Cyclox®
Ukraine
Table of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT CIKLOX® (CIKLOX®)
Composition:
Active substance: escitalopram oxalate;
1 tablet contains escitalopram oxalate equivalent to 10 mg or 20 mg of escitalopram;
Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal silicon dioxide, purified talc, magnesium stearate, coating "Opadry white 03F58750" (hypromellose, titanium dioxide (E 171), macrogol, talc).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
oval, biconvex tablets of white or almost white color, film-coated, with a break line on one side and smooth on the other side.
Pharmacotherapeutic group. Antidepressants. Selective serotonin reuptake inhibitors (SSRIs). ATC code N06A B10.
Pharmacological properties.
Pharmacodynamics.
Escitalopram is a selective serotonin reuptake inhibitor (SSRI) characterized by high affinity for the primary binding site. It also binds to the allosteric site of the serotonin transporter, although its affinity for this site is 1000 times lower.
Escitalopram has either no or very weak affinity for a number of receptors, including serotonin 5-HT1A and 5-HT2 receptors, dopamine D1 and D2 receptors, α1-, α2-, and β-adrenergic receptors, histamine H1 receptors, muscarinic cholinergic receptors, benzodiazepine receptors, and opioid receptors.
Inhibition of 5-HT reuptake is the only plausible mechanism of action that can explain the pharmacological and clinical effects of escitalopram.
Pharmacodynamic effects
In one double-blind, placebo-controlled ECG study in healthy subjects, QTc interval prolongation (corrected according to Fridericia's formula) from baseline was 4.3 ms (90% CI: 2.2, 6.4) with a 10 mg/day dose and 10.7 ms (90% CI: 8.6, 12.8) with a supratherapeutic dose of 30 mg/day (see sections "Contraindications", "Special precautions", "Interaction with other medicinal products and other forms of interaction", "Adverse reactions", "Overdose").
Clinical efficacy
Major depressive episodes
The efficacy of escitalopram in the acute treatment of major depressive episodes was demonstrated in 3 out of 4 double-blind, placebo-controlled, short-term (8-week) studies. In a long-term relapse prevention study, 274 patients who responded to escitalopram treatment at doses of 10 or 20 mg/day during an initial 8-week open-label phase were randomized to continue escitalopram at the same dose or switch to placebo for up to 36 weeks. In this study, patients continuing escitalopram had a statistically significantly longer time to relapse over the subsequent 36 weeks compared to those receiving placebo.
Social anxiety disorder
Escitalopram was shown to be effective in treating social anxiety disorder in three short-term (12-week) studies as well as in a 6-month relapse prevention study. Efficacy of escitalopram at doses of 5, 10, and 20 mg was demonstrated in a 24-week dose-optimization study.
Generalized anxiety disorder
Escitalopram at doses of 10 and 20 mg/day was effective in 4 out of 4 placebo-controlled studies.
According to pooled data from three studies with similar designs involving a total of 421 patients receiving escitalopram and 419 patients receiving placebo, response rates were 47.5% and 28.9%, respectively, and remission rates were 37.1% and 20.8%, respectively. A sustained effect was observed from the first week of treatment.
The maintenance effect of escitalopram at a dose of 20 mg/day was demonstrated in a 24–76-week randomized study on treatment maintenance involving 373 patients who responded to the drug during an initial 12-week open-label treatment phase.
Obsessive-compulsive disorder
In a randomized, double-blind clinical trial, escitalopram at a dose of 20 mg/day demonstrated superiority over placebo in the total score on the Y-BOCS (Yale-Brown Obsessive Compulsive Scale) after 12 weeks of treatment. After 24 weeks, advantages of escitalopram treatment were observed at both 10 mg/day and 20 mg/day compared to placebo.
The efficacy of the drug in preventing relapse was demonstrated for escitalopram at doses of 10 and 20 mg/day in patients who responded to escitalopram during a 16-week open-label period and were then included in a 24-week randomized, double-blind, placebo-controlled phase.
Pharmacokinetics.
Absorption
Absorption is nearly complete and not affected by food intake. Maximum plasma concentration (Tmax) is reached within 4 hours after repeated administration.
As with racemic citalopram, the absolute bioavailability of escitalopram is expected to be approximately 80%.
