Tsipramil

General characteristics. Structure:

Active ingredient: 24,98 mg or 49,96 mg of a tsitalopram of hydrobromide that there correspond 20 mg or 40 mg of a tsitalopram.

Excipients: starch corn, lactoses monohydrate, коповидон, glycerin of 85%, microcrystallic cellulose, sodium of a kroskarmeloz, magnesium stearate.

Cover: gipromelloza 5, macrogoal 400, titanium dioxide (Е 171).

TsIPRAMIL is antidepressant, the selective serotonin reuptake inhibitor (SSRI).

Pharmacological properties:

Pharmacodynamics. Tsitalopram is the superselective serotonin reuptake inhibitor (SSRI) without influence or with the minimum influence on capture of noradrenaline, dopamine and piperidic acid. Tsitalopram has no absolutely or has very weak ability to contact a number of receptors, including 5-HT1A-, 5-HT2-serotoninovye, D1-and D2-dopamine, α1-, α2-and β-adrenergic receptors, H1 - histamine, muskarinovy holinoretseptor, benzodiazepine and opioid receptors. Suppression of a stage of a REM sleep (REM) is considered a predictor of antidepressive action. As well as tricyclic antidepressants, others SIOZS and MAO inhibitors, to tsitalopra suppresses a REM sleep and increases deep medlennovolnovy a dream.

In the research with a single dose conducted on healthy volunteers, to tsitalopra did not reduce salivation and in one research on healthy volunteers had no significant effect on cardiovascular indicators. Tsitalopram does not exert impact on content in growth hormone blood serum. Tsitalopram, as well as others SIOZS, can increase the content of prolactin in plasma.

In double blind placebo - controlled research ECG on healthy volunteers QTc change (correction on a formula of Friderichia) in comparison with basic data made 7,5 (90% a confidence interval 5,9-9,1) ms for a dose of 20 mg/days and 16,7 (90% a confidence interval 15,0-18,4) ms for a dose of 60 mg/days.

Pharmacokinetics. Absorption. Drug absorption almost full also does not depend on meal (the average time of achievement of the maximum concentration in a blood plasma (Tmax) about 3 hours). Bioavailability at intake makes about 80%.

Distribution. The seeming volume of distribution (Vd) the beta makes about 12-17 l/kg. Linkng of a tsitalopram and its main metabolites with proteins of plasma makes less than 80%.

Biotransformation. Tsitalopram is metabolized to active metabolites: demetiltsitaloprama, didemetiltsitaloprama, tsitaloprama-N-oxide and inactive derivative deaminated propionic acid. All active metabolites are also SIOZS though their action is weaker, than initial connection.

Major component in a blood plasma is not changed tsitalopra. Concentration of a demetiltsitalopram and didemetiltsitalopram makes usually 30-50% and 5-10% of concentration of a tsitalopram, respectively. Biotransformation of a tsitalopram in demetiltsitalopra is mediated by CYP2C19 isoenzymes (about 38%), CYP3A4 (about 31%) and CYP2D6 (about 31%).

Removal. The elimination half-life (T½) makes approximately 1½ days. The system clearance of plasma (Cls) of a tsitalopram makes about 0,3-0,4 l/min, and clearance at oral administration (Cloral) about 0,4 l/min.

Tsitalopram is brought mainly through a liver (85%) and through kidneys (15%); 12-23% of a daily dose are removed with urine in the form of not changed tsitalopram. The hepatic (residual) clearance makes about 0,3 l/min, and renal clearance - about 0,05-0,08 l/min.

Linearity. Kinetics of a tsitalopram linear. Equilibrium concentration in plasma is reached within 1-2 weeks. Average equilibrium concentration makes near the 300th nmol/l (165-405 nmol/l) against the background of a daily dose of 40 mg.

Elderly patients (> 65 years). It is shown that at elderly patients owing to reduction in the rate of metabolism longer elimination half-life of drug (1,5-3,75 days) and smaller indicators of clearance (0,08-0,3 l/min) is observed. Equilibrium concentration is approximately twice higher at elderly, than at the young patients receiving the same dose.

Reduced function of a liver. Tsitalopram is more slowly brought at patients with abnormal liver functions. The elimination half-life of a tsitalopram is approximately twice more, and equilibrium concentration is approximately twice higher in comparison with patients with normal function of a liver at reception of the same dose.

