ESCITALOPRAM VIATRIS 5 mg Film-coated tablet, scored/28

Film-coated tablet.

White, film-coated tablet marked "EC|5" on one side and "G" on the other side. The tablets are circular in shape with a diameter of 5,5 mm.

ESCITALOPRAM VIATRIS 5 mg, film-coated tablet: each tablet contains 5 mg of escitalopram (as oxalate).

Excipients with known effect:

ESCITALOPRAM VIATRIS 5 mg, film-coated tablet contains 0,4 mg of lactose (as lactose monohydrate).

Excipients:

Treatment of major depressive episodes.

Treatment of panic disorder with or without agoraphobia.

Treatment of « social anxiety disorder » (social phobia).

Treatment of generalised anxiety disorder.

Treatment of obsessive-compulsive disorders.

Dosage

Safety at dosages above 20 mg per day has not been demonstrated.

Major depressive episodes

The usual dose is 10 mg as a single intake per day. Depending on the individual therapeutic response, the dose may be increased up to 20 mg per day, the maximum dose.

Generally, the antidepressant effect is obtained after 2 to 4 weeks of treatment. After the disappearance of symptoms, continuation of treatment for at least 6 months is necessary to consolidate the therapeutic effect.

Panic disorder with or without agoraphobia

An initial dosage of 5 mg per day is recommended during the first week of treatment, before an increase to 10 mg per day. Depending on the individual therapeutic response, the dosage may be increased up to a maximum of 20 mg per day.

The maximum efficacy is reached after approximately 3 months of treatment. Treatment should be continued for several months.

Social anxiety disorder

The usual dose is 10 mg as a single intake per day. Two to four weeks are generally required to obtain relief of symptoms. Thereafter, depending on the individual therapeutic response, the dose may be reduced to 5 mg per day or increased up to a maximum of 20 mg per day.

Social anxiety disorder is a chronic condition, and continuation of treatment for twelve weeks is recommended to consolidate the therapeutic response. Prolonged treatment of responding patients has been studied over 6 months and may be considered on a case-by-case basis to prevent relapse; the benefit of treatment should be reassessed at regular intervals.

The term "social anxiety disorder" is well defined and corresponds to a specific condition, which must be distinguished from simple excessive shyness. Drug treatment is indicated only if this disorder significantly disrupts social or professional activities.

The relative place of this treatment compared with cognitive behavioural therapy has not been evaluated. Drug treatment forms part of the overall therapeutic strategy.

Generalised anxiety disorder

The initial dose is 10 mg as a single intake per day. Depending on individual therapeutic response, the dose may be increased up to a maximum of 20 mg per day.

Long-term treatment of responder patients at a dose of 20 mg per day has been studied for at least 6 months. The benefits of treatment and the dose should be re-evaluated at regular intervals (see section Pharmacodynamics).

Obsessive compulsive disorder

The initial dose is 10 mg as a single intake per day. Depending on individual therapeutic response, the dose may be increased up to a maximum of 20 mg per day.

As OCD is a chronic condition, patients should be treated for a period sufficient to ensure the disappearance of symptoms.

The benefits of treatment and the dose should be re-evaluated at regular intervals (see section Pharmacodynamics).

Elderly patients (> 65 years)

The initial dose is 5 mg as a single daily dose. This dose may be increased to 10 mg per day depending on the individual patient's response (see section Pharmacokinetics).

The efficacy of escitalopram in social anxiety disorder has not been studied in elderly subjects.

Paediatric population

Escitalopram is not recommended in children and adolescents under 18 years of age (see section Warnings and precautions).

Renal impairment

No dose adjustment is necessary in cases of mild or moderate renal impairment. Caution is recommended in patients with severe renal impairment (ClCR less than 30 ml/min) (see section Pharmacokinetics).

Hepatic impairment

An initial dose of 5 mg per day is recommended during the first two weeks of treatment in patients with mild to moderate hepatic impairment. Depending on individual therapeutic response, the dose may be increased to 10 mg per day. Caution is advised in patients with severely reduced hepatic function, and dose increases should be particularly cautious (see section Pharmacokinetics).

Slow metabolisers of CYP2C19

In patients known to be slow metabolisers of the CYP2C19 isoenzyme, an initial dose of 5 mg per day is recommended during the first two weeks of treatment. Depending on individual therapeutic response, the dose may be increased to 10 mg per day (see section Pharmacokinetics).

Symptoms observed on discontinuation of treatment

Abrupt discontinuation should be avoided. When stopping escitalopram treatment, the dose should be reduced gradually over a period of at least one to two weeks in order to reduce the risk of withdrawal symptoms (see sections Warnings and precautions and Adverse effects). If intolerable symptoms occur following a dose reduction or on discontinuation of treatment, return to the previously prescribed dose may be considered. The physician may subsequently resume the dose reduction, but more gradually.

Method of administration

Escitalopram tablets are administered as a single daily dose, with or without meals.

Hypersensitivity to the active substance or to any of the excipients listed in section Composition.

Combination with a non-selective and irreversible monoamine oxidase inhibitor (MAOI) is contraindicated due to the risk of serotonin syndrome with agitation, tremor, hyperthermia, etc. (see section Interactions).

Combination of escitalopram with reversible MAO-A inhibitors (e.g.: moclobemide) or with the reversible non-selective MAO inhibitor linezolid is contraindicated due to the risk of serotonin syndrome (see section Interactions).

Escitalopram is contraindicated in patients presenting with acquired or congenital prolongation of the QT interval.

Escitalopram is contraindicated in combination with other medicinal products known to induce QT interval prolongation (see section Interactions).

These warnings and precautions for use apply to the therapeutic class of SSRIs (Selective Serotonin Reuptake Inhibitors).

Use in children and adolescents under 18 years

The use of escitalopram is not recommended in children and adolescents under 18 years of age. Suicide-related behaviours (suicide attempts and suicidal thoughts) and hostility-related behaviours (mainly aggression, oppositional behaviour and anger) were more frequently observed in clinical trials in children and adolescents treated with antidepressants compared with those treated with placebo. If, based on clinical need, a decision to treat is nevertheless taken, the patient should be carefully monitored for the emergence of suicidal symptoms. In addition, no long-term safety data are available in children and adolescents concerning growth, maturation and cognitive and behavioural development.

Paradoxical anxiety

Some patients suffering from panic disorder may experience an exacerbation of anxiety symptoms at the start of antidepressant treatment. This paradoxical reaction generally subsides during the first 2 weeks of treatment. It is therefore advised to start treatment at a low dose in order to reduce the risk of occurrence of this anxiogenic effect (see section Dosage and administration).

Convulsions

Escitalopram should be discontinued if a patient experiences convulsions for the first time or if the frequency of convulsions increases (for patients with previously diagnosed epilepsy). SSRIs should be avoided in patients with unstable epilepsy. In cases of controlled epilepsy, close monitoring of patients is recommended.

Manic episodes

SSRIs should be used with caution in patients with a history of manic episodes or hypomania. SSRIs should be discontinued in case of a manic episode.

Diabetes

SSRI treatment in diabetic patients may disrupt glycemic balance (hypoglycemia or hyperglycemia). An dose adjustment of insulin or oral antidiabetic agents may prove necessary.

Suicide/suicidal ideation or clinical worsening

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 appear during the first few weeks or longer of treatment, patients should be closely monitored until such improvement occurs. General clinical experience suggests that the risk of suicide may increase in the early phases of recovery.

Other psychiatric disorders for which escitalopram is prescribed may also be associated with an increased risk of suicide-related events. Furthermore, these disorders may coexist with a major depressive episode. The precautions observed when treating patients with a major depressive episode should therefore also be applied to patients treated for other psychiatric disorders.

Patients with a history of suicidal behaviour or those expressing significant suicidal ideas before starting treatment are at higher risk of suicidal ideation or suicidal behaviour, and must be closely monitored during treatment. A meta-analysis of placebo-controlled clinical trials on the use of antidepressants in adults with psychiatric disorders showed an increased risk of suicidal behaviour in patients under 25 years of age treated with antidepressants compared with those receiving placebo.

Close monitoring of patients, and in particular of those at high risk, must accompany drug treatment, particularly at the start of treatment and during dose changes. Patients (and their families or caregivers) must be advised to monitor for the occurrence of clinical worsening, the emergence of suicidal ideas/behaviours and any abnormal change in behaviour, and to seek medical advice immediately if these symptoms occur.

Akathisia/psychomotor restlessness

The use of SSRIs/SNRIs has been associated with the development of akathisia, characterised by subjectively unpleasant or distressing restlessness and a need to move often, together with an inability to sit or stand still. These symptoms most often occur during the first few weeks of treatment. Increasing the dose may be detrimental for patients who develop these symptoms.

Hyponatraemia

Rare cases of hyponatraemia, probably due to inappropriate secretion of antidiuretic hormone (SIADH), have been reported with SSRIs. This hyponatraemia generally disappears when treatment is stopped. Caution is recommended in patients at risk such as elderly people, patients with cirrhosis, or in case of concomitant use with other hyponatraemia-inducing medicinal products.

Haemorrhage

Cutaneous haemorrhagic disorders, such as ecchymoses and purpura, have been reported with SSRIs. Caution is recommended in particular in patients treated with oral anticoagulants or medicinal products known to impair platelet function (for example, among antipsychotics: atypicals or phenothiazines, most tricyclic antidepressants, acetylsalicylic acid, non-steroidal anti-inflammatory drugs (NSAIDs), ticlopidine, dipyridamole) and in patients with a known tendency to bleeding. SSRIs and SNRIs may increase the risk of postpartum haemorrhage (see sections Fertility, pregnancy and breastfeeding, Adverse effects).

E.C.T (electroconvulsive therapy)

Due to the limited clinical data available on the administration of an SSRI concomitantly with electroconvulsive therapy, caution is recommended.

Serotonin syndrome

Caution is recommended if escitalopram is combined with serotonergic medicines such as sumatriptan or other triptans, buprenorphine, tramadol and tryptophan. Rare cases of serotonin syndrome have been described in patients combining treatment with SSRIs and serotonergic medicines. Symptoms such as agitation, tremor, myoclonus and hyperthermia may indicate the occurrence of such a syndrome. In this case, this combination must be stopped immediately and symptomatic treatment initiated (see section Interactions).

St John's wort

Concomitant intake of herbal preparations containing St John's wort (Hypericum perforatum) may lead to an increase in the frequency of adverse effects (see section Interactions).

Symptoms observed on discontinuation of treatment

The occurrence of withdrawal symptoms upon discontinuation of treatment is frequent, particularly if discontinuation is abrupt (see section Adverse effects). In clinical studies, adverse reactions observed on discontinuation of treatment occurred in approximately 25 % of patients treated with escitalopram and 15 % of patients receiving placebo.

The risk of withdrawal symptoms occurring upon discontinuation of treatment may depend on several factors, including the duration of treatment, the dosage and the relative magnitude of the dose reduction.

The most frequently reported reactions are: dizziness, sensory disturbances (including paraesthesia and electric shock-like sensations), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, hyperhidrosis, headache, diarrhoea, palpitations, emotional instability, irritability and visual disturbances.

Generally, these symptoms are of mild to moderate intensity; however, they may be of severe intensity in some patients. They usually occur during the very first days after discontinuation of treatment, but very rare cases have been reported in patients who had inadvertently forgotten a dose.

Generally, these symptoms are spontaneously reversible and usually subside within 2 weeks, although they may be prolonged in some cases (2 or 3 months, or even longer). It is therefore recommended to gradually decrease the doses of escitalopram over a period of several weeks or months, according to the needs of the patient (see "Symptoms observed upon discontinuation of treatment", section Dosage and administration).

Coronary artery disease

Due to limited clinical experience, caution is recommended in patients with coronary artery disease (see section Preclinical safety).

Prolongation of the QT interval

Escitalopram has been shown to cause a dose-dependent prolongation of the QT interval. Cases of QT interval prolongation and ventricular arrhythmia, including torsades de pointes, have been reported since marketing, particularly in women and in patients with hypokalaemia, pre-existing QT interval prolongation or other cardiac conditions (see sections Contraindications, Interactions, Adverse effects, Overdose and Pharmacodynamics).

Caution is recommended in patients with significant bradycardia, recent acute myocardial infarction or uncompensated heart failure.

Electrolyte abnormalities, such as hypokalaemia or hypomagnesaemia, increase the risk of malignant arrhythmias and must be corrected before starting any treatment with escitalopram.

If a patient with a stabilised cardiac condition is treated, an electrocardiogram (ECG) check should be considered before starting treatment.

If signs of cardiac arrhythmia occur during treatment with escitalopram, it must be discontinued and an ECG should be performed.

Sexual dysfunction

Selective serotonin reuptake inhibitors (SSRIs)/serotonin and noradrenaline (or norepinephrine) reuptake inhibitors (SNRIs) could cause symptoms of sexual dysfunction (see section Adverse effects). Cases of sexual dysfunction whose symptoms have persisted despite discontinuation of treatment with SSRIs/SNRIs have been reported.

