Estsitalopram (escitalopram)

	Estsitalopram (escitalopram) ESTSITALOPRAM (Escitalopram) Synonym: Tsipraleks Chemical name: S - (+) -1-[3-(Dimetilamino) propyl] -1 - (p-ftorfenil) -5 - ftalankarbonitril (as certified) Description: Antidepressant Group SIOZS, S-enantiomer tsitaloprama. Estsitaloprama oxalate powder-white or slightly yellow. Easy soluble in methanol and dimetilsulfokside difficult soluble in water and ethanol, slightly soluble in ethylacetate, nerastvorim in heptane. Molecular mass-414.40. Pharmacology: Farmakologicheskoe-action antidepressant. The mechanism of antidepressant allegedly linked to increased activity in serotoninergicheskoy TSNS by inhibition reverse takeover neyronalnogo serotonin. The studies in vitro and in vivo in animals shows the ability estsitaloprama vysokoselektivno ingibirovat neyronalny reverse takeover serotonin in the nervous with minimal effect on the reverse takeover noradrenalina and dofamina. Estsitalopram is at least 100 times more potent inhibitor reverse takeover serotonin than the R-enantiomer. Tolerance in modelling antidepressant effect is not developed with a long (up to 5 weeks), a rat. Estsitalopram not working or have very little ability to communicate with serotonin (5-HT1-7) or other receptors, including with alpha and beta adrenoretseptorami, dofaminovymi (D1-5) gistaminovymi (H1-3) muskarinovymi (M1-5) and BZ receptor (antagonism to muskarinovym, gistaminovym adrenergic receptors and, presumably, makes various antiholinergicheskie, sedatives, other cardiovascular side effects of psychotropic LS). Estsitalopram also not associated or has a very low affinity to the various ion channels, including Na +, K +, Cl- and Ca + + channels. Pharmacokinetics Pharmacokinetics estsitaloprama is linear and dozozavisimy admission of single and multiple doses (range 10-30 mg / day). Tablets and solution for the reception inside containing estsitaloprama definition, bioekvivalentny. Absorption estsitaloprama not depend on the meals. When you receive inside a single dose 20 mg Tm s about 5 hours Linking estsitaloprama with human plasma protein-about 56%. When you receive one every day equilibrium concentration in plasma set for about 1 week therapy. In the equilibrium state level estsitaloprama plasma young healthy subjects in the 2,2-2,5 times the concentration after a single dose. Product predominantly in the liver education demetiltsitaloprama S (S DTST) and S didemetiltsitaloprama (S DDTST). In vitro studies using human liver mikrosom indicate involvement izofermentov CYP3A4 and CYP2 S19 in the N-demethylation estsitaloprama. In human blood plasma dominates estsitalopram to unchanged. In equilibrium concentration of S DTST plasma is approximately 1 / 3 of concentration estsitaloprama. The level of the S DDTST not been determined for most actors. In vitro studies have shown that the pharmacological activity estsitaloprama (inhibition of reverse takeover serotonin) than any S DTST at least seven times, DDTST S-27 times, which shows that metabolites not make a substantial contribution to the antidepressant effect estsitaloprama. DTST S and S DDTST not interact or have a very weak affinostyu to serotonin (5-HT1-7) or other receptors, including Alpha and Beta adrenoretseptoram, dofaminovym (D1-5) gistaminovym (H1-3) muskarinovym (M1-5) BZ receptor and is not associated with various ion channels, including Na +, K + and Ca + + channels Cl-. Showing that after taking into estsitalopram determined to unchanged in urine (about 8%) and in the form of S DTST-10%. Oral keel clearance estsitaloprama-600 ml / min, with about 7% of kidney. Terminal T1 / 2 approximately 27-32 h. Dependence pharmacokinetics parameters of some factors Age. Pharmacokinetic parameters estsitaloprama admission single and multiple doses in people over 65 and younger people are comparable. When you receive the recommended dose (10 mg) of the elderly by about 50% and AUC increased T1 / 2 Cm s not changed. Paul. Using multiple estsitaloprama doses (10 mg / day for 3 weeks) in 18 men (9 elderly and the young 9) and 18 women (9 elderly and the young 9) found no difference in AUC values, Cm s and T1 / 2. The need to adjust the dose according to sex is not available. Lower liver function. For most patients with the liver function estsitaloprama recommended dose is 10 mg. Reduced kidney function. No information on the pharmacokinetic parameters estsitaloprama patient c pronounced renal insufficiency (Cl kreatinina with less than 20 ml / min). Pregnancy Introduction to pregnant rats at doses estsitaloprama 6, 12, 24 or 48 mg / kg / day from late pregnancy until the removal of the breast, resulting in a slight increase in mortality descendants and delay growth dose 48 mg / kg / day (approximately 24 the MRDCH times when calculating mg / m2). In the same dose was low for maternal toxicity (clinical signs, reducing allowances weight and eating). The dose 12 mg / kg / day, in which no adverse