ESCITALOPRAM OXALATE (Generic for LEXAPRO)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-May administer escitalopram with or without food. If nausea occurs, administer after a meal.
Oral Solid Formulations
-Tablets: The 10 mg and 20 mg tablets are scored and may be cut in half if needed.

Oral Liquid Formulations
-Oral solution: Measure dosage with an oral syringe or calibrated measuring device to ensure dose accuracy.

The safety and efficacy of escitalopram in pediatric patients is established for children and adolescents 7 years of age and older. Adverse events were collected in 576 pediatric patients as young as 6 years old with major depressive disorder (n = 286 escitalopram) during double-blind placebo-controlled trials. In general, the safety profile in pediatric patients during clinical trials was similar to that seen in adults and was consistent with the known safety and tolerability profile for escitalopram.

Adverse gastrointestinal (GI) effects are among the most frequently reported adverse reactions during treatment with SSRIs, including escitalopram. During clinical evaluation of escitalopram, vomiting was reported in more than 2% of pediatric patients. Xerostomia (6% to 9%), nausea (15% to 18%), constipation (3% to 5%), indigestion or dyspepsia (3%), abdominal pain (2%), vomiting (3%), flatulence (2%), diarrhea (8%), and dental pain (toothache 2%) occurred more frequently with escitalopram than placebo during adult trials. Clinical trial data indicate that xerostomia, constipation, diarrhea, and indigestion are dose-related effects. Escitalopram oral solution contains sorbitol, which may contribute to symptoms of diarrhea, especially if the patient is receiving additional liquid medications containing sorbitol. Abdominal cramping, pyrosis (heartburn), gastroenteritis, increased appetite, and weight gain were also reported during clinical trials. Patients treated with escitalopram in controlled trials did not differ from placebo-treated patients with regard to clinically important changes in body weight. Adverse GI effects reported during postmarketing use include dysphagia, gastroesophageal reflux, pancreatitis, rectal hemorrhage, and weight loss. Because decreased appetite and weight loss have been observed during use of SSRIs in pediatric patients, periodic monitoring of weight and height are recommended in pediatric individuals receiving escitalopram.

Central nervous system (CNS) side effects reported during clinical trials of adult patients with major depressive disorder or generalized anxiety disorder and occurring more frequently with escitalopram than placebo included dizziness (5%), insomnia (9 to 12%), drowsiness (6 to 13%), decreased appetite (3%), headache (24%), paresthesias (2%), lethargy (3%), abnormal dreams (3%), and increased sweating (hyperhidrosis, 4 to 5%). Clinical trial data indicate that insomnia, drowsiness, dizziness, and hyperhidrosis are dose-related effects. The most common adverse event associated with discontinuation in pediatric patients during pediatric trials was insomnia (1% of patients). Although the frequencies are unknown, the following effects have been reported during postmarketing use: abnormal gait, akathisia, amnesia, asthenia, ataxia, choreoathetosis, dysarthria, dyskinesia, dystonic reaction, extrapyramidal disorder, fall, feeling abnormal, hypoesthesia, migraine, myoclonia, nightmares, nystagmus, pseudoparkinsonism, restless legs syndrome (RLS), seizures, tardive dyskinesia, tremor, and vertigo.

Monitor all antidepressant-treated patients for any indication for worsening of depression or the condition being treated and the emergence of suicidal behaviors or suicidal ideation, especially during the initial few months of drug therapy and after dosage changes. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in the absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. Neuropsychiatric effects reported during premarketing clinical trials of escitalopram included somnolence (6 to 13%), impaired concentration, and irritability. Psychiatric effects that have been reported during postmarketing use of escitalopram include acute psychosis, aggression, agitation, anger (hostility), anxiety, apathy, confusion, depersonalization, delirium, delusion, disorientation, feeling unreal, visual and auditory hallucinations, mood swings (emotional lability), nervousness, panic reaction, paranoia, and restlessness. Antidepressants can precipitate hypomania or mania in predisposed individuals. Manic symptoms and suicidal ideation appear to be more prevalent in children with or at high risk for bipolar disorder on antidepressants; monitor such patients closely. In a study of 52 pediatric and young adult patients (mean age: 15 years; range: 7 to 22 years) with bipolar disorder or subthreshold manic symptoms and exposure to antidepressants, 50% developed antidepressant-induced mania and 25.5% had new-onset suicidal ideation. Worsening depression and suicidal ideation, including suicide attempts and completed suicide, have been reported during postmarketing use of escitalopram.

Hyponatremia was reported during premarketing evaluation of escitalopram. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) has been reported during postmarketing use of the drug. Selective serotonin reuptake inhibitors (SSRIs) may cause hyponatremia, which is frequently the result of SIADH. In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SSRI. Patients receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, fainting, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of the SSRI, as well as implementation of the appropriate medical interventions.

Platelet dysfunction (i.e., impaired platelet aggregation) may occur during treatment with selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematoma, petechiae, hemorrhage). Hematologic effects including ecchymosis, GI bleeding (i.e., hemorrhage), hemolytic anemia, hypoprothrombinemia, elevated INR, anemia, aplastic anemia, idiopathic thrombocytopenic purpura (ITP), agranulocytosis, leukopenia, and thrombocytopenia have been reported postmarketing, however, causality to the drug has not been established. An increased risk of bleeding complications is possible in patients receiving antiplatelet or anticoagulant medications concurrently with escitalopram.