Acute angle-closure glaucoma

SSRIs, including escitalopram, may have an effect on pupil diameter, leading to mydriasis. This mydriatic effect may narrow the angle of the eye, leading to increased intraocular pressure and angle-closure glaucoma, particularly in predisposed patients.

Escitalopram should therefore be used with caution in patients with angle-closure glaucoma or a history of glaucoma.

Excipients

This medicine contains lactose. Its use is not recommended in patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases). 

This medicine contains less than 1 mmol of sodium per tablet (23 mg), that is to say essentially without sodium.

PHARMACODYNAMIC INTERACTIONS

Contraindicated combinations

 Non-selective and irreversible MAOIs

Cases of severe reactions have been reported in patients treated with an SSRI in combination with a non-selective and irreversible monoamine oxidase inhibitor (MAOI), or in patients who recently discontinued SSRI treatment and started treatment with such an MAOI (see section Contraindications). In a few cases, patients presented with serotonin syndrome (see section Adverse effects).

Escitalopram is contraindicated in combination with a non-selective and irreversible MAOI. Treatment with escitalopram must start at least 14 days after stopping an irreversible MAOI. At least 7 days must elapse between the end of escitalopram treatment and the start of treatment with a non-selective and irreversible MAOI.

Selective and reversible MAO-A inhibitor (moclobemide)

The combination of escitalopram with a MAO-A inhibitor, such as moclobemide, is contraindicated due to the risk of serotonin syndrome (see section Contraindications). In cases of absolute necessity, treatment may be initiated at the minimum recommended dose and clinical monitoring must be reinforced.

Non-selective and reversible MAO inhibitor (linezolid)

The antibiotic linezolid is a non-selective and reversible MAO inhibitor and must not be administered to patients treated with escitalopram. If absolutely necessary, it must be administered at the minimum dose and under close clinical monitoring (see section Contraindications).

Selective and irreversible MAO-B inhibitor (selegiline)

In case of combination with selegiline (an irreversible MAO-B inhibitor), caution is recommended due to the risk of serotonin syndrome. Doses of selegiline up to 10 mg per day have been administered safely in combination with racemic citalopram.

Prolongation of the QT interval

No pharmacokinetic or pharmacodynamic study of escitalopram combined with treatments prolonging the QT interval has been performed. A cumulative effect of escitalopram and these treatments cannot be excluded. Consequently, concomitant administration of escitalopram and treatments prolonging the QT interval, such as class IA and III antiarrhythmics, antipsychotics (example: phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (example: sparfloxacin, moxifloxacin, intravenous erythromycin, pentamidine, antimalarial treatments in particular halofantrine), certain antihistamines (astemizole, hydroxyzine, mizolastine), is contraindicated.

Associations requiring precautions for use

Serotonergic medicines

The combination with serotonergic medicinal products, for example buprenorphine, tramadol, sumatriptan and other triptans, may lead to serotonin syndrome (see section Warnings and precautions).

Medicines lowering the epileptogenic threshold

SSRIs may lower the seizure threshold. Caution is recommended when combined with other medicinal products that may lower the seizure threshold (e.g., antidepressants (tricyclics, SSRIs), neuroleptics (phenothiazines, thioxanthenes and butyrophenones), mefloquine, bupropion and tramadol).

Lithium, tryptophan

Potentiation of effects has been reported with concomitant administration of SSRIs and lithium or tryptophan, warranting precautions when such combinations are used.

St John's wort

Concomitant use of herbal preparations containing St John's wort (Hypericum perforatum) may lead to an increased incidence of adverse effects (see section Warnings and precautions).

Haemorrhage

The effects of oral anticoagulants may be altered when combined with escitalopram. Coagulation tests in patients treated with oral anticoagulants must be carefully monitored, in particular at the start and stop of escitalopram treatment (see section Warnings and precautions).

Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of bleeding (see section Warnings and precautions).

Alcohol

No pharmacodynamic or pharmacokinetic interaction is expected between escitalopram and alcohol. Nevertheless, as with other psychotropic medicinal products, combination with alcohol is not advised.

Medicinal products inducing hypokalaemia/hypomagnesaemia

Caution is recommended when concomitantly using medicinal products that induce hypokalaemia/hypomagnesaemia, as these abnormalities increase the risk of malignant arrhythmias (see section Warnings and precautions).