effects, about 6 times higher MRDCH when calculating mg / m2. The study embrio / Preliminary development in rats, a estsitaloprama pregnant rats inside in doses 56, 112 or 150 mg / kg / day during organogeneza was accompanied by a decrease weight of fruit and delay ossifikatsii with two higher doses (approximately 56-fold excess MRDCH 20 mg / day, the calculation in mg / m2). Toxicity for maternal (clinical signs, reducing allowances weight and eating), a moderate dose of 56 mg / kg / day, there was at all dose levels. The dose 56 mg / kg / day, in which no impact on the development of the fetus, about 28 times MRDCH when calculating mg / m2. It found no teratogenic in a dose tested (more than 75 times higher MRDCH when calculating mg / m2). Neteratogennye effects A newborn who exposure estsitaloprama and other SIOZS inhibitors or reverse takeover serotonin and noradrenalina III in the late trimester pregnancies mother developed complications requiring extended hospitalization, respiratory support, nutrition through the probe. Such complications may occur immediately after delivery. Reported clinical symptoms included: respiratory distress, cyanosis, simple, convulsions, temperature instability, difficulty in feeding, vomiting, hypoglycemia, hypotension, giperrefleksiyu, tremor, nervous agitation, irritability, constant crying. These symptoms are associated with a direct toxic effect SIOZS inhibitors or reverse takeover serotonin and noradrenalina, or perhaps are manifestations of reactions to the lifting of the newborn. In some cases the clinical picture was similar to the development serotoninovogo syndrome. Impact estsitaloprama definition of birth and delivery in humans is unknown. Clinical trials Many depressive disorder Performance estsitaloprama certified in the treatment of depression was established in March Placebo-controlled study of eight weeks from the adult ambulatory patients (ages 18-65) with depressed disorders (in accordance with the criteria DSM-IV). The main criterion for the effectiveness of all three studies was change in total score on the scale of the Montgomery-Asberg (MADRS). A study of fixed-dose compared with 10 and 20 mg / day estsitaloprama definition, placebo and 40 mg / day tsitaloprama showed that the improvement was significantly greater in group expressed patients who took 10 and 20 mg / day estsitaloprama, compared with placebo (as the assessment on MADRS). Performance indicators in the group of patients receiving 10 or 20 mg / day estsitaloprama were similar. In another study with a fixed dose estsitaloprama NC 10 mg / day improvement was significantly higher in this group compared with placebo (in accordance with the assessment by MADRS). In a study using different ranges of doses estsitaloprama, titruemyh in the interval between 10 and 20 mg / day, compared to placebo and different doses tsitaloprama, titruemyh between 20 and 40 mg / day, the improvement in the group, received a estsitaloprama definition, it was much higher compared with placebo (in accordance with the assessment by MADRS). Analysis of the data revealed no clinical studies of age, sex, race and no patients showed any of the characteristics of patients that have an impact on the effectiveness of treatment. Effectiveness of estsitaloprama supportive therapy for the treatment of depression was estimated to Placebo-controlled study with a 36-week open phase. The study included 274 patients with depressed disorders (in accordance with the criteria DSM-IV), which were responderami 8-week after an initial treatment of acute and then randomizirovany estsitalopramom to continue therapy at the same dose (10 or 20 mg / day) , or placebo. Response to therapy in the open phase of the study defined as a reduction in MADRS scores on the scale? 12. Relapse during the Double study defined as an increase in the number of points on a scale MADRS? 22 or repeal therapy because of poor clinical response. In patients receiving prodolzhavshih estsitalopram for 36 weeks, the time of remission was significantly higher than placebo. Adequate controlled study estsitaloprama effectiveness in the treatment of hospitalized patients with depression were not conducted. Generalized disturbing disorder (GTR) Estsitaloprama effectiveness in the treatment of generalized anxiety disorder was demonstrated in three mnogotsentrovyh Placebo-controlled studies with a duration of eight weeks of doses of 10-20 mg per day. The study included patients aged 18 to 80 years diagnosed with GTR (in accordance with the criteria DSM-IV). In all three studies improvement in the employment estsitaloprama was reliably higher compared with placebo (assessment conducted by the Hamilton anxiety scale, HAM-A). These groups were too few patients with particular ethnic or age to assess their impact on the effect of therapy. Response to treatment is not dependent on the sex of patients. Performance estsitaloprama with long-term (more than 8 weeks) treatment GTR in controlled tests are not systematically evaluated. Panic disorder Performance estsitaloprama was shown in the Double 10-week randomized study involving 351 patients (J. Waugh, Goa K.L., 2004). Application: Thank depressive disorder, generalized disturbing disorder (Physicians Desk Reference, 2005). Depression, panic disorder (eg with agorafobiey) (State Register of drugs, T. 2, 2004). Contraindications: Hypersensitivity, simultaneous reception of MAO inhibitors (see "Precautions"). Restrictions apply to: Children's age (safety and efficacy of the children are not identified). Application of pregnancy and breast feeding: Pregnancy. Perhaps if the expected effect of therapy over the potential risk to the fetus (adequate and well estsitaloprama studies of safety in pregnant women has not conducted). If a patient takes over estsitalopram III trimester of pregnancy, the physician must carefully evaluate the correlation risk / benefit and should consider the possibility of lifting development reactions (a drug discontinuation syndrome) in the newborn (see "Pharmacology; Neteratogennye effects). The doctor can decide on the Phase III in the treatment estsitalopramom term. Forage chest. Nursing women should either stop breastfeeding, or reception estsitaloprama definition. Adverse actions: The tables are presented side effects, the frequency of which expressed as a percentage and the number of patients who have had at least one case of a side of the observation period. To factions side effects noted in various studies, standard terminology used by the WHO. Side effects leading to the cessation of treatment Many depressive disorder A Double Placebo-controlled trials in depression patients 6% of the 715 patients who received estsitalopram, interrupted treatment because of side effects, compared to 2% of 592 patients receiving placebo. In studies with a fixed dose of patients receiving 10 mg / day estsitaloprama and abandoned treatment because of side effects, not significantly different from the one in patients receiving placebo. The percentage of patients receiving fixed-dose estsitaloprama 20 mg / day and ceased treatment was 10%, which is significantly different from any of the patients who received 10 mg / d (4%) and placebo (3%). Side effects that had caused the cessation of treatment estsitalopramom at least 1% of patients with a frequency of 2 times more placebo-nausea (2%), violation of ejaculation (2% male patients). Generalized disturbing disorder A Double Placebo-controlled trials in patients GTR, 8% of the 429 patients who received 10-20 mg / day estsitaloprama, interrupted treatment because of side effects, compared with 4% of 427 patients receiving placebo. Side effects that had caused the cessation of treatment estsitalopramom at least 1% of patients with a frequency of 2 times more placebo-nausea (2%), insomnia (1%), fatigue (1%). Generalized disturbing disorder The most common side effects associated with hosting estsitaloprama (frequency occurrences 5% or more) is not equivalent to the frequency of occurrences in the placebo group, i.e. admission estsitaloprama observed at least two times more often than in placebo group were nausea, violation of ejaculation (mainly delay) men, insomnia, fatigue, and drive down anorgazmiya. Networking: LS acting agent. Must be careful while admission to other LS central action. Alcohol. While estsitalopram not potentsiruet effects of alcohol (these clinical studies), as with other psychotropic medicines, the simultaneous application estsitaloprama and alcohol is not recommended. MAO inhibitors. C incompatible MAO inhibitors (see Contraindications, "and" Precautions "). Funds affecting blood coagulability (NPVS, acid Aspirin, warfarin, etc). . The release of platelets serotonin plays an important role in hemostasis. Epidemiological studies (case-control study, and cohort study) demonstrated a link between the use of psychotropic substances affecting reverse takeover serotonin and frequency of bleeding from the upper divisions beds. In two studies simultaneous application NPVS, including acetylsalicylic acid, potentsirovalo risk of bleeding. While these studies have focused on krovotecheniyah from lower divisions ZHKT have reason to believe that there may bleeding and other localizations, so while receiving estsitaloprama and affecting blood coagulability, and requires careful control of blood collapse. Lithium. Lithium may reinforce serotoninergichesky estsitaloprama effect, if joint application must be careful. Sumatriptan. There are rare postmarketingovye reports on the development of patient weaknesses giperrefleksii violations and the coordination of movements using SIOZS and sumatriptana. If the application sumatriptana and SIOZS (such as fluoxetin, Fluvoxamine, Paroxetine, Sertraline, Citalopram, estsitalopram) clinically justified, it is recommended that appropriate monitoring of the patient. Carbamazepine. Carbamazepine, indutsiruya mikrosomalnye liver enzymes can increase estsitaloprama keel clearance, which should be kept in mind while appointing these LS. Ritonavir. Joint use of a single dose of ritonavir (600 mg), and a substrate, and a potent inhibitor CYP3A4, and estsitaloprama (20 mg) was not accompanied by any change in the pharmacokinetics of ritonavir or estsitaloprama. In in vitro studies found no effect of inhibition of CYP3A4 estsitaloprama, CYP1 A2, CYP2 S9, S19 and CYP2 CYP2E1. Based on these data, it is a weak effect on metabolism, indirectly by the group tsitohroma P450 enzymes in vivo. CYP3A4 and CYP2 S9 inhibitors. In vitro studies show that the CYP3A4 and CYP2 S9 are major enzymes involved in metabolism estsitaloprama. However, a joint reception estsitaloprama (20 mg) and ritonavir (600 mg), a strong CYP3A4 inhibitor, had no meaningful effect on the pharmacokinetics estsitaloprama. Since estsitalopram product different enzyme systems, inhibition of the enzyme can significantly reduce estsitaloprama keel clearance. LAN, metaboliziruyuschiesya with izofermenta tsitohroma P450 CYP2D6. In vitro studies have not identified estsitaloprama inhibition effect on CYP2D6. In addition, the equilibrium levels of the racemate tsitaloprama not differ significantly from the weak and strong CYP2D6 metabolizantov. This indicates unlikely clinically meaningful effect on the metabolism of CYP2D6 inhibitors estsitaloprama. However, limited data in vivo showed moderate inhibition effect CYP2D6- estsitaloprama: joint use estsitaloprama (21 mg / day for 21 days) with antidepressant drugs dezipraminom (single dose of 50 mg), CYP2D6 substrate, resulting in 40% increase in S max and 100% increase Dezipramina AUC. Clinical significance of this observation is unknown. Nevertheless, in a joint admission estsitaloprama and LS, metaboliziruyuschihsya CYP2D6 shows with caution. Metoprolol. Admission healthy volunteers 20 mg / day estsitaloprama 21 days resulted in a 50% increase in S max and 82% increase in AUC metoprolola (single dose of 100 mg). When the plasma level metoprolola fell kardioselektivnosti. Joint Admission and estsitaloprama metoprolola had no clinically significant effect on AD and CHSS. Esbjorn therapy. No clinical studies on the sharing of ECT therapy and estsitaloprama. Since estsitalopram-active isomer racemate tsitaloprama not apply these two LS at the same time. Overdose: In clinical trials estsitaloprama were reported overdose (600 mg) without a fatal outcome. Treatment: achieving and maintaining road airways for adequate ventilation and oxygenation, Washing stomach and the use of activated carbon. We recommend close observation and monitoring of vital functions, including as heart, symptomatic and supportive therapy. Because of the large volume of estsitaloprama unlikely efficiency, such as forced Diurez, dialysis, and gemoperfuziya exchange blood transfusions. The specific Antidote missing. Treatment: achieving and maintaining road airways for adequate ventilation and oxygenation, Washing stomach and the use of activated carbon. We recommend close observation and monitoring of vital functions, including as heart, symptomatic and supportive therapy. Because of the large volume of estsitaloprama unlikely efficiency, such as forced Diurez, dialysis, and gemoperfuziya exchange blood transfusions. The specific Antidote missing. Dosing and Administration: inside once a day, regardless of the meal. Initial dose, depending on the evidence, 5-10 mg / day, if necessary dose can be increased to a maximum of 20 mg per day. For patients older than 65 years should be reduced to a daily dose of 50%: elementary-5 mg, the maximum is 10 mg per day. In patients with liver function violations recommended initial dose for the first 2 weeks of treatment, 5 mg / day (in the future may be increased depending on the individual patient's responses). If any function of the kidneys light and medium gravity adjusting dose is not required. The course of treatment is a long, determined by the treating physician. Precautions: The combination of MAO inhibitors (see Contraindications ") In joint admission drugs from the group reverse takeover serotonin inhibitors in combination with MAO inhibitors have been reported in patients of serious, sometimes fatal, reactions, including HYPERTHERMIA, stiffness, mioklonus, instability of the vital functions of possible rapid fluctuations, change in mental state (including excessive azhitatsiyu until deliriya and coma). It was reported the same reaction from patients who had received MAO inhibitors shortly after the end of treatment SIOZS. In some cases, signs have similarities with the neuroleptic malignant syndrome. Furthermore, the limited information on the joint use of MAO inhibitors SIOZS and received on animals showed synergistic action of the PA in terms of pressure and behavioral stimulation. Therefore, should not be combined with estsitalopram MAO inhibitors