Lenuxin^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter Poland, Co. Ltd. (Poland)

Contact Information

GEDEON RICHTER Plc. (Hungary)

ATC Code

N06AB10 (Escitalopram)

Active Substance

Escitalopram

Dosage Form

Lenuxin®

Film-coated tablets, 10 mg: 14 or 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, round, biconvex, with an engraving “N 54” on one side and a score on the other side, white or almost white on the cross-section.

Excipients: microcrystalline cellulose, croscarmellose sodium, talc, silicified microcrystalline cellulose 90 (Prosolv 90) (microcrystalline cellulose 98%, colloidal silicon dioxide 2%), silicified microcrystalline cellulose HD90 (Prosolv HD90) (microcrystalline cellulose 98%, colloidal silicon dioxide 2%), magnesium stearate.

Coating composition: Opadry II white 33G 28523 (hypromellose 6cP (2910) 40%, titanium dioxide (E171) 25%, lactose monohydrate 21%, macrogol 3350 8%, glycerol triacetate (triacetin) 6%).

14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Psychoanaleptics. Antidepressants. Selective serotonin reuptake inhibitors

Pharmacological Action

Escitalopram is an antidepressant, a selective serotonin reuptake inhibitor (SSRI) with high affinity for the primary binding site. Escitalopram also binds to the allosteric binding site of the transporter protein, with an affinity 1000 times lower.

Escitalopram has no or very low ability to bind to a number of receptors, including: serotonin 5-HT_1A, 5-HT₂ receptors, dopamine D₁ and D₂ receptors, α₁-, α₂-, β-adrenergic receptors, histamine H₁ receptors, muscarinic cholinergic receptors, benzodiazepine and opioid receptors.

Inhibition of serotonin reuptake is the only mechanism of action explaining the pharmacological and clinical effect of escitalopram.

Pharmacokinetics

Absorption

Absorption is almost complete and does not depend on food intake. The mean time to reach C_max in plasma is 4 hours after multiple administration. As with the citalopram racemate, the absolute bioavailability of escitalopram is about 80%.

Distribution

The apparent Vd (V_d,β/F) after oral administration ranges from 12 to 26 L/kg. The binding of escitalopram and its main metabolites to plasma proteins is less than 80%. Escitalopram kinetics are linear. C_ss is reached in about 1 week. A mean C_ss of 50 nmol/L (range 20 to 125 nmol/L) is achieved at a daily dose of 10 mg.

Metabolism

Escitalopram is metabolized in the liver to demethylated and didemethylated metabolites. Both are pharmacologically active. The nitrogen may also be oxidized to an N-oxide metabolite. The parent substance and its metabolites are partially excreted in the form of glucuronides. After multiple administration, the mean concentration of demethyl and didemethyl metabolites is typically 28-31% and less than 5%, respectively, of the escitalopram concentration. The biotransformation of escitalopram to the demethylated metabolite occurs mainly via the CYP2C19 isoenzyme, with possible involvement of the CYP3A4 and CYP2D6 isoenzymes.

Excretion

T_1/2 after multiple administration is about 30 hours. Oral clearance is about 0.6 L/min. The main metabolites of escitalopram have a longer T_1/2. Escitalopram and its main metabolites are excreted by the liver (metabolic pathway) and kidneys; most is excreted by the kidneys as metabolites.

Special patient groups

Elderly patients (over 65 years). In elderly patients (over 65 years), Escitalopram is eliminated more slowly than in younger patients. Systemic exposure (AUC) in elderly patients is 50% greater than in young healthy volunteers.

Patients with impaired liver function. In patients with mild or moderate hepatic impairment (Child-Pugh classes A and B), the T_1/2 of escitalopram is approximately 2 times longer and the AUC is 60% greater than in patients with normal liver function.

Patients with impaired renal function. In the case of racemic citalopram, patients with impaired renal function (CrCl 10-53 mL/min) have a longer T_1/2 and a slight increase in AUC. Plasma metabolite concentrations have not been studied, but they may be elevated.

Polymorphism. In patients with low activity of the CYP2C19 isoenzyme, the concentration of escitalopram may be 2 times higher than in patients with high activity of this isoenzyme. No significant changes in the plasma AUC of escitalopram were found with low activity of the CYP2D6 isoenzyme.

