Escitalopram is a selective serotonin reuptake inhibitor (SSRI) (5-HT) 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 binding to a number of receptors, including 5-HT1A, 5-HT2, dopamine D1 and D2 receptors, α1-, α2-, β-adrenergic receptors, histamine H1-, muscarinic cholinergic, benzodiazepine and opiate receptors.
Inhibition of 5-HT serotonin reuptake is only a possible mechanism of action that could 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 the Friederich formula) was 4.3 msec (90% confidence interval: 2.2, 6.4) at a dose of 10 mg/day and 10.7 msec (90% confidence interval: 8.6, 12.8) at a dose above the therapeutic dose of 30 mg/day (see sections 4.3, 4.4, 4.5, 4.8 and 4.8).
Clinical efficacy
Depression
Escitalopram has been shown to be effective in the acute treatment of depression in three of four double-blind, placebo-controlled, short-term (8-week) studies. In a long-term relapse prevention study, 274 patients who responded to treatment during an initial 8-week open-label treatment phase with escitalopram 10 or 20 mg/day were randomly assigned to continue escitalopram at the same dose or placebo for 36 weeks. In this study, patients who continued to take escitalopram had a significantly longer time to relapse at 36 weeks compared with those who took placebo.
Social anxiety disorder
Escitalopram was effective in three short-term (12-week) studies and in responders in a 6-month relapse prevention study in social anxiety disorder. A 24-week dose-finding study demonstrated efficacy of 5, 10, and 20 mg escitalopram.
In a 12-week randomized, double-blind clinical trial, the efficacy of 20 mg/day and placebo differed in terms of overall Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores. After 24 weeks, escitalopram 10 and 20 mg/day were superior to placebo.
Prevention of relapse was demonstrated for doses of 10 and 20 mg/day of escitalopram in patients who had responded to escitalopram in the 16-week open-label period and who entered a 24-week randomized double-blind, placebo-controlled period.
Pharmacokinetics.
Absorption
Absorption is almost complete and independent of food intake. The mean time to reach maximum concentration (mean Tmax) is 4 hours after multiple dosing. As with racemic citalopram, the absolute bioavailability of escitalopram is expected to be about 80%.
Distribution
The apparent volume of distribution (Vd,β/F) after oral administration is approximately 12-26 l/kg. The binding of escitalopram and its major metabolites to plasma proteins is less than 80%.
Metabolism
Escitalopram is metabolized in the liver to the demethylated and didemethylated metabolites. Both are pharmacologically active. Alternatively, nitrogen can also be oxidized to the N-oxide metabolite. Both metabolites and the parent compound are partly excreted as glucuronides. After multiple administration, the average concentration of the demethylated and didemethyl metabolites is usually 28-31% and . respectively.
Breeding
Escitalopram has linear kinetics. Steady-state plasma concentrations are reached in approximately 1 week. The mean steady-state concentration is 50 nmol/l (range 20 to 125 nmol/l) achieved with a daily dose of 10 mg.
Elderly patients (> 65 years)
Escitalopram appears to be eliminated more slowly in elderly patients than in younger patients. Systemic exposure (AUC) in elderly patients is 50% higher than in young healthy volunteers (see section 4.2).
Decreased liver function
In patients with mild or moderate hepatic impairment (Child-Pugh A and B criteria), the half-life of escitalopram was almost doubled and the AUC was 60% higher than in subjects with normal hepatic function (see section 4.2).
Reduced kidney function
In patients with reduced renal function (creatinine clearance (CLcr) 10-53 ml/min), an increase in the half-life of racemic citalopram and a slight increase in AUC were observed. The concentration of metabolites in the blood plasma has not been studied, but it can be assumed that it is increased (see section "Method of administration and dosage").
Polymorphism
Insufficient activity of the CYP2C19 isoenzyme resulted in double the plasma concentrations of the drug compared to normal metabolism of escitalopram. Insufficient activity of the CYP2D6 isoenzyme resulted in no significant changes in AUC (see section "Method of administration and dosage").
Indication
· Treatment of major depressive episodes.
· Treatment of panic disorder with or without agoraphobia.
· Treatment of social anxiety disorder (social phobia).
· Treatment of obsessive-compulsive disorder.
· Treatment of generalized anxiety disorders.
Contraindication
Hypersensitivity to escitalopram or to any other ingredient of the drug.
Concomitant treatment with non-selective irreversible monoamine oxidase inhibitors (MAO inhibitors) due to the risk of serotonin syndrome with agitation, tremor, hyperthermia, etc. (see section "Interaction with other medicinal products and other types of interactions").
The combination of escitalopram with irreversible MAO-A inhibitors (e.g. moclobemide) or the reversible non-selective MAO inhibitor linezolid due to the risk of serotonin syndrome (see section "Interaction with other medicinal products and other types of interactions").
Escitalopram administration to patients with known prolongation of the QT interval or with congenital long QT syndrome.
Taking escitalopram with drugs known to increase the QT interval (see section "Interaction with other medicinal products and other types of interactions").
Interaction with other medicinal products and other types of interactions
Pharmacodynamic interactions
Contraindicated combinations
Irreversible non-selective MAO inhibitors
Serious reactions have been reported in patients receiving SSRIs in combination with non-selective, irreversible MAOIs and in patients who have recently discontinued SSRIs and switched to MAO inhibitors (see section 4.3). Serotonin syndrome has occasionally been reported (see section 4.8).
Concomitant use of escitalopram with non-selective irreversible MAO inhibitors is contraindicated. Treatment with escitalopram can only be started 14 days after the last use of irreversible MAO inhibitors. Treatment with non-selective irreversible MAO inhibitors can only be started 7 days after the end of treatment with escitalopram.
Concomitant use of escitalopram with the MAO-A inhibitor moclobemide is contraindicated due to the risk of serotonin syndrome (see section 4.3). If the combination is considered necessary, the lowest recommended doses should be used initially under close medical supervision (see section 4.3).
Reversible, non-selective MAO inhibitor (linezolid)
Concomitant use of escitalopram with the antibiotic linezolid is contraindicated in patients taking escitalopram. If the combination is considered necessary, the lowest recommended doses should be used initially under close medical supervision (see section 4.3).
Due to the risk of serotonin syndrome, the combination of escitalopram with selegiline requires caution. For concomitant use with racemic citalopram, doses of selegiline up to 10 mg/day are safe.
QT interval prolongation
Pharmacokinetic and pharmacodynamic studies of escitalopram in combination with other drugs that increase the QT interval have not been conducted. A cumulative effect of escitalopram and these drugs cannot be excluded. Therefore, concomitant administration of escitalopram with drugs that increase the QT interval, such as class IA and III antiarrhythmics, neuroleptics (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobials (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, antimalarials, in particular halofantrine), certain antihistamines (astemizole, mizolastine) is contraindicated.
Combinations requiring caution when used
Concomitant use with serotonergic drugs (e.g. tramadol, sumatriptan and other triptans) may lead to serotonin syndrome.
Drugs that lower the seizure threshold
SSRIs can lower the seizure threshold. Caution is required when escitalopram is used concomitantly with other drugs that can lower this threshold, such as antidepressants (tricyclines, SSRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquine, bupropion and tramadol).
Lithium, tryptophan
There have been reports of enhanced effects when SSRIs are used in combination with lithium or tryptophan, so caution is recommended when co-prescribing SSRIs with these drugs.
Hypericum
Concomitant use of SSRIs and herbal preparations containing St. John's wort (Hypericum perforatum) may increase the frequency of adverse reactions (see section "Special warnings and precautions for use").
Anticoagulants
The effects of anticoagulants may be altered by concomitant use with escitalopram. Patients taking oral anticoagulants should be carefully monitored for coagulation before and after use of escitalopram.
Concomitant use of nonsteroidal anti-inflammatory drugs may increase the tendency to bleed (see section "Special warnings and precautions for use")
Alcohol
Escitalopram is not expected to have any pharmacodynamic or pharmacokinetic interactions with alcohol. However, as with other psychotropic drugs, concomitant use of escitalopram and alcohol is not recommended.
Pharmacokinetic interactions
Effect of other medicinal products on the pharmacokinetics of escitalopram
The metabolism of escitalopram is mainly mediated by CYP2C19. CYP3A4 and CYP2D6 may also be involved, although to a lesser extent. The enzyme CYP2D6 is thought to be a partial catalyst for the metabolism of the main metabolite S-DCT (demethylated escitalopram).
Concomitant use of escitalopram and omeprazole 30 mg once daily (CYP2C19 inhibitor) causes a moderate increase (approximately 50%) in escitalopram plasma concentrations.
Concomitant use of escitalopram and cimetidine 400 mg twice daily (a moderately potent general enzyme inhibitor) results in a modest increase (approximately 70%) in escitalopram plasma concentrations. Escitalopram should be used with caution in combination with cimetidine. Dose adjustment may be necessary.
Therefore, caution should be exercised when escitalopram is co-administered with CYP2C19 inhibitors (e.g. omeprazole, esomeprazole, fluvoxamine, lansoprazole, ticlopidine) or cimetidine. Monitoring for adverse effects may require a reduction in the escitalopram dose.
Effect of escitalopram on the pharmacokinetics of other drugs
Escitalopram is an inhibitor of the CYP2D6 enzyme. Caution should be exercised when escitalopram is administered concomitantly with drugs metabolised by this enzyme, as well as with drugs with a narrow therapeutic index, such as flecainide, propafenone and metoprolol (used in heart failure), or with some CNS-active drugs metabolised primarily by CYP2D6, such as the antidepressants desipramine, clomipramine and nortriptyline; and the antipsychotics risperidone, thioridazine and haloperidol. Dose adjustment may be necessary.
Concomitant use with desipramine or metoprolol results in a twofold increase in plasma levels of these two CYP2D6 substrates.
In vitro studies have shown that escitalopram may also cause weak inhibition of CYP2C19. Therefore, caution is recommended when co-administering medicinal products metabolised by CYP2C19.
Application features
The specifics of use apply to all SSRIs.
Children
Elicea should not be prescribed to children (under 18 years of age). In clinical trials, a higher incidence of suicidal behavior (suicide attempts and thoughts), hostility (predominantly aggression, confrontational tendencies and irritability) was observed among children treated with antidepressants compared to those who took placebo. If the clinical situation still requires the appointment of such treatment, the patient should be carefully monitored for the timely detection of suicidal symptoms. In addition, there are no data on the subsequent safety in children with regard to growth, puberty and cognitive and behavioral development.
Paradoxical anxiety
Some patients with panic disorder may experience an increase in anxiety symptoms when starting antidepressant treatment. This paradoxical reaction usually resolves within the first two weeks of treatment. To reduce the likelihood of anxiogenic effects, it is recommended to prescribe low initial doses (see section "Dosage and administration").
Convulsions
Escitalopram should be discontinued if the patient develops seizures for the first time or if there is an increase in their frequency (in patients with a previous diagnosis of epilepsy). SSRIs are not recommended for patients with unstable epilepsy, and patients with controlled epilepsy require close monitoring.
SSRIs should be used with caution in patients with a history of mania/hypomania. SSRIs should be discontinued if the patient develops a manic phase.
Diabetes mellitus
In patients with diabetes mellitus, treatment with SSRIs may affect glycemic control (hypoglycemia or hyperglycemia). Dosage adjustments of insulin and/or oral hypoglycemic agents may be required.
Suicide/suicidal thoughts or clinical worsening
Depression is associated with a risk of suicidal thoughts, self-harm and suicide. This risk persists until sustained remission is achieved. As improvement may not occur within the first few weeks of treatment or longer, patients should be closely monitored until improvement occurs. There is clinical evidence that the risk of suicide may be increased 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. Patients should be closely monitored during treatment with other psychiatric disorders due to the possibility of concomitant depression.