PHARMACOKINETIC INTERACTIONS

Effects of other medicinal products on the pharmacokinetics of escitalopram

The metabolism of escitalopram involves essentially the CYP2C19 isoenzyme pathway. To a lesser extent, the CYP3A4 and CYP2D6 isoenzymes may also contribute. The S-DCT (demethylated escitalopram), the major metabolite, appears to be partially catabolised by the CYP2D6 isoenzyme.

Concomitant administration of escitalopram and omeprazole (an inhibitor of the CYP2C19 isoenzyme) at a dose of 30 mg once daily resulted in a moderate increase (of approximately 50 %) in escitalopram plasma concentrations.

Concomitant administration of escitalopram with cimetidine (a moderately potent non-specific enzyme inhibitor) at a dose of 400 mg twice daily showed a moderate increase (of approximately 70 %) in escitalopram plasma concentrations.

Caution is recommended when escitalopram is administered in combination with cimetidine. A dose adjustment may be necessary.

Caution is therefore recommended when combined with inhibitors of the CYP2C19 isoenzyme (e.g., omeprazole, esomeprazole, fluconazole, fluvoxamine, lansoprazole, ticlopidine) or cimetidine. A reduction in the escitalopram dose may prove necessary depending on monitoring of undesirable effects during concomitant treatment.

Effects of escitalopram on the pharmacokinetics of other medicinal products

Escitalopram is an inhibitor of the CYP2D6 isoenzyme. Caution is recommended when combined with medicinal products mainly metabolised by this isoenzyme and having a narrow therapeutic margin, such as flecainide, propafenone and metoprolol (when used in myocardial infarction), or certain CNS medicinal products mainly metabolised by CYP2D6, such as antidepressants like desipramine, clomipramine and nortriptyline, or antipsychotics like risperidone, thioridazine and haloperidol. A dose adjustment may be justified.

Combination with desipramine or metoprolol doubles the plasma concentration of these 2 substrates of CYP2D6.

In vitro studies have shown that escitalopram may also cause weak inhibition of CYP2C19. Caution is recommended when combined with medicinal products metabolised by CYP2C19.

Pregnancy

Clinical data on exposure to escitalopram during pregnancy are limited.

Animal studies have shown reproductive toxicity (see section Preclinical safety). Escitalopram should not be prescribed during pregnancy unless clearly necessary and only after careful evaluation of the benefit/risk ratio.

The newborn should be monitored if the mother has continued escitalopram until late pregnancy, particularly during the third trimester. Abrupt discontinuation of treatment should be avoided during pregnancy.

The following symptoms may occur in the newborn after maternal use of SSRIs/SNRIs late in pregnancy: respiratory distress, cyanosis, apnoea, convulsions, unstable temperature, feeding difficulties, vomiting, hypoglycaemia, hypertonia, hypotonia, hyperreflexia, tremor, tremulousness, irritability, lethargy, persistent crying, somnolence and sleep disturbances. These symptoms may be due to serotonergic effects or be related to treatment discontinuation. In the majority of cases, the complications begin immediately or very soon (< 24 hours) after birth.

Epidemiological data suggest that use of SSRIs during pregnancy, particularly late in pregnancy, may increase the risk of persistent pulmonary hypertension of the newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies. In the general population, the risk of PPHN is 1 to 2 cases per 1000 pregnancies. Data from observational studies indicate an increased risk (less than 2 times higher) of postpartum haemorrhage following exposure to SSRIs/SNRIs in the month preceding birth (see sections Warnings and precautions, Adverse effects).

Breast-feeding

Escitalopram is likely to be excreted in human milk. Therefore, breast-feeding is not recommended during treatment.

Fertility

Data in animals have shown that citalopram may affect semen quality (see section Preclinical safety.).

Reported cases in men treated with SSRIs have shown that the effect on sperm quality is reversible.

No impact on human fertility has been observed to date.

Although escitalopram has not shown impairment of cognitive and psychomotor functions, it may, like any psychotropic product, impair judgement or abilities. The patient should therefore be warned of the potential risk of impairment of their ability to drive vehicles and use machines.

Undesirable effects are mainly noted during the first or second week of treatment and usually subside thereafter in intensity and frequency.

Tabulated list of adverse reactions

Adverse reactions known for the SSRI class and also reported for escitalopram in placebo-controlled studies or spontaneously reported since marketing are listed below by system organ class and by frequency.

