Medopram

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MЕDOPRAM® (MEDOPRAM)

Composition:

Active substance: escitalopram;

One film-coated tablet contains escitalopram (as escitalopram oxalate) 5 mg, 10 mg, 20 mg;

Excipients: sodium croscarmellose, microcrystalline cellulose silicated (colloidal silicon dioxide, microcrystalline cellulose), talc, magnesium stearate;

Film coating: Opadry II White (lactose monohydrate, hypromellose, titanium dioxide (E 171), macrogol).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

5 mg tablets – almost white, round, biconvex film-coated tablets, marked with "E" on one side;

10 mg tablets – almost white, oval, biconvex film-coated tablets, with a deep break line on one side and marked "A A" on the other side;

20 mg tablets – almost white, oval, biconvex film-coated tablets, with a deep break line on one side and marked "E E" on the other side.

Pharmacotherapeutic group. Antidepressants. Selective serotonin reuptake inhibitors. ATC code N06AB10.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Escitalopram is a selective serotonin reuptake inhibitor (SSRI) with high affinity for the primary binding site. It also binds to the allosteric site of the serotonin transporter with 1000-fold lower affinity. Escitalopram has no or very weak affinity for a number of receptors, including 5-HT_1A, 5-HT₂, dopamine D₁ and D₂ receptors, α₁-, α₂-, and β-adrenergic receptors, histamine H₁, muscarinic cholinergic, benzodiazepine, and opioid receptors. Inhibition of serotonin (5-HT) reuptake is the only plausible mechanism of action that can explain the pharmacological and clinical effects of escitalopram.

Pharmacodynamic effects. In a double-blind, placebo-controlled ECG study in healthy volunteers, the change from baseline in QTc (corrected using Fridericia's formula) was 4.3 msec (90% confidence interval [CI]: 2.2; 6.4) at a dose of 10 mg/day and 10.7 msec (90% CI: 8.6; 12.8) at a supratherapeutic dose of 30 mg/day (see sections "Contraindications", "Interaction with other medicinal products and other forms of interaction", "Special warnings and precautions for use", "Overdose", and "Undesirable effects").

Clinical efficacy

Major depressive episodes. The efficacy of escitalopram in the treatment of major depressive episodes during the acute phase was demonstrated in 3 out of 4 double-blind, placebo-controlled, short-term (8-week) studies. In a long-term relapse prevention study, 274 patients who responded to treatment with escitalopram at a dose of 10 or 20 mg/day during an initial 8-week open-label phase were randomized to continue escitalopram at the same dose or placebo for up to 36 weeks. In this study, patients continuing escitalopram had a statistically significantly longer time to relapse over the subsequent 36 weeks compared to those receiving placebo.

Social anxiety disorder. Escitalopram was shown to be effective in the treatment of social anxiety disorder in three short-term (12-week) studies as well as in a 6-month relapse prevention study. In a 24-week dose-ranging study, efficacy of escitalopram was demonstrated at doses of 5, 10, and 20 mg.

Generalized anxiety disorder. Escitalopram at doses of 10 and 20 mg/day was effective in 4 out of 4 placebo-controlled studies. According to pooled data from three studies with similar designs, involving a total of 421 patients receiving escitalopram and 419 patients receiving placebo, 47.5% and 28.9% of patients responded to treatment, respectively, and remission occurred in 37.1% and 20.8% of patients, respectively. A sustained effect was observed from the first week of treatment. The maintenance effect of escitalopram at a dose of 20 mg/day was demonstrated in a 24-76 week randomized treatment maintenance study involving 373 patients who responded to the drug during the initial 12-week open-label treatment.

Obsessive-compulsive disorder. In a randomized, double-blind clinical trial, escitalopram at a dose of 20 mg/day demonstrated superiority over placebo in the total score on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) after 12 weeks of treatment. After 24 weeks, advantages of escitalopram use were observed both at 10 mg/day and 20 mg/day compared to placebo. The efficacy of the drug in preventing relapse was demonstrated for escitalopram at doses of 10 and 20 mg/day in patients who responded to escitalopram during a 16-week open-label period and were included in a 24-week randomized, double-blind, placebo-controlled phase.

Pharmacokinetics.

Absorption. Absorption is almost complete and independent of food intake. The median time to reach maximum concentration (median Tmax) after repeated administration is 4 hours. As with racemic citalopram, the absolute bioavailability of escitalopram is expected to be approximately 80%.

Distribution. The apparent volume of distribution (Vd,β/F) after oral administration is approximately 12–26 L/kg. Plasma protein binding of escitalopram and its main metabolites is less than 80%.

Biotransformation. Escitalopram is metabolized in the liver to demethylated and didemethylated metabolites. Both are pharmacologically active. Alternatively, oxidation of nitrogen to form an N-oxide metabolite is possible. Both the parent compound and metabolites are partially excreted as glucuronides. After repeated dosing, mean concentrations of the demethylated and didemethylated metabolites typically amount to 28–31% and <5% of escitalopram concentration, respectively. The biotransformation of escitalopram to its demethylated metabolite occurs primarily via the cytochrome CYP2C19. Some contribution of CYP3A4 and CYP2D6 enzymes is also possible.

Elimination. The elimination half-life (t½β) after repeated administration is approximately 30 hours. Oral plasma clearance (Cl_oral) is approximately 0.6 L/min. The main metabolites have a longer half-life. Escitalopram and its main metabolites are believed to be eliminated via the liver (metabolic pathway) and kidneys, with the majority being excreted in urine as metabolites.

Linearity. The pharmacokinetics of escitalopram are linear. Steady-state concentrations are reached after approximately 1 week. Mean steady-state concentrations of 50 nmol/L (range: 20–125 nmol/L) are achieved with a daily dose of 10 mg.

Elderly patients (aged 65 years and older). Escitalopram appears to be eliminated more slowly in elderly patients than in younger patients. Systemic exposure (AUC) in elderly patients is approximately 50% higher than in younger healthy volunteers (see section "Dosage and administration").

Impaired liver function. In patients with mild to moderate hepatic impairment (Child-Pugh criteria A and B), the elimination half-life of escitalopram was nearly doubled, and exposure was 60% higher than in individuals with normal liver function (see section "Dosage and administration").

Impaired renal function. In patients with impaired renal function (creatinine clearance CL_cr 10–53 mL/min), administration of racemic citalopram resulted in a prolonged elimination half-life and a slight increase in exposure. Plasma concentrations of metabolites have not been studied but may be elevated (see section "Dosage and administration").

Polymorphism. In individuals with poor CYP2C19 isoenzyme activity, plasma concentrations of escitalopram are doubled compared to those with normal escitalopram metabolism. In individuals with CYP2D6 deficiency, no significant changes in AUC were observed (see section "Dosage and administration").

Clinical characteristics.

Indications.

Treatment of major depressive episodes, panic disorders with or without agoraphobia, social anxiety disorders (social phobia), generalized anxiety disorders, obsessive-compulsive disorders.

Contraindications.

Hypersensitivity to escitalopram or to any of the excipients of the medicinal product. Concomitant use with non-selective irreversible monoamine oxidase inhibitors (MAO inhibitors) due to the risk of serotonin syndrome with agitation, tremor, hyperthermia, and other symptoms (see section "Interaction with other medicinal products and other forms of interaction"). Combined use of escitalopram with reversible MAO-A inhibitors (e.g., moclobemide) or the reversible non-selective MAO inhibitor linezolid is contraindicated due to the risk of serotonin syndrome (see section "Interaction with other medicinal products and other forms of interaction"). Escitalopram is contraindicated in patients with QT interval prolongation syndrome (congenital or acquired). Escitalopram must not be used concomitantly with medicinal products capable of prolonging the QT interval (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Pharmacodynamic interactions

Contraindicated combinations

Irreversible non-selective MAO inhibitors. Serious reactions have been reported in patients taking SSRIs in combination with irreversible non-selective MAO inhibitors, and in patients who recently discontinued SSRIs and started MAO inhibitors (see section "Contraindications"). In some cases, serotonin syndrome occurred (see section "Adverse reactions"). The combination of escitalopram with irreversible non-selective MAO inhibitors is contraindicated. Escitalopram treatment should be initiated no earlier than 14 days after discontinuation of irreversible MAO inhibitors. Treatment with irreversible non-selective MAO inhibitors may be started only 7 days after stopping escitalopram.

Reversible selective MAO-A inhibitor (moclobemide). Due to the risk of serotonin syndrome, concomitant use of escitalopram with the MAO-A inhibitor moclobemide is contraindicated. If use of this combination is considered necessary, minimal recommended doses should be administered under close clinical supervision (see section "Contraindications").

Reversible non-selective MAO inhibitor (linezolid). The antibiotic linezolid is a reversible non-selective MAO inhibitor and should not be prescribed to patients taking escitalopram. If such a combination is necessary, minimal doses of both agents should be used under close clinical supervision (see section "Contraindications").

Irreversible selective MAO-B inhibitor (selegiline). Combination with selegiline (an irreversible MAO-B inhibitor) requires caution due to the risk of serotonin syndrome. Selegiline at doses up to 10 mg daily has been safely used concomitantly with racemic citalopram.

QT interval prolongation. Pharmacokinetic and pharmacodynamic studies of combined use of escitalopram with other medicinal products that prolong the QT interval have not been conducted. When escitalopram is used concomitantly with such agents, an additive effect cannot be excluded. Therefore, concomitant use of escitalopram with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotics (e.g., phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g., sparfloxacin, moxifloxacin, intravenous erythromycin, pentamidine, antimalarials including halofantrine), and certain antihistamines (including astemizole, hydroxyzine, mizolastine), is contraindicated.

Combinations requiring caution during use.

Serotonergic medicinal products. Concomitant use with serotonergic agents (e.g., opioids including tramadol, and triptans including sumatriptan) may lead to serotonin syndrome (see section "Special precautions for use").

Medicinal products that lower the seizure threshold. SSRIs may lower the seizure threshold. Caution is recommended when co-administering agents capable of lowering the seizure threshold (e.g., antidepressants (tricyclics, SSRIs), neuroleptics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion, and tramadol).

Lithium, tryptophan. Cases of enhanced effects have been reported with concomitant use of SSRIs and lithium or tryptophan. Therefore, co-administration of these agents with escitalopram should be done cautiously.

St. John’s wort. Concomitant use of SSRIs and herbal preparations containing St. John’s wort (Hypericum perforatum) may lead to an increased frequency of adverse reactions (see section "Special precautions for use").

Anticoagulants. The effects of anticoagulants may be altered when used concomitantly with escitalopram. In patients taking oral anticoagulants, careful monitoring of the coagulation system is required before and after initiating escitalopram. Concomitant use of nonsteroidal anti-inflammatory drugs may increase the risk of bleeding (see section "Special precautions for use").

Alcohol. Escitalopram does not exhibit pharmacodynamic or pharmacokinetic interactions with alcohol. However, as with other psychotropic medicinal products, combination with alcohol is not recommended.

Medicinal products causing hypokalemia/hypomagnesemia. Caution is required when using medicinal products that may cause hypokalemia/hypomagnesemia concomitantly, as this increases the risk of developing malignant arrhythmias (see section "Special precautions for use").

Pharmacokinetic interactions

Effect of other agents on escitalopram pharmacokinetics. Escitalopram is primarily metabolized via CYP2C19. Enzymes CYP3A4 and CYP2D6 may also play a minor role in its metabolism. The enzyme CYP2D6 is considered a partial catalyst in the metabolism of the main metabolite S-DCT (demethylated escitalopram).

Concomitant administration of escitalopram and omeprazole 30 mg once daily (a CYP2C19 inhibitor) results in a moderate (approximately 50%) increase in escitalopram plasma concentration.

Concomitant administration of escitalopram and cimetidine 400 mg twice daily (a moderately potent non-specific enzyme inhibitor) causes a moderate (approximately 70%) increase in escitalopram plasma concentration. Caution should be exercised when combining escitalopram with cimetidine. Dose adjustment may be necessary. Therefore, escitalopram should be used cautiously when administered concomitantly with CYP2C19 inhibitors (e.g., omeprazole, esomeprazole, fluconazole, fluvoxamine, lansoprazole, ticlopidine) or with cimetidine. Dose reduction of escitalopram may be required depending on clinical assessment (see section "Special precautions for use").