Because of the high risk of suicidal thoughts and actions during treatment, patients with a history of such conditions or with a significant level of suicidal ideation before starting treatment should be carefully monitored. A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressants compared with placebo in patients under 25 years of age. Drug therapy should be accompanied by careful monitoring of patients, especially those at increased risk, particularly at the beginning of treatment and after dose changes.
Patients and caregivers should be alerted to the need to monitor for any clinical worsening, suicidal behaviour or thoughts, and unusual changes in behaviour. The need to seek emergency medical attention should these symptoms occur should be emphasized.
Akathisia/psychomotor agitation
The use of SSRIs/serotonin norepinephrine reuptake inhibitors (SNRIs) has been associated with the development of akathisia, characterised by a subjectively unpleasant or distressing restlessness and need to move, often accompanied by an inability to sit or stand still. This is most often observed in the first weeks of treatment. In patients who experience these symptoms, an increase in dose may be harmful.
Hyponatremia
Isolated cases of hyponatremia, probably caused by inappropriate antidiuretic hormone secretion, have been reported with SSRIs, which usually resolved upon discontinuation of treatment. The drug should be used with caution in patients at risk, such as the elderly, patients with cirrhosis of the liver, or patients taking concomitant medications that may cause hyponatremia.
Hemorrhages
Cutaneous hemorrhages such as ecchymosis and purpura have been reported with SSRIs. Therefore, caution should be exercised when treating patients with bleeding tendencies, especially when concomitantly taking oral anticoagulants, medicinal products known to affect platelet function (e.g. atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, ticlopidine, dipyridamole).
Electroconvulsive therapy (ECT)
There is currently only limited clinical experience with the combination of SSRIs with ECT, so caution is recommended.
Serotonin syndrome
Caution is required when using escitalopram in combination with drugs that have serotonergic effects, such as sumatriptan and other triptans, tramadol and tryptophan.
Serotonin syndrome has been reported in isolated cases in patients receiving SSRIs in combination with serotonergic medicinal products. This condition may be characterised by a combination of symptoms such as agitation, tremor, myoclonus and hyperthermia. In such cases, the SSRI and the serotonergic medicinal product should be discontinued immediately and symptomatic treatment should be initiated.
Hypericum
Concomitant use of SSRIs and herbal preparations containing St. John's wort (Hypericum perforatum) may increase the frequency of adverse reactions (see section "Interaction with other medicinal products and other types of interactions").
Withdrawal symptoms observed upon discontinuation of treatment
The risk of withdrawal symptoms depends on many factors, including the duration and dose of therapy and the gradualness of dose reduction. The most commonly reported adverse reactions are: dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and restless dreams), agitation or anxiety, vomiting and/or nausea, tremor, confusion, increased sweating, headache, diarrhoea, palpitations, emotional lability, irritability and visual disturbances. These symptoms are generally mild to moderate, but in some patients they may be more severe. Symptoms usually occur within the first few days after discontinuation of treatment, although very rarely such symptoms have been reported after accidentally missing only one dose.
These symptoms are usually short-lived and resolve within 2 weeks, but in some individuals they may persist for 2-3 months or more. In this case, it is recommended to discontinue escitalopram by gradually reducing the dose over a period of several weeks to several months, depending on the patient's condition.
Coronary heart disease (CHD)
Due to limited clinical experience, caution is required when treating patients with coronary artery disease.
QT prolongation
Escitalopram has been shown to cause a dose-dependent increase in the QT interval. Cases of QT prolongation and ventricular arrhythmias, including torsade de pointes, have been reported mainly in female patients with hypokalaemia or pre-existing QT prolongation or other cardiac disease. Caution should be exercised in patients with significant bradycardia, patients with recent acute myocardial infarction and those with decompensated heart failure.
Electrolyte imbalances, such as hypokalemia and hypomagnesemia, increase the risk of malignant arrhythmias and should be corrected before starting treatment with escitalopram.
Before starting treatment, patients with heart disease should have an ECG. If cardiac arrhythmias occur during treatment with escitalopram, treatment should be discontinued and an ECG should be performed.
Special precautions for excipients
Elicea contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy or breastfeeding
Pregnancy
Clinical data on the use of escitalopram during pregnancy are limited. In reproductive toxicity studies conducted with escitalopram in rats, embryo-fetal toxic effects were observed, but there was no increase in the incidence of anomalies. Elicea should be used during pregnancy only if clearly indicated and only after a careful assessment of the risk-benefit ratio.
Newborns whose mothers used Elicea in late pregnancy, especially in the third trimester, should be observed. Abrupt discontinuation of the drug during pregnancy should be avoided. Respiratory distress syndrome, cyanosis, apnea, convulsions, temperature instability, difficulty sucking, vomiting, hypoglycemia, hypertension, hypotension, hyperreflexia, tremor, nervous excitement, irritability, drowsiness, constant crying, lethargy, and difficulty falling asleep have been reported in newborns whose mothers used SSRIs/NSAIDs in late pregnancy. These disorders may be a manifestation of serotonergic effects or withdrawal syndrome. In most cases, complications began immediately or after a short time (
Epidemiological data have shown that the use of SSRIs during pregnancy, especially in late pregnancy, may increase the risk of persistent pulmonary hypertension of the newborn (PPHN). The observed risk is approximately 5 cases per 1000 pregnancies. The incidence of PPHN in the general population is 1-2 cases per 1000 pregnancies.
Breastfeeding period
It is assumed that escitalopram passes into breast milk, therefore it is recommended to stop breastfeeding during treatment.
Fertility
Animal data have shown that citalopram may affect sperm quality. Human cases with some SSRIs have shown that the effects on sperm quality are reversible.
No other effects on fertility were observed.
Ability to influence reaction speed when driving vehicles or other mechanisms
Escitalopram does not generally affect intellectual or psychomotor functioning, but it should be borne in mind that as a psychotropic drug it may affect decision-making and abilities. Patients should be warned of the potential risk of affecting the ability to drive and use machines.
Method of administration and doses
The safety of doses above 20 mg per day has not been established.
Elicia is used once a day, regardless of meals.
Major depressive episode.
The effect usually develops 2-4 weeks after the start of treatment. After the symptoms disappear, treatment should be continued for at least 6 months to consolidate the achieved effect.
Panic disorder with or without agoraphobia
The recommended dose is 5 mg in the first week of treatment, which is then increased to 10 mg/day. Depending on the individual patient's response, the dose can be further increased to a maximum of 20 mg/day.
Maximum effectiveness is achieved within approximately 3 months. Therapy lasts for several months and depends on the severity of the disease.
Social anxiety disorder (social phobia)
The usual dose is 10 mg once daily. Relief of symptoms usually occurs within 2-4 weeks. Depending on the individual patient's response, the dose may be further reduced to 5 mg or increased to a maximum of 20 mg/day.
Since social anxiety disorder is a chronic condition, the recommended duration of treatment is 12 weeks to maintain the effect achieved. Long-term use in patients who have responded to treatment has been studied for 6 months and may be prescribed, depending on the individual response of the patients, to prevent relapses. The therapeutic benefit of treatment should be regularly reviewed.
Social anxiety disorder has a well-defined diagnostic terminology for a specific condition, which should not be confused with hypertrophic shyness. Pharmacotherapy is indicated only for a disorder that significantly affects a person's professional and social activities.
The effectiveness of this treatment compared to cognitive behavioral therapy has not been evaluated. Pharmacotherapy should be part of an overall therapeutic strategy.
Generalized anxiety disorders
The usual dose is 10 mg once daily. Depending on individual sensitivity, the dose may be increased to a maximum of 20 mg/day.
