Escitalopram

DEA NFLIS-Drug Category -> Antidepressants

Pharmaceuticals -> Nervous system -> Psychoanaleptics

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> SRRIs (Selective Serotonin Reuptake Inhibitors)

Pharmaceuticals -> Listed in ZINC15

Antidepressants -> Selective serotonin reuptake inhibitors (SSRI)

Breast Feeding; Lactation; Milk, Human; Antidepressive Agents; Serotonin Uptake Inhibitors; Antidepressive Agents, Second-Generation

9.5

pKa = 9.80 (amine moiety) /Trimethylamine/ (conjugate acid)

Fine white to slightly yellow powder. Crystals from acetone. MP: 147-148 °C. Specific optical rotation: +12.31 deg at 25 °C/D (c = 1 in methanol). Freely soluble in methanol, DMSO; soluble in isotonic saline; sparingly soluble in water, ethanol. slightly soluble in ethyl acetate; insoluble in heptane /Escitalopram oxalate/

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P270, P272, P273, P280, P301+P317, P302+P352, P321, P330, P333+P317, P362+P364, P391, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including escitalopram oxalate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Escitalopram oxalate/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Escitalopram oxalate/

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary. /Escitalopram oxalate/

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature 2-8 °C. Store with desiccant. /Escitalopram oxalate/

Store at 25 °C (77 °F); excursions permitted to 15 - 30 °C (59-86 °F).

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /Escitalopram oxalate/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product. /Escitalopram oxalate/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. /Escitalopram oxalate/

Precautions for safe handling: Avoid contact with skin and eyes. Provide appropriate exhaust ventilation at places where dust is formed. /Escitalopram oxalate/

Appropriate engineering controls: General industrial hygiene practice. /Escitalopram oxalate/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Escitalopram oxalate/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Escitalopram oxalate/

Skin protection: Handle with gloves. /Escitalopram oxalate/

Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. /Escitalopram oxalate/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator.For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Escitalopram oxalate/

Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of escitalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for Escitalopram. (L1712)

Although the antidepressant and anxiolytic effects of selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors are well-documented, less is known about their cognitive effects. Escitalopram, a selective serotonin reuptake inhibitor, and atomoxetine, a selective noradrenaline reuptake inhibitor, were used to evaluate the interaction between noradrenergic and serotonergic neurotransmission in the modulation of contextual fear conditioning in rats. Contextual fear-conditioning test was used to investigate the acute effects of escitalopram, alone or in combination with atomoxetine, in different stages of learning and memory in rats. Furthermore, microdialysis in freely moving animals was used to investigate the effect of escitalopram on serotonin, dopamine, and noradrenaline levels in the rat hippocampus. Escitalopram significantly increased conditioned responses when applied before the acquisition, but decreased responses, when applied before the recall test. When administered during memory consolidation, escitalopram dose-dependently enhanced conditioned responding. These effects were blocked by atomoxetine. Escitalopram (at a dose that affects memory consolidation) increased hippocampal serotonin levels fourfold without changing dopamine or noradrenaline. Atomoxetine, at dose levels that blocked the effects of escitalopram on contextual fear conditioning, increased the extracellular levels of noradrenaline eightfold but did not change dopamine or serotonin. A combined treatment of escitalopram and atomoxetine caused a significant attenuation of escitalopram-induced increase in serotonin levels, while noradrenaline levels were not affected. These findings indicate that escitalopram affects fear memory in rats, likely modulated by increases in serotonin levels in the brain. This effect is impaired by atomoxetine, probably due to a noradrenaline-mediated decrease in serotonin levels. Further studies are warranted to study the effects of potential differences among antidepressant therapies on long-term cognitive outcomes.

A 63-year-old woman with a history of long-standing depression, maintained on escitalopram, presented with altered mental status. Patient had recently been prescribed dextromethorphan-promethazine cough syrup 2?weeks prior for an upper respiratory tract infection. On admission, she was lethargic and obtunded and found to have inducible myoclonus on examination. The rest of her physical exam was unremarkable. Pertinent lab and imaging findings showed QTc prolongation on ECG, negative electroencephalogram and CT head findings, essentially normal blood tests and a negative toxicology screen. The patient was admitted to the step down unit for close observation; both escitalopram and the cough syrup were suspended and was supportively managed. Overnight the patient's mental status improved and the serial EcGs showed resolution of the prolonged QTc. Patient was discharged home without further complication.