Distribution
The apparent volume of distribution (Vd,β/F) after oral administration is approximately 12 to 26 L/kg. The bioavailability of escitalopram is approximately 80%. Protein binding of escitalopram and its main metabolites is less than 80%.
Biological transformation
Metabolism occurs in the liver, producing demethylated and didemethylated metabolites. Both are pharmacologically active. Alternatively, nitrogen oxidation may occur, forming an N-oxide metabolite. Both the parent compound and metabolites are partially excreted as glucuronides. With repeated administration, mean concentrations of the demethylated and didemethylated metabolites are typically 28–31% and <5% of the escitalopram concentration, respectively. The biotransformation of escitalopram to the demethylated metabolite is primarily mediated by CYP2C19. Some involvement of CYP3A4 and CYP2D6 enzymes in this process is also possible.
Elimination
The elimination half-life (t½β) after repeated administration is approximately 30 hours. Oral plasma clearance (Cloral) is approximately 0.6 L/min. The main metabolites have longer half-lives. Escitalopram and its main metabolites are eliminated via the liver (metabolic pathway) and kidneys. The majority of the dose is excreted in urine as metabolites.
Linearity
The pharmacokinetics of escitalopram are linear. Steady-state concentrations are reached after approximately 1 week. Mean steady-state concentrations of 50 nmol/L (range: 20–125 nmol/L) are achieved with a daily dose of 10 mg.
Elderly patients
In patients aged 65 years and older, escitalopram is eliminated more slowly than in younger patients. Systemic exposure (AUC) in healthy elderly volunteers is approximately 50% higher than in younger healthy volunteers (see section "Dosage and administration").
Hepatic impairment
In patients with mild to moderate hepatic impairment (Child-Pugh classes A and B), the elimination half-life is twice as long and exposure is 60% higher compared to individuals with normal liver function (see section "Dosage and administration").
Renal impairment
In patients with reduced renal function (CLcr 10–53 mL/min), administration of racemic citalopram resulted in a prolonged elimination half-life and slightly increased exposure. Plasma metabolite concentrations have not been studied but may be elevated (see section "Dosage and administration").
Polymorphism
Patients with poor CYP2C19 metabolic function had plasma escitalopram concentrations twice as high as those with normal CYP2C19 function. No significant changes in exposure were observed with reduced CYP2D6 function (see section "Dosage and administration").
Clinical characteristics.
Indications.
- Major depressive episodes.
- Panic disorder with or without agoraphobia.
- Social anxiety disorder (social phobias).
- Obsessive-compulsive disorder.
- Generalized anxiety disorders.
Contraindications.
- Hypersensitivity to escitalopram or to any of the excipients.
- Concomitant treatment with non-selective, irreversible monoamine oxidase inhibitors (MAOIs) is contraindicated due to the risk of serotonin syndrome with agitation, tremor, hyperthermia, and other symptoms (see section "Interaction with other medicinal products and other forms of interaction").
- Combined use of escitalopram with reversible MAO-A inhibitors (e.g., moclobemide) or with the reversible non-selective MAO inhibitor linezolid is contraindicated due to the risk of serotonin syndrome (see section "Interaction with other medicinal products and other forms of interaction").
- Escitalopram is contraindicated in patients with known QT interval prolongation or congenital long QT syndrome.
- Escitalopram is contraindicated for concomitant use with medicinal products that can prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction").
Interaction with other medicinal products and other forms of interaction.
Pharmacodynamic interactions
Contraindicated combinations.
Non-selective irreversible MAOIs
Serious reactions have been reported in patients taking SSRIs in combination with non-selective irreversible MAOIs, and in patients who have recently discontinued SSRIs and started MAOI treatment (see section "Contraindications"). In some cases, serotonin syndrome developed (see section "Adverse reactions").
Combination of escitalopram with non-selective irreversible MAOIs is contraindicated. Treatment with escitalopram should be initiated no earlier than 14 days after discontinuation of irreversible MAOIs. Treatment with non-selective irreversible MAOIs should not be initiated earlier than 7 days after discontinuation of escitalopram.
Reversible selective MAO-A inhibitor (moclobemide)
Due to the risk of serotonin syndrome, combination of escitalopram with the MAO-A inhibitor moclobemide is contraindicated (see section "Contraindications"). If this combination is necessary, the lowest recommended doses should be used initially with enhanced clinical monitoring.
Non-selective reversible MAO inhibitor (linezolid)
The antibiotic linezolid is a non-selective reversible MAO inhibitor and should not be administered to patients receiving escitalopram. If such a combination is necessary, minimal doses of both agents should be used under close clinical supervision (see section "Contraindications").
Selective irreversible MAO-B inhibitor (selegiline)
Combination with selegiline (irreversible MAO-B inhibitor) requires caution due to the risk of serotonin syndrome.
Selegiline at doses up to 10 mg/day has been safely used concomitantly with racemic citalopram.
QT interval prolongation
Pharmacokinetic and pharmacodynamic studies of combined use of escitalopram with other medicinal products that prolong the QT interval have not been conducted. When escitalopram is used concomitantly with such agents, an additive effect cannot be excluded. Therefore, concomitant use of escitalopram with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotics (e.g., phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g., sparfloxacin, moxifloxacin, intravenous erythromycin, pentamidine, antimalarials including halofantrine), and certain antihistamines (e.g., astemizole, hydroxyzine, mizolastine), is contraindicated.
Combinations requiring caution in use
Serotonergic medicinal products
Concomitant use with serotonergic medicinal products (e.g., opioids (including tramadol) and triptans (including sumatriptan)) may lead to serotonin syndrome (see section "Special precautions for use").
MEDICINAL PRODUCTS THAT LOWER SEIZURE THRESHOLD
SSRIs may lower the seizure threshold. Caution is recommended when co-administering medicinal products that may lower the seizure threshold (e.g., antidepressants (tricyclics, SSRIs), neuroleptics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion, and tramadol).
Lithium, tryptophan
Cases of enhanced effects have been reported with concomitant use of SSRIs and lithium or tryptophan. Therefore, caution is recommended when prescribing these agents together.
St. John’s wort
Concomitant use of SSRIs and herbal preparations containing St. John’s wort (Hypericum perforatum) may lead to an increased frequency of adverse reactions (see section "Special precautions for use").
Anticoagulants
The effects of anticoagulants may be altered by concomitant use with escitalopram. If patients are taking oral anticoagulants, careful monitoring of the coagulation system is required before and during treatment with escitalopram (see section "Special precautions for use").
Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) may increase the risk of bleeding (see section "Special precautions for use").
Alcohol
Escitalopram does not exhibit pharmacodynamic or pharmacokinetic interaction with alcohol. However, as with other psychotropic medicinal products, combination with alcohol is not recommended.
MEDICINAL PRODUCTS CAUSING HYPOKALEMIA/HYPOMAGNESEMIA
Caution should be exercised when using medicinal products that may cause hypokalemia/hypomagnesemia concomitantly, as this increases the risk of developing malignant arrhythmias (see section "Special precautions for use").
Pharmacokinetic interactions
Effect of other medicinal products on the pharmacokinetics of escitalopram
The metabolism of escitalopram is primarily mediated by CYP2C19. Enzymes CYP3A4 and CYP2D6 may also play a minor role in its metabolism. The metabolism of the main metabolite S-DCT (demethylated escitalopram) appears to be partially catalyzed by CYP2D6.
Concomitant administration of escitalopram and omeprazole 30 mg once daily (a CYP2C19 inhibitor) results in a moderate (approximately 50%) increase in plasma concentration of escitalopram.
Concomitant use of escitalopram and cimetidine 400 mg twice daily (a moderate general enzyme inhibitor) led to a moderate (approximately 70%) increase in plasma concentration of escitalopram. Caution should be exercised when combining escitalopram with cimetidine. Dose adjustment may be necessary (see section "Special precautions for use").
Therefore, caution is advised when using escitalopram concomitantly with CYP2C19 inhibitors (e.g., omeprazole, esomeprazole, fluconazole, fluvoxamine, lansoprazole, ticlopidine) and cimetidine, particularly when prescribing the upper limit doses of escitalopram. Dose reduction of escitalopram may be necessary depending on clinical assessment (see section "Special precautions for use").
