Each film-coated tablet contains: Escitalopram oxalate equivalent to escitalopram 10 mg.
Pharmacotherapeutic Group: Antidepressants, selective serotonin re-uptake inhibitors.
Pharmacology: Escitalopram is a selective inhibitor of serotonin (5-HT) re-uptake with high affinity for the primary binding site.
It also binds to an allosteric site on the serotonin transporter, with a 1000 fold lower affinity. Allosteric modulation of the serotonin transporter enhances binding of escitalopram to the primary binding site, resulting in more complete serotonin re-uptake inhibition. Escitalopram has no or low affinity for a number of receptors including 5-HT1A, 5-HT2, DA D1, and D2 receptors, α1, α2, β-adrenoceptors, histamine H1, muscarine cholinergic, benzodiazepine, and opioid receptors.
The inhibition of 5-HT re-uptake is the only likely mechanism of action explaining the pharmacological and clinical effects of escitalopram.
Escitalopram is the S-enantiomer of the racemate (citalopram) and is the enantiomer to which the therapeutic activity is attributed. Pharmacological studies have shown that the R-enantiomer is not inert but counteracts the serotonin-enhancing and consequent pharmacological properties of the S-enantiomer.
Pharmacokinetics: Absorption: Absorption is almost complete and independent of food intake. Mean time to maximum concentration (mean Tmax) is 4 hours after multiple dosing. As with racemic citalopram, the absolute bioavalability of escitalopram is expected to be about 80%.
Distribution: The apparent volume of distribution (Vdβ /F) after oral administration is about 12 to 26 l/kg. The plasma protein binding is below 80% for escitalopram and its main metabolites.
Biotransformation: Escitalopram is metabolized in the liver to the demethylated and didemethylated metabolites. Both of these are pharmacologically active. Alternatively, the nitrogen may be oxidized to form the N-oxide metabolite. Both parent substance and metabolites are partly excreted as glucoronides. After multiple dosing, the mean concentrations of the demethyl and didemethyl metabolites are usually 28-31% and <5% respectively, of the escitalopram concentration. Biotransformation of escitalopram to the demethylated metabolite is mediated primarily by CYP2C19. Some contribution by the enzymes CYP3A4 and CYP2D6 is possible.
Elimination: The elimination half-life (t½β) after multiple dosing is about 30 hours and the oral plasma clearance (Cloral) is about 0.6 l/minute. The major metabolites have a significantly longer half-life. Escitalopram and major metabolites are assumed to be eliminated by both the hepatic (metabolic) and the renal routes, with the major part of the dose excreted as metabolites in the urine.
There is linear pharmacokinetics. Steady-state plasma levels are achieved in about 1 week. Average steady-state concentrations of 50 nmol/l (range 20 to 125 nmol/l) are achieved at a daily dose of 10 mg.
Special populations: Elderly patients (>65 years): Escitalopram appears to be eliminated more slowly in elderly patients compared to younger. Systemic exposure (AUC) is about 50% higher in elderly compared to young healthy volunteers.
Reduced hepatic function: In patients with mild or moderate hepatic impairment (Child-Pugh criteria A and B), the half-life of escitalopram was about twice as long and the exposure was about 60% higher than in subjects with normal liver function.
Reduced renal function: With racemic citalopram, a longer half-life and a minor increase in exposure have been observed in patients with reduced renal function (Clcr 10-53 ml/minute). Plasma concentrations of the metabolites have not been studied, but they may be elevated.
Polymorphism: It has been observed that poor metabolizers with respect to CYP2C19 have twice as high a plasma concentration of escitalopram as extensive metabolizers. No significant change in exposure was observed in poor metabolizers with respect to CYP2D6.
Treatment of major depressive episodes.
Safety of daily doses above 20 mg has not been demonstrated.
Escitalopram is administered as a single daily dose and may be taken with or without food.
Major depressive episodes: Usual dosage is 10 mg once daily. Depending on individual patient response, the dose may be increased to a maximum of 20 mg daily.
Usually 2-4 weeks are necessary to obtain antidepressant response. After the symptoms resolve, treatment for at least 6 months is required for consolidation of the response.
Special populations: Elderly patients (>65 years of age): Initial treatment with half the usually recommended dose and a lower maximum dose should be considered.
Children and adolescents (<18 years): Escitalopram should not be used in the treatment of children and adolescents under the age of 18 years.
Reduced renal function: Dosage adjustment is not necessary in patients with mild or moderate renal impairment. Caution is advised in patients with severely reduced renal function (Clcr less than 30 ml/minute).