Linezolid, an anti-infective agent that is also a reversible monoamine oxidase (MAO) inhibitor, has been associated with drug interactions resulting in serotonin syndrome, including some associated with serotonin-reuptake inhibitors (SSRIs). Because of this potential risk, linezolid generally should not be used in patients receiving escitalopram. However, the FDA states that certain life-threatening or urgent situations may necessitate immediate linezolid treatment in a patient receiving a serotonergic drug. In such emergency situations, the availability of alternative anti-infectives should be considered and the benefits of linezolid should be weighed against the risk of serotonin syndrome. If linezolid is indicated in such emergency situations, escitalopram must be immediately discontinued and the patient monitored for symptoms of CNS toxicity for 2 weeks or until 24 hours after the last linezolid dose, whichever comes first. Treatment with escitalopram may be resumed 24 hours after the last linezolid dose. If nonemergency use of linezolid is being planned for a patient receiving escitalopram, escitalopram should be withheld for at least 2 weeks prior to initiating linezolid. Treatment with escitalopram should not be initiated in a patient receiving linezolid; when necessary, escitalopram may be started 24 hours after the last linezolid dose.

Potential pharmacologic interaction (potentially serious serotonin syndrome) when isoniazid, an antituberculosis agent that appears to have some monoamine oxidase (MAO)-inhibiting activity, is used concomitantly with escitalopram.

For more Interactions (Complete) data for Escitalopram (18 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 5500(SRC), determined from a structure estimation method(2), indicates that escitalopram is expected to be immobile in soil(SRC). A pKa of 9.8 for the amine moiety of escitalopram (based upon trimethylamine)(3) indicates that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Escitalopram is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.1X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2018).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 5500(SRC), determined from a structure estimation method(2), indicates that escitalopram is expected to adsorb to suspended solids and sediment(SRC). A pKa of 9.8 for the amine moiety of escitalopram (based upon trimethylamine)(3) indicates escitalopram will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 140(SRC), from an estimated log Kow of 3.74(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Biodegradation data in water were not available(SRC, 2018).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), escitalopram, which has an estimated vapor pressure of 1.1X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase escitalopram is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4 hrs(SRC), calculated from its rate constant of 9.2X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(2). Particulate-phase escitalopram may be removed from the air by wet and dry deposition(SRC). Escitalopram does not contain chromophores that absorb at wavelengths >290 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight(SRC).

Although escitalopram and SSRIs have a lower toxicity profile than older antidepressants, they have still been associated with significant adverse effects. The most frequently reported adverse effects include insomnia, sexual dysfunction (particularly reduced libido, anorgasmia, and male ejaculatory delay), nausea, increased sweating, fatigue, and somnolence. QT prolongation and serotonin syndrome are rare but potentially severe adverse effects associated with escitalopram.