Indications

For use in adults aged 18 years and older

• Depressive episodes of any severity;
• Panic disorder with or without agoraphobia;
• Social anxiety disorder (social phobia);
• Generalized anxiety disorder;
• Obsessive-compulsive disorder.

ICD codes

Dosage Regimen

The drug is taken orally once a day, regardless of meals.

Depressive episodes

Usually 10 mg once a day is prescribed. Depending on the individual patient’s response, the dose may be increased to a maximum of 20 mg/day. The antidepressant effect usually develops after 2-4 weeks of treatment. After the symptoms of depression disappear, it is necessary to continue therapy to consolidate the achieved effect for at least 6 months.

Panic disorder with or without agoraphobia

During the first week of treatment, a dose of 5 mg/day is recommended, which is then increased to 10 mg/day. Depending on the individual patient’s response, the dose may be increased to a maximum of 20 mg/day. The maximum therapeutic effect is achieved approximately 3 months after the start of treatment. Therapy lasts for several months.

Social anxiety disorder

The usual dose is 10 mg once a day. Symptom relief usually occurs after 2-4 weeks. Subsequently, depending on the individual patient’s response to treatment, the dose can be reduced to 5 mg/day or increased to a maximum of 20 mg/day.

Social anxiety disorder is a chronic disease; to consolidate the therapeutic effect, the recommended duration of the treatment course is 12 weeks. Given the results of studies of long-term use of the drug for 6 months, it may be prescribed to prevent relapse of the disease depending on the individual patient’s response. In this case, the effectiveness of therapy should be regularly assessed.

Social anxiety disorder is a disease with clear diagnostic criteria and should not be confused with excessive shyness. Pharmacotherapy is indicated only if the disease is accompanied by significant impairment of professional activity and social functioning. A comparison of drug treatment with cognitive behavioral therapy has not been conducted. Pharmacotherapy is part of an overall treatment strategy.

Generalized anxiety disorder

The initial dose is 10 mg once a day. Depending on the individual patient’s response to treatment, the dose can be increased to a maximum of 20 mg/day.

Among patients who responded to treatment, studies of long-term therapy (for at least 6 months) with the drug at a dose of 20 mg/day were conducted. It is necessary to regularly assess the effectiveness of treatment and the adequacy of the dose.

Obsessive-compulsive disorder

Usually 10 mg once a day is prescribed. Depending on the individual patient’s response, the dose may subsequently be increased to a maximum of 20 mg/day. Since obsessive-compulsive disorder is a chronic disease, the course of treatment should be long enough to ensure complete relief from symptoms. It is necessary to regularly assess the effectiveness of treatment and the adequacy of the dose.

Discontinuation of treatment

Abrupt withdrawal of the drug should be avoided; when discontinuing treatment, the dose should be gradually reduced over 1-2 weeks to avoid the occurrence of “withdrawal” syndrome. If intolerable symptoms occur during dose reduction or after discontinuation of treatment, resumption of the drug at the previously prescribed dose should be considered. The physician may then recommend continuing to reduce the dose, but at a slower rate.

Special patient groups

Elderly patients are recommended to be prescribed half the usual recommended dose – 5 mg/day. The maximum dose is 10 mg/day.

Studies of the effectiveness of escitalopram in the treatment of social anxiety disorder in elderly patients have not been conducted.

Lenuxin^® should not be used in children and adolescents under 18 years of age (efficacy and safety have not been established).

Renal impairment in patients with mild or moderate renal impairment dose adjustment is not required. In patients with severe renal impairment (CrCl less than 30 mL/min) the drug should be prescribed with caution.

Hepatic impairment: in mild and moderate hepatic impairment the recommended initial dose for the first 2 weeks of treatment is 5 mg/day. Depending on the individual patient’s response, the dose may be increased to 10 mg/day. In patients with severe hepatic impairment exceptional caution should be exercised when prescribing treatment and when increasing the dose.

Reduced activity of the CYP2C19 isoenzyme: for patients with low activity of the CYP2C19 isoenzyme, the recommended initial dose for the first 2 weeks of treatment is 5 mg/day. Depending on the individual patient’s response, the dose may be increased to 10 mg/day.