Reduced function of kidneys. Tsitalopram is more slowly brought at patients with a small or moderate renal failure that, however, has no significant effect on pharmacokinetics of a tsitalopram. Now there is no information concerning treatment of patients with heavy renal failures (clearance of creatinine <30 ml/min.).

Polymorphism. The researches in vivo showed that metabolism of a tsitalopram does not differ in clinically significant polymorphism of oxidation of sparteine/debrisoquine (CYP2D6). At patients with weak activity of an isoenzyme of CYP2C19 as a precautionary measure the recommended initial dose should not exceed 10 mg a day.

Indications to use:

Depressive episodes of average and heavy degree and prevention of their recurrence. Panic frustration with/without agoraphobia.

Route of administration and doses:

Tsipramil appoint orally once a day. Drug can be accepted regardless of meal at any time. Tablets 20 and 40 of mg can be halved.

Depressions. Tsipramil appoint 20 mg once a day. Depending on individual response of the patient the dose can be increased to maximum – 40 mg a day. The antidepressive effect usually develops in 2-4 weeks after an initiation of treatment. Therapy by antidepressants has symptomatic character and has to continue during a sufficient span, usually not less than 6 months after full elimination of symptoms of a depression in order to avoid development of a recurrence. At patients with a recurrent (unipolar) depression the necessary maintenance therapy can proceed within several years for prevention of development of new episodes.

Panic frustration. Within the first week of treatment the recommended single dose makes 10 mg/days orally, then the dose raises to 20 mg a day. Depending on individual response of the patient the dose can be increased to maximum – 40 mg/days. At treatment of panic frustration the maximum therapeutic effect of a tsitalopram is reached approximately in 3 months after an initiation of treatment and remains at therapy continuation.

Elderly patients (65 years are more senior). It is necessary to reduce a daily dose for elderly patients to a half of the recommended dose, i.e. to 10-20 mg. The recommended maximum dose for elderly patients makes 20 mg/days.

Children and teenagers (up to 18 years). Tsipramil it is not necessary to apply at children and teenagers 18 years are younger (see the section "Special Instructions"). Besides, there is no sufficient volume of data of long-term researches on safety of use of drug for the children and teenagers concerning growth, maturing, cognitive and behavioral development.

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 (the clearance of creatinine is lower than 30 ml/min.) should apply Tsipramil with care.

Reduced function of a liver. At a slight and moderate liver failure the recommended initial dose within the first two weeks of treatment makes 10 mg/days. Depending on individual reaction of the patient the dose can be increased to maximum – 20 mg/days. Patients with the expressed liver failure need to use drug with care, careful titration of a dose is required.

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

Treatment termination. It is necessary to avoid the sharp termination of treatment. At the termination of therapy by Tsipramil the dose has to decrease gradually within at least 1-2 weeks to avoid emergence of reactions of "cancellation". If at reduction of a dose or the termination of treatment tsitalopramy there are intolerable symptoms, return to the previous dose or resuming of administration of drug is possible. Afterwards the dose decline can be continued, but more gradually.

Features of use:

Use for children and teenagers is younger than 18 years. Should not appoint antidepressants children and teenagers aged up to 18 years. During clinical trials among the children and teenagers accepting antidepressants more often than in group of placebo cases of suicide behavior (attempts of a suicide and suicide thoughts) and hostility were noted (with dominance of an agressive behavior, tendency to confrontation and irritations).

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

Paradoxical alarm. At some patients with panic frustration at the beginning of therapy by antidepressants strengthening of alarm can be observed. Such paradoxical reaction usually takes place within the first two weeks after an initiation of treatment.

To reduce probability of emergence of anksiogenny action it is recommended to use low initial doses.

Hyponatremia. At use of SIOZS it was reported about exceptional cases of development of the hyponatremia arising, apparently, owing to inadequate secretion of antidiuretic hormone (ADG). This reaction in general was reversible in case of the treatment termination by drug. The risk of emergence was higher at elderly women.

Suicide / suicide thoughts or clinical deterioration. The depression is connected with the increased risk of emergence of suicide thoughts, drawings self-damages and suicides (the suicide phenomena). This risk remains until development of stable remission. As within the first several weeks of treatment or even a bigger period improvement can not be noted, patients have to be under constant observation for early detection of such improvement. Clinical experience demonstrates that the risk of suicide increases at early stages of recovery.