IDENTIFICATION AND USE: Escitalopram is a second-generation antidepressive agent. It is used for the acute and maintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age. HUMAN STUDIES: Antidepressant discontinuation syndrome (ADS) frequently occurs in patients who undergo an abrupt discontinuation of their antidepressant medication. For escitalopram ADS was observed in 14 of 25 patients. Frequent symptoms were dizziness (44%), muscle tension (44%), chills (44%), confusion or trouble concentrating (40%), amnesia (28%), and crying (28%). Major manifestations of escitalopram overdose were serotonin toxicity, QT prolongation, and bradycardia. Other symptoms accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol, included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, and somnolence. Acute renal failure has been very rarely reported accompanying overdose. Escitalopram does not appear to be associated with an increased risk for major malformations but appears to increase the risk for low birth weight. In addition, the higher rates of spontaneous abortions have been observed. A case of serotonin toxicity due to in utero exposure to escitalopram was described. In human peripheral lymphocytes sister chromatid exchange increase caused by 5 and 10 ug/mL of escitalopram was found, while no increase was observed in DNA damage and micronucleus (MN) formation. Racemic form of the drug was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes. ANIMAL STUDIES: In a one-year toxicology study, 5 of 10 beagle dogs receiving oral racemic drug doses of 8 mg/kg/day died suddenly between weeks 17 and 31 following initiation of treatment. Sudden deaths were not observed in rats at doses of racemic drug up to 120 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, racemic metabolites caused QT prolongation. Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with racemic drug. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day. Similar findings were not present in rats receiving 24 mg/kg/day of racemic drug for two years, in mice receiving up to 240 mg/kg/day of racemic drug for 18 months, or in dogs receiving up to 20 mg/kg/day of racemic drug for one year. In two rat embryo/fetal development studies, oral administration of racemic drug (32, 56, or 112 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased embryo/fetal growth and survival and an increased incidence of fetal abnormalities (including cardiovascular and skeletal defects) at the high dose. This dose was also associated with maternal toxicity in rats. In a rabbit study, no adverse effects on embryo/fetal development were observed at doses of racemic citalopram of up to 16 mg/kg/day. Racemic drug was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Racemic drug was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. ECOTOXICITY STUDIES: There were noticeable gender differences in the behavior responses to escitalopram in zebrafish. At the end of exposures, both length and weight of the females exposed to 1.50 ug/L escitalopram were significantly less than the group of control fish. In addition, males exposed to 1.50 ug/L escitalopram were significantly shorter than control fish.

The current maximum recommended dose of escitalopram is 20 mg PO daily. For out-of-hospital isolated SSRI overdoses in patients with minor symptoms (typically less than 5 times their treatment dosage), management should involve at-home observation and close coordination with a local poison control center.

The antidepressant, antiobsessive-compulsive, and antibulimic actions of escitalopram are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Escitalopram blocks the reuptake of serotonin at the serotonin reuptake pump of the neuronal membrane, enhancing the actions of serotonin on 5HT_1A autoreceptors. SSRIs bind with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs.

/AQUATIC SPECIES/ Selective serotonin re-uptake inhibitors are pharmaceuticals used to treat a range of psychological disorders. They are frequently found in surface waters in populated areas. In recent years, they have been shown to affect the behavior of various aquatic organisms in a way that can have ecological effects. In this study, ...zebrafish of both sexes /were exposed/ to nominally 0.00, 0.15 and 1.50 ug/L Escitalopram in flow-through tanks for three weeks. Subsequently, ten swimming behavior parameters were quantified using high-resolution video tracking. There were noticeable gender differences in the behavior responses to Escitalopram. Female fish exposed to 1.50 ug/L Escitalopram had a lower maximum swimming velocity, stopped less often and exhibited increased boldness (reduced thigmotaxis) compared to controls. Male fish exposed to 1.50 ug/L had a lower maximum swimming velocity compared to control fish. At the end of exposures, both length and weight of the females exposed to 1.50 ug/L Escitalopram were significantly less than the group of control fish. In addition, males exposed to 1.50 ug/L Escitalopram were significantly shorter than control fish. The behavior, weight and body length of the fish exposed to nominally 0.15 ug/L was not significantly different from control fish in either sex. The results of this study demonstrate that Escitalopram can affect subtle but ecologically important aspects of fish behavior and lends further credibility to the assumption that Escitalopram is an environmentally active pharmaceutical.

Using a structure estimation method based on molecular connectivity indices(1), the Koc of escitalopram can be estimated to be 5500(SRC). According to a classification scheme(2), this estimated Koc value suggests that escitalopram is expected to be immobile soil. The pKa of the amine moiety of escitalopram (based upon trimethylamine) is 9.8(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