Reduced hepatic function: An initial dose of 5 mg daily for the first two weeks of treatment is recommended. Depending on individual patient response, the dose may be increased to 10 mg daily.
Caution and extra careful dose titration is advised in patients with severely reduced hepatic function.
Poor metabolizers of CYP2C19: For patients who are known to be poor metabolizers with respect to CYP2C19, an initial dose of 5 mg daily during the first two weeks of treatment is recommended. Depending on individual patient response, the dose may be increased to 10 mg daily.
Discontinuation symptoms: When stopping treatment with escitalopram, the dose should be gradually reduced over a period of at least one to two weeks in order to avoid possible discontinuation symptoms.
Clinical data on escitalopram overdose are limited and many cases involve concomitant overdoses of other drugs. In the majority of cases mild or no symptoms have been reported. Fatal cases of escitalopram overdose have rarely been reported with escitalopram alone; the majority of cases have involved overdose with concomitant medications. Doses between 400 and 800 mg of escitalopram alone have been taken without any severe symptoms.
Symptoms: Symptoms seen in reported overdose of escitalopram include symptoms mainly related to the central nervous system (ranging from dizziness, tremor, and agitation to rare cases of serotonin syndrome, convulsion, and coma), the gastrointestinal system (nausea/vomiting) and the cardiovascular system (hypotension, tachycardia, QT prolongation, and arrhythmia) and electrolyte/fluid balance conditions (hypokalemia, hyponatremia).
In addition, some of the symptoms seen in reported overdose of racemic citalopram (>600 mg) are somnolence, unconsciousness, change in ECG with ST-T changes, broadening of QRS complex and respiratory depression. Overdose with escitalopram could result in similar symptoms.
Treatment: There is no specific antidote. Establish and maintain an airway, ensure adequate oxygenation and respiratory function. Gastric lavage and the use of activated charcoal should be considered. Gastric lavage should be carried out as soon as possible after oral ingestion. Cardiac and vital signs monitoring are recommended along with general symptomatic supportive measures.
Hypersensitivity to escitalopram or to any of the excipients.
Concomitant treatment with nonselective, irreversible monoamine oxidase inhibitors (MAO inhibitors).
Concomitant treatment with pimozide.
Suicidality and antidepressant drugs: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of escitalopram or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Escitalopram is not approved for use in pediatric patients less than 18 years of age. (See Clinical worsening and suicide risk: Use in children and adolescents under 18 years of age as under Precautions).
Use in children and adolescents under 18 years of age: Escitalopram should not be used in the treatment of children and adolescents under age of 18 years. Suicide related behaviors (suicide attempt and suicidal thoughts), and hostility (predominantly aggression, oppositional behavior and anger) were more frequently observed among children and adolescents treated with antidepressants compared on those treated with placebo. If based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the appearance of suicidal symptoms.
The following precautions apply to therapeutic class of SSRI (Selective Serotonin Re-uptake Inhibitors).
Coronary heart disease: Due to limited clinical response, caution is advised in patients with coronary heart disease.
Paradoxical anxiety: Some patients with panic disorder may experience increased anxiety symptoms at the beginning of treatment with antidepressants. The paradoxical reaction usually subsides within the first two weeks of treatment. A low starting dose is advised to reduce the likelihood of an anxiogenic effect.
Seizures: The medicinal product should be discontinued in any patient who develops seizures. SSRIs should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored. SSRIs should be discontinued if there is an increase in seizure frequency.
Mania: SSRIs should be used with caution in patients with a history of mania/hypomania. SSRIs should be discontinued in any patient entering a manic phase.
Diabetes: In patients with diabetes, treatment with an SSRI may alter glycemic control. Insulin and/or oral hypoglycemic dosage may need to be adjusted.
Suicide/suicidal thoughts: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which escitalopram is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. In addition, there is a possibility of an increased risk of suicidal behavior in young adults.
Patients (and caregivers of patients) should be alerted about the need to monitor for the emergence of such events and to seek medical advice immediately if these symptoms present.
Akathisia/psychomotor restlessness: The use of SSRIs/SNRIs has been associated with the development of akathisia, characterized by a subjectively unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. This is most likely to occur within the first few weeks of treatment. In patients who develop these symptoms, increasing the dose may be detrimental.
Hyponatremia: Hyponatremia, probably due to inappropriate antidiuretic hormone secretion (SIADH), has been reported rarely with the use of SSRIs and generally resolves on discontinuation of therapy. Caution should be exercised in patients at risk, such as the elderly, cirrhotic patients, or patients concomitantly treated with medications known to cause hyponatremia.
