Ципралекс

General characteristics. Structure:

Active ingredient: 6,39 mg, 12,77 mg or 25,54 mg of an estsitalopram of oxalate that 5 mg, 10 mg or  20 mg of an estsitalopram are equivalent.

Excipients: talc, croscarmellose sodium, cellulose microcrystallic, silicon dioxide colloid, magnesium stearate.

Cover: gipromelloza, macrogoal 400, titanium dioxide (Е 171).

Pharmacological properties:

Pharmacodynamics. Estsitalopram is antidepressant, the selective serotonin reuptake inhibitor (SSRI) with high affinity to primary place of binding. Estsitalopram also contacts the allosteric place of binding of protein conveyor, affinity smaller in one thousand times. Allosteric modulation of protein conveyor strengthens binding of an estsitalopram in primary place of binding that leads to more complete inhibition of the return serotonin reuptake.

Estsitalopram has no absolutely or has very weak ability to contact a number of receptors, including: serotoninovy 5-HT1A, 5-NT2 receptors, dopamine D1 and D2 receptors, α1-, α2-, β-adrenergic receptors, histamine H1 muskarinovy cholinergic, benzodiazepine and opiate receptors.

Pharmacokinetics. Absorption almost full also does not depend on meal. The average time of achievement of the maximum concentration in a blood plasma (Tmax) makes 4 hours after repeated use. Absolute bioavailability of an estsitalopram makes about 80%.

The seeming distribution volume (Vd, β/F) after oral administration makes from 12 to 26 l/kg. Linkng of an estsitalopram and its main metabolites with proteins of a blood plasma is lower than 80%. Estsitalopram is metabolized in a liver to demetilirovanny and didemetilirovanny metabolites. Both of them are pharmacological active. Nitrogen can be oxidized to a N-oxide metabolite. The main substance and its metabolites are partially emitted in the form of glucuronides. After repeated use average concentration demetil-and didemetil-metabolites usually makes 28-31% and less than 5%, respectively, of concentration of an estsitalopram. Biotransformation of an estsitalopram in a demetilirovanny metabolite happens mainly to the help of an isoenzyme of CYP2C19. Perhaps some participation of isoenzymes of CYP3A4 and CYP2D6. At persons with weak activity of an isoenzyme of CYP2C19 concentration of an estsitalopram is twice higher, than in cases with high activity of this isoenzyme. Considerable changes of concentration of drug in cases with weak activity of an isoenzyme of CYP2D6 it was revealed not.

The elimination half-life (T1/2) after repeated use makes about 30 hours. The clearance at oral administration (Cloral) makes about 0,6 l/min. At the main metabolites of an estsitalopram the elimination half-life is more long. Estsitalopram and his main metabolites are removed by a liver (a metabolic way) and kidneys; the most part is removed in the form of metabolites with urine.

The kinetics of an estsitalopram is linear. Equilibrium concentration is reached approximately in 1 week. Average equilibrium concentration the 50th nmol/l (from 20 to 125 nmol/l) is reached at a daily dose of 10 mg.

At elderly (65 years are more senior) to estsitalopra it is removed more slowly, than at younger patients. The amount of the substance which is in a system blood-groove (AUC) calculated by means of a pharmacokinetic indicator "the area under a curve" at elderly is 50% more, than at young healthy volunteers.

Indications to use:

- Depressive episodes of any severity.
- Panic frustration with/without agoraphobia.
- Social alarming frustration (social phobia).
- Generalized alarming frustration.
- Obsessivno-kompulsivnoye frustration.

Route of administration and doses:

Ципралекс appoint orally once a day regardless of meal.

Depressive episodes.

Usually appoint 10 mg once a day. Depending on individual reaction of the patient the dose can be increased to maximum – 20 mg/days.

The antidepressive effect usually develops in 2-4 weeks after an initiation of treatment. After disappearance of symptoms of a depression, at least, within 6 months it is necessary to continue therapy for fixing of the gained effect.

Panic frustration with/without agoraphobia.

Within the first week of treatment the dose of 5 mg/days which then increases to 10 mg/days is recommended. Depending on individual reaction of the patient the dose can be increased to maximum – 20 mg/days.

The maximum therapeutic effect is reached approximately in 3 months after an initiation of treatment. Therapy lasts several months.

Social alarming frustration (social phobia).

Usually appoint 10 mg once a day. Depending on individual reaction of the patient the dose can be increased to maximum – 20 mg/days. Weakening of symptoms usually develops in 2-4 weeks after an initiation of treatment.

As social alarming frustration is a disease with a chronic current, the minimum recommended duration of a therapeutic course makes 3 months. For prevention of a recurrence of a disease drug can be appointed within 6 months or longer depending on individual reaction of the patient. It is recommended to carry out assessment of the carried-out treatment regularly.

Generalized alarming frustration.

Usually appoint 10 mg once a day. Depending on individual reaction of the patient the dose can be increased to maximum – 20 mg/days.

The minimum recommended duration of a therapeutic course makes 3 months. For prevention of a recurrence of a disease prolonged use of drug is allowed (6 months and longer). It is recommended to carry out assessment of the carried-out treatment regularly.

Obsessivno-kompulsivnoye frustration.

Usually appoint 10 mg once a day. Depending on individual reaction of the patient the dose can be increased afterwards to maximum – 20 mg/days.

As obsessivno-compulsive frustration is a disease with a chronic current, the course of treatment has to be rather long for ensuring full disposal of symptoms and last, at least, 6 months. For prevention of a recurrence treatment is recommended not less than 1 year.

Elderly patients (65 years are more senior).

It is recommended to apply a half of usually recommended dose (i.e. only 5 mg/days) and lower maximum dose (10 mg/days).

Reduced function of kidneys. At a slight and moderate renal failure of correction of doses it is not required. Patients with the expressed renal failure (KK lower than 30 ml/min.) should appoint Tsipraleks with care.

Reduced function of a liver. The recommended initial dose within the first two weeks of treatment makes 5 mg/days. Depending on individual reaction of the patient the dose can be increased to 10 mg/days.

Reduced activity of an isoenzyme of CYP2C19. For patients with weak activity of an isoenzyme of CYP2C19 the recommended initial dose within the first two weeks of treatment makes 5 mg/days. Depending on individual reaction of the patient the dose can be increased to 10 mg/days.

Treatment termination. At the termination of treatment by Tsipraleks the dose should be reduced gradually within 1-2 weeks in order to avoid emergence of a syndrome of "cancellation".

Features of use:

Should not appoint antidepressants children and teenagers aged up to 18 years because of the increased risk of emergence of suicide behavior (attempts of a suicide and suicide thoughts), hostility (with dominance of an agressive behavior, tendency to confrontation and irritations). In case of acceptance on the basis of clinical assessment of the decision on the beginning of therapy by antidepressants the patient has to be under careful observation.

At use of the drugs belonging to the SIOZS therapeutic group, including estsitalopra, it is necessary to consider the following.

At some patients with panic frustration in an initiation of treatment antidepressants strengthening of alarm can be observed. Similar paradoxical reaction usually disappears within the first two weeks of treatment. To reduce probability of emergence of anksiogenny effect it is recommended to use low initial doses.

It is necessary to cancel to estsitalopra in case of primary development of convulsive attacks or in case of strengthening of their frequency (at patients with earlier diagnosed epilepsy). SIOZS should not be applied at patients with unstable epilepsy; at controlled attacks careful observation is necessary.

Estsitalopram has to be applied with care at patients with a mania/hypomania in the anamnesis. At development of a maniacal state to estsitalopra it has to be cancelled.

Patients with a diabetes mellitus have a treatment estsitalopramy can change concentration of glucose in blood. Therefore correction of doses of insulin and/or peroral hypoglycemic drugs can be required.

The depression is connected with the increased risk of emergence of suicide thoughts, drawings to itself injuries and a suicide (the suicide phenomena). This risk remains before the expressed remission. As improvements it can not be observed within the first several weeks of therapy or even a bigger period, patients have to be under constant observation before improvement of their state.
The general clinical practice shows that at early stages of recovery increase in risk of suicide is possible.