Frequencies are derived from clinical studies; they have not been corrected for placebo.

Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), or not known (cannot be estimated from the available data).

	Very common	Common	Uncommon	Rare	Very rare	Frequency not known
Blood and lymphatic system disorders						Thrombocytopenia
Immune system disorders				Anaphylactic reaction
Endocrine disorders						Inappropriate ADH secretion, hyperprolactinaemia
Metabolism and nutrition disorders		Loss of appetite or increased appetite, weight gain	Weight loss			Hyponatremia, anorexia1
Psychiatric disorders		Anxiety, restlessness, abnormal dreams. In men and women: decreased libido In women: anorgasmia	Bruxism, agitation, nervousness, panic attacks, confusional state	Aggressiveness, depersonalization, hallucinations		Mania, suicidal ideas, suicidal behavior2
Nervous system disorders	Headache	Insomnia, drowsiness, dizziness, paresthesias, tremors	Dysgeusia, sleep disorders, syncope	Serotonin syndrome		Dyskinesias, abnormal movements, convulsions, psychomotor agitation/akathisia1
Eye disorders			Mydriasis, visual disturbances
Ear and labyrinth disorders			Tinnitus
Cardiac disorders			Tachycardia	Bradycardia		Prolongation of the QT interval, ventricular arrhythmia including torsades de pointes
Vascular disorders						Orthostatic hypotension
Respiratory, thoracic and mediastinal disorders		Sinusitis, yawning	Epistaxis
Gastrointestinal disorders	Nausea	Diarrhea, constipation, vomiting, dry mouth	Gastrointestinal haemorrhages (including rectal bleeding)
Hepatobiliary disorders						Hepatitis, abnormal liver function tests
Skin and subcutaneous tissue disorders		Hyperhidrosis	Urticaria, alopecia, skin rash, pruritus			Ecchymoses, angioedema
Musculoskeletal and systemic disorders		Arthralgia, myalgia
Renal and urinary disorders						Urinary retention
Disorders of the reproductive system and breast		In men: ejaculation disorders, impotence	In women: metrorrhagia, menorrhagia			Galactorrhoea In men: priapism Postpartum haemorrhage3
General disorders and administration site conditions		Fatigue, fever	Oedema

1 These adverse reactions have been reported for the SSRI therapeutic class.

2 Cases of suicidal thoughts and behaviours have been reported during treatment with escitalopram or shortly after discontinuation (see section Warnings and precautions).

3. This event has been reported for the therapeutic class of SSRIs and SNRIs (see sections Warnings and precautions, Fertility, pregnancy and breastfeeding).

Prolongation of the QT interval

Cases of QT interval prolongation and ventricular arrhythmia, including torsades de pointes, have been reported since marketing, particularly in women and in patients with hypokalaemia, pre-existing QT interval prolongation or other cardiac disorders (see sections Contraindications, Warnings and precautions, Interactions, Overdose and Pharmacodynamics).

Class effects

Epidemiological studies, carried out mainly in patients aged 50 years and over, show an increased risk of bone fractures in patients receiving selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants. The mechanism leading to this risk is unknown.

Symptoms observed on discontinuation of treatment

Discontinuation of SSRI/SNRI treatment (particularly when abrupt) usually leads to the occurrence of withdrawal symptoms. The most frequently reported reactions are the following: dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, hyperhidrosis, headache, diarrhoea, palpitations, emotional instability, irritability and visual disturbances. Generally, these events are of mild to moderate intensity and are spontaneously resolving. However, they may be of severe intensity and/or prolonged in some patients.

It is therefore advised that, when treatment with escitalopram is no longer needed, doses be gradually reduced (see sections Dosage and administration and Warnings and precautions).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr/

Toxicity

Clinical data on escitalopram overdose are limited and often include concomitant overdose of several medicinal products. In the majority of cases, few or no symptoms have been reported. Fatal cases of escitalopram overdose have rarely been reported with escitalopram alone; the majority of cases involved concomitant overdose of several medicinal products. Doses of escitalopram alone between 400 and 800 mg have been taken without any severe symptoms appearing.

Symptoms

The symptoms reported in cases of overdose with escitalopram mainly concern the central nervous system (ranging from dizziness, tremors and agitation, to rare cases of serotonin syndrome, convulsions and coma), the gastrointestinal system (nausea/vomiting) and the cardiovascular system (hypotension, tachycardia, prolongation of the QT interval and arrhythmia) and fluid and electrolyte balance (hypokalaemia, hyponatraemia).

Treatment

There is no specific antidote for escitalopram. Adequate ventilation and oxygenation of the patient must be established. Gastric lavage and administration of activated charcoal should be considered. Gastric lavage must be performed as soon as possible after ingestion of the medicinal product. Medical monitoring will focus on vital signs and cardiac function.

Electrocardiogram monitoring is recommended in cases of overdose, in patients with congestive heart failure/bradyarrhythmia, in patients using treatments that prolong the QT interval, or in patients with a metabolic disorder (for example: hepatic impairment).

Pharmacotherapeutic class: ANTIDEPRESSANT / SELECTIVE SEROTONIN REUPTAKE INHIBITOR, ATC code: N 06 AB 10

Mechanism of action

Escitalopram is a selective serotonin reuptake inhibitor (5-HT) with high affinity for the primary binding site. It also binds to an allosteric site on the serotonin transporter, with an affinity 1000 times lower.

Escitalopram has little or no affinity for a number of receptors, including the 5-HT1A, 5-HT2, dopaminergic D1 and D2, α1-, α2- and β-adrenergic, histaminergic H1, cholinergic (muscarinic) receptors, and for benzodiazepine and opiate receptors.

Inhibition of 5-HT reuptake is the only probable mechanism of action explaining the pharmacological and clinical properties of escitalopram.

Pharmacodynamic effects

In a double-blind, placebo-controlled ECG study in healthy subjects, the mean change in QTc (using the Fridericia correction formula) from baseline and versus placebo was 4,3 msec (CI 90%: 2,2; 6,4) at a dose of 10 mg/day and 10,7 msec (CI 90%: 8,6; 12,8) at the supratherapeutic dose of 30 mg/day (see sections Contraindications, Warnings and precautions, Interactions, Adverse effects and Overdose).

Clinical efficacy and safety

Major depressive episodes

Escitalopram demonstrated efficacy in the acute treatment of major depressive episodes in 3 of 4 short-term (8 weeks) double-blind studies versus placebo. In a long-term relapse prevention study, 274 patients who had responded during an initial open-label treatment phase of 8 weeks with escitalopram at 10 or 20 mg per day were randomised to continue treatment with escitalopram at the same dose or placebo, for a duration of up to 36 weeks.

In this study, patients who received escitalopram for 36 weeks had a significantly longer time to relapse than those who received placebo.

Social anxiety disorder

In social anxiety disorder, escitalopram proved effective both in 3 short-term studies (12 weeks) and in a relapse prevention study conducted over 6 months in responder patients. The efficacy of doses of 5, 10 and 20 mg per day was demonstrated in a dose-finding study over 24 weeks.

Generalised anxiety disorder

Escitalopram at doses of 10 and 20 mg per day proved effective in the 4 placebo-controlled studies.

Pooled data from 3 studies of similar methodology, comprising 421 patients treated with escitalopram and 419 patients treated with placebo, showed 47,5% and 28,9% responders, respectively, as well as 37,1% and 20,8% of patients in remission. A sustained effect appeared from the first week.

Maintenance of efficacy of escitalopram at a dose of 20 mg per day was demonstrated in a randomised efficacy maintenance study conducted over 24 to 76 weeks in 373 patients who had responded to an initial open-label treatment phase of 12 weeks.

Obsessive compulsive disorder

In a randomised, double-blind clinical study, escitalopram at a dose of 20 mg per day differed from placebo on the total score on the Y-BOCS scale after 12 weeks of treatment.

After 24 weeks of treatment, escitalopram at doses of 10 and 20 mg per day proved superior to placebo.

Escitalopram demonstrated efficacy in relapse prevention, at doses of 10 and 20 mg/day, in a randomised, double-blind, placebo-controlled study of 24 weeks in patients responding to escitalopram after 16 weeks of open-label treatment.

Absorption

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

Distribution

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

Biotransformation

Escitalopram is metabolised by the liver into demethylated and didemethylated metabolites. Both are pharmacologically active. In addition, the nitrogen may be metabolised by oxidation into an N-oxide metabolite.

Escitalopram and its metabolites are partly excreted in glucuroconjugated form. After repeated doses, mean concentrations of the demethylated and didemethylated metabolites reach 28-31% and less than 5% of the escitalopram concentration, respectively.

Biotransformation of escitalopram to its demethylated metabolite mainly involves the isoenzyme CYP2C19, with a possible contribution from the isoenzymes CYP3A4 and CYP2D6.

Elimination

The elimination half-life (t½β) after repeated doses is approximately 30 hours and the oral plasma clearance (Coral) is approximately 0,6 l/min. The major metabolites have a significantly longer half-life.

Escitalopram and its major metabolites appear to be eliminated by the hepatic route (hepatic metabolism) and by the renal route. The major part is eliminated in the form of urinary metabolites.

Linearity

The pharmacokinetics are linear. The steady-state plasma concentration is reached within one week. A mean steady-state concentration of 50 nmol/l (from 20 to 125 nmol/l) is reached for a dose of 10 mg per day.

Elderly patients (> 65 years)

Escitalopram appears to be eliminated more slowly in elderly subjects than in young patients.

Systemic exposure (AUC) is approximately 50 % higher in elderly subjects compared with healthy young volunteers (see section Dosage and administration).

Hepatic impairment

In patients with mild to moderate hepatic impairment (Stages A and B of the Child-Pugh classification) the half-life of escitalopram is approximately twice as long and exposure is approximately 60 % higher compared with subjects with normal hepatic function (see section Dosage and administration).

Renal impairment

A longer half-life and a minor increase in AUC have been observed with racemic citalopram in patients with reduced renal function (ClCR : 10 to 53 ml/min). Plasma concentrations of the metabolites have not been studied but they could be increased (see section Dosage and administration).

Polymorphism

It has been observed that poor metabolisers for the CYP2C19 isoenzyme have a plasma concentration of escitalopram 2 times higher than that of extensive metabolisers. No significant change in AUC has been observed in poor metabolisers for the CYP2D6 isoenzyme (see section Dosage and administration).

Full conventional preclinical studies have not been performed with escitalopram because the additional toxicokinetic and toxicological studies conducted in rats with escitalopram and citalopram showed similar results. Therefore, the data obtained with citalopram can be extrapolated to escitalopram.

In comparative toxicological studies in rats, escitalopram and citalopram caused cardiac toxicity including congestive heart failure after several weeks of treatment, at doses that also caused general toxic effects.

Cardiotoxicity appears to be correlated with peak plasma concentrations rather than with systemic exposure (AUC). The peak plasma concentrations of escitalopram, for which no adverse effect was observed, are 8 times higher than those reached in the clinic, whereas the AUC is only 3 to 4 times higher than that reached in the clinic. The AUC values of citalopram, for the S-enantiomer, are 6 to 7 times higher than the exposure reached in the clinic.

These observations are probably related to an increased influence on biogenic amines, secondary to the primary pharmacological effects, leading to haemodynamic effects (reduction of coronary flow) and ischaemia. However, the exact mechanism inducing cardiotoxicity in rats is not clear. Clinical experience with citalopram and experience from clinical trials with escitalopram do not indicate that these observations have clinical correlation.

An increase in phospholipid content in certain tissues, for example in the lung, epididymis and liver, has been observed in rats after prolonged treatment over long periods with escitalopram and citalopram. These observations on the epididymis and liver have been found in humans at similar exposures. This effect is reversible after discontinuation of treatment.

Accumulation of phospholipids (phospholipidosis) in animals has been observed with many cationic amphiphilic drugs. The relevance of this phenomenon to humans is not known.

In developmental studies in rats, embryotoxic effects (decreased foetal weight and reversible delayed ossification) were observed at exposures, in terms of AUC, higher than those reached in the clinic. No increase in the frequency of malformations was found.

A pre- and post-natal study showed a decrease in litter survival during the lactation period at exposures, in terms of AUC, higher than those reached in the clinic.

Animal data have shown decreased fertility and pregnancy indices, a decrease in the number of implantations and abnormal sperm upon exposure to citalopram doses much higher than therapeutic doses. No animal data on this subject are available for escitalopram.

3 years.

Store at a temperature not exceeding 25°C.

Blister packs : store in the original package.

Polypropylene bottle : keep the bottle tightly closed.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400930105801 (Plq/28x1). CIP 3400930105146 (Fl/28).

Price:

3,61 euros (Plq/28x1). 3,61 euros (Fl/28).

Remb Séc soc at 65% (Plq/28x1, Fl/28) in the indications:

• Indication(s) listed in the marketing authorisation (AMM) on the date of publication of this order (Plq/28x1, Fl/28)

Collection.