Hypertension, palpitations, and chest pain (unspecified) were considered treatment-emergent adverse effects during premarketing evaluation of escitalopram, however the incidence is unknown. Adverse cardiac effects including atrial fibrillation, bradycardia, heart failure, hypotension, hypertensive crisis, myocardial infarction, orthostatic hypotension, sinus tachycardia, syncope, torsade de pointes (TdP), ventricular arrhythmia (unspecified), and ventricular tachycardia have been reported postmarketing. Other vascular effects that have been reported during postmarketing use of escitalopram include deep vein thrombosis, peripheral vasodilation, phlebitis, thrombosis, and stroke. During a placebo-controlled electrocardiogram (ECG) study, there were no escitalopram-treated patients with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose compared to 0.2% of placebo-treated patients. Escitalopram was also evaluated for QT prolongation in a randomized, placebo and moxifloxacin (400 mg/day) controlled, crossover study in 113 healthy adults. The maximum mean (95% upper confidence bound) difference in the QTcF interval from the placebo arm to the escitalopram 10 mg/day arm and 30 mg/day arm was 4.5 (6.4) msec and 10.7 (12.7) msec, respectively. Based on the established exposure-response relationship, the predicted QTcF change from the placebo arm under the Cmax for an escitalopram dose of 20 mg was 6.6 (7.9) msec. Administration of escitalopram 30 mg/day resulted in a mean Cmax of 1.7 times the Cmax for a 20 mg/day dose at steady state. Exposure to the 30 mg dose was similar to steady state concentrations expected in CYP2C19 poor metabolizers receiving the 20 mg dose. QT prolongation is reported as a possible side effect of overdosage and has been reported postmarketing.

General side effects reported during clinical trials of adult patients with major depressive disorder or generalized anxiety disorder and occurring more frequently with escitalopram than placebo included fatigue (5 to 8%) and influenza-like symptoms (5%). Fever was also reported during premarketing evaluation of escitalopram. General disorders that have been reported during postmarketing use of escitalopram include edema (unspecified), and malaise.

Allergy (unspecified) and rash (unspecified) were reported in premarketing evaluation of escitalopram. Allergic and dermatologic effects reported during postmarketing use of escitalopram include alopecia, dermatitis or rash (unspecified), angioedema, anaphylactoid reactions, skin flushing, erythema multiforme, photosensitivity reaction, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and urticaria. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported during postmarketing use of escitalopram according to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Manifestations of DRESS typically include pyrexia, rash, facial swelling, and/or lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Early manifestations of DRESS such as pyrexia and lymph node involvement may be present without evidence of a rash. Escitalopram should be promptly discontinued and appropriate medical treatment should be initiated in patients presenting with a rash or symptoms indicative of DRESS in whom an unrelated etiology cannot be identified.

Nasal congestion occurred in at least 2% of escitalopram-treated pediatric patients during clinical evaluation. Rhinitis (5%), sinusitis (3%), and yawning (2%) were reported during clinical trials for major depressive disorder and generalized anxiety disorder at rates greater than with placebo. Other respiratory effects reported during premarketing evaluation included bronchitis, cough, sinus congestion, and sinus headache. Dyspnea, anosmia, hyposmia, and pulmonary embolism have been reported with postmarketing use.

Blurred vision and tinnitus were reported during premarketing evaluation of escitalopram. Diplopia, angle-closure glaucoma (ocular hypertension), mydriasis, and visual impairment (unspecified) have been reported with postmarketing use.

Similar to other SSRIs, escitalopram is extensively metabolized in the liver. Hepatobiliary effects that have been reported during postmarketing use of escitalopram include fulminant hepatitis, hepatic failure, hepatic necrosis, hepatitis, increased bilirubin (hyperbilirubinemia), and elevated hepatic enzymes.

Menstrual disorder (menstrual irregularity) was reported more frequently in adult females receiving escitalopram than placebo during clinical trials (2%). Libido decrease, ejaculation disorders, impotence, and anorgasmia are some of the sexual side effects reported in adult patients. Other reproductive effects reported during premarketing evaluation included menstrual cramps (dysmenorrhea). Menorrhagia has been reported with postmarketing use. Similar to other SSRIs, hyperprolactinemia has occurred during treatment with escitalopram, and may be associated with some adverse reproductive effects of the drug in males or females. Priapism has been reported during postmarketing use of escitalopram and with other SSRIs. Priapism is a medical emergency; discontinue escitalopram if priapism develops and promptly initiate appropriate medical treatment.

Urinary system effects reported during premarketing clinical trials included increased urinary frequency. Urinary tract infection (UTI) was reported in at least 2% of escitalopram-treated pediatric patients and more frequently than in placebo-treated pediatric patients during clinical trial evaluation. Urinary effects reported during postmarketing use include acute renal failure (unspecified), dysuria, and urinary retention.

During clinical trial evaluation, back pain occurred in at least 2% of escitalopram-treated pediatric patients and more frequently than in placebo-treated patients. Arthralgia, myalgia, jaw stiffness, and limb pain have also been reported during clinical evaluation, although incidences are unknown. Musