Miracetol (Tablets) Instructions for Use

Marketing Authorization Holder

NANOLEK LLC (Russia)

ATC Code

N06AB10 (Escitalopram)

Active Substance

Escitalopram (Rec.INN registered by WHO)

Dosage Forms

	Miracetol	Film-coated tablets, 10 mg: 28 pcs.
		Film-coated tablets, 20 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white, oval, with a score on one side.

Excipients: croscarmellose sodium 4.5 mg, microcrystalline cellulose 100 mg, colloidal silicon dioxide 1.475 mg, talc 5 mg, magnesium stearate 1.25 mg.

Film coating composition Opadry II 85 F18422 white (polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide).

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

Film-coated tablets white, oval, with a score on one side.

Excipients: croscarmellose sodium 9 mg, microcrystalline cellulose 200 mg, colloidal silicon dioxide 2.95 mg, talc 10 mg, magnesium stearate 2.5 mg.

Film coating composition Opadry II 85 F18422 white (polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide).

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

Clinical-Pharmacological Group

Antidepressant

Pharmacotherapeutic Group

Antidepressant

Pharmacological Action

Escitalopram is an antidepressant, a selective serotonin reuptake inhibitor (SSRI). Inhibition of serotonin reuptake leads to an increase in the concentration of this neurotransmitter in the synaptic cleft, enhancing and prolonging its action on postsynaptic receptor sites.

Escitalopram has no or very weak ability to bind to a number of receptors, including: serotonin 5-HT_1A, 5-HT₂ receptors, dopamine D₁ and D₂ receptors, α₁-, α₂-, β₃-adrenergic receptors, histamine H₁, muscarinic cholinergic, benzodiazepine and opioid receptors.

Pharmacokinetics

Absorption is independent of food intake. The bioavailability of escitalopram is about 80%. The mean time to reach C_max in plasma is about 4 hours after multiple administration. The apparent volume of distribution (V_d,f/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 is metabolized in the liver to demethylated and didemethylated metabolites. Both are pharmacologically active. 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. Some involvement of the CYP3A4 and CYP2D6 isoenzymes is possible. In individuals with weak CYP2C19 isoenzyme activity, the concentration of escitalopram may be twice as high as in cases with high activity of this isoenzyme. No significant changes in drug concentration were found in cases with weak CYP2D6 isoenzyme activity.

The elimination half-life (T_1/2) after multiple administration is about 30 hours. The oral clearance (Cl_oral) is about 0.6 L/min. The main metabolites of escitalopram have a longer half-life.

Escitalopram and its main metabolites are eliminated by the liver (metabolic pathway) and kidneys. Most is excreted as metabolites in the urine. The kinetics of escitalopram are linear. Steady-state concentration (Css) is reached after about 1 week. A mean Css of 50 nmol/L (range 20 to 125 nmol/L) is achieved with a daily dose of 10 mg.

In elderly patients (over 65 years)

In the elderly (over 65 years), Escitalopram is eliminated more slowly than in younger patients. The amount of substance in the systemic circulation, calculated using the pharmacokinetic parameter AUC, is 50% greater in the elderly than in young healthy volunteers.

Reduced liver function

In patients with mild or moderate liver dysfunction (Child-Pugh criteria A and B), the T_1/2 of escitalopram is approximately twice as long, and the AUC is approximately 60% higher than in patients with normal liver function.

Reduced renal function

In patients with reduced renal function (creatinine clearance (CL_cr 10-53 ml/min)), a prolongation of T_1/2 and a slight increase in AUC are observed compared to racemic citalopram. The plasma concentration of metabolites was not determined, but it is likely that it may also increase.

Indications

Depressive disorders of any severity. Panic disorders with/without agoraphobia.

ICD codes

Dosage Regimen

Orally. Miracetol is prescribed to adults once a day, regardless of meals.

Depressive disorders

Usually prescribed 10 mg once daily. Depending on the individual patient 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, therapy should be continued for at least another 6 months to consolidate the achieved effect.

Panic disorders with/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 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.

Elderly patients (over 65 years)

It is recommended to use half the usual recommended dose (i.e., only 5 mg/day) and a lower maximum dose (10 mg/day).

Reduced renal function

No dose adjustment is required for mild to moderate renal impairment. Patients with severe renal impairment (creatinine clearance below 30 ml/min) should be prescribed Miracetol at the minimum therapeutic doses, gradually increasing them based on tolerance and effectiveness.

Reduced liver function

The recommended initial dose during the first two weeks of treatment is 5 mg/day. Depending on the individual patient response, the dose may be increased to 10 mg/day.

Reduced cytochrome CYP2C19 activity

For patients with weak CYP2C19 isoenzyme activity, the recommended initial dose during the first two weeks of treatment is 5 mg/day. Depending on the individual patient response, the dose may be increased to 10 mg/day.

Discontinuation of treatment

When discontinuing treatment with Miracetol, the dose should be gradually reduced over 1-2 weeks to avoid the occurrence of withdrawal syndrome.

Adverse Reactions

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

Nervous system disorders: rarely – asthenia, excessive fatigue, drowsiness or insomnia, anxiety, tremor, agitation, amnesia, apathy, extrapyramidal disorders, mood changes, aggressive behavior, hallucinations, depersonalization, emotional lability, euphoria, manic disorders, panic, psychotic disorders, serotonin syndrome (agitation, confusion, diarrhea, hyperthermia, hyperreflexia, ataxia, tremor, increased sweating, excitement, uncontrolled behavior).

Digestive tract disorders: rarely – dry mouth, nausea, vomiting, hypersalivation, flatulence, diarrhea, abdominal pain, anorexia.

Cardiovascular system disorders: rarely – bradycardia, decreased blood pressure, orthostatic hypotension, arrhythmia.

Hematopoietic organ disorders: rarely – thrombocytopenia, bleeding.

Sensory organ disorders: rarely – mydriasis, accommodation paresis, taste disturbance.

Reproductive system disorders: sexual dysfunction – ejaculation disorder, decreased libido, impotence; menstrual cycle disorders.

Allergic reactions: skin rash, rarely – toxic epidermal necrolysis, rhinitis, sinusitis.

Other: rarely – hyperthermia, polyuria, mastodynia, galactorrhea, hyponatremia, urination disorder, arthralgia, myalgia, yawning, teeth grinding, increase or decrease in body weight, dyspnea.

In addition, after long-term use, abrupt discontinuation of Miracetol therapy in some patients may lead to the occurrence of withdrawal syndrome. Upon abrupt discontinuation of escitalopram, adverse reactions such as dizziness, headache and nausea may occur, the severity of which is insignificant and the duration is limited.

Contraindications

Hypersensitivity, childhood, pregnancy, lactation period, concurrent administration with monoamine oxidase inhibitors (MAOIs), sumatriptan and other serotonergic drugs.

With caution. Presence of drug dependence (including history), hepatic and/or renal failure, manic disorders, seizure disorders, pregnancy, lactation period, elderly age, childhood (efficacy and safety of use not established); pharmacologically uncontrolled epilepsy, depression with suicide attempts, diabetes mellitus, tendency to bleeding; concurrent use with drugs that lower the seizure threshold, cause hyponatremia; with ethanol; with drugs metabolized with the participation of the CYP2C19 isoenzyme system.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation.

Use in Hepatic Impairment

With caution: hepatic failure.

In reduced liver function, the recommended initial dose during the first two weeks of treatment is 5 mg/day. Depending on the individual patient response, the dose may be increased to 10 mg/day.

Use in Renal Impairment

With caution: renal failure.

No dose adjustment is required for mild to moderate renal impairment. Patients with severe renal impairment (creatinine clearance below 30 ml/min) should be prescribed Miracetol at the minimum therapeutic doses, gradually increasing them based on tolerance and effectiveness.

Pediatric Use

Contraindicated in children.

Geriatric Use

In elderly patients, it is recommended to use half the usual recommended dose (i.e., only 5 mg/day) and a lower maximum dose (10 mg/day).

In the elderly (over 65 years), Escitalopram is eliminated more slowly than in younger patients. The amount of substance in the systemic circulation, calculated using the pharmacokinetic parameter AUC, is 50% greater in the elderly than in young healthy volunteers.

Special Precautions

The use of antidepressants, including escitalopram, especially in children, adolescents and young people under 24 years of age, may lead to an increase in suicidal behavior. For this reason, especially at the beginning of the course of treatment and during the first months of treatment, when changing the drug dose, both upwards and downwards, or when discontinuing the drug, patients should be closely monitored for suicidal behavior or other changes, such as agitation and/or irritability.

Paradoxical anxiety

In some patients with panic disorders, manifestations of anxiety may be observed at the beginning of treatment with antidepressants. In most cases, these paradoxical reactions resolve within 2 weeks of starting therapy. To reduce the likelihood of an anxiogenic effect, low initial doses are recommended.

Seizure threshold

If seizure episodes develop, the drug should be discontinued immediately. SSRIs should not be prescribed to patients with uncontrolled epilepsy; in case of controlled seizures, careful monitoring is necessary. If the frequency of seizures increases, SSRIs, including Escitalopram, should be discontinued.

Mania

SSRIs should be used with caution in patients with a history of manic disorders. If a manic state develops, Escitalopram should be discontinued.

Diabetes mellitus

In patients with diabetes mellitus, treatment with SSRIs may change blood glucose levels. Therefore, adjustment of insulin and/or oral hypoglycemic drug doses may be required.

Hyponatremia

Cases of hyponatremia, possibly associated with impaired secretion of antidiuretic hormone (ADH), have been reported with the use of SSRIs. For this reason, SSRIs should be prescribed with caution to persons at risk of developing hyponatremia: the elderly, patients with liver cirrhosis and those taking drugs that can cause hyponatremia.

Hemorrhages

Cases of skin hemorrhages: ecchymosis and purpura, have been observed with the use of SSRIs. SSRIs should be used with caution in patients with a tendency to bleeding, as well as those taking oral anticoagulants and drugs affecting blood clotting (for example, atypical antipsychotics and phenothiazine, most tricyclic antidepressants, acetylsalicylic acid and NSAIDs – non-steroidal anti-inflammatory drugs).

ECT (electroconvulsive therapy)

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

Reversible, selective MAO-A inhibitors

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

Serotonin syndrome

Caution should be exercised when co-administering escitalopram and serotonergic drugs such as sumatriptan, other substances of the triptan group, tramadol and tryptophan. However, the development of serotonin syndrome in patients receiving serotonergic drugs and SSRIs simultaneously has been extremely rare. Signs such as agitation, tremor, myoclonus and hyperthermia may indicate the development of this syndrome. In this case, the simultaneous use of the SSRI and the serotonergic drug should be discontinued immediately and symptomatic therapy initiated.

Use in children

The use of the drug in children is not recommended, as its efficacy and safety in children have not been fully studied.

Effect on ability to drive vehicles or machinery

Although Escitalopram does not affect psychomotor activity, it is not recommended to drive vehicles or machinery during the treatment period.

Overdose

Symptoms: dizziness, tremor, agitation, increased sweating, drowsiness, depression of consciousness of varying severity, convulsions, sinus tachycardia, ECG changes (changes in ST segment and T wave, QRS complex widening, QT interval prolongation), arrhythmia, ventricular arrhythmia, cyanosis, respiratory depression, vomiting, rhabdomyolysis, metabolic acidosis, hypokalemia, very rarely – acute renal failure.

Treatment: there is no specific antidote. Treatment is symptomatic and supportive – gastric lavage, adequate oxygenation. Monitoring of cardiovascular and respiratory system functions.

Drug Interactions

MAO inhibitors (MAOIs)

In patients taking selective serotonin reuptake inhibitors (SSRIs) concomitantly with monoamine oxidase inhibitors (MAOIs), or in patients starting MAOI treatment immediately after SSRI therapy, serious adverse reactions may occur. Escitalopram should not be prescribed concomitantly with MAOIs. Treatment with escitalopram should be started 14 days after discontinuation of a course of irreversible MAOIs and at least 1 day after cessation of therapy with the reversible MAO-A inhibitor moclobemide. Treatment with escitalopram should be discontinued 7 days before starting treatment with MAOIs.

Combinations of drugs requiring careful prescribing: Serotonergic drugs.

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

Drugs that lower the seizure threshold

Miracetol may lower the seizure threshold. Therefore, caution is required when co-prescribing other drugs that lower the seizure threshold (antidepressants (tricyclics, other SSRIs), neuroleptics (phenothiazines, thioxanthenes, butyrophenones), mefloquine, bupropion and tramadol).

Lithium, tryptophan

Miracetol enhances the pharmacological effects of tryptophan (enhanced serotonergic effect) and the toxic effects of lithium preparations.

Hypericum perforatum (St. John’s wort)

Concomitant administration of SSRIs and preparations containing St. John’s wort (Hypericum perforatum) may lead to an increased incidence of side effects.

Anticoagulants and other medicines affecting blood coagulation

Impaired blood coagulation may occur with the concomitant administration of escitalopram and oral anticoagulants and other medicines that affect blood coagulation (for example, atypical antipsychotics and phenothiazines, most tricyclic antidepressants, acetylsalicylic acid and non-steroidal anti-inflammatory drugs, ticlopidine and dipyridamole). In such cases, monitoring of blood coagulation parameters is necessary.

Alcohol (ethanol)

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

Pharmacokinetic interactions

Effect of other medicines on the pharmacokinetics of escitalopram

Escitalopram is primarily metabolized with the participation of the CYP2C19, CYP3A4, and CYP2D6 isoenzymes. Caution should be exercised when co-administered with CYP2C19 inhibitors (omeprazole, esomeprazole, fluvoxamine, lansoprazole, ticlopidine) or with cimetidine. Concomitant use of escitalopram with omeprazole (a CYP2C19 inhibitor) at a single daily dose of 30 mg led to an increase (approximately 50%) in the plasma concentration of escitalopram. Caution should also be exercised when prescribing high doses of escitalopram concomitantly with high doses of cimetidine, which is a strong inhibitor of the CYP2D6, CYP3A4, and CYP1A2 isoenzymes. A dose reduction of escitalopram may be required depending on adverse reactions.

Effect of escitalopram on the pharmacokinetics of other medicines

Escitalopram is an inhibitor of the CYP2D6 isoenzyme. Caution should be exercised when co-administering escitalopram and medicines metabolized by this isoenzyme that have a narrow therapeutic index, for example, flecainide, propafenone, and metoprolol (in cases of use for heart failure) or medicinal products primarily metabolized via CYP2D6 and acting on the CNS, for example, antidepressants – desipramine, clomipramine, nortriptyline, or antipsychotics – risperidone, thioridazine, haloperidol. In these cases, a dose adjustment may be required because the plasma concentration of escitalopram increases.

Concomitant administration of escitalopram and desipramine or metoprolol leads to a twofold increase in the concentration of the latter two drugs, which should be taken into account when selecting doses.

Escitalopram may weakly inhibit the CYP2C19 isoenzyme. Therefore, caution is recommended when using escitalopram concomitantly with medicinal products metabolized by CYP2C19.

Storage Conditions

Store the medicine at a temperature not exceeding 25°C (77°F). Keep out of the reach of children.

Shelf Life

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

Dispensing Status

The medicine 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.