Other mental disturbances for which treatment appoint to tsitalopra can be connected with the increased risk of emergence of the suicide 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, as at treatment of patients with a depressive episode.

The patients having suicide tendencies in the anamnesis or patients with the significant level of reflection on suicide subjects prior to treatment are more subject to risk of emergence 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 high degree of suicide 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.

Akathisia / psychomotor concern. Use of drugs of the SIOZS/SIOZSN group contacts development of the akathisia which is characterized by feeling of subjectively unpleasant or intolerable motive concern, restlessness and need to move. Often patients in such state cannot quietly sit or stand. Most often this state arises within the first weeks of treatment. With such symptoms increase in a dose can cause a sharp aggravation of symptoms in patients.

Mania. At patients with bipolar affective disorder development of a maniacal phase is possible. At development of a maniacal state reception of a tsitalopram should be stopped.

Convulsive attacks. At reception of antidepressants there is a risk of developing of convulsive attacks. At any patient in case of developing of a convulsive attack tsitalopra should cancel. Tsitalopram it is not necessary to apply at patients with unstable epilepsy; at controlled attacks careful observation is necessary. In case of increase in frequency of attacks tsitalopra should cancel.

Diabetes mellitus. At patients with a diabetes mellitus use of SIOZS can change concentration of glucose in blood. In this case dose adjustment of insulin and/or peroral hypoglycemic drugs can be required.

Serotoninovy syndrome. In rare instances at reception of SIOZS it was reported about development of a serotoninovy syndrome. The combination of such symptoms as agitation, a myoclonus and a hyperthermia can indicate development of this state. At emergence of such phenomena tsitalopra should cancel and begin a symptomatic treatment immediately.

Serotonergic drugs. Tsitalopram it is not necessary to apply together with the drugs possessing serotonergic action such as суматриптан or other triptanes, трамадол, oxytriptane and tryptophane.

Bleeding. There are messages on development of skin hemorrhages, such as an ecchymoma, gynecologic, gastrointestinal bleedings and other hemorrhagic complications from integuments or mucous membranes against the background of reception of SIOZS. It is necessary to be careful at the simultaneous use of SIOZS and drugs influencing function of thrombocytes or drugs which can increase risk of developing of bleedings, and also at treatment of patients with hemorrhagic frustration in the anamnesis.

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

MAO A reversible selection inhibitors. The concomitant use of a tsitalopram and MAO A inhibitors is not recommended because of risk of development of a serotoninovy syndrome.

The St. John's Wort which is made a hole. It is not necessary to apply at the same time to tsitalopra and the drugs containing a St. John's Wort made a hole (Hypericum perforatum) since it can increase risk of emergence of undesirable reactions.

Psychosis. Treatment of psychotic patients with a depressive episode can strengthen manifestations of psychotic symptoms.

Cancellation symptoms at the termination of therapy of SIOZS. Symptoms of cancellation arise rather often, especially at the sharp termination of therapy. The probability of emergence of symptoms of cancellation can depend on a number of factors, including the treatment duration, a dose of drug and rate of its decrease.
It was most often reported about development of the following manifestations: dizziness, disorders of sensitivity (including paresthesia), sleep disorders (including sleeplessness and bright dreams), agitation or alarm, nausea and/or vomiting, a tremor, confusion of consciousness, perspiration, a headache, diarrhea, tachycardia, emotional lability, irritability and vision disorders. Usually these manifestations happen easy or moderate severity, however at some patients they can have difficult character.

Usually such manifestations develop during the first days after drug withdrawal, however there are separate messages on development of similar states in patients which accidentally missed reception of the next dose. In most cases these complications are stopped within 2 weeks though at certain patients the symptomatology can remain within 2-3 months or longer. Therefore before the termination of a course of reception of a tsitalopram it is recommended to reduce gradually a drug dose during the period from several weeks to several months, depending on a condition of the patient (see the section "Route of Administration and Doses").

Lengthening of an interval of QT. It was revealed what to tsitalopra causes dozozavisimy lengthening of an interval of QT. In the post-registration period it was reported about cases of lengthening of an interval of QT and ventricular arrhythmias, including torsade de pointes, it is preferential at female patients, with a hypopotassemia or the preexisting lengthening of an interval of QT or other heart diseases.

Drug is recommended to be used with care at patients with significant bradycardia, at the patients who recently had a myocardial infarction or with dekompensirovanny heart failure.