Adverse Reactions

Adverse reactions most often occur in the 1st or 2nd week of treatment with the drug and then usually become less intense and occur less frequently with continued therapy.

Undesirable adverse reactions are presented according to system-organ classes in accordance with MedDRA and with an indication of the frequency of occurrence: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), unknown (frequency of occurrence cannot be estimated from existing data).

¹These phenomena have been reported during the use of drugs belonging to the SSRI class.

²Cases of suicidal ideation and suicidal behavior have been reported during escitalopram use or shortly after drug discontinuation.

³This adverse event has been reported as a class effect for SSRI/SNRI class drugs.

Description of selected adverse reactions

Cardiac disorders

Cases of QT interval prolongation and ventricular arrhythmia were noted mainly in female patients, with hypokalemia, with pre-existing QT interval prolongation or with other heart diseases.

Musculoskeletal and connective tissue disorders

In patients aged 50 years and older, an increased risk of fractures was identified during the use of SSRIs and tricyclic antidepressants, the mechanism of which has not been established.

Withdrawal syndrome after treatment discontinuation

Discontinuation of SSRI/SNRI drugs (especially abrupt) often leads to the occurrence of “withdrawal” symptoms. The most common are dizziness, sensory disturbances (including paresthesia and electric shock sensations), sleep disorders (including insomnia and intense dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, increased sweating, headache, diarrhea, palpitations, emotional lability, irritability, visual disturbances. Typically these effects are mild or moderate and resolve quickly, but in some patients they may be more severe and/or last longer. It is recommended to discontinue the drug gradually by reducing its dose.

Contraindications

• Hypersensitivity to escitalopram or to any of the excipients included in the drug;
• History of QT interval prolongation, including congenital long QT syndrome;
• Concomitant use with non-selective irreversible MAO inhibitors.
• Concomitant use with reversible MAO inhibitors, MAO-A (e.g., moclobemide) or reversible non-selective MAO inhibitors (linezolid);
• Concomitant use of pimozide;
• Concomitant use of drugs that can prolong the QT interval.

With caution

Severe renal failure (CrCl less than 30 mL/min), hyponamia, mania, pharmacologically uncontrolled epilepsy, significant suicidal behavior, diabetes mellitus, elderly age (over 65 years), electroconvulsive therapy (ECT), severe hepatic impairment, bleeding tendency; concomitant use with drugs that lower the seizure threshold, with MAO-B inhibitor (selegiline), serotonergic drugs, lithium, tryptophan, drugs containing St. John’s wort (Hypericum perforatum), oral anticoagulants and drugs affecting blood clotting, drugs that can cause hyponatremia, drugs metabolized by the CYP2C19 isoenzyme, ethanol; pregnancy, breastfeeding period.

Use in Pregnancy and Lactation

Pregnancy

There are limited data on the use of escitalopram during pregnancy.

Preclinical studies of escitalopram have demonstrated reproductive toxicity.

Escitalopram during pregnancy should be used only in cases of extreme necessity and after careful assessment of the benefit/risk ratio.

If escitalopram was continued in late pregnancy, especially in the third trimester, the newborn should be monitored. Sudden withdrawal of the drug during pregnancy should be avoided.

If escitalopram was continued until delivery or was discontinued shortly before delivery, the newborn may develop “withdrawal” symptoms.

If the mother took SSRIs/SNRIs (selective serotonin and norepinephrine reuptake inhibitors) in late pregnancy, the following adverse effects may develop in the newborn: respiratory depression, cyanosis, apnea, seizure disorders, temperature instability, feeding difficulties, vomiting, hypoglycemia, hypertonia, muscle hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying, drowsiness, poor sleep. These symptoms may be due to the development of “withdrawal” syndrome or serotonergic effects. In most cases, such complications occur within 24 hours after birth.

Epidemiological study data suggest that the use of SSRIs during pregnancy, especially in late stages, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). The observed risk was about 5 cases per 1000 pregnancies. In the general population, 1-2 cases of PPHN per 1000 pregnancies are observed.

Observational data indicate an increased (less than 2-fold) risk of postpartum hemorrhage after the use of SSRI/SNRI class drugs within one month before delivery.

Breastfeeding period

Escitalopram is expected to pass into breast milk, therefore breastfeeding is not recommended during treatment with escitalopram.