Effect of escitalopram on the pharmacokinetics of other medicinal products
Escitalopram is an inhibitor of the CYP2D6 enzyme. Caution is recommended when using escitalopram concomitantly with medicinal products that are primarily metabolized by this enzyme and have a narrow therapeutic index, such as flecainide, propafenone, and metoprolol (used in heart failure), or with certain central nervous system-acting medicinal products primarily metabolized by CYP2D6, such as antidepressants (e.g., desipramine, clomipramine, nortriptyline) and antipsychotics (e.g., risperidone, thioridazine, haloperidol). Dose adjustment may be required.
Combination with desipramine or metoprolol resulted in a doubling of plasma levels of these two CYP2D6 substrates.
In vitro studies have shown that escitalopram may also cause slight inhibition of CYP2C19.
Caution is recommended when using escitalopram concomitantly with medicinal products metabolized by CYP2C19.
Special precautions for use.
The following special precautions apply to the therapeutic class of selective serotonin reuptake inhibitors (SSRIs).
Children. The medicinal product should not be administered to children. During clinical trials, a higher incidence of suicidal behaviour (suicide attempts and suicidal thoughts), hostility (predominantly aggression, oppositional behaviour, and anger) was observed in children treated with antidepressants compared to those receiving placebo. If clinical necessity requires initiation of such treatment, careful monitoring of the patient is essential to detect suicidal symptoms promptly. In addition, there are no data on long-term safety in children regarding growth, sexual maturation, and cognitive and behavioural development.
Paradoxical anxiety
Some patients with panic disorders may experience increased anxiety at the beginning of antidepressant treatment. This paradoxical reaction usually resolves within two weeks of treatment. To reduce the likelihood of an anxiogenic effect, a low initial dose is recommended (see section "Dosage and administration").
Seizures
Escitalopram should be discontinued if a patient experiences a first seizure or an increase in seizure frequency (in patients with a confirmed diagnosis of epilepsy). SSRIs should be avoided in patients with unstable epilepsy, and patients with controlled epilepsy should be closely monitored.
Mania
SSRIs should be used with caution in patients with a history of mania/hypomania. If a manic state develops, SSRIs should be discontinued.
Diabetes mellitus
In patients with diabetes mellitus, treatment with SSRIs may alter glycaemic control (hypoglycaemia or hyperglycaemia). The dose of insulin and/or oral hypoglycaemic agents may require adjustment.
Suicide, suicidal thoughts, or clinical worsening
Depression is associated with a risk of suicidal thoughts, self-harm, and suicide. This risk persists until sustained remission is achieved. Since improvement may not occur during the first few weeks of treatment or longer, patients should be closely monitored until their condition improves. It is known that the risk of suicide may increase in the early stages of recovery.
Other psychiatric disorders for which escitalopram is used may also be associated with a risk of suicidal behaviour. Moreover, these conditions may be comorbid with major depressive disorder. These warnings also apply to the treatment of patients with other psychiatric disorders.
Patients with a history of suicidal behaviour prior to treatment initiation have the highest risk of suicidal thoughts or attempts and require close monitoring throughout treatment.
A meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders demonstrated an increased risk of suicidal behaviour with antidepressants compared to placebo in patients under 25 years of age. Close monitoring of high-risk patients is particularly necessary at the beginning of treatment and when the dose is changed.
Patients and their caregivers should be warned to monitor for any worsening of symptoms, suicidal behaviour or thoughts, and unusual changes in behaviour, and to seek immediate medical advice if these symptoms occur.
Akathisia/psychomotor agitation
The use of SSRIs/ SNRIs has been associated with the development of akathisia—a condition characterised by an unpleasant, distressing sense of restlessness and an urge to move, often accompanied by an inability to sit or stand still. This condition is most likely during the first few weeks of treatment. Dose escalation may worsen symptoms in patients who develop such symptoms.
Hyponatraemia
Hyponatraemia, possibly related to syndrome of inappropriate antidiuretic hormone secretion (SIADH), is rare during SSRI treatment and usually resolves after discontinuation of therapy. SSRIs should be used with caution in patients at risk (elderly patients, patients with liver cirrhosis, or those receiving concomitant treatment with drugs that may cause hyponatraemia).