Electrolytic disturbances, such as hypopotassemia and hypomagnesiemia, increase risk of developing of malignant arrhythmias and therefore have to be corrected prior to therapy tsitalopramy.

At patients with the compensated heart diseases before an initiation of treatment it is necessary to conduct research ECG. In case of any symptoms of cardiac arrhythmias against the background of treatment tsitalopramy, the last it is necessary to cancel and conduct research ECG.

Excipients. Tablets contain lactoses monohydrate. Patients with hereditary intolerance of a galactose, deficit of lactase or disturbance of absorption of glucose galactose should not receive treatment by this drug.

Use at pregnancy and during breastfeeding. The published data on pregnant women (more than 2500 complete cases) did not show formation of any malformation and фето-/neonatal toxicity under the influence of a tsitalopram. Nevertheless, to tsitalopra it should not be used during pregnancy without emergency and careful assessment of potential risks and advantage.

If use of a tsitalopram continues on late durations of gestation, especially in the third trimester, newborns have to be under observation. It is necessary to avoid sharp drug withdrawal during pregnancy.

In case of reception by mother of SIOZS/SIOZSN on late durations of gestation at newborns the following symptoms can be observed: a respiratory distress, cyanosis, an apnoea, convulsive attacks, instability of body temperature, difficulty when feeding, vomiting, a hypoglycemia, a muscular hypertension, a hypomyotonia, a hyperreflexia, a tremor, the increased neuroreflex irritability, irritability, a lethargy, constant crying, drowsiness and an uneasy dream. These symptoms can arise owing to development of a syndrome of "cancellation" or serotonergic action. In most cases complications develop directly later or soon (<24 hours) after the delivery.

Epidemiological data allow to assume that use of SIOZS during pregnancy, especially on late terms, can increase risk of development of steady pulmonary hypertensia in newborns. The observed risk made about 5 cases on 1000 pregnancies. In the general population the risk of emergence of this frustration makes 1-2 cases on 1000 pregnancies.

Tsitalopram gets into breast milk. It is considered that babies receive about 5% of the maternal daily dose of a tsitalopram calculated on weight (in mg/kg). No effects for children were observed. However, the available information is not enough for assessment of risks for the child. Therefore during treatment tsitalopramy feeding by a breast is not recommended.

Influence on ability to drive the car and to work with mechanisms. Tsitalopram has the minimum or moderate ability to influence ability to drive the car and to work with mechanisms. Psychoactive drugs can influence decision-making process and ability to react to emergency situations. Patients should be warned about potentially possible influence on ability to drive the car and to work with mechanisms.

Side effects:

The undesirable effects observed at Tsipramil's reception are usually expressed poorly and have tranzitorny character. Most often they arise on the first or second week of treatment and usually significantly weaken in process of therapy continuation.

For the following reactions dependence on the used dose is found: the increased sweating, dryness in a mouth, sleeplessness, drowsiness, diarrhea, nausea and weakness.

The emergence of the undesirable reactions connected with reception of SIOZS and/or tsitalopram, observed at ≥ by 1% of patients, which were taking part in double blind placebos controlled researches given about frequency and during the post-registration period is given below. Frequency is specified as follows: 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), it is unknown (it is impossible to estimate on the basis of the existing data).

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

From immune system: it is unknown – hypersensitivity, 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, decrease in body weight; infrequently – increase in appetite, increase in body weight; seldom – a hyponatremia; it is unknown – a hypopotassemia.

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

From a nervous system: very often – drowsiness, sleeplessness; often – a tremor, paresthesias, dizziness, disturbance of attention; infrequently - a syncope; seldom – big convulsive attacks, dyskinesia, disturbances of flavoring feelings; it is unknown – convulsive frustration, a serotoninovy syndrome, extrapyramidal frustration, an akathisia, motive frustration.

From organs of sight: infrequently – a mydriasis (expansion of pupils); it is unknown - vision disorders.

From an acoustic organ and labyrinth disturbances: often – a sonitus.

From cardiovascular system: very often – a heart consciousness; infrequently – bradycardia, tachycardia; seldom – bleedings; it is unknown – lengthening of an interval of QT on the electrocardiogram, ventricular arrhythmia, including the pirouette type (torsade de pointes), orthostatic hypotension.

From respiratory system, bodies of a thorax and a mediastinum: often - yawning; it is unknown – nasal bleeding.

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

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

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

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

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

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

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

Epidemiological researches preferential 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 mechanism resulting in this risk is unknown.

Cases of lengthening of an interval of QT and ventricular arrhythmias, including arrhythmias on the pirouette type (torsade de pointes), were registered during the post-registration period, is preferential at female patients, with a hypopotassemia or with already existing lengthening of an interval of QT and other heart diseases.

Cancellation of a tsitalopram (especially sharp) often leads to emergence of symptoms of "cancellation". Most often there are dizziness, disorders of sensitivity (including paresthesias), frustration of a dream (including sleeplessness and intensive dreams), agitation or alarm, nausea and/or vomiting, a tremor, confusion of consciousness, sweating, a headache, diarrhea, a heart consciousness, 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. If therapy tsitalopramy is not required, recommended to carry out gradual drug withdrawal by decrease in its dose any more.

Interaction with other medicines:

Pharmakodinamichesky interaction. Cases of development of a serotoninovy syndrome at combined use of a tsitalopram were described with moklobemidy and buspirony.

Contraindicated combinations. MAO inhibitors. Simultaneous use of a tsitalopram and MAO inhibitors can lead to serious undesirable effects, including a serotoninovy syndrome.

Cases serious and sometimes lethal reactions at the patients who are at the same time receiving SIOZS and monoamine oxidase inhibitor (IMAO) including irreversible IMAO селегилин and reversible IMAO линезолид and моклобемид, and also at the patients who recently stopped reception of SIOZS and began reception of IMAO were described.

In some of the presented cases the signs reminding a serotoninovy syndrome were noted.

Symptoms of interaction of a tsitalopram with IMAO included: a hyperthermia, rigidity, a myoclonus, vegetative instability with bystry fluctuations of indicators of the vital functions, changes of the mental status which included confusion of consciousness, the irritability and excessive agitation progressing in a delirium and a coma.

The drugs extending QT interval. Pharmacokinetic and pharmakodinamichesky researches of interaction between tsitalopramy and the medicines extending QT interval were not conducted. Summation of effect of a tsitalopram and these drugs cannot be excluded. Thus, simultaneous use of a tsitalopram and the medicines extending an interval of QT, such as antiaritmik of the classes IA and III, anti-psychotics (for example, derivative a fenotiazina, Pimozidum, a haloperidol), tricyclic antidepressants, some antimicrobic means (for example, спарфлоксацин, moxifloxacin, erythromycin IV, pentamidine, antimalarial means, in particular галофантрин), some antihistamines (астемизол, мизоластин), etc., contraindicated.

Pimozidum. In a research the single dose of Pimozidum in a dose of 2 mg the examinees taking the racemic form of a tsitalopram in a dose of 40 mg/days within 11 days led to increase in AUC and Cmax values of Pimozidum, though not always. Combined use of Pimozidum and tsitalopram led to average lengthening of an interval of QTc approximately on 10 ms. Considering development of interaction at a low dose of Pimozidum, the concomitant use of a tsitalopram and Pimozidum is contraindicated.

The combinations demanding care. Selegilin (MAO B selection inhibitor). Researches of pharmacokinetic and pharmakodinamichesky interaction at simultaneous use of a tsitalopram (20 mg/days) and a selegilina (10 mg/days) (a dose selection in MAO B relation) did not reveal any clinically significant interactions. Simultaneous use of a tsitalopram and selegilin (in the dose exceeding 10 mg a day) is not recommended.

Serotonergic drugs. Lithium and tryptophane. In clinical trials of simultaneous use of lithium and a tsitalopram no pharmakodinamichesky interactions were revealed. However it was reported about strengthening of action at co-administration of SIOZS with lithium or tryptophane therefore use of similar combinations has to be carried out with care. Monitoring of level of lithium in blood is carried out in the usual mode. Combined use with such serotonergic drugs as трамадол and суматриптан, can lead to strengthening of serotonergic effects. There will be no exact data on possible interaction, a combination of a tsitalopram to agonists of 5-HT receptors yet, such as суматриптан and other triptanes, it is not recommended.

The St. John's Wort which is made a hole. Dynamic interaction of SIOZS with the vegetable drugs containing a St. John's Wort made a hole (Hypericum perforatum) can lead to increase in frequency of side reactions. Pharmacokinetic interaction was not studied.