/HUMAN EXPOSURE STUDIES/ Citalopram, a selective serotonin reuptake inhibitor, is used as a neuroendocrine probe in human subjects to assess serotonin function as reflected in prolactin and plasma cortisol release. Citalopram is a racemic mixture of equal proportions of the S(+) and R(-) enantiomers. Inhibition of serotonin reuptake and, consequently, antidepressant activity is associated, almost exclusively, with the S(+) enantiomer ("escitalopram"). Studies in animal models indicate that the presence of the R(-) isomer may interfere with the serotonin reuptake activity of escitalopram. The current study compared the neuroendocrine effects of citalopram and escitalopram in healthy human volunteers. Plasma cortisol and prolactin levels following a single oral dose of citalopram (40 mg) or escitalopram (20 mg) were compared in samples taken every 15-30 min over a period of 240 min. Plasma citalopram concentration was determined at the same intervals. Escitalopram and citalopram caused equivalent increases in plasma cortisol and prolactin. The administration of dexamethasone prior to the escitalopram challenge blocked the evoked increase in cortisol. This is the first study to prove that a single dose of escitalopram acts centrally and not peripherally, providing further support of the use of oral escitalopram as a probe for brain serotonergic function.

/SIGNS AND SYMPTOMS/ Antidepressant discontinuation syndrome (ADS) frequently occurs in patients who undergo an abrupt discontinuation of their antidepressant medication. We evaluated 25 consecutive outpatients with depression who discontinued their use of escitalopram. The presence of ADS was evaluated according to the Antidepressants Discontinuation Syndrome checklist. Antidepressant discontinuation syndrome was observed in 14 of 25 patients. Frequent symptoms were dizziness (44%), muscle tension (44%), chills (44%), confusion or trouble concentrating (40%), amnesia (28%), and crying (28%). The treatment doses and plasma concentrations of escitalopram were significantly higher in patients with ADS than in patients without ADS. No group differences were observed regarding age, sex, or duration of escitalopram treatment before the discontinuation. These findings suggest that a higher dose and lower clearance of escitalopram lead to a higher risk of ADS. Very slow tapering is recommended for all patients.

/SIGNS AND SYMPTOMS/ A review of escitalopram overdoses to a clinical toxicology unit was undertaken. Patient demographics, details of the ingestion, clinical effects, including evidence of serotonin toxicity, complications (arrhythmias and seizures), ICU admission, and length of stay were obtained. QT and QRS intervals were manually measured on ECGs by using a standardized approach. In a subgroup of 34 prospectively recruited patients, escitalopram was detected in blood from 33 patients. Medians and interquartile ranges (IQR) were reported, and QT versus pulse rate was plotted on a QT nomogram to investigate QT prolongation. Median ingested dose in the 79 presentations was 140 mg (IQR 75 to 260 mg; range 20 to 560 mg), and escitalopram was the only drug ingested or all coingested drugs were nontoxic in 46 cases. Median length of stay for patients receiving clinically important coingestants was 19 hours (IQR 9 to 33 hours) compared with that of patients receiving escitalopram alone (median 12 hours; IQR 7 to 19 hours). Serotonin toxicity occurred in 7 of the 46 escitalopram-alone ingestions (15%) but in only 1 of the 33 patients coingesting other medications. Common features were inducible clonus and hyperreflexia. Central nervous system depression and ICU admission were rare in escitalopram-alone overdoses compared with those in cases with sedative coingestants. Bradycardia (pulse rate <60 beats/min) occurred in 11 cases (14%) and an abnormal QT-HR pair in 11 (14%), which was associated with normal or slow pulse rates. There were no deaths, seizures, or arrhythmias. Major manifestations of escitalopram overdose were serotonin toxicity, QT prolongation, and bradycardia. The study suggests a potential for cardiac arrhythmias in escitalopram overdose.

/SIGNS AND SYMPTOMS/ Symptoms most often accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol, included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes (including QT prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose.

For more Human Toxicity Excerpts (Complete) data for Escitalopram (23 total), please visit the HSDB record page.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including escitalopram oxalate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Escitalopram oxalate/

N06AB10

N - Nervous system

QN - Nervous system

Escitalopram belongs to a class of medications called selective serotonin re-uptake inhibitors (SSRIs). These agents cause an increase in serotonin levels in neuronal synapses by preventing the re-uptake of serotonin (5-HT) into the presynaptic terminals of serotonergic neurons. As compared to other SSRIs, it appears to have a relatively quick onset of effect due to its potency. SSRIs as a class have been associated with abnormal bleeding, particularly in patients receiving concomitant therapy with other medications affecting hemostasis, and with the development of serotonin syndrome. Use escitalopram with caution in patients with a higher-than-baseline risk of bleeding and in patients receiving concomitant therapy with other serotonergic drugs. Escitalopram may also cause a discontinuation syndrome with abrupt removal of the drug, and should be slowly tapered if discontinuation of therapy is warranted.