It is recommended to continue treatment for 3 months to consolidate the effect. Long-term treatment for 6 months has been shown to prevent relapse and can be prescribed individually; the benefits of treatment should be regularly assessed.
Obsessive-compulsive disorder
The initial dose is 10 mg once daily. Depending on the individual patient's response, the dose may be increased to a maximum of 20 mg/day.
Because obsessive-compulsive disorder is a chronic condition, patients should be treated for a sufficient period to ensure resolution of symptoms. The therapeutic benefit of treatment and dosage should be reviewed regularly.
Elderly patients (over 65 years of age)
The initial dose is 5 mg once daily. Depending on the individual patient's response, the dose may be further increased to 10 mg/day.
The efficacy of escitalopram in social anxiety disorder has not been studied in elderly patients.
Patients with renal impairment
No dose adjustment is required in patients with moderate to mild renal impairment. Caution should be exercised in patients with severe renal impairment (CLcr less than 30 mL/min).
Patients with liver dysfunction
For patients with moderate and mild hepatic impairment, the recommended initial dose in the first two weeks is 5 mg/day. Depending on the individual patient response, the dose may be increased to 10 mg/day. In severe hepatic impairment, caution and careful dose titration are required.
Weak CYP2C19 activity
For patients with known low CYP2C19 enzyme activity, the recommended starting dose in the first two weeks is 5 mg/day.
Depending on the individual patient response, the dose may be further increased to 10 mg/day.
Withdrawal symptoms observed upon discontinuation of treatment
Abrupt discontinuation of this drug should be avoided. When discontinuing treatment, the dose of escitalopram should be gradually reduced at intervals of at least 1-2 weeks to prevent withdrawal reactions (see sections "Special instructions for use" and "Adverse reactions"). If intolerable symptoms occur during dose reduction or after discontinuation of treatment, the previously prescribed dose may be resumed. In the future, the doctor may continue to reduce the dose, but more gradually.
Children.
The drug Elitsia should not be used to treat children (under 18 years of age).
Overdose
Toxicity
Clinical data on overdose with escitalopram are limited, and in many cases overdoses with concomitant medications are available. In most cases symptoms were absent or mild. Fatalities have been reported rarely with overdose with escitalopram alone; most of these cases involved overdose with concomitant medications. Doses of escitalopram alone in the range of 400 to 800 mg did not cause severe symptoms.
Symptoms
Symptoms reported with escitalopram overdose generally involved the central nervous system (ranging from dizziness, tremor, agitation to rare cases of serotonin syndrome, convulsions and coma), the digestive system (nausea/vomiting), the cardiovascular system (hypotension, tachycardia, QT prolongation and arrhythmia), and electrolyte and fluid balance (hypokalaemia, hyponatraemia).
There is no specific antidote. Maintain and ensure a patent airway, respiratory function and adequate oxygenation. Gastric lavage and activated charcoal should be performed. Gastric lavage should be performed as soon as possible after oral administration. Continuous monitoring of cardiovascular function and vital signs is recommended in conjunction with general symptomatic supportive measures. ECG monitoring is recommended in case of overdose in patients with congestive heart failure/bradyarrhythmias, in patients taking concomitant medications that prolong the QT interval, or in patients with altered metabolism, e.g. due to impaired liver function.
Adverse reactions
Adverse reactions most often occur in the first and second weeks of treatment and subsequently become less intense, and their frequency decreases with continued treatment.
Adverse reactions common to all SSRIs and escitalopram, observed in placebo-controlled studies and in clinical use, are listed below by organ system and frequency.
The frequency of events is taken from clinical trials, not adjusted for placebo.
Frequency classification: very common (≥1/10), common (≥1/100 -
Organ system classes
Frequency
Side effect
Blood and lymphatic system disorders
Unknown
Thrombocytopenia
On the part of the immune system
Rarely
Anaphylactic reaction
From the endocrine system
Unknown
Disorder of antidiuretic hormone secretion
Metabolism and nutrition
Often
Decreased appetite, increased appetite, weight gain