Effect of escitalopram on the pharmacokinetics of other medicinal products. Escitalopram is an inhibitor of the CYP2D6 enzyme. Caution is required when prescribing escitalopram concomitantly with drugs primarily metabolized by this enzyme and having a narrow therapeutic index, such as flecainide, propafenone, and metoprolol (used in heart failure), or with certain CNS-acting drugs mainly metabolized by CYP2D6, such as antidepressants (e.g., desipramine, clomipramine, nortriptyline) and antipsychotics (e.g., risperidone, thioridazine, haloperidol). Dose adjustment may be necessary. Combination with desipramine or metoprolol resulted in a doubling of plasma levels of these two CYP2D6 substrates. In vitro studies have demonstrated that escitalopram may also cause minor inhibition of CYP2C19. Caution is recommended when using escitalopram concomitantly with medicinal products metabolized by CYP2C19.

Special precautions for use.

The special precautions listed below apply to the therapeutic class of SSRIs.

Children. The medicinal product should not be administered to children. In clinical trials, a higher incidence of suicidal behaviour (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and irritability) was observed in children treated with antidepressants compared to those receiving placebo. If clinical necessity requires initiation of such treatment, careful monitoring of the patient is essential to detect suicidal symptoms promptly. Furthermore, there is a lack of data on the long-term safety in children regarding growth, sexual maturation, and cognitive and behavioural development.

Paradoxical anxiety. In some patients with panic disorders, increased anxiety may occur at the beginning of treatment with antidepressants. This paradoxical reaction usually resolves within two weeks of treatment. To reduce the likelihood of an anxiogenic effect, a low initial dose is recommended (see section "Dosage and administration").

Seizures. The drug should be discontinued if a patient experiences a first seizure or an increase in seizure frequency (in patients with a prior diagnosis of epilepsy). SSRIs should be avoided in patients with unstable epilepsy, and careful monitoring is required in patients with controlled epilepsy.

Mania. SSRIs should be used with caution in patients with a history of mania/hypomania. If a manic episode occurs, SSRIs should be discontinued.

Diabetes mellitus. In patients with diabetes mellitus, treatment with SSRIs may affect glycaemic control (hypoglycaemia or hyperglycaemia). The dose of insulin and/or oral hypoglycaemic agents may require adjustment.

Suicide/suicidal thoughts or worsening of clinical condition. Depression is associated with a risk of suicidal ideation, self-harm and suicide. This risk persists until a sustained remission is achieved. Since improvement may not occur during the first few weeks of treatment or longer, patients should be closely monitored until their condition improves. It is known that the risk of suicide may increase in the early stages of recovery. Other psychiatric disorders for which escitalopram is used may also be associated with an increased risk of suicidal behaviour. In addition, these conditions may be comorbid with major depressive disorder. These warnings also apply to the treatment of patients with other psychiatric disorders.

Patients with a history of suicidal behaviour prior to treatment initiation are at the highest risk of suicidal thoughts or attempts and require close monitoring throughout treatment. A meta-analysis of clinical trials revealed an increased risk of suicidal behaviour in patients under 25 years of age treated with antidepressants compared to those receiving placebo. Close monitoring of high-risk patients is particularly necessary at the beginning of treatment and when the dose is changed.

Patients and their caregivers should be informed about the need to monitor for any worsening of symptoms, suicidal behaviour or thoughts, and unusual changes in behaviour, and to seek immediate medical advice if such symptoms develop.

Akathisia/psychomotor agitation. The use of SSRIs/SSRI-NDRI combinations is associated with the development of akathisia – a condition characterised by a distressing and unpleasant feeling of restlessness and a need to move, often accompanied by an inability to sit or stand still. This condition is most likely to occur during the first few weeks of treatment. Dose escalation may be harmful in patients who develop such symptoms.