Hemorrhage: There have been reports of cutaneous bleeding abnormalities, such as ecchymoses and purpura, with SSRIs. Caution is advised in patients taking SSRIs, particularly with concomitant use of oral anticoagulants; medicinal products known to affect platelet function (e.g., atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and nonsteroidal anti-inflammatory medicinal product (NSAIDs), ticlopidine and dipyridamole) and in patients with known bleeding tendencies.
ECT (electroconvulsive therapy): There is limited clinical experience of concurrent administration of SSRIs and ECT, therefore caution is advisable.
Reversible, selective MAO-A inhibitors: The combination of escitalopram with MAO-A inhibitors is generally not recommended due to the risk of onset of a serotonin syndrome. For information on concomitant treatment with non-selective, irreversible MAO-inhibitors see Interactions.
Serotonin syndrome: Caution is advisable if escitalopram is used concomitantly with medicinal products with serotonergic effects such as sumatriptan or other triptans, tramadol, and tryptophan.
In rare cases, serotonin syndrome has been reported in patients using SSRIs concomitantly with serotonergic medicinal products. A combination of symptoms, such as agitation, tremor, myoclonus and hyperthermia may indicate the development of this condition. If this occurs treatment with the SSRI and the serotonergic medicinal product should be discontinued immediately and symptomatic treatment initiated.
St. John's Wort: Concomitant use of SSRIs and herbal remedies containing St. John's Wort (Hypericum perforatum) may result in an increased incidence of adverse reactions.
Discontinuation symptoms seen when stopping treatment: Discontinuation symptoms when stopping treatment are common, particularly if discontinuation is abrupt.
The risk of discontinuation symptoms may be dependent on several factors including the duration and dose of therapy and the rate of dose reduction. Dizziness, sensory disturbances (including paresthesia and electric shock sensation), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea, and/or vomiting, tremor, confusion, sweating, headache, diarrhea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity.
They usually occur within the first few days of discontinuation treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that escitalopram should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs.
Pregnancy: For escitalopram only limited clinical data are available regarding exposure in pregnancy. Escitalopram should not be used during pregnancy unless clearly necessary and only after careful consideration of the risk/benefit ratio.
In reproductive toxicity studies performed in rats with escitalopram, embryofetotoxic effects were observed, but no increased incidence of malformations.
Neonates should be observed if maternal use of escitalopram continues into the later stages of pregnancy, particularly in the third trimester. Abrupt discontinuation should be avoided during pregnancy.
The following symptoms may occur in the neonate after maternal SSRI/SNRI use in later stages of pregnancy: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, somnolence and difficulty sleeping. These symptoms could be due to either serotonergic effects or discontinuation symptoms. In a majority of instances the complications begin immediately or soon (<24 hours) after delivery.
Lactation: It is expected that escitalopram will be excreted into human milk. Consequently, breast-feeding is not recommended during the treatment.
Adverse reactions are most frequent during the first or second week of treatment and usually decrease in intensity and frequency with continued treatment. (See table.)
Click on icon to see table/diagram/image
The following adverse drug reactions have been reported for the therapeutic class of SSRls: psychomotor restlessness/akathisia and anorexia.
Cases of QT-prolongation have been reported during the post-marketing period, predominantly in patients with pre-existing cardiac disease. No causal relationship has been established.
Discontinuation symptoms seen when stopping treatment:
Discontinuation of SSRIs/SNRIs (particularly when abrupt) commonly leads to discontinuation symptoms. Dizziness, sensory disturbances (including paresthesia and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, sweating, headache, diarrhea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions. Generally these events are mild to moderate and are self-limiting, however, in some patients they may be severe and/or prolonged. It is therefore advised that when escitalopram treatment is no longer required, gradual discontinuation by dose tapering should be carried out.
Effects on ability to drive and use machines:
although escitalopram has been shown not to affect intellectual function or psychomotor performace, any psychoactive medicinal product may impair judgement or skills. Patients should be cautioned about the potential risk of an influence on their ability to drive a car and operate machinery.
Pharmacodynamic interactions: Contraindicated combinations: Irreversible nonselective MAOIs: Cases of serious reactions have been reported in patients receiving an SSRI in combination with a nonselective monoamine oxidase inhibitor (MAOI) and in patient who have recently discontinued SSRI treatment and have been started on MAOI treatment. In some cases, the patient developed serotonin syndrome.
Escitalopram is contraindicated in combination with nonselective, irreversible MAOIs. Escitalopram may be started 14 days after discontinuing treatment with an irreversible MAOIs and at least one day after discontinuing treatment with the reversible MAOI (RIMA), moclobemide. At least 7 days should elapse after discontinuing escitalopram treatment, before starting a irreversible nonselective MAOIs.
Pimozide: Co-administration of a single dose of pimozide 2 mg to subjects treated with racemic citalopram 40 mg/day for 11 days caused an increase in AUC and Cmax of pimozide, although not consistently. The co-administration of pimozide and citalopram resulted in a mean increase in the QTc interval of approximately 10 msecond. Due to the interaction noted at a low dose of pimozide, concomitant administration of escitalopram and pimozide is contraindicated.
Inadvisable combinations: Reversible, selective MAO-A inhibitor (moclobemide): Due to the risk of serotonin syndrome, the combination of escitalopram with a MAO-A inhibitor is contraindicated. If the combination proves necessary, it should be started at the minimum recommended dosage and clinical monitoring is strongly recommended.
Combinations requiring precautions for use: Irreversible selective MAO-B inhibitor (selegiline): In combination with selegiline (irreversible MAO-B inhibitor), caution is required due to the risk of developing serotonin syndrome. Selegiline doses up to 10 mg/day have been safely co-administered with racemic escitalopram.
Serotonergic medicinal products: Co-administration with serotonergic medicinal products (e.g. tramadol, sumatriptan and other triptans) may lead to serotonin syndrome.
Medicinal products lowering the seizure threshold: SSRIs can lower the seizure threshold Caution is advised when concomitantly using other medicinal products capable of lowering the seizure threshold (e.g., antidepressants [tricyclics, SSRIs], neuroleptics [phenothiazines, thioxanthenes and butyrophenones], mefloquin, bupropion and tramadol).
Lithium, tryptophan: There have been reports of enhanced effects when SSRIs have been given together with lithium or tryptophan, therefore concomitant use of SSRIs with these medicinal products should be undertaken with caution.
St. John's wort: Concomitant use of SSRIs and herbal remedies containing St. John's wort (Hypericum perforatum) may result in an increased incidence of adverse reactions.
Hemorrhage: Altered anticoagulant effects may occur when escitalopram is combined with oral anticoagulants. Patients receiving oral anticoagulant therapy should receive careful coagulation monitoring when escitalopram is started or stopped.
Alcohol: No pharmacodynamic or pharmacokinetic interactions are expected between escitalopram and alcohol. However, as with other psychotropic medicinal products, the combination with alcohol is not advisable.
Pharmacokinetic interactions: Influence of other medicinal products on the pharmacokinetics of escitalopram: The metabolism of escitalopram is mainly mediated by CYP2C19. CYP3A4 and CYP2D6 may also contribute to the metabolism although to a smaller extent. The metabolism of the major metabolite S-DCT (demethylated escitalopram) seems to be partly catalyzed by CYP2D6.
Co-administration of escitalopram with omeprazole (a CYP2C19 inhibitor) resulted in moderate (approximately 50%) increase in the plasma concentrations of escitalopram.
Co-administration of escitalopram with cimetidine (moderately potent general enzyme-inhibitor) resulted in moderate (approximately 70%) increase in the plasma concentrations of escitalopram.
Caution should thus be exercised at the upper end of the dose range of escitalopram when used concomitantly with CYP2C19 inhibitors (e.g., omeprazole, esomeprazole, fluoxetine, fluvoxamine, lansoprazole, ticlopidine) and with cimetidine. A reduction in the dose of escitalopram may be necessary based on clinical judgment.
Effect of escitalopram on the pharmacokinetic of other medicinal products: Escitalopram is an inhibitor of the enzyme CYP2D6. Caution is recommended when escitalopram is co-administered with medicinal products that are mainly metabolized by this enzyme, and that have a narrow therapeutic index, e.g., flecainide, propafenone and metoprolol (when used in cardiac failure), or some CNS acting medicinal products that are mainly metabolized by CYP2D6, e.g., antidepressants such as desipramine, clomipramine and nortriptyline or antipsychotics like risperidone, thioridazine and haloperidol. Dosage adjustment may be warranted.
Co-administration with desipramine or metoprolol resulted in a two-fold increase in the plasma levels of these two CYP2D6 substrates.
In vitro studies have demonstrated that escitalopram may also cause weak inhibition of CYP2C19. Caution is recommended with concomitant use of medicinal products that are metabolized by CYP2C19.
Store at temperature below 30°C, protect from light.
N06AB10 - escitalopram ; Belongs to the class of selective serotonin reuptake inhibitors. Used in the management of depression.