Fertility

Preclinical study data have shown that some SSRIs may affect sperm quality; such preclinical data for escitalopram are lacking. Reports on the use of some SSRIs in humans have shown that the effect of these drugs on sperm quality is reversible. So far, no effect of escitalopram on human fertility has been observed.

Use in Hepatic Impairment

In mild and moderate hepatic impairment, the recommended initial dose for the first 2 weeks of treatment is 5 mg/day. Depending on the individual patient’s response, the dose may be increased to 10 mg/day. In patients with severe hepatic impairment, exceptional caution should be exercised when prescribing treatment and when increasing the dose.

Use in Renal Impairment

In patients with mild or moderate renal impairment, no dose adjustment is required. Patients with severe renal impairment (creatinine clearance below 30 ml/min) should be administered the drug with caution.

Pediatric Use

Contraindicated in children and adolescents under the age of 18 years.

Geriatric Use

For elderly patients (over 65 years of age), it is recommended to prescribe half the usual recommended dose – 5 mg/day. The maximum dose is 10 mg/day.

Special Precautions

When using drugs belonging to the SSRI therapeutic group, including Escitalopram, the following should be considered.

Use in children and adolescents under 18 years

Antidepressants should not be prescribed to children and adolescents under 18 years of age suffering from depression and other mental illnesses due to an increased risk of suicidal behavior (suicide attempts and suicidal thoughts), hostility (with a predominance of aggressive behavior, confrontational tendencies, and irritability).

If a decision is made based on clinical assessment to initiate antidepressant therapy, the patient should be under close observation for early detection of behavioral disturbances or changes, as well as suicidal tendencies.

Furthermore, there is insufficient long-term safety data on the use of the drug in children regarding growth, maturation, and cognitive and behavioral development.

Paradoxical anxiety

In some patients with panic disorder, increased anxiety may be observed at the beginning of SSRI treatment.

Such a paradoxical reaction usually disappears within the first two weeks of treatment.

To reduce the likelihood of an anxiogenic effect, the use of low initial doses is recommended.

Seizures

The drug should be discontinued if seizures develop for the first time or if their frequency increases (in patients with previously diagnosed epilepsy).

SSRIs should not be used in patients with unstable epilepsy; in patients with controlled seizures, careful observation is necessary.

Caution is required when using escitalopram concomitantly with other medicinal products that lower the seizure threshold.

Mania/hypomania

Escitalopram should be used with caution in patients with a history of mania/hypomania. If a manic state develops, Escitalopram should be discontinued.

Diabetes mellitus

In patients with diabetes mellitus, treatment with escitalopram may alter blood glucose concentrations. Therefore, adjustment of the dose of insulin and/or oral hypoglycemic drugs may be required.

Suicidal thoughts, suicide attempts, or worsening of the disease

Depression is associated with an increased risk of suicidal thoughts, self-harm, and suicide (suicidal events).

This risk persists until significant remission occurs.

Since improvement may not be observed during the first few weeks of therapy or even longer, patients should be under constant observation until their condition improves, as there is a possibility of clinical worsening and/or the emergence of suicidal manifestations (thoughts and behavior) or self-harm.

General clinical practice indicates that the risk of suicide may increase in the early stages of recovery.

Other mental conditions for which Escitalopram is prescribed may also be associated with an increased risk of suicidal events and phenomena.

Furthermore, these conditions may be comorbid with a depressive episode.

When treating patients with other mental disorders, the same precautions should be observed as when treating patients with a depressive episode.

Patients with a history of suicidal behavior or patients with a significant degree of suicidal ideation prior to treatment are at greater risk of suicidal thoughts or suicide attempts, therefore they must be closely monitored during treatment.

A meta-analysis of placebo-controlled clinical trials of antidepressants involving adult patients with mental disorders showed that there is an increased risk of suicidal behavior in patients under 25 years of age when taking antidepressants compared with placebo.

Drug treatment of these patients, and in particular patients at high risk of suicide, should be accompanied by careful monitoring, especially in the early stages of treatment and during dose changes.

Patients (and patient caregivers) should be warned to monitor for any signs of clinical worsening, suicidal behavior or thoughts, as well as unusual changes in behavior, and to seek immediate medical advice if these symptoms appear.

Akathisia and psychomotor agitation

The use of SSRIs/SNRIs is associated with the development of akathisia, characterized by the development of subjectively unpleasant or distressing restlessness and a need to move constantly, often combined with an inability to sit or stand still.

This most often manifests during the first few weeks of treatment.

In patients with such symptoms, increasing the dose may lead to worsening.

Hyponatremia

Hyponatremia, possibly associated with impaired ADH secretion, rarely occurs during SSRI use and usually resolves upon discontinuation of therapy.

Caution should be exercised when prescribing escitalopram and other SSRIs to individuals at risk of developing hyponatremia: the elderly, patients with liver cirrhosis, and those taking drugs that can cause hyponatremia.

Bleeding

Skin hemorrhages (ecchymosis and purpura) may develop when taking SSRIs.

Escitalopram should be used with caution in patients prone to bleeding, as well as in those taking oral anticoagulants and medicinal products that affect blood clotting (for example, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and NSAIDs, ticlopidine and dipyridamole).

Postpartum hemorrhage

The use of SSRIs and SNRIs may increase the risk of postpartum hemorrhage.

Electroconvulsive therapy (ECT)

Since clinical experience with the simultaneous use of escitalopram and ECT is limited, caution should be exercised in such cases.

Serotonin syndrome

Escitalopram should be used with caution concomitantly with medicinal products that have serotonergic effects (for example, sumatriptan or other triptans, tramadol and tryptophan).

In rare cases, serotonin syndrome has developed in patients taking Escitalopram and other SSRIs simultaneously with serotonergic drugs.

Its development may be indicated by a combination of symptoms such as agitation, tremor, myoclonus and hyperthermia.

If this occurs, simultaneous treatment with SSRIs and serotonergic drugs should be discontinued immediately and symptomatic treatment initiated.

Reversible selective MAO inhibitors

Combining Escitalopram and MAO inhibitors is not recommended due to the risk of serotonin syndrome.

St. John’s wort (Hypericum perforatum)

When SSRIs are used concomitantly with herbal preparations containing St. John’s wort (Hypericum perforatum), an increase in the number of adverse reactions may be observed.

Sexual dysfunction

SSRIs/SNRIs may cause symptoms of sexual dysfunction.

Cases of long-term sexual dysfunction have been reported where symptoms persisted even after discontinuation of SSRIs/SNRIs.

Coronary heart disease

Due to limited experience of use in patients with coronary heart disease, caution is recommended when using the drug.

QT interval prolongation

Escitalopram has been found to cause a dose-dependent prolongation of the QT interval.

Post-marketing cases of QT interval prolongation and ventricular arrhythmia, including torsades de pointes, have been reported, mainly in female patients, with hypokalemia, or pre-existing QT interval prolongation, or other heart diseases.

Caution is required when using the drug in patients with significant bradycardia or in patients with a recent acute myocardial infarction or decompensated heart failure.

Electrolyte imbalances, such as hypokalemia and hypomagnesemia, increase the risk of malignant arrhythmias; these imbalances must be corrected before starting treatment with escitalopram.

In patients with stable cardiovascular disease, an ECG should be performed before starting treatment.

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

Angle-closure glaucoma

SSRIs, including Escitalopram, may change pupil size, exerting a mydriatic effect.

In this case, narrowing of the lateral angle of the eye is possible, leading to increased intraocular pressure and angle-closure glaucoma, especially in patients predisposed to this condition.

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

Discontinuation symptoms upon treatment cessation

‘Discontinuation’ symptoms are common when treatment is stopped, especially if treatment is stopped abruptly.

In clinical trials, discontinuation adverse events were observed in approximately 25% of patients treated with escitalopram and in 15% of patients treated with placebo.

The risk of ‘discontinuation’ symptoms may depend on several factors, including the duration of therapy and the dose of the drug, as well as the rate of dose reduction.

Reactions such as 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, increased sweating, headache, diarrhea, palpitations, emotional lability, irritability, and visual disturbances were most frequently reported.

Usually these symptoms are mild or moderate, but in some patients they can be severe.

Usually symptoms occur within the first few days after discontinuation of treatment, but there have been very rare reports of such symptoms occurring in patients who accidentally missed a dose.

As a rule, these symptoms resolve on their own, usually within two weeks, although in some patients they may be prolonged (2-3 months or more).

Therefore, when discontinuing treatment, gradual dose reduction over several weeks or months is recommended, depending on the patient’s condition.

Excipients

The drug contains lactose monohydrate. Patients with rare hereditary lactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Lenuxin^®.

Effect on ability to drive and operate machinery

Despite available data indicating that Escitalopram does not affect intellectual function and psychomotor activity, the use of psychoactive medicinal products may lead to impaired critical assessment of one’s actions or deterioration of skills.

During the treatment period, it is not recommended to drive vehicles or operate machinery.

Overdose

Data on escitalopram overdose are limited, and in many such cases there was also an overdose of other drugs.

In most cases, overdose symptoms are absent or mild.

Fatal cases of escitalopram overdose (without taking other drugs) are rare; in most cases, an overdose of other drugs also occurs.

When escitalopram was taken at a dose of 400-800 mg as monotherapy, no clinically significant overdose symptoms occurred.

Symptoms: mainly symptoms from the CNS (from dizziness, tremor and agitation to rare cases of serotonin syndrome, seizure disorders and coma), from the gastrointestinal tract (nausea/vomiting), cardiovascular system (arterial hypotension, tachycardia, QT interval prolongation and arrhythmia) and electrolyte imbalances (hypokalemia, hyponatremia).

Treatment: There is no specific antidote.

Symptomatic and supportive therapy is recommended.

Normal airway patency, oxygenation and lung ventilation should be ensured.

Gastric lavage should be performed and activated charcoal administered.

Gastric lavage should be performed as soon as possible after drug intake.

Monitoring of cardiac function and other vital organs is recommended.

ECG monitoring in case of overdose is recommended for patients with congestive heart failure, with bradyarrhythmia, with concomitant use of drugs that prolong the QT interval, as well as for patients with metabolic disorders, for example, with impaired liver function.

Drug Interactions

Pharmacodynamic interactions

Contraindicated combinations

Non-selective irreversible MAO inhibitors

Serious adverse reactions have been reported with the concomitant use of SSRIs and non-selective irreversible MAO inhibitors, as well as when starting MAO inhibitors in patients who had recently discontinued SSRIs.

In some cases, patients developed serotonin syndrome.

Concomitant use of Escitalopram with non-selective irreversible MAO inhibitors is contraindicated.

Escitalopram may be started 14 days after discontinuation of irreversible MAO inhibitors.

At least 7 days should pass after the end of escitalopram intake before starting non-selective irreversible MAO inhibitors.

Reversible selective MAO-A inhibitor (moclobemide)

Due to the risk of serotonin syndrome, concomitant use of Escitalopram with MAO-A inhibitors, such as moclobemide, is contraindicated.

If the use of such a drug combination is deemed clinically necessary, it is recommended to start with the lowest possible doses and conduct constant clinical monitoring of the patient’s condition.

Escitalopram can be started at least 1 day after discontinuation of the reversible MAO-A inhibitor moclobemide.

Reversible non-selective MAO inhibitor (linezolid)

The antibiotic linezolid is a reversible non-selective MAO inhibitor, and therefore it is not recommended to prescribe it to patients receiving Escitalopram. If such combination therapy is proven necessary, it should be prescribed at the minimum dose and under close patient supervision.

Irreversible MAO-B inhibitor (selegiline)

Due to the risk of serotonin syndrome, caution is required when taking escitalopram concomitantly with the irreversible MAO-B inhibitor selegiline. Concomitant use of selegiline in doses up to 10 mg/day and the racemate citalopram is safe.

Drugs that prolong the QT interval

Pharmacokinetic and pharmacodynamic studies of the use of escitalopram in combination with other drugs that prolong the QT interval have not been conducted.

The possibility of an additive effect of using escitalopram in combination with these drugs cannot be excluded.

Therefore, combined use of escitalopram with drugs that prolong the QT interval, such as class IA and III antiarrhythmic drugs, antipsychotics (e.g., phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, some antimicrobial drugs (e.g., sparfloxacin, moxifloxacin, intravenous erythromycin, pentamidine, antimalarial drugs, especially halofantrine), some antihistamines (astemizole, mizolastine), is contraindicated.

Combinations requiring caution

Serotonergic drugs

Concomitant use with serotonergic drugs (e.g., tramadol, sumatriptan and other triptans) may lead to the development of serotonin syndrome.

Lenuxin^® should be used with caution concomitantly with opioids (e.g., buprenorphine (as monotherapy or in combination with naloxone), pethidine, tramadol), as the risk of developing serotonin syndrome, a potentially life-threatening condition, is increased.

Drugs that lower the seizure threshold

SSRIs may lower the seizure threshold. Caution is required when using escitalopram concomitantly with other medicinal products that lower the seizure threshold (tricyclic antidepressants; SSRIs; antipsychotics – phenothiazine, thioxanthene and butyrophenone derivatives; mefloquine; bupropion; tramadol).

Lithium and tryptophan

Cases of enhanced effects of escitalopram have been reported with concomitant use of escitalopram and lithium or tryptophan; thus, caution should be exercised when using SSRIs concomitantly with these drugs.

St. John’s wort (Hypericum perforatum)

Concomitant use of escitalopram and St. John’s wort preparations may lead to an increase in the number of adverse reactions.

Anticoagulants and other agents affecting blood clotting

Concomitant use of escitalopram with oral anticoagulants and other agents affecting blood clotting (e.g., atypical antipsychotics and phenothiazine derivatives, most tricyclic antidepressants, acetylsalicylic acid and NSAIDs, ticlopidine and dipyridamole) may lead to impaired blood clotting.

In such cases, regular monitoring of blood coagulation is necessary at the beginning or end of escitalopram therapy.

Concomitant use with NSAIDs may lead to an increased number of bleedings.

Drugs causing hypokalemia/hypomagnesemia

Caution should be exercised when using escitalopram concomitantly with drugs that cause hypokalemia/hypomagnesemia, as these imbalances increase the risk of malignant arrhythmias.

Ethanol

Escitalopram does not interact pharmacodynamically or pharmacokinetically with ethanol. However, as with other psychotropic medicinal products, concomitant use of escitalopram and alcohol is not recommended.

Pharmacokinetic interactions

Effect of other drugs on the pharmacokinetics of escitalopram

The metabolism of escitalopram is primarily mediated by the CYP2C19 isoenzyme.

To a lesser extent, the CYP3A4 and CYP2D6 isoenzymes may be involved in the metabolism.

The metabolism of the main metabolite, demethylated escitalopram, appears to be partially catalyzed by the CYP2D6 isoenzyme.

Concomitant use of escitalopram and omeprazole at a dose of 30 mg once daily (an inhibitor of the CYP2C19 isoenzyme) leads to a moderate (approximately 50%) increase in the plasma concentration of escitalopram.

Concomitant use of escitalopram and cimetidine at a dose of 400 mg twice daily (a moderate inhibitor of the CYP2D6, CYP3A4 and CYP1A2 isoenzymes) leads to an increase (approximately 70%) in the plasma concentration of escitalopram.

Caution should be exercised when using escitalopram in combination with cimetidine.

Dose adjustment may be necessary.

Thus, the maximum possible doses of escitalopram should be used with caution simultaneously with inhibitors of the CYP2C19 isoenzyme (for example, omeprazole, esomeprazole, fluconazole, fluvoxamine, lansoprazole, ticlopidine) and cimetidine. When escitalopram and the above-mentioned drugs are used simultaneously, a dose reduction of escitalopram may be required based on clinical assessment.

Effect of escitalopram on the pharmacokinetics of other drugs

Escitalopram is an inhibitor of the CYP2D6 isoenzyme. Caution should be exercised when using escitalopram concomitantly with drugs metabolized by this isoenzyme and having a narrow therapeutic index, for example, flecainide, propafenone and metoprolol (when used for heart failure), or drugs mainly metabolized via the CYP2D6 isoenzyme and acting on the CNS, for example, antidepressants: desipramine, clomipramine, nortriptyline, or antipsychotics: risperidone, thioridazine, haloperidol. In these cases, dose adjustment may be required.

Concomitant use of escitalopram and desipramine or metoprolol leads to a twofold increase in the concentration of the latter two drugs.

Escitalopram may slightly inhibit the CYP2C19 isoenzyme. Therefore, caution is recommended when using escitalopram concomitantly with drugs metabolized by CYP2C19.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.