Other mental states for which treatment appoint to estsitalopra can be connected with the increased risk of emergence of suicide events and the phenomena also. Besides, these states can be the accompanying pathology in relation to a depressive episode. At treatment of patients with other mental disorders it is necessary to observe the same precautions that at treatment of patients with a depressive episode.

The patients having suicide behavior in the anamnesis or patients with the significant level of reflection on suicide subjects prior to treatment are more subject to risk of suicide thoughts or attempts of a suicide therefore during treatment behind them careful observation has to be conducted. Placebo meta-analysis - controlled clinical trials of antidepressants with participation of adult patients with mental disturbances showed that at reception of antidepressants patients more young have than 25 years an increased risk of suicide behavior in comparison with placebo reception. Drug treatment of these patients and, in particular, patients with a suicide high risk, has to be followed by careful observation, especially at an early stage of treatment and at changes of a dose.

Patients (and the persons who are looking after patients) have to be warned about need to control any manifestations of clinical deterioration, suicide behavior or thoughts, and also unusual changes in behavior, and to address immediately for medical consultation at emergence of these symptoms.

Reception of SIOZS/SIOZSN is associated with development of the akathisia which is characterized by development of subjectively unpleasant or oppressing concern and the need for the constant movement is frequent in combination with inability to sit or stand quietly. It is most often shown within the first several weeks of treatment. At patients with such symptoms increase in a dose can lead to deterioration.

The hyponatremia which is perhaps connected with disturbance of secretion of antidiuretic hormone (ADG) against the background of reception of SIOZS arises seldom and usually disappears at therapy cancellation. Care has to be shown at purpose of an estsitalopram and others by SIOZS to the persons entering into risk group of development of a hyponatremia: elderly, sick with cirrhosis and accepting the drugs capable to cause a hyponatremia.

At reception of SIOZS cases of development of skin hemorrhages (an ecchymoma and a purpura) were noted. It is necessary to apply with care to estsitalopra at the patients accepting the peroral anticoagulants and drugs influencing coagulability of blood and also at patients with tendency to bleedings.

As clinical experience of simultaneous use of SIOZS and electroconvulsive therapy (EST) is limited, at simultaneous use of an estsitalopram and EST it is necessary to be careful.

It is not recommended to combine to estsitalopra and MAO A inhibitors because of risk of development of a serotoninovy syndrome. It is necessary to apply with care to estsitalopra along with the medicines possessing serotonergic action, for example, sumatriptany or other triptanes, tramadoly and tryptophane. At the patients accepting to estsitalopra and others SIOZS along with serotonergic drugs, in rare instances developed a serotoninovy syndrome. The combination of such symptoms as agitation, a tremor, a myoclonus and a hyperthermia can indicate its development. If it occurred, it is necessary to stop immediately simultaneous treatment of SIOZS and serotonergic drugs and to begin a symptomatic treatment.

Alcohol. Estsitalopram does not enter with alcohol pharmakodinamichesky or pharmacokinetic interaction. However, as well as in a case with other psychotropic medicines, simultaneous use of an estsitalopram and alcohol is not recommended.

Use at pregnancy and during breastfeeding. There are limited data on reception of an estsitalopram during pregnancy.

If reception of an estsitalopram continued on late durations of gestation, especially in the third trimester, then for the newborn it is necessary to establish observation. If reception of an estsitalopram continued up to childbirth or was stopped shortly before childbirth, at the newborn development of symptoms of "cancellation" is possible.

In case of reception by mother of SIOZS/SIOZSN on late durations of gestation at the newborn the following side effects can develop: respiratory depression, cyanosis, an apnoea, convulsive frustration, jumps of temperature, difficulty with feeding, vomiting, a hypoglycemia, a hypertension, a hypomyotonia, a hyperreflexia, a tremor, the increased nervnokreflektorny excitability, irritability, a lethargical sleep, constant crying, drowsiness, a bad dream. These symptoms can arise owing to development of a syndrome of "cancellation" or serotonergic action. In most cases similar complications arise within 24 hours after the birth.

Estsitalopram during pregnancy it is necessary to accept only in cases of emergency and after careful assessment of a ratio advantage/risk.

Data of epidemiological researches allow to assume that use of SIOZS during pregnancy, especially on late terms, can increase risk of development of steady pulmonary hypertensia in the newborn.

It is expected that to estsitalopra will be выделятья with breast milk therefore during treatment estsitalopramy feeding by a breast is not recommended.

Influence on ability to drive the car or mechanisms. In spite of the fact that Tsipraleks does not influence intellectual functions and psychomotor activity, during treatment by the patient it is not recommended to drive the car or mechanisms.

Side effects:

Side effects most often develop on the first or second week of treatment and then usually become less intensive and arise less often at therapy continuation.

The side effects arising at administration of drugs, belonging to class SIOZS and noted at reception of an estsitalopram are listed below. Information is provided on the basis of these placebos - controlled clinical trials and spontaneous messages.

Frequency is specified as: very often (≥1/10), it is frequent (from ≥1/100 to <1/10), infrequently (from ≥1/1000 to <1/100), is rare (from ≥1/10000 to <1/1000), is very rare (<1/10000), or it is unknown (frequency of emergence cannot be estimated on the basis of the existing data).

From blood and lymphatic system: it is unknown – thrombocytopenia.

From immune system: seldom – anaphylactic reactions.

From endocrine system: it is unknown – insufficient secretion of antidiuretic hormone (ADG).
Metabolic disturbances and frustration of food: often – a loss of appetite, increase in appetite, increase in weight; infrequently – weight reduction; it is unknown – a hyponatremia, anorexia.

From mentality: often – alarm, concern, unusual dreams, decrease in a libido, an anorgazmiya (at women); infrequently – a bruxism, agitation, nervousness, the panic attacks, confusion of consciousness; seldom – aggression, depersonalization, hallucinations; it is unknown – a mania, suicide thoughts, suicide behavior. Cases of emergence of suicide thoughts and behavior were noted at reception of an estsitalopram and right after therapy cancellation.

From a nervous system: often – sleeplessness, drowsiness, dizziness, paresthesias, a tremor; infrequently – disturbances of flavoring feelings, a sleep disorder, syncopal states; seldom – a serotoninovy syndrome; it is unknown – dyskinesia, motive disturbances, convulsive frustration, psychomotor excitement / akathisia.

From organs of sight: infrequently – a mydriasis (mydriasis), vision disorders.

From an acoustic organ and labyrinth disturbances: infrequently – тиннитус (sonitus).

From cardiovascular system: infrequently – tachycardia; seldom – bradycardia; it is unknown – lengthening of an interval of QT on the electrocardiogram, orthostatic hypotension.

From respiratory system, bodies of a thorax and a mediastinum: often – sinusitis, yawning; infrequently – nasal bleeding

From digestive tract: very often – nausea; often – diarrhea, locks, vomiting, dryness in a mouth; infrequently – gastrointestinal bleeding (including rectal bleeding).

From a liver and biliary tract: it is unknown – hepatitis, disturbances of functional indicators of a liver.

From skin and hypodermic fabrics: often – the increased perspiration; infrequently – a small tortoiseshell, an alopecia, rash, an itch; it is unknown – an ecchymoma, a Quincke's disease.

From skeletal and muscular and connecting fabric: often – an arthralgia, a mialgiya.

From kidneys and urinary tract: it is unknown – an ischuria.

From reproductive system and a mammary gland: often – impotence, disturbance of an ejaculation; infrequently – a metrorrhagia (uterine bleeding), a menorrhagia; it is unknown – a galactorrhoea, a priapism.

From an organism in general and disturbances in an injection site: often – weakness, a hyperthermia; infrequently – hypostases.

During the post-registration period cases of lengthening of an interval of QT, generally at patients with earlier existing heart diseases were noted. In double-blind placebos - controlled researches ECG at healthy volunteers change from basic QTc value (correction on a formula of Friderichia) made 4,3 ms at a dose of 10 mg/days and 10,7 ms – at 30 mg/days.

Epidemiological researches with participation of patients at the age of 50 years are also more senior showed existence of the increased risk of bone changes at the patients accepting SIOZS and tricyclic antidepressants. The origins of this risk are not established.

Cancellation of drugs of the SIOZS/SIOZSN group (the selection inhibitors of the return capture of noradrenaline and serotonin) (especially sharp) often leads to emergence of symptoms of "cancellation". Most often there are dizziness, disorders of sensitivity (including paresthesias and feelings of passing of current), frustration of a dream (including sleeplessness and intensive dreams), agitation or alarm, nausea and/or vomiting, a tremor, confusion of consciousness, the increased sweating, a headache, diarrhea, heartbeat, emotional instability, irritability, visual disturbances. As a rule these effects are expressed poorly or moderately and quickly pass, however, at some patients they can be shown in more acute form and/or is longer. It is recommended to carry out gradual drug withdrawal by decrease in its dose.

Interaction with other medicines:

Pharmakodinamichesky interaction. MAO non-selective irreversible inhibitors. It was reported about emergence of serious undesirable reactions at a concomitant use of SIOZS and the MAO non-selective irreversible inhibitors, and also at the beginning of reception of MAO inhibitors by patients, shortly before it stopped reception of SIOZS. In certain cases at patients the serotoninovy syndrome developed.

It is forbidden to apply to estsitalopra along with the MAO non-selective irreversible inhibitors. Reception of an estsitalopram can be begun in 14 days after cancellation of reception of the MAO irreversible inhibitors. Before reception of the MAO non-selective irreversible inhibitors there have to pass not less than 7 days after the end of reception of an estsitalopram.

MAO A reversible selection inhibitor (моклобемид). Because of risk of development of a serotoninovy syndrome estsitalopra are not recommended to apply along with MAO A inhibitor moklobemidy. If reception of such combination of drugs is recognized as clinically necessary, it is recommended to begin with minimum possible doses, and also to carry out continuous clinical monitoring of a condition of the patient. Reception of an estsitalopram can be begun, at least, in one day after cancellation of the MAO A reversible inhibitor of a moklobemid.

MAO B irreversible inhibitor (селегилин). Because of risk of development of a serotoninovy syndrome it is necessary to be careful at reception of an estsitalopram along with the MAO B irreversible inhibitor selegiliny.

Serotonergic medicines. Combined use with serotonergic medicines (for example, tramadoly, sumatriptany and other triptanes) can lead to development of a serotoninovy syndrome.

The medicines reducing a threshold of convulsive readiness. SIOZS can reduce a threshold of convulsive readiness. It is required to show care at simultaneous with estsitalopramy use of other medicines reducing a threshold of convulsive readiness (tricyclic antidepressants, SIOZS, antipsychotic drugs (neuroleptics) – derivatives of a fenotiazin, thioxanthene and phenyl propyl ketone, a meflokhin, a bupropion and a tramadol).

Lithium, tryptophane. As cases of strengthening of action at simultaneous use of SIOZS and lithium or tryptophane are registered, it is recommended to show care at simultaneous use of an estsitalopram with these drugs.

The St. John's Wort which is made a hole. Simultaneous use of SIOZS and the drugs containing a St. John's Wort made a hole (Hypericum perforatum) can lead to increase in number of side effects.

The anticoagulants and means influencing coagulability of blood. Disturbance of coagulability of blood can arise at simultaneous use of an estsitalopram with the peroral anticoagulants and medicines influencing coagulability of blood (for example, atypical neuroleptics and derivatives of a fenotiazin, the majority of tricyclic antidepressants, acetylsalicylic acid and non-steroidal anti-inflammatory drugs, tiklopidiny and Dipiridamolum). In similar cases at the beginning or the end of therapy estsitalopramy careful monitoring of coagulability of blood is necessary.

The concomitant use with non-steroidal anti-inflammatory drugs can lead to increase in number of bleedings.

Pharmacokinetic interaction. Influence of other medicines on pharmacokinetics of an estsitalopram. Metabolism of an estsitalopram is generally carried out with the participation of CYP2C19 isoenzyme. To a lesser extent isoenzymes of CYP3A4 and CYP2D6 can take part in metabolism. Metabolism of the main metabolite – a demetilirovanny estsitalopram – probably, is partially catalyzed by CYP2D6 isoenzyme.

Simultaneous use of an estsitalopram and omeprazol (CYP2C19 isoenzyme inhibitor) brings to moderate (about 50%) to increase in concentration of an estsitalopram in a blood plasma.

The concomitant use of an estsitalopram and Cimetidinum (inhibitor of isoenzymes CYP2D6, CYP3A4 and CYP1A2) leads to increase (about 70%) in concentration of an estsitalopram in a blood plasma.

Thus, it is necessary to apply the greatest possible doses of an estsitalopram along with CYP2C19 isoenzyme inhibitors (for example, omeprazoly, fluoxetine, fluvoksaminy, lansoprazoly, tiklopidiny) and Cimetidinum with care. At a concomitant use of an estsitalopram and the above-stated drugs on the basis of clinical assessment reduction of a dose of an estsitalopram can be required.

Influence of an estsitalopram on pharmacokinetics of other medicines. Estsitalopram is CYP2D6 isoenzyme inhibitor. It is necessary to show care at the simultaneous use of an estsitalopram and medicines which are metabolized by means of this isoenzyme and having a small therapeutic index, for example, of a flekainid, a propafenona and a metoprolola (in use cases at heart failure) or the medical supplies which are generally metabolized by means of CYP2D6 and operating on TsNS, for example, of antidepressants: desipramine, klomipramin, nortriptilin or antipsychotic drugs: risperidona, thioridazine, haloperidol. In these cases dose adjustment can be required.

Simultaneous use of an estsitalopram and desipramine or metoprolol leads to double increase in concentration of two last drugs.

Estsitalopram can slightly inhibit CYP2C19 isoenzyme. Therefore it is recommended to show care at simultaneous use of an estsitalopram and medicines, metabolized CYP2C19 isoenzyme.

Contraindications:

Hypersensitivity to an estsitalopram and other components of drug; concomitant use of non-selective irreversible inhibitors of a monoaminooxidase (MAO); concomitant use of Pimozidum.

With care: the expressed renal failure (the clearance of creatinine (CC) is lower than 30 ml/min.), a mania and a hypomania, pharmacological uncontrollable epilepsy, the expressed suicide behavior, a diabetes mellitus, cirrhosis, tendency to bleedings; a concomitant use with MAO A inhibitor (moklobemidy) and MAO B inhibitor (selegiliny); serotonergic medicines; the drugs reducing a threshold of convulsive readiness; the lithium, tryptophanes, medicines containing the St. John's Wort which is made a hole; the peroral anticoagulants and medicines influencing coagulability of blood; the drugs capable to cause a hyponatremia; the drugs which are metabolized with participation of an isoenzyme of CYP2C19; ethanol; electroconvulsive therapy; advanced age, children's and teenage age (up to 18 years); pregnancy, breastfeeding period.

Overdose:

Data on overdose estsitalopramy are limited, in many such cases there was also an overdose other drugs. In most cases symptoms of overdose are not shown or shown poorly.

Overdose cases estsitalopramy (without reception of other drugs) with a lethal outcome are single, also the overdose and other drugs in most cases takes place.

Symptoms. At overdose estsitalopramy generally there are symptoms from the central nervous system (from dizziness, a tremor and agitation prior to exceptional cases of development of a serotoninovy syndrome, convulsive frustration and a coma), from digestive tract (nausea/vomiting), cardiovascular system (hypotension, tachycardia, lengthening of an interval of QT and arrhythmia) and disturbances of electrolytic balance (a hypopotassemia, a hyponatremia).

Treatment. The specific antidote does not exist. It is necessary to provide normal passability of respiratory tracts, oxygenation and ventilation of the lungs. It is necessary to carry out a gastric lavage and to appoint absorbent carbon. The gastric lavage should be carried out as soon as possible after administration of drug. It is recommended to control indicators of cardiac performance and other vitals and to carry out a symptomatic and maintenance therapy.

Storage conditions:

At a temperature not above 25 °C. To store in places, unavailable to children. A period of storage - 3 years. Not to use after the termination of the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 5 mg, 10 mg and 20 mg. Packagings: 5 mg – 28 pieces; 10 mg – 14 pieces, 28 pieces and 56 pieces; 20 mg – 28 pieces. On 14 tablets in a blister strip packaging (blister) from PVH/PE/PVDH and aluminum foil. 1, 2 or 4 blisters with the application instruction in a cardboard pack.