Bleeding
Skin haemorrhages, ecchymoses, and purpura may occur during SSRI treatment. SSRIs/SNRIs may increase the risk of postpartum haemorrhage (see sections "Use during pregnancy or breastfeeding" and "Adverse reactions"). SSRIs should be used with caution in patients receiving concomitant oral anticoagulants, drugs affecting platelet function (e.g. atypical antipsychotics, phenothiazines, tricyclic antidepressants, acetylsalicylic acid and non-steroidal anti-inflammatory drugs, dipyridamole, and ticlopidine), and in patients with a predisposition to bleeding.
Electroconvulsive therapy (ECT)
Clinical experience with the concomitant use of SSRIs and ECT is limited; therefore, caution is recommended.
Reversible, selective MAO-A inhibitors
Combining escitalopram with MAO-A inhibitors is contraindicated due to the risk of serotonin syndrome.
Serotonin syndrome
Caution is advised when using escitalopram concomitantly with serotonergic agents such as triptans (including sumatriptan), opioids (including tramadol), and tryptophan.
Serotonin syndrome has been reported in isolated cases in patients taking SSRIs concomitantly with other serotonergic medicinal products. A combination of symptoms such as agitation, tremor, myoclonus, and hyperthermia may indicate the development of this condition. In such cases, SSRIs and the serotonergic agent should be discontinued immediately, and symptomatic treatment initiated.
St. John's wort
Concomitant use of SSRIs and herbal preparations containing St. John's wort (Hypericum perforatum) may lead to an increased frequency of adverse reactions (see section "Interaction with other medicinal products and other forms of interaction").
Withdrawal symptoms
Withdrawal symptoms upon discontinuation of treatment, especially abrupt discontinuation, are common (see section "Adverse reactions"). In clinical trials, adverse reactions during discontinuation occurred in approximately 25% of patients receiving escitalopram and in 15% of patients receiving placebo.
The risk of withdrawal symptoms may depend on several factors, including duration and dose of treatment, and the rate of dose reduction. Dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, increased sweating, headache, diarrhoea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported symptoms. These symptoms are usually mild to moderate in severity, but may be severe in some patients. They typically occur within the first few days after stopping treatment, although very rare reports of such symptoms have occurred in patients who accidentally missed a dose. These withdrawal symptoms usually resolve spontaneously within 2 weeks, but may be prolonged (2–3 months or longer) in some patients. Therefore, it is recommended to gradually discontinue escitalopram treatment by tapering the dose over several weeks or months, depending on the patient's condition (see section "Dosage and administration").
Sexual dysfunction
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) may cause symptoms of sexual dysfunction (see section "Adverse reactions"). There have been reports of persistent sexual dysfunction, where symptoms continued despite discontinuation of SSRIs/SNRIs.
Ischaemic heart disease
Due to limited clinical experience, caution is recommended when using the drug in patients with ischaemic heart disease.
QT interval prolongation
Escitalopram has been shown to cause dose-dependent QT interval prolongation. In the post-marketing period, cases of QT interval prolongation and ventricular arrhythmias, including polymorphic ventricular tachycardia (torsade de pointes), have been reported, primarily in women, patients with hypokalaemia, and patients with pre-existing QT prolongation or other cardiac diseases (see sections "Pharmacodynamics", "Contraindications", "Interaction with other medicinal products and other forms of interaction", "Overdose", and "Adverse reactions").
The medicinal product should be used with caution in patients with marked bradycardia and in patients with recent acute myocardial infarction or decompensated heart failure.
Electrolyte imbalances such as hypokalaemia and hypomagnesaemia increase the risk of malignant arrhythmias and should be corrected before initiating escitalopram treatment.
In patients with stable cardiac disease, a thorough assessment of ECG parameters should be performed before initiating escitalopram treatment.
If signs of cardiac arrhythmia occur during escitalopram treatment, the medicinal product should be discontinued and an ECG performed.
Closed-angle glaucoma
SSRIs, including escitalopram, may affect pupil size, leading to mydriasis. This mydriatic effect may potentially narrow the angle of the eye, resulting in increased intraocular pressure and closed-angle glaucoma, particularly in predisposed patients. Therefore, escitalopram should be used with caution in patients with closed-angle glaucoma or a history of glaucoma.