Escitalopram, like other selective serotonin re-uptake inhibitors, enhances serotonergic activity by binding to the orthosteric (i.e. primary) binding site on the serotonin transporter (SERT), the same site to which endogenous 5-HT binds, and thus prevents the re-uptake of serotonin into the presynaptic neuron. Escitalopram, along with [paroxetine], is also considered an allosteric serotonin re-uptake inhibitor - it binds to a secondary allosteric site on the SERT molecule to more strongly inhibit 5-HT re-uptake. Its combination of orthosteric and allosteric activity on SERT allows for greater extracellular 5-HT levels, a faster onset of action, and greater efficacy as compared to other SSRIs. The sustained elevation of synaptic 5-HT eventually causes desensitization of 5-HT_1A auto-receptors, which normally shut down endogenous 5-HT release in the presence of excess 5-HT - this desensitization may be necessary for the full clinical effect of SSRIs and may be responsible for their typically prolonged onset of action. Escitalopram has shown little-to-no binding affinity at a number of other receptors, such as histamine and muscarinic receptors, and minor activity at these off-targets may explain some of its adverse effects.

The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).

The elimination half-life of escitalopram is 27-32 hours, though this is increased by approximately 50% in the elderly and doubled in patients with reduced hepatic function. The elimination half-life of escitalopram's primary metabolite, S-desmethylcitalopram, is approximately 54 hours at steady state.

Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27-32 hours.

The metabolism of escitalopram is mainly hepatic, mediated primarily by CYP2C19 and CYP3A4 and, to a lesser extent, CYP2D6. Oxidative N-demethylation by the CYP enzyme system results in S-desmethylcitalopram (S-DCT) and S-didesmethylcitalopram (S-DDCT) - these metabolites do not contribute to the pharmacologic activity of escitalopram, and exist in the plasma in small quantities relative to the parent compound (28-31% and <5%, respectively). There is also some evidence that escitalopram is metabolized to a propionic acid metabolite by monoamine oxidase A and B in the brain, and that these enzymes constitute the major route of escitalopram metabolism in the brain.

The antidepressant escitalopram is predominantly metabolized by the polymorphic CYP2C19 enzyme. The authors investigated the effect of CYP2C19 genotype on exposure and therapeutic failure of escitalopram in a large patient population. A total of 4,228 escitalopram serum concentration measurements from 2,087 CYP2C19-genotyped patients 10-30 hours after drug intake were collected retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into subgroups based on CYP2C19 genotype: those carrying inactive (CYP2C19Null) and gain-of-function (CYP2C19*17) variant alleles. The between-subgroup differences in escitalopram exposure (endpoint: dose-harmonized serum concentration) and therapeutic failure (endpoint: switching to another antidepressant within 1 year after the last escitalopram measurement) were evaluated by multivariate mixed model and chi-square analysis, respectively. Compared with the CYP2C19*1/*1 group, escitalopram serum concentrations were significantly increased 3.3-fold in the CYP2C19Null/Null group, 1.6-fold in the CYP2C19*Null/*1 group, and 1.4-fold in the CYP2C19Null/*17 group, whereas escitalopram serum concentrations were significantly decreased by 10% in the CYP2C19*1/*17 group and 20% in the CYP1C19*17/*17 group. In comparison to the CYP2C19*1/*1 group, switches from escitalopram to another antidepressant within 1 year were 3.3, 1.6, and 3.0 times more frequent among the CYP2C19Null/Null, CYP2C19*1/*17, and CYP1C19*17/*17 groups, respectively. The CYP2C19 genotype had a substantial impact on exposure and therapeutic failure of escitalopram, as measured by switching of antidepressant therapy. The results support the potential clinical utility of CYP2C19 genotyping for individualization of escitalopram therapy.