The anticoagulants and means influencing coagulability of blood. It is necessary to be careful at purpose of a tsitalopram to the patients receiving treatment by the anticoagulants, drugs influencing functions of thrombocytes such as non-steroidal anti-inflammatory drugs (NPVS), acetylsalicylic acid, Dipiridamolum and тиклопидин, or other drugs (for example, atypical anti-psychotics, fenotiazina, tricyclic antidepressants) which can increase risk of developing of bleedings.

Electroconvulsive therapy (EST). The risks or advantages of simultaneous use of EST and a tsitalopram given clinical trials, showing, no.

Alcohol. No pharmakodinamichesky or pharmacokinetic interactions between tsitalopramy and alcohol were revealed. Nevertheless, joint reception of a tsitalopram and alcohol is not recommended.

The drugs reducing a threshold of convulsive readiness. SIOZS can reduce a threshold of convulsive readiness. It is recommended to be careful at combined use with other drugs capable to reduce a threshold of convulsive readiness (for example, antidepressants [tricyclic, SIOZS], neuroleptics [fenotiazina, thioxanthenes and phenyl propyl ketones], мефлохин, бупропион and трамадол).

Desipramine, Imipraminum. In pharmacokinetic researches changes of level neither a tsitalopram, nor Imipraminum were not revealed though the level of desipramine, the main metabolite of Imipraminum, was increased. At simultaneous use of a tsitalopram and desipramine the level of the last in a blood plasma was increased. The desipramine dose decline can be required.

Neuroleptics. Experience of use of a tsitalopram did not reveal clinically significant interactions with neuroleptics. However, as well as in case of other SIOZS, the possibility of pharmakodinamichesky interaction is not excluded.

Pharmacokinetic interactions. Biotransformation of a tsitalopram to a demetiltsitalopram is mediated by isoenzymes of system of P450 CYP2C19 cytochrome (about 38%), CYP3A4 (about 31%) and CYP2D6 (about 31%). The fact that to tsitalopra it is metabolized more than one isoenzyme, says that braking of its biotransformation is improbable as degree of inhibition of one of enzymes can be compensated by others. Therefore co-administration of a tsitalopram with other medicines has very low probability of pharmacokinetic interactions.

Food. It was not reported that meal influences absorption and other pharmacokinetic properties of a tsitalopram.

Influence of other medicines on pharmacokinetics of a tsitalopram. At combined use кетоконазол (strong inhibitor of an isoenzyme CYP3A4) did not change pharmacokinetics of a tsitalopram. Pharmacokinetic researches of interaction of lithium and a tsitalopram did not reveal any interactions.

Cimetidinum (strong inhibitor of isoenzymes CYP2D6, 3A4 and 1A2) caused moderate increase in level of equilibrium concentration of a tsitalopram. It is recommended to be careful at purpose of a tsitalopram in combination with Cimetidinum. Dose adjustment can be required.

Influence of a tsitalopram on pharmacokinetics of other medicines. The researches фармакокинетического/фармакодинамического of interaction of a tsitalopram and a metoprolol (CYP2D6 isoenzyme substrate) showed 2-fold increase in concentration of a metoprolol, but statistically significant increase in action of a metoprolol at arterial pressure and a cordial rhythm at healthy volunteers is noted. It is necessary to be careful at combined use of a metoprolol and tsitalopram. Dose adjustment can be required.

Tsitalopram and to demetiltsitalopra are insignificant inhibitors of isoenzymes CYP2C9, CYP2E1 and CYP3A4 and only weak CYP1A2, CYP2C19 and CYP2D6 inhibitors in comparison with others SIOZS which are considered as considerable inhibitors.

Levomepromazinum, digoxin, carbamazepine. Any changes or significant changes only very little clinically were observed at simultaneous use of a tsitalopram with CYP1A2 substrates (clozapine and theophylline), CYP2C9 (warfarin), CYP2C19 (Imipraminum and Mephenytoinum), CYP2D6 (sparteine, Imipraminum, amitriptyline, рисперидон) and CYP3A4 (warfarin, carbamazepine (and its metabolite carbamazepine-epoxide) and to triazoles).

No pharmacokinetic interaction was observed between tsitalopramy and levomepromazinum or digoxin (that demonstrates to what to tsitalopra does not induce and does not inhibit a P-glycoprotein).