Hyponatraemia. Hyponatraemia, possibly related to impaired secretion of antidiuretic hormone, occurs rarely during SSRI treatment and usually resolves upon discontinuation of therapy. SSRIs should be used with caution in patients at risk (elderly patients, patients with liver cirrhosis, or those receiving concomitant treatment with drugs that may cause hyponatraemia).

Bleeding. Skin haemorrhages, ecchymoses and purpura may occur during SSRI treatment. SSRIs/SSRI-NDRI combinations may increase the risk of postpartum haemorrhage (see sections "Use during pregnancy or breastfeeding", "Adverse reactions"). SSRIs should be used with caution in patients receiving concomitant treatment with oral anticoagulants, drugs affecting platelet function (e.g. atypical antipsychotics, phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and non-steroidal anti-inflammatory drugs, ticlopidine and dipyridamole), and in patients with a known predisposition to bleeding.

Electroconvulsive therapy (ECT). Clinical experience with the concomitant use of SSRIs and ECT is limited; therefore, caution is recommended.

Serotonin syndrome. Caution is required when escitalopram is used concomitantly with serotonergic agents, such as triptans (including sumatriptan), opioids (including tramadol) and tryptophan.

Serotonin syndrome has been reported in isolated cases in patients taking SSRIs concomitantly with serotonergic medicinal products. The combination of symptoms such as agitation, tremor, myoclonus and hyperthermia may indicate the development of this condition. In such cases, SSRIs and the serotonergic medicinal product should be discontinued immediately, and symptomatic treatment should be initiated.

St. John’s wort. Concomitant use of SSRIs and herbal preparations containing St. John’s wort (Hypericum perforatum) may lead to an increased frequency of adverse reactions (see section "Interaction with other medicinal products and other forms of interaction").

Withdrawal symptoms observed upon discontinuation of treatment. Withdrawal symptoms upon discontinuation of treatment, particularly abrupt discontinuation, are common (see section "Adverse reactions"). In clinical trials, adverse reactions associated with discontinuation were observed in approximately 25% of patients in the escitalopram group and in 15% of patients in the placebo group. The risk of withdrawal symptoms depends on several factors, including duration and dose of treatment, and the gradualness of dose reduction. Dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, vomiting and/or nausea, tremor, confusion, increased sweating, headache, diarrhoea, tachycardia, emotional instability, irritability and visual disturbances are the most commonly reported reactions. These symptoms are usually mild to moderate in severity, but may be severe in some patients. They typically occur within the first few days after discontinuation of treatment, although very rarely, such symptoms have been reported after missing just a single dose. These symptoms are usually transient and resolve within 2 weeks, but in some individuals may be more prolonged (2–3 months or longer). In such cases, it is recommended to discontinue escitalopram gradually by tapering the dose over several weeks to several months, depending on the patient's condition.

Sexual dysfunction. SSRIs/SSRI-NDRI combinations may cause symptoms of sexual dysfunction (see section "Adverse reactions"). There have been reports of persistent sexual dysfunction, where symptoms continued despite discontinuation of SSRIs/SSRI-NDRI.

Ischaemic heart disease. Due to limited clinical experience, caution is recommended when using the drug in patients with ischaemic heart disease.

QT interval prolongation. Escitalopram has been shown to cause dose-dependent prolongation of the QT interval. Cases of QT interval prolongation and ventricular arrhythmias, including torsade de pointes, have been reported, primarily in women, patients with hypokalaemia or pre-existing QT prolongation, or those with other cardiac diseases. The drug should be used with caution in patients with marked bradycardia, patients with recent acute myocardial infarction, or those with decompensated heart failure. Electrolyte imbalances such as hypokalaemia and hypomagnesaemia increase the risk of developing malignant arrhythmias and should be corrected prior to initiating escitalopram treatment. In patients with stable cardiac disease, a thorough assessment of ECG parameters should be performed before initiating escitalopram treatment. If cardiac arrhythmias occur during treatment with escitalopram, treatment should be discontinued and an ECG performed.

Closed-angle glaucoma. SSRIs, including escitalopram, may affect pupil size, leading to mydriasis. This mydriatic effect may potentially narrow the angle of the eye, resulting in increased intraocular pressure and closed-angle glaucoma, particularly in predisposed patients. Therefore, escitalopram should be used with caution in patients with closed-angle glaucoma or a history of glaucoma.