Escitalopram is metabolized to S-demethylcitalopram (S-DCT) and S-didemethylcitalopram (S-DDCT). In humans, unchanged escitalopram is the predominant compound in plasma. At steady state, the concentration of the escitalopram metabolite S-DCT in plasma is approximately one-third that of escitalopram. The level of S-DDCT was not detectable in most subjects. In vitro studies show that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT1-7) or other receptors including alpha- and beta-adrenergic, dopamine (D1-5), histamine (H1-3), muscarinic (M1-5), and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na+, K+, Cl-, and Ca++ channels. In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the Ndemethylation of escitalopram.

Mainly hepatic. Escitalopram undergoes <i>N</i>-demethylation to <i>S</i>-demethylcitalopram (S-DCT) and <i>S</i>-didemethylcitalopram (S-DDCT). CYP3A4 and CYP2C19 are the enzymes responsible for this <i>N</i>-demethylation reaction. Route of Elimination: Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and <i>S</i>-demethylcitalopram (S-DCT) is about 8% and 10%, respectively. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance. Escitalopram is metabolized to S-DCT and <i>S</i>-didemethylcitalopram (S-DDCT). Half Life: 27-32 hours

4O4S742ANY

ESCITALOPRAM

Established Pharmacologic Class [EPC] - Serotonin Reuptake Inhibitor

Mechanisms of Action [MoA] - Serotonin Uptake Inhibitors

Escitalopram is a Serotonin Reuptake Inhibitor. The mechanism of action of escitalopram is as a Serotonin Uptake Inhibitor.

ESCITALOPRAM

Absorption of escitalopram following oral administration is expected to be almost complete, with an estimated absolute bioavailability of approximately 80%. Tmax occurs after about 4-5 hours. Cmax and AUC appear to follow dose proportionality - at steady state, patients receiving 10mg of escitalopram daily had a Cmax of 21 ng/mL and a 24h AUC of approximately 360 ng*h/mL, while patients receiving 30mg daily had a roughly 3-fold increase in both Cmax and 24h AUC, comparatively.

After oral administration of escitalopram, approximately 8% of the total dose is eliminated in the urine as unchanged escitalopram and 10% is eliminated in the urine as S-desmethylcitalopram. The apparent hepatic clearance of escitalopram amounts to approximately 90% of the total dose.

Escitalopram appears to distribute extensively into tissues, with an apparent volume of distribution of approximately 12-26 L/kg.

The oral plasma clearance of escitalopram is 600 mL/min, of which approximately 7% is due to renal clearance.

/MILK/ Escitalopram is excreted in human breast milk. Limited data from women taking 10-20 mg escitalopram showed that exclusively breast-fed infants receive approximately 3.9% of the maternal weight-adjusted dose of escitalopram and 1.7% of the maternal weight-adjusted dose of desmethylcitalopram.

The absolute bioavailability of citalopram is about 80% relative to an intravenous dose, and the volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable. The binding of escitalopram to human plasma proteins is approximately 56%.

Serotonin Uptake Inhibitors; Antidepressive Agents, Second-Generation

MEDICATION

Use (kg; approx.) in Germany (2009): >750

Labeled indications include major depressive disorder (MDD) and generalized anxiety disorder (GAD). Unlabeled indications include treatment of mild dementia-associated agitation in nonpsychotic patients.

Direct resolution of the racemic /citalopram/ ... was not possible, but, e.g., with (+)-di-p-toluoyltartaric acid the open-chained intermediate 4-(4-dimethylamino)-1-(4'-fluorophenyl)-1-(hydroxybutyl)-3-(hydroxymethyl)benzonitrile can be easily resolved, and upon reaction with methanesulfonyl chloride in toluene and in presence of triethylamine the (-)-enantiomer precursor can be converted into the desired pure enantiomeric ... /escitalopram/.

Escitalopram is the (S)-isomer of the racemic citalopram. The isomer is produced by resolution of the enantiomer and conversion to the oxalate salt. /Escitalopram oxalate/