or appoint him for the first two weeks after their removal. After treatment estsitalopramom also should take a break of at least two weeks before the MAO inhibitors. A development serotoninovogo syndrome in 2 patients receiving both antibiotic linezolid, which is non-selective reversible MAO inhibitor. Although the effectiveness of estsitaloprama supportive therapy for the treatment of depression has been demonstrated in Placebo-controlled study of 36 weeks duration, however, a doctor appointed estsitalopram for long-term therapy, should periodically evaluate the usefulness of the LS for each patient. Clinical deterioration and the risk of suicide In regard to the possibility of degradation and suicidal attempts among depressed patients need careful monitoring of patients, particularly in the early course of therapy and a change of dosage (as promotions, and at lower). Relatives of patients receiving drugs in the treatment of depression or other mental or other illnesses, you need to know about the need for the patient. They should be wary whenever a azhitatsii, irritability, aggressiveness or other symptoms of the behavior of patients, as well as whenever a propensity for suicide and immediately report these symptoms to treating doctor. In appointing estsitaloprama patients should prescribe a minimum number of tablets to reduce the risk of overdose. Ending treatment estsitalopramom There are reports of the emergence of patient-effects resulting from the termination of treatment or other estsitalopramom SIOZS inhibitors or reverse takeover serotonin and noradrenalina, especially with the sharp reversal. These may include: identity, irritability, azhitatsiyu, dizziness, sensitivity violation (including paresteziyu, feeling shock, electrocution), anxiety, sensory consciousness, headache, suspended, emotional Lability, insomnia, gipomaniyu. Therefore, the abolition estsitaloprama should gradually by lowering doses to reduce the risk of cancellation syndrome, the recommended monitoring of the patient. Abnormal bleeding There have been reports of cases of bleeding in patients with admission psychotropic substances that affect serotonin reverse takeover (see "Synergy"). It should warn patients of the need to be careful when mixed reception from estsitaloprama NPVS, including with acetylsalicylic acid or other medicines that affect coagulation. Giponatriemiya One case was reported against the backdrop giponatriemii estsitalopramom treatment. Several cases giponatriemii syndrome of inappropriate secretion or ADG were in the treatment ratsematom tsitaloprama. All of the patients returned to normal after estsitaloprama or tsitaloprama and / or medical intervention. Enabling mania / gipomanii A Placebo-controlled trials in patients with depression Mania / gipomaniya was observed in 1 (0.1%) of 715 patients receiving estsitalopram, and there were no cases in the placebo group (592 patients). Like other drugs, estsitalopram should be appointed with caution to patients with mania in history. With the development of obsessive estsitalopram should be abolished. C udorogi During clinical trials estsitaloprama been cases of a convulsing. It is therefore necessary to carefully appoint estsitalopram patients with spasmodic in the history of seizures. Doing upset should stop receiving the drug. The impact on cognitive ability and motor activity The study in healthy volunteers who received doses of 10 mg / day, no lower intellectual and psychomotor speed reactions. However, as any psychoactive drug, can reduce judgement, the process of thinking, motor skills, patients should be alerted to the need to be careful when dealing with potentially dangerous machinery, and while driving a car. The application in patients with concomitant diseases Clinical experience with estsitaloprama if patients opportunistic diseases is limited. Must be careful when diseases involving violations metabolism or hemodynamic. There has been a systematic observations in patients with myocardial infarction or unstable heart disease, because these patients premarketingovyh excluded from clinical research. The abuse and dependence Studies on animals show low ability tsitaloprama Dependence. Systematic observations of the human ability to assess the potential to cause estsitaloprama abuse, tolerance, physical dependence is not held. But be careful monitoring of patients whose pre observed abuse drugs. Application patients older In controlled tests estsitaloprama effectiveness in patients with depression and GTR approximately 6% of 1144 patients were aged 60 years and older. Elderly patients in these studies were estsitaloprama daily dose between 10 and 20 mg. The number of elderly patients has not been sufficient to adequately assess the efficacy and safety according to the age of LS. However, we can not exclude the possibility of heightened sensitivity among some patients to the LS.
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