Medopram® contains lactose. Patients with rare hereditary conditions such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Special warnings regarding excipients. One tablet of Medopram® contains less than 1 mmol (23 mg) of sodium, i.e. the preparation can be considered essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. Clinical data on the use of escitalopram in pregnant women are limited.

Animal studies have shown reproductive toxicity. Escitalopram is contraindicated during pregnancy, except in cases where a careful evaluation of risks and benefits has clearly demonstrated the necessity of treatment. Close monitoring of newborns whose mothers received escitalopram during pregnancy, particularly in the third trimester, is recommended. Abrupt discontinuation of the drug during pregnancy should be avoided. Newborns whose mothers received SSRIs/SSRI-NDRI in late pregnancy may develop symptoms such as respiratory distress, cyanosis, apnoea, seizures, temperature fluctuations, feeding difficulties, vomiting, hypoglycaemia, hypertension, hypotonia, hyperreflexia, tremor, nervous agitation, irritability, apathy, persistent crying, somnolence and sleep disturbances. These symptoms may be due to serotonergic effects or may represent withdrawal symptoms. In most cases, such complications occur immediately or shortly (within 24 hours) after delivery. Epidemiological data have shown that the use of SSRIs during pregnancy may increase the risk of persistent pulmonary hypertension in newborns (up to 5 cases per 1000 pregnancies, according to observational data). In the general population, the rate is 1–2 cases per 1000 pregnancies.

Period of breastfeeding. Escitalopram is expected to pass into breast milk; therefore, breastfeeding is not recommended during treatment.

Fertility. Animal studies have shown that escitalopram may affect sperm quality. Reports on the use of certain SSRIs in humans have indicated that the effect on sperm quality is reversible. No effect on human fertility has been observed to date.

Ability to influence reaction speed when driving or operating machinery.

Generally, escitalopram does not affect intellectual performance or psychomotor functions, but it should be considered that, as a psychotropic medicinal product, it may affect decision-making and abilities. Patients should be warned about the potential risk of impaired ability to drive a vehicle or operate machinery.

Dosage and Administration.

The safety of doses higher than 20 mg per day has not been established.

Medopram is administered orally once daily, independent of food intake.

Major Depressive Episode. The usual dose is 10 mg once daily. Depending on individual patient sensitivity, the daily dose may be increased up to the maximum of 20 mg.

Antidepressant effect usually occurs within 2–4 weeks. After symptom remission, treatment should be continued for at least 6 months to consolidate the therapeutic effect.

Panic Disorders with or without Agoraphobia. A starting dose of 5 mg per day is recommended during the first week, prior to increasing to 10 mg per day. Thereafter, the dose may be increased up to the maximum of 20 mg per day, depending on individual patient sensitivity.

Maximum efficacy in treating panic disorders is achieved within 3 months. The duration of treatment is several months and depends on disease severity.

Social Anxiety Disorder (Social Phobia). The usual dose is 10 mg once daily.

Typically, 2–4 weeks of therapy are required to alleviate symptoms. Thereafter, depending on individual patient response, the dose may be reduced to 5 mg or increased up to the maximum of 20 mg per day. Social anxiety disorder is a chronic condition, and treatment should be continued for at least 12 weeks to consolidate therapeutic effect. Long-term treatment for up to 6 months has been shown to prevent relapse and may be prescribed individually based on patient response; therapeutic benefit should be regularly evaluated.

Social anxiety disorder is a clearly defined diagnostic term for a specific disorder and should not be confused with excessive shyness. Pharmacotherapy is indicated only when this disorder significantly impairs professional functioning and social activity. The efficacy of pharmacotherapy compared to cognitive-behavioral therapy has not been evaluated. Pharmacotherapy should be part of a comprehensive treatment strategy.

Generalized Anxiety Disorder. The usual dose is 10 mg once daily. Depending on individual sensitivity, the dose may be increased up to a maximum of 20 mg per day.

Long-term treatment has been studied for at least 6 months in patients receiving a 20 mg daily dose; treatment benefits should be regularly assessed (see section "Pharmacodynamics").

Obsessive-Compulsive Disorder (OCD). The usual initial dose is 10 mg once daily. Depending on individual sensitivity, the dose may be increased up to 20 mg per day. OCD is a chronic disorder, and treatment should continue for a sufficient duration to ensure complete symptom remission, which may take several months or longer. Treatment benefit and dosage should be regularly evaluated at defined intervals.

Elderly Patients (aged 65 years and older). The initial dose is 5 mg per day. Depending on individual sensitivity and severity of depression, the daily dose may be increased up to a maximum of 10 mg per day. The efficacy of escitalopram in social anxiety disorder has not been studied in elderly patients.

Pediatric Population. Escitalopram should not be used for the treatment of children and adolescents (under 18 years of age) (see section "Special Warnings and Precautions for Use").

Patients with Renal Impairment. Dose adjustment is not required in patients with mild to moderate renal impairment. The drug should be used with caution in patients with severe renal impairment (Clcr <30 mL/min).

Patients with Hepatic Impairment. The recommended initial dose for the first two weeks of treatment is 5 mg per day in patients with mild to moderate hepatic insufficiency. Depending on individual patient response, the dose may be increased to 10 mg per day. The drug should be used with caution and carefully titrated in patients with severe hepatic insufficiency.

Poor CYP2C19 Metabolizers. For patients known to be poor metabolizers of the CYP2C19 enzyme, the recommended initial dose for the first two weeks of treatment is 5 mg per day. Depending on individual patient response, the dose may be increased to 10 mg per day.

Discontinuation Symptoms Observed upon Treatment Cessation. Abrupt discontinuation of the drug should be avoided. When stopping treatment with escitalopram, the dose should be gradually reduced over at least 1–2 weeks to minimize the risk of discontinuation symptoms (see sections "Special Warnings and Precautions for Use" and "Adverse Reactions"). If intolerable symptoms occur after dose reduction or discontinuation, consideration should be given to reinstating the previously prescribed dose. Thereafter, the physician may continue dose reduction, but more gradually.

Children. Antidepressants should not be used for the treatment of children and adolescents (under 18 years of age). Suicidal behavior (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behavior, and anger) have been observed more frequently in clinical trials among children and adolescents treated with antidepressants compared to those receiving placebo. If a clinical decision to prescribe is made, careful monitoring for the emergence of suicidal symptoms is essential.

Children. Medopram® should not be used for the treatment of children (under 18 years of age).

Overdose.

Toxicity. Clinical data on escitalopram overdose are limited, and in many cases, co-ingestion of other drugs was involved. In most cases, overdose symptoms were mild or absent. Reports of fatal outcomes following escitalopram overdose are rare and mostly involved concomitant overdose with other medicinal products. Doses of escitalopram ranging from 400–800 mg have not caused severe symptoms.

Symptoms. Signs of escitalopram overdose are primarily related to the central nervous system (from dizziness, tremor, and agitation to rare cases of serotonin syndrome, seizures, and coma), gastrointestinal tract (nausea, vomiting), cardiovascular system (hypotension, tachycardia, QT interval prolongation, arrhythmias), and fluid/electrolyte imbalances (hypokalemia, hyponatremia).

Treatment. There is no specific antidote. Maintain adequate respiratory function and ensure proper oxygenation. Gastric lavage and activated charcoal may be considered. Continuous monitoring of cardiac and vital functions, along with symptomatic and supportive treatment, is recommended. ECG monitoring is advised in cases of overdose for patients with congestive heart failure/bradyarrhythmias, patients concurrently taking drugs that prolong the QT interval, and patients with impaired drug metabolism, such as those with hepatic insufficiency.

Side effects

Adverse reactions most commonly occur during the first or second week of treatment and usually decrease in frequency and intensity with continued treatment. The adverse reactions known for SSRIs and escitalopram, observed during placebo-controlled clinical trials and in post-marketing experience, are listed below by system organ class and frequency: 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 the available data).

Blood and lymphatic system disorders: frequency not known – thrombocytopenia.

Immune system disorders: rare – anaphylactic reactions.

