Tsitalopram

General characteristics. Structure:

Active ingredient: 12,5 mg, 25,0 mg and 50,0 mg of a tsitalopram hydrobromide that there correspond 10 mg, 20 mg and 40 mg of a tsitalopram.

Excipients: cellulose microcrystallic, starch prezhelatinizirovanny, magnesium stearate, Opadray of II (polyvinyl alcohol, macrogoal, talc, titanium dioxide).

The drug appointed by the specialist doctor (usually the psychiatrist) at depressive episodes of average and heavy degree, and also panic frustration. Tsitalopram does not exert impact on serumal levels of prolactin and a growth hormone. Tsitalopram does not worsen cognitive/intellectual functions and psychomotor function and practically does not possess sedation. Tsitalopram has no the expressed toxicity concerning heart, however, care is necessary if high doses of Tsitalopram are appointed (more than 40 mg a day) or if along with Tsitalopram other medicines, especially those which influence increase in an interval of QT on the electrocardiogram are appointed.

Tsitalopram treats antidepressants of new generation with good tolerance, low toxicity and high safety in case of overdoses.

Pharmacological properties:

Pharmacodynamics. Tsitalopram – the antidepressant relating to group of the selective serotonin reuptake inhibitors (SSRI). Has the expressed ability to suppress the return serotonin reuptake, has no or has very weak ability to contact a number of receptors, including receptors of piperidic acid (GAMK), H1-histamine, D1-and D2 - dopamine; alfa1-, alfa2-, beta and adrenergic; benzodiazepine and m-holinoretseptory that causes almost total absence of such undesirable effects as negative hrono-, dromo-and inotropic action, orthostatic hypotension, sedation and dryness in a mouth. Tsitalopram only in very small degree inhibits CYP2D6 isoenzyme, and, therefore, practically does not interact with the medicines which are metabolized this enzyme. Thus, side effects and toxic action it is shown in much smaller degree.

The antidepressive effect usually develops after 2-4 weeks of treatment.

Tsitalopram does not exert impact on serumal levels of prolactin and a growth hormone.

Tsitalopram does not worsen cognitive/intellectual functions and psychomotor function and practically does not possess sedation.

Tsitalopram in doses of the exceeding 40 mg a day can cause abnormal changes of electric activity of heart (lengthening of an interval of QT on an ECG).

Pharmacokinetics. Bioavailability of a tsitalopram makes 80% and practically does not depend on meal. The maximum concentration (Cmax) in plasma is reached on average in 3 hours. The pharmacokinetics has linear dozozavisimy character at reception single and repeated doses (a dose in the range of 10-60 mg a day). At reception of 1 times a day equilibrium concentration in plasma is established in 7-14 days of therapy. Distribution volume – about 12-17 l/kg. Linkng with proteins of plasma - no more than 80%. In plasma is present at not changed look. Gets into breast milk.

It is metabolized by demethylation, deamination and oxidation with P450 cytochrome participation (isoenzymes of CYP3A4 and CYP2C19, to a lesser extent CYP2D6) with formation pharmacological of less active metabolites. The inhibition of one of these enzymes can be compensated by other enzymes. Time of semi-removal (T1/2) of a tsitalopram makes 1,5 days (36 hours). Removal is carried out by kidneys (15%) and a liver (85%). 12-23% of a tsitalopram are removed in an invariable look through kidneys. Hepatic clearance – about 0,3 l/min, renal clearance – 0,05-0,08 l/min.

Patients are aged more senior than 65 years. More long elimination half-life and lower sizes of clearance due to decrease in a metabolism is observed.

Insufficiency of function of a liver. At patients with reduced function of a liver to tsitalopra it is removed more slowly. The elimination half-life of a tsitalopram is almost twice increased and equilibrium concentration of a tsitalopram in plasma are almost twice higher in comparison with patients with normal function of a liver after reception of a similar dose.

Insufficiency of function of kidneys. At patients with easy and moderate degree of depression of function of kidneys removal of a tsitalopram proceeds more slowly without significant influence on pharmacokinetics. Care is required from patients with a heavy renal failure (the clearance of creatinine is lower than 30 ml/min.).

Indications to use:

Depressive episodes of average and heavy degree. Panic frustration.

Route of administration and doses:

Tsitalopram accept inside once a day (without chewing, washing down with a small amount of liquid). Drug can be used regardless of meal at any time, it is desirable to accept drug at the same time days.

Depression. Therapy of a depression begin with reception 20 mg of a tsitalopram a day. Depending on individual reaction of the patient and weight of a depression the dose can be increased to maximum - 40 mg a day.

Panic frustration. At panic frustration within 1 week the recommended dose - 10 mg a day, then the dose raises to 20 mg a day. The daily dose, depending on individual reaction of the patient, can be increased further to 40 mg a day.

Patients at the age of 65 years are more senior. The recommended daily dose for elderly makes 10-20 mg. Depending on individual reaction and weight of a depression the dose can be raised a maximum to 20 mg a day.

Impaired renal function. At a chronic renal failure of weak and moderate degree of manifestation of correction of the mode of dosing it is not required. Care in the choice of a dose is required from patients with a heavy renal failure (the clearance of creatinine is lower than 30 ml/min.).

The broken function of a liver. At patients with a slight and moderate liver failure the initial dose makes 10 mg a day within the first two weeks. Depending on reaction the dose can be increased to 20 mg a day. Extreme care in the choice of a dose is required from patients with a heavy liver failure.

Patients with low activity of an isoenzyme of CYP2C19. At patients with low activity of an isoenzyme of CYP2C19 the initial dose makes 10 mg a day within two weeks. Depending on reaction the dose can be increased to 20 mg a day.

Treatment duration. The effect is shown in 2-4 weeks, duration of a course of treatment is defined by a condition of the patient, efficiency and portability of the carried-out therapy and averages 6 months.

Features of effect of drug at its cancellation. The symptomatology which can be noted at sharp cancellation of a tsitalopram is not characteristic. It most often dizziness, headache, paresthesias, sleep disorder, adynamy, nervousness, tremor, nausea and/or vomiting.

In case of completion of treatment tsitalopra need to cancel gradually within several weeks to avoid a syndrome of "cancellation". In most cases for this purpose there are enough about 2 weeks, but in each separate case the doctor resolves this issue individually: term or more can be necessary 2-3 months for some patients.

Features of use:

The children's age up to 18 years is a contraindication for use of a tsitalopram as efficiency and safety of its use at this age is not established.

Due to a possibility of suicide attempts, at patients with a depression careful observation of patients in an initiation of treatment and purpose of minimal effective doses is necessary for decrease in risk of overdose. This precaution has to be observed also at treatment of other mental disorders because of a possibility of a simultaneous disease of a depressive episode.

The risk of suicide actions which can remain up to achievement of essential remission is inherent to the expressed depressions. In this regard in an initiation of treatment the combination with HP from group of benzodiazepines or antipsychotic HP and constant medical control can be shown (to charge to authorized representatives storage and delivery of HP). At treatment of panic frustration with prescription of antidepressants and/or benzodiazepines, at some patients in response to begun treatments considerably the alarm or concern amplifies. This state (called by specialists "a pathological disinhibition" or simply "paradoxical alarm", the term it is not approved yet) is considered as an unusual occurrence though this pathological reaction was repeatedly documentary recorded in scientific literature. This "paradoxical alarm" usually decreases within the first several weeks after an initiation of treatment. It is recommended to begin with a low dose to reduce risk of paradoxical alarm. Drug withdrawal in this case is recommended if similar paradoxical reaction it is long does not disappear and if similar complications of therapy exceed advantage of the carried-out treatment.

At children, teenagers and young people (24 years are younger) with a depression, etc. mental disturbances antidepressants, in comparison with placebo, increase risk of emergence of suicide thoughts and suicide behavior. Therefore at purpose of a tsitalopram or any other antidepressants at this category of patients it is necessary to correlate risk of a suicide and advantage of their use. In short-term researches at people 24 years are more senior the risk of a suicide did not increase, and at people 65 years are more senior decreased a little. During treatment by antidepressants for all patients observation for the purpose of early identification of suicide bents has to be established.

It is necessary to apply Tsitalopram with care at a renal failure (clearance of creatinine lower than 30 ml/min.), hypomanias, manias, pharmacological uncontrollable epilepsy, a depression with suicide attempts, a diabetes mellitus, cirrhosis, tendency to bleedings; a concomitant use with the medicines reducing a threshold of convulsive readiness and causing a hyponatremia with ethanol, and also with the medicines which are metabolized CYP2C19 isoenzyme.

Tsitalopram can cause dozozavisimy lengthening of an interval of QT that can lead to disturbance of a cordial rhythm.

The hyponatremia develops because of disturbances of secretion of antidiuretic hormone, especially high risk level at women of advanced age.

Treatment by Tsitalopram can change glycemic control at patients with a diabetes mellitus. The dose of insulin and/or peroral hypoglycemic means has to be corrected.

Development of the akathisia which is characterized by the constant or periodically arising feeling of internal motive concern and shown in inability long to sit quietly in one pose or to be left long without the movement is seldom possible. Passes within the first weeks of treatment.

Patients with bipolar disorder can have manias. Then treatment tsitalopramy needs to be stopped.

It is necessary to apply with care to tsitalopra with medicinal dependence (including in the anamnesis) and epileptic seizures in the anamnesis.

Tsitalopram it is not necessary to apply in combination with inhibitors of a monoaminooxidase (MAO) (see the section "Contraindications" and "Interaction with Other Medicines").

At poorly and moderately expressed renal failures dose adjustment is not required, at heavy renal failures it is required to be careful. At an abnormal liver function administration of drug is limited to the minimum recommended doses. The dose decline of a tsitalopram is required from elderly patients.

At development of a maniacal state drug should be cancelled.

Clinical experience of simultaneous use of SIOZS and electroconvulsive therapy is insufficient therefore care is required.

In an initiation of treatment there can be sleeplessness and feelings of concern that can be solved by correction of an initial dose.

The sharp termination of therapy by Tsitalopram can lead to a syndrome of "cancellation". There can be such undesirable reactions, such as dizziness, headaches, nausea. To avoid emergence of a syndrome of "cancellation" gradual drug withdrawal within several weeks is necessary.

Use by pregnant women, women during breastfeeding. It is not necessary to appoint to tsitalopra to pregnant women and the nursing women if the potential clinical advantage does not prevail over theoretical risk since safety of drug during pregnancy and a lactation at the woman is not established.

Use of a tsitalopram in the third trimester of pregnancy can negatively affect psychophysical development of the newborn. The following disturbances at newborns whose mothers accepted selective serotonin reuptake inhibitors up to childbirth are possible: respiratory insufficiency, cyanosis, asthma, spasms, instability of temperature, difficulty of feeding, vomiting, hypoglycemia, muscular hypertension or hypotonia, hyperreflexia, tremor, nervousness, irritability, slackness, constant crying, drowsiness and sleeplessness.

Epidemiological data demonstrate that use of SIOZS during pregnancy, especially on late durations of gestation, can increase risk of persistent pulmonary hypertensia of newborns. The observed risk was in 5 cases on 1000 pregnancies. In the general population risk from 1 to 2 cases of persistent pulmonary hypertensia of newborns on 1000 pregnancies.

Similar disturbances can demonstrate serotonergic effects or emergence of a syndrome of "cancellation". In case of use of a tsitalopram during pregnancy its reception should not be interrupted sharply.

Data on possible influence of drug on ability to manage vehicles, mechanisms. Tsitalopram it is necessary to apply with care at persons whose activity is connected with mechanisms or management of moving means. Tsitalopram does not reduce mental abilities and speed of psychomotor reactions, however at patients it is possible to expect some decrease in attention and concentration owing to the available disease, side reactions from the carried-out treatment or for that and another together.

Side effects:

As well as in case of use of other drugs of the SIOZS group, against the background of use of a tsitalopram undesirable side reactions are noted, however they have tranzitorny character and are expressed poorly.

Side reactions against the background of use of a tsitalopram are observed within the first one-two weeks of treatment and usually significantly weaken in process of improvement of a condition of patients.

Frequency of side reactions: very often - ≥ 10%; often - ≥ 1%, but <10%; infrequently - ≥ 0,1%, but <1%; seldom - ≥ 0,01%, but <0,1%; very seldom - <0,01%.

Emergence of the following side reactions is possible:

Allergic reactions: infrequently – hypersensitivity; very seldom – anaphylactic reactions.

From the central nervous system: very often – drowsiness, a headache, a tremor, dizziness; often – migraine, paresthesia, frustration of a dream; infrequently – extrapyramidal frustration, spasms; seldom – a serotoninovy syndrome (a combination of excitement, a tremor, a myoclonus and a hyperthermia); frequency is unknown – psychomotor excitement, an akathisia.

From the mental sphere: very often – agitation, nervousness; often – decrease in a libido, disturbance of an orgasm (at women), concern, confusion of consciousness, drowsiness, disturbance of concentration of attention, strange dreams, amnesia; infrequently – aggression, depersonalization, hallucinations, manias, euphoria, increase in a libido; frequency is unknown – the panic attacks, a bruxism, suicide thoughts.

From the alimentary system: very often - dryness in a mouth, nausea, a lock; often - vomiting, a meteorism, diarrhea, an abdominal pain, hepatitis; frequency is unknown – gastrointestinal bleedings.

From cardiovascular system: very often – a heart consciousness; often – tachycardia, arterial hypertension, orthostatic hypotension; seldom - bradycardia, a lowering of arterial pressure, arrhythmia; frequency is unknown – lengthening of an interval of QT on an ECG.

From bodies of a hemopoiesis: seldom – hemorrhages (for example, gynecologic bleedings, digestive tract bleedings, ecchymomas and other forms).

From sense bodys: very often – accommodation disturbance; often – disturbance of taste, a vision disorder, infrequently – a ring in ears.

From respiratory system: often – rhinitis, sinusitis; infrequently – cough; seldom – диспноэ.

From reproductive system: often - disturbance of sexual function, namely disturbance of an ejaculation, decrease in a libido, impotence, disturbances of a menstrual cycle; seldom - a galactorrhoea.

From an urinary system: often – an urodynia, a polyuria.

Metabolic disturbances: often – a loss of appetite, loss of weight, increase in appetite; seldom – insufficient secretion of antidiuretic hormone (ADG), an increase in weight, a hyponatremia; hypopotassemia.

From integuments: very often – the increased perspiration, it is frequent – skin rash, an itch; infrequently – a photosensitization, a small tortoiseshell, an alopecia, a purpura; frequency is unknown - a Quincke's disease, bruises.

From a musculoskeletal system: infrequently – a mialgiya, an arthralgia, increase in risk of injuries and changes.

Laboratory indicators: often – change of laboratory indicators of function of a liver; infrequently – increase in activity of "hepatic" enzymes, change of the electrocardiogram (lengthening of an interval of QT), a hyponatremia.

Others: seldom - a hyperthermia, yawning, increase or decrease in body weight.

Interaction with other medicines:

Contraindicated combined use:

With MAO inhibitors. The accompanying treatment by MAO inhibitors contraindicated (both non-selective, and selection) in connection with risk of development of serious side effects, including a serotoninovy syndrome. Tsitalopram it is not necessary to apply in a combination, including, with selegiliny, moklobemidy, linezolidy (antibiotic), etc., and also within 14 days after the termination of their reception. Treatment by MAO inhibitors can be begun not earlier than in 7 days after the termination of reception of a tsitalopram.

With the means extending QT interval. Use with the medicines extending QT interval such as antiaritmik (procaineamide, Amiodaronum, etc.), antipsychotic means / neuroleptics (for example, derivative a fenotiazina, Pimozidum, a haloperidol), tricyclic antidepressants and SIOZS (fluoxetine), antimicrobic drugs is inadmissible (makrolidny antibiotics and their analogs, for example, erythromycin, кларитромицин; derivative hinolona and ftorkhinolona: спарфлоксацин, moxifloxacin; pentamidine), H1 blockers - histamine receptors (астемизол, мизоластин), antifungal means of an azolovy row (кетоконазол, флуконазол), домперидон, ондансетрон as to tsitalopra in doses of the exceeding 40 mg a day can cause abnormal changes of electric activity of heart (lengthening of an interval of QT on an ECG) and to lead to disturbance of a cordial rhythm (including development of arrhythmias in the pirouette type) which can be fatal.

Pimozidum. Simultaneous use of Pimozidum and tsitalopram is contraindicated as their combined use extends QT interval. It belongs also to such means as amitriptyline, Maprotilinum, венлафаксин, терфенадин, a haloperidol, Droperidolum, Chlorpromazinum, thioridazine.

Combined use of Tsitalopram has to be carried out with care:

Tsitalopram can reduce a threshold of convulsive readiness. It is required to show care at a concomitant use of other means reducing a threshold of convulsive readiness (tricyclic antidepressants, SIOZS, neuroleptics – derivatives of a fenotiazin, thioxanthene and phenyl propyl ketone; meflokhina and tramadola).

At simultaneous use of a tsitalopram and tryptophane cases of strengthening of effect of drug are registered. It is desirable not to combine with reception of a tsitalopram serotonergic drugs, such as суматриптан or other triptanes, and also трамадол.

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

At simultaneous use Cimetidinum causes moderate increase in equilibrium concentration of a tsitalopram in blood. Therefore it is recommended to show care at purpose of the maximum doses of a tsitalopram along with use of high doses of Cimetidinum.

At simultaneous use of a tsitalopram with the indirect anticoagulants and other means influencing a blood coagulation (blood coagulation disturbance can arise 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 tsitalopramy regular monitoring of coagulability of blood is necessary.

At co-administration with warfarin the prothrombin time increases for 5%.

Interaction of a tsitalopram with alcohol is not revealed. However, as well as in a case with other psychotropic medicines, the simultaneous use of a tsitalopram and alcohol is not recommended.

In the researches in vitro it is revealed that to tsitalopra turns into the demetilirovanny derivatives with participation of isoenzymes of CYP2C19 and CYP3A4, and also with a small contribution of an isoenzyme of CYP2D6. It is proved that the inhibition of one of enzymes can be compensated by other enzymes. An inhibiting effect of a tsitalopram on these and other isoenzymes of P450 cytochrome weak or insignificant therefore to tsitalopra has low ability for clinically significant medicinal interactions known for this situation. At the same time care is necessary if it to tsitalopra is appointed together with drugs which are metabolized mainly by an isoenzyme of CYP2D6 and have at the same time a low therapeutic index. Though clinical data on repeated and dose pharmacokinetic researches are not available, there are these in vitro (model of microsomes of a liver of the person) which show delay of formation of demetilirovanny derivatives of a tsitalopram for 45-60% and for 75-85% in comparison with control after addition of a ketokonazol and an omeprazol, respectively. It can prove necessary care in these cases at appointment together with tsitalopramy such strong CYP3A4 inhibitors as кетоконазол, итраконазол, флуконазол, or such strong CYP2C19 inhibitors as омепразол, esomeprazole, флувоксамин, тиклопидин, ланзопразол as their joint reception with tsitalopramy can significantly reduce clearance of a tsitalopram. Therefore the maximum recommended dose of a tsitalopram for the patients accepting jointly CYP2C19 isoenzyme drugs-inhibitors should not exceed 20 mg/day including because the risk of lengthening of an interval of QT increases.

Combined use of a tsitalopram with Imipraminum or desipramine does not influence concentration of Imipraminum and tsitalopram, but increases concentration of desipramine; desipramine dose adjustment can be necessary.

Contraindications:

· Hypersensitivity to a tsitalopram or to any of the excipients which are a part of this drug.

· Tsitalopram it is not necessary to apply in combination with inhibitors of a monoaminooxidase (MAO), including selegiliny, moklobemidy, linezolidy (antibiotic), and also within 14 days after the termination of their reception. Treatment by MAO inhibitors can be begun not earlier than in 7 days after the termination of reception of a tsitalopram.

· Tsitalopram is contraindicated at simultaneous use with the medicines extending QT interval on an ECG (in particular, with Pimozidum), and also at inborn lengthening of an interval of QT.

· The children's age up to 18 years is a contraindication for use of a tsitalopram as efficiency and safety of its use at this age is not established.

Overdose:

Overdose symptoms: spasms, drowsiness, tachycardia, bradycardia, hypomyotonia or hypertension, nausea, vomiting, tremor, serotoninovy syndrome, agitation, dizziness, expansion of pupils, stupor, perspiration, cyanosis of integuments, heart failure, blockade of legs of a ventriculonector, hyperventilation of lungs, atrial arrhythmia, ventricular arrhythmia, coma.

The coma and lethal cases of overdose tsitalopramy are extremely rare, most of them include simultaneous overdose with other medicines.

Overdose treatment: the specific antidote is absent. At overdose the gastric lavage has to be carried out as soon as possible. A symptomatic treatment and supporting. Medical observation is recommended, at a loss of consciousness and disturbance of breath – an intubation, and also careful monitoring of an ECG and other vital signs as the risk of the fatal arrhythmias accompanied with sinus tachycardia, a nodal rhythm is high, lengthening of an interval of QT, in particular, development of arrhythmia like "pirouette", ventricular arrhythmia is possible.

Storage conditions:

In the place protected from light at a temperature not over 25 ºС. To store in the place, unavailable to children. Period of validity 3 years. Not to apply after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets film coated 10 mg, 20 mg and 40 mg. On 10 tablets in a blister strip packaging from a film of the polyvinyl chloride and printing aluminum foil varnished. 1, 2, 3, 4 or 5 blister strip packagings together with the application instruction place in a pack from a cardboard.