced over at least 1–2 weeks to minimize the risk of withdrawal reactions (see sections "Special Instructions" and "Adverse Reactions"). If intolerable symptoms occur after dose reduction or discontinuation of the drug, resumption of treatment at the previously prescribed dose may be considered. Subsequently, the physician may continue to reduce the dose, but 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 cases of sertraline overdose have been reported both with sertraline alone 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 reactions such as drowsiness, gastrointestinal disturbances (e.g., nausea and vomiting), tachycardia, tremor, agitation, and dizziness. Coma has been reported less frequently.
Cases of QTc interval prolongation/ventricular tachycardia of the "torsades de pointes" type have been reported after sertraline overdose; therefore, ECG monitoring is recommended in all cases of sertraline overdose (see sections "Pharmacodynamics", "Interaction with other medicinal products and other forms of interactions", and "Special Instructions").
Treatment.
There are no specific antidotes for sertraline. It is recommended to ensure and maintain airway patency and adequate oxygenation and ventilation, if necessary. In the treatment of overdose, administration of activated charcoal, which may be used in combination with a laxative, may be as effective or more effective than gastric lavage. Induction of emesis is not recommended. Recommended monitoring includes cardiac monitoring (e.g., ECG) and vital signs, together with general symptomatic and supportive therapy. Given the large volume of distribution of sertraline, measures 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) occurred in 14% of men taking sertraline compared to 0% of patients receiving placebo. These adverse reactions are dose-dependent and often resolve spontaneously with continued therapy.
The adverse reaction profile commonly 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 studies.
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 long-term 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 listed below. Combined data from clinical trials and post-marketing surveillance (frequency unknown) are presented.
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*§.
Metalbolic and nutritional 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*§, pyromania*§, 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 warnings and precautions for use"), dyskinesia, hyperesthesia, cerebral vasospasm (including transient cerebral vasoconstriction syndrome and Call-Fleming syndrome)*§, psychomotor agitation**∗§** (see section "Special warnings and 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, excessive sweating, diarrhea, fever, hypertension, rigidity, and tachycardia§.
Eye disorders.
Common: visual disturbances*;
Uncommon: mydriasis*;
Rare: scotoma, glaucoma, diplopia, photophobia, hyphema*§, anisocoria*§, visual disorders§, lacrimation disorders.
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 "Pharmacodynamics", "Interaction with other medicinal products and other forms of interaction", and "Special warnings and precautions for use"), bradycardia, QTc interval prolongation* (see sections "Pharmacodynamics", "Interaction with other medicinal products and other forms of interaction", and "Special warnings and precautions for use").
Vascular disorders.
Common: hot flushes*;
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: liver function abnormalities, serious liver function abnormalities (including hepatitis, jaundice, and liver failure).
Skin and subcutaneous tissue disorders.
Common: hyperhidrosis, rash*;
Uncommon: periorbital edema*, urticaria*, alopecia*, pruritus*, purpura*, dermatitis, dry skin, facial swelling, cold sweat;
Rare: rare cases of severe skin reactions such as Stevens-Johnson syndrome* and toxic epidermal necrolysis*§, skin reaction*§, photosensitivity§, angioneurotic edema, hair texture abnormalities, 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 disorders;
Frequency not known: trismus*.
Renal and urinary disorders.
Uncommon: pollakiuria, 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 disturbances*, thirst;
Rare: hernia, drug intolerance.
Investigations.
Common: weight gain*;
Uncommon: increased alanine aminotransferase levels*, increased aspartate aminotransferase levels*, weight loss*;
Rare: increased blood cholesterol levels*, abnormal clinical laboratory test results, sperm quality abnormalities, platelet function abnormalities*§.
Injury, poisoning and procedural complications.
Common: injury.
Surgical and medical procedures.
Rare: vasodilation procedure.
* Adverse reactions reported during the post-marketing period.
§ 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 therapeutic class of SSRIs/SNRIs (see sections "Special warnings and precautions for use" and "Use during pregnancy or breastfeeding").
Discontinuation symptoms observed upon stopping sertraline
Discontinuation of sertraline treatment (especially abrupt discontinuation) usually leads to discontinuation 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 reactions are usually mild or moderate in severity and resolve spontaneously; however, in some patients they may be severe and/or prolonged. Therefore, when sertraline treatment is no longer required, gradual discontinuation by stepwise dose reduction is recommended (see sections "Special warnings and precautions for use" and "Dosage and administration").
Use in elderly patients
Use of SSRIs or 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 warnings and precautions for use").
Use in children
In over 600 children receiving sertraline, the overall adverse reaction profile was generally similar to that observed in adult clinical trials. The following adverse reactions were recorded in controlled 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, restlessness, 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 (see sections "Pharmacodynamics", "Interaction with other medicinal products and other forms of interaction", and "Special warnings and precautions for use"), suicide attempts, seizures, extrapyramidal disorder, paresthesia, depression, hallucinations, purpura, hyperventilation, anemia, liver function abnormalities, increased alanine aminotransferase levels, 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, hot flushes.
Frequency not known: enuresis.
Class-specific effects
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 medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals, patients, or their legal representatives should report all suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua
Shelf life. 2 years.
Storage conditions.
Store in original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.
Packaging.
15 tablets in a blister; 2 blisters per carton.
Prescription status. Prescription only.
Manufacturer. Farmex Avanzed Laboratories S.L.
Manufacturer's address and location of operations.
A-431 Km 19, Almodóvar del Río, 14720, Spain.
Marketing authorization holder.
JSC "Pharmaceutical Company "Darnytsia".