Endocrine disorders: frequency not known – disturbance in antidiuretic hormone secretion.

Nutrition and metabolism disorders: common – decreased or increased appetite, weight gain; uncommon – weight loss; frequency not known – hyponatremia, anorexia¹.

Psychiatric disorders: common – anxiety, restlessness, abnormal dreams, decreased libido, anorgasmia (in women); uncommon – bruxism, agitation, nervousness, panic attacks, confusion; rare – aggression, depersonalization, hallucinations; frequency not known – suicidal thoughts and suicidal behavior², mania.

Nervous system disorders: very common – headache; common – insomnia, somnolence, dizziness, paraesthesia, tremor; uncommon – taste disturbance, sleep disorders, loss of consciousness; rare – serotonin syndrome; frequency not known – dyskinesia, movement disorders, convulsions, psychomotor restlessness/akathisia¹.

Eye disorders: uncommon – pupil dilation, blurred vision.

Ear and labyrinth disorders: uncommon – tinnitus.

Cardiac disorders: uncommon – tachycardia; rare – bradycardia; frequency not known – QT interval prolongation on electrocardiogram, ventricular arrhythmia including torsade de pointes.

Vascular disorders: frequency not known – orthostatic hypotension.

Respiratory system disorders: common – sinusitis, yawning; uncommon – epistaxis.

Gastrointestinal disorders: very common – nausea; common – diarrhea, constipation, vomiting, dry mouth; uncommon – gastrointestinal hemorrhage (including rectal bleeding).

Hepatobiliary disorders: frequency not known – hepatitis, changes in liver function tests.

Skin and subcutaneous tissue disorders: common – increased sweating; uncommon – urticaria, rash, alopecia, pruritus; frequency not known – edema, bruising.

Musculoskeletal and connective tissue disorders: common – arthralgia, myalgia.

Renal and urinary disorders: frequency not known – urinary retention.

Reproductive system and breast disorders: common – ejaculation disorders, impotence (in men); uncommon – metrorrhagia, menorrhagia (in women); frequency not known – galactorrhea, priapism (in men), postpartum hemorrhage³.

General disorders: common – fatigue, pyrexia; uncommon – edema.

1 These cases are known for the entire SSRI class of drugs.

2 Cases of suicidal thoughts and behavior have been reported during treatment with escitalopram or shortly after discontinuation.

3 Such cases have been reported for the therapeutic class of SSRIs or SNRIs (see sections "Special precautions" and "Use during pregnancy or breastfeeding").

QT interval prolongation. Cases of QT interval prolongation and ventricular arrhythmia, including torsade de pointes, have been reported during the post-marketing period, primarily in female patients with hypokalemia, pre-existing QT prolongation, or other cardiac diseases.

Class effects. Epidemiological studies, mainly conducted in patients aged 50 years and older, have shown an increased risk of bone fractures in patients taking SSRIs and tricyclic antidepressants. The mechanism leading to this risk is not yet known.

Withdrawal symptoms. Discontinuation of SSRIs/SNRIs, especially abrupt discontinuation, often leads to withdrawal symptoms. The most commonly reported reactions include: dizziness, sensory disturbances (paraesthesia, electric shock sensations), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, vomiting and/or nausea, tremor, confusion, increased sweating, headache, diarrhea, palpitations, emotional lability, irritability, and visual disturbances. In general, these symptoms are mild or moderate, but in some patients they may be severe and/or prolonged. Therefore, if continued treatment with escitalopram is not required, the drug should be discontinued gradually by tapering the dose.

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

Shelf life. 2 years.

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

Packaging. 10 tablets in a blister, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Medochemie Limited / Medochemie Limited.
2. Farmaceutisch Analytisch Laboratorium Duiven B.V. / Farmaceutisch Analytisch Laboratorium Duiven B.V.

Manufacturer's address and place of business.

1. Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus / Agios Athanassios Industrial Area, Michail Irakleous 2, Agios Athanassios, Limassol, 4101, Cyprus.
2. Dijkgraaf 30, Duiven, 6921 RL, Netherlands / Dijkgraaf 30, Duiven, 6921 RL, Netherlands.