Contraindications:

Hypersensitivity to a tsitalopram or any of excipients. A concomitant use with inhibitors of a monoaminooxidase (MAO) (including selegiliny in a dose it is higher than 10 mg/days). Time interval between the end of reception of the MAO irreversible inhibitors and the beginning of reception of a tsitalopram has to make not less than 14 days. In case of use of the MAO A reversible inhibitors duration of a break is defined according to the instruction on a medical use of these drugs. Treatment by MAO inhibitors can be begun not earlier than in 7 days after the termination of reception of a tsitalopram.

Concomitant use with linezolidy if it is impossible to carry out careful observation of the patient and monitoring of arterial pressure.

Concomitant use with Pimozidum. The established lengthening of an interval of QT or the inborn extended QT interval.

Concomitant use with the drugs extending QT interval.

Children's and teenage age (up to 18 years) (efficiency and safety of use are not confirmed).

Hereditary intolerance of a galactose, insufficiency of lactase or disturbance of absorption of glucose and galactose.

With care: lengthening of an interval of QT in the anamnesis; ventricular arrhythmia, including torsade de pointes; considerable bradycardia; recently postponed acute myocardial infarction; dekompensirovanny heart failure; a hypopotassemia and/or a hypomagnesiemia (electrolytic disturbances have to be corrected prior to treatment tsitalopramy); the expressed renal failure (the clearance of creatinine is lower than 30 ml/min.); the expressed liver failure (careful selection of a dose is recommended); the expressed suicide behavior (careful observation of patients before improvement of a state in several weeks after an initiation of treatment is required); a diabetes mellitus (dose adjustment of insulin and/or peroral hypoglycemic drugs can be required); tendency to bleedings (especially at simultaneous use with the drugs influencing function of thrombocytes or drugs which can increase risk of developing of bleedings); concomitant use with MAO B inhibitor selegiliny, serotonergic medicines; the drugs reducing a threshold of convulsive readiness; Cimetidinum (increase in equilibrium concentration of a tsitalopram), metoprololy (increase in concentration of a metoprolol), lithium and tryptophane (action strengthening), the medicines containing the St. John's Wort which is made a hole (strengthening of side effects); the peroral anticoagulants and medicines influencing coagulability of blood (increase in risk of developing of bleedings); the drugs which are weak metabolites of an isoenzyme of CYP2C19 (it is necessary to lower an initial dose); ethanol; electroconvulsive therapy; advanced age is more senior than 65 years (it is necessary
dose decline); pregnancy, breastfeeding period.

More detailed information on instructions and precautionary measures is specified in the sections "Interaction with Other Medicines and Other Forms of Interaction", "Special Instructions", "Use at Pregnancy and during Breastfeeding".

Overdose:

Clinical data on overdose of a tsitalopram are limited and in many cases are connected with the accompanying overdose of other drugs or alcohol. Cases of overdose of a tsitalopram with a lethal outcome were registered, however, the majority of lethal cases was connected with the accompanying overdose of other medicines.

Symptoms. At overdose the following symptoms were attested: spasms, tachycardia, drowsiness, lengthening of an interval of QT, a lump, vomiting, a tremor, hypotension, a cardiac standstill, nausea, a serotoninovy syndrome, agitation, bradycardia, dizziness, blockade of ventriculonectors, lengthening of the QRS complex, hypertensia, a mydriasis, arrhythmia on the pirouette type, a stupor, sweating, cyanosis, a hyperventilation, and also atrial and ventricular disturbances of a rhythm.

Treatment. The specific antidote is absent. A symptomatic treatment and supporting. The gastric lavage has to be executed and absorbent carbon and osmotic laxatives are given (for example, sodium sulfate). In case of consciousness disturbance the patient has to be intubated. It is necessary to carry out monitoring of an ECG and indicators of the vital functions. ECG monitoring is recommended in case of overdose at patients with congestive heart failure / bradyarrhythmias, at the patients receiving the accompanying treatment by the drugs extending QT interval or at patients with metabolism disturbances, for example, at a liver failure.

Storage conditions:

List B. To store at a temperature not above 30 °C. To store in places, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated 20 mg and 40 mg. Packagings: 20 mg - 14, 28 and 56 pieces; on 14 tablets in the blister from PVC, an Al-foil. 1, 2 or 4 blisters with the application instruction in a cardboard pack. 40 mg - 28 pieces. On 14 tablets in the blister from PVC, an Al-foil. 2 blisters with the application instruction in a cardboard pack.