Excipients
This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e. it is essentially "sodium-free".
Use during pregnancy or breastfeeding.
Pregnancy
Clinical data on the use of escitalopram for the treatment of pregnant women are limited.
Animal studies have shown reproductive toxicity.
Escitalopram is contraindicated during pregnancy, except in cases where a careful risk-benefit assessment has clearly demonstrated the necessity of treatment. Close monitoring of newborns whose mothers have taken escitalopram during pregnancy, particularly in the third trimester, is recommended. Abrupt discontinuation of the drug during pregnancy should be avoided.
Newborns whose mothers have taken SSRIs/SNRIs during late pregnancy may experience symptoms such as respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulties, vomiting, hypoglycaemia, hypertension, hypotension, hyperreflexia, tremor, nervousness, irritability, apathy, persistent crying, somnolence, and sleep disturbances. These symptoms may be due to serotonergic effects or may represent withdrawal symptoms. In most cases, such complications occur immediately or shortly (within 24 hours) after delivery.
Epidemiological data indicate that the use of SSRIs in pregnant women, especially during late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (up to 5 cases per 1000 pregnant women, based on observational data). In the general population, 1 to 2 cases per 1000 pregnant women occur.
Observational data suggest an increased risk (by <2 times) of postpartum haemorrhage after use of SSRIs or SNRIs within one month before delivery (see sections "Special precautions for use" and "Adverse reactions").
Breastfeeding
Since escitalopram passes into breast milk, breastfeeding is not recommended during treatment.
Fertility
Animal studies have shown that escitalopram may affect sperm quality. Reports on the use of some SSRIs in humans have indicated that the effect on sperm quality is reversible. No effect on human fertility has been observed to date.
Ability to drive and use machines.
Although escitalopram does not affect intellectual or psychomotor performance, any psychoactive drug may impair skills or the ability to think rationally. Patients should be warned about the potential risk of impaired ability to drive or operate machinery.
Dosage and Administration
The safety of doses exceeding 20 mg per day has not been established.
Cyclox® is administered orally once daily to adults, independent of food intake.
Major Depressive Episode
The usual dose is 10 mg once daily. Depending on individual patient sensitivity, the daily dose may be increased to a maximum of 20 mg.
Antidepressant effect usually occurs within 2–4 weeks. After symptom remission, treatment should be continued for at least 6 months to consolidate the therapeutic effect.
Panic Disorders, with or without Agoraphobia
A starting dose of 5 mg per day is recommended during the first week, prior to increasing to 10 mg per day. The dose may subsequently be increased up to a maximum of 20 mg per day, depending on individual patient sensitivity.
Maximum therapeutic effect in panic disorders is achieved within 3 months. Treatment duration lasts several months and depends on disease severity.
Social Anxiety Disorder (Social Phobia)
The usual dose is 10 mg once daily. Usually, 2–4 weeks of therapy are required to alleviate symptoms. Subsequently, depending on individual patient response, the dose may be reduced to 5 mg or increased up to a maximum of 20 mg per day. Social anxiety disorder is a chronic condition, and treatment should be continued for at least 12 weeks to consolidate the therapeutic effect.
Long-term treatment for 6 months has been shown to prevent relapse and may be prescribed individually; the benefits of continued treatment should be regularly evaluated.
Social anxiety disorder is a clearly defined diagnostic term for a specific disorder and should not be confused with excessive shyness.
Pharmacological therapy is indicated only if the disorder significantly impairs professional or social functioning.
The relative efficacy of pharmacotherapy compared to cognitive-behavioral therapy has not been established. Pharmacotherapy is one component of an overall patient management strategy.
Generalized Anxiety Disorder
The usual dose is 10 mg once daily. Depending on individual sensitivity, the dose may be increased up to a maximum of 20 mg per day.
Long-term treatment has been studied for at least 6 months in patients receiving a daily dose of 20 mg; the benefits of treatment should be regularly evaluated (see section "Pharmacodynamics").
Obsessive-Compulsive Disorder (OCD)
The usual initial dose is 10 mg once daily. Depending on individual sensitivity, the dose may be increased up to 20 mg per day.
OCD is a chronic disorder, and treatment should continue for a sufficient duration to ensure complete symptom remission, which may take several months or longer. The benefit of treatment and dosage should be regularly assessed (see section "Pharmacodynamics").
Elderly Patients (aged 65 years and older)
The initial dose is 5 mg per day. Depending on individual sensitivity and severity of depression, the daily dose may be increased up to a maximum of 10 mg per day (see section "Pharmacokinetics").
The efficacy of escitalopram in elderly patients with social anxiety disorder has not been evaluated.
Pediatric Population
Cyclox® should not be used to treat children and adolescents (under 18 years of age) (see section "Children").
Renal Impairment
No dosage adjustments are required in patients with mild to moderate renal impairment. The drug should be used with caution in patients with severe renal impairment (CLCR <30 mL/min) (see section "Pharmacokinetics").
Hepatic Impairment
The recommended initial dose for patients with mild or moderate hepatic impairment is 5 mg per day for the first two weeks of treatment. Depending on individual patient response, the dose may be increased to 10 mg per day. The drug should be used with caution and dose titration should be carefully considered in patients with severe hepatic impairment (see section "Pharmacokinetics").
Reduced CYP2C19 Isoenzyme Activity
For patients with low CYP2C19 isoenzyme activity, the recommended initial dose for the first two weeks of treatment is 5 mg per day. Depending on individual patient response, the dose may be increased to 10 mg per day (see section "Pharmacokinetics").
Withdrawal Symptoms upon Discontinuation
Abrupt discontinuation of the drug should be avoided. When stopping treatment with escitalopram, the dose should be gradually reduced over at least 1–2 weeks to minimize the risk of withdrawal symptoms (see sections "Special Precautions" and "Adverse Reactions"). If intolerable symptoms occur after dose reduction or discontinuation, consideration should be given to resuming the previously prescribed dose. The physician may then continue tapering the dose more gradually.
Children
Antidepressants should not be used to treat children and adolescents (under 18 years of age). Suicidal behavior (suicidal attempts and suicidal thoughts) and hostility (mainly aggression, oppositional behavior, and anger) have been observed more frequently in clinical trials among children and adolescents treated with antidepressants compared to those receiving placebo. If, based on clinical judgment, a decision to prescribe is made, careful monitoring for the emergence of suicidal symptoms is required.
Overdose
Toxicity. Clinical data on escitalopram overdose are limited. Many cases involve concomitant overdose with other medicinal products. In most cases, mild symptoms or asymptomatic overdose were reported. Reports of fatal outcomes following escitalopram overdose are rare and mostly involve concomitant overdose with other medications. Doses of escitalopram ranging from 400–800 mg have not caused any severe symptoms.
Symptoms.
Signs of escitalopram overdose are primarily related to the central nervous system (from dizziness, tremor, and agitation to rare cases of serotonin syndrome, seizures, and coma), gastrointestinal system (nausea, vomiting), cardiovascular system (hypotension, tachycardia, QT interval prolongation, arrhythmias), and fluid/electrolyte imbalances (hypokalemia, hyponatremia).
Treatment.
There is no specific antidote. Maintain adequate respiratory function and ensure proper oxygenation. Gastric lavage should be performed as soon as possible after oral ingestion, followed by administration of activated charcoal. Continuous monitoring of cardiac and vital functions, along with symptomatic and supportive treatment, is recommended.
In cases of overdose, ECG monitoring is recommended for patients with congestive heart failure, bradyarrhythmias, those taking concomitant medications that prolong the QT interval, and those with impaired drug metabolism, such as patients with hepatic impairment.
Side effects
Adverse reactions most commonly occur during the first or second week of treatment and usually their frequency and intensity gradually decrease with continued treatment.
Adverse reactions known for SSRIs and escitalopram, observed during placebo-controlled studies and in clinical practice, are listed below by system organ class and frequency. Frequency is defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), or frequency not known (cannot be estimated from available data).
Blood and lymphatic system disorders: frequency not known – thrombocytopenia.
Immune system disorders: rare – anaphylactic reactions.
Endocrine disorders: frequency not known – syndrome of inappropriate antidiuretic hormone secretion, hyperprolactinemia.
Metabolism and nutrition disorders: common – decreased or increased appetite, weight gain; uncommon – weight loss; frequency not known – hyponatremia, anorexia1.
Psychiatric disorders: common – anxiety, restlessness, abnormal dreams, decreased libido, anorgasmia in women; uncommon – bruxism (teeth grinding), agitation, nervousness, panic attacks, confusion; rare – aggression, depersonalization, hallucinations; frequency not known – mania, suicidal thoughts, suicidal behavior2.
Nervous system disorders: very common – headache; common – insomnia, somnolence, dizziness, paraesthesia, tremor; uncommon – taste disturbance, sleep disorder, syncope (fainting); rare – serotonin syndrome; frequency not known – dyskinesia, movement disorders, seizures, psychomotor restlessness/akathisia1.
Eye disorders: uncommon – mydriasis (pupil dilation), visual disturbance.
Ear and labyrinth disorders: uncommon – tinnitus (ringing in the ears).
Cardiac disorders: uncommon – tachycardia; rare – bradycardia; frequency not known – QT interval prolongation on electrocardiogram, ventricular arrhythmia, including torsade de pointes.
Vascular disorders: frequency not known – orthostatic hypotension.
Respiratory, thoracic and mediastinal disorders: common – sinusitis, yawning; uncommon – epistaxis (nosebleed).
Gastrointestinal disorders: very common – nausea; common – diarrhea, constipation, vomiting, dry mouth; uncommon – gastrointestinal hemorrhage (including rectal).
Hepatobiliary disorders: frequency not known – hepatitis, changes in liver function tests.
Skin and subcutaneous tissue disorders: common – increased sweating; uncommon – rash, alopecia (hair loss), urticaria, pruritus; frequency not known – ecchymosis (bruising), edema.
Musculoskeletal and connective tissue disorders: common – arthralgia, myalgia.
Renal and urinary disorders: frequency not known – urinary retention.
Reproductive system and breast disorders: common – males: ejaculation disorders, impotence; uncommon – females: uterine bleeding (metrorrhagia), menorrhagia; frequency not known – galactorrhea; males: priapism; females: postpartum hemorrhage3.
General disorders and administration site conditions: common – fatigue, increased body temperature (pyrexia); uncommon – edema.
1 These cases are known for the entire SSRI class.
2 Cases of suicidal thoughts and behavior have been reported during treatment with escitalopram or shortly after discontinuation (see section "Special precautions").
3 Cases have been reported for the therapeutic class of SSRIs or SNRIs (see sections "Use during pregnancy or breastfeeding", "Special precautions").
QT interval prolongation
During the post-marketing period, cases of QT interval prolongation and ventricular arrhythmias, including polymorphic ventricular tachycardia (torsade de pointes), have been reported, primarily in women, patients with hypokalemia, and patients with pre-existing QT prolongation or other cardiac conditions (see sections "Contraindications", "Special precautions", "Interaction with other medicinal products and other forms of interaction", "Overdose", and "Pharmacodynamics").
Class effects
Epidemiological studies, conducted mainly in patients aged 50 years and older, have demonstrated an increased risk of bone fractures in patients receiving selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants. The mechanism leading to this increased risk is currently unknown.
Withdrawal symptoms
Discontinuation of SSRIs (especially abrupt) usually leads to withdrawal symptoms. Dizziness, sensory disturbances (including paraesthesia and electric shock sensations), sleep disturbances (including insomnia and vivid dreams), agitation or anxiety, nausea and/or vomiting, tremor, confusion, increased sweating, headache, diarrhea, palpitations, emotional instability, irritability, and visual disturbances are the most commonly reported reactions. Generally, these symptoms are mild to moderate and transient, but may be severe and/or prolonged in some patients. Therefore, it is recommended to gradually discontinue treatment with escitalopram by dose reduction (see sections "Special precautions", "Dosage and administration").
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life.
3 years.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach and sight of children.
Packaging.
14 tablets per blister, 2 or 4 blisters per cardboard pack.
Prescription status.
Prescription only.
Manufacturer.
Kusum Healthcare Pvt Ltd.
Manufacturer's address and location of operations.
Plot No. M-3, Indore Special Economic Zone, Phase-II, Pithampur, Distt. Dhar, Madhya Pradesh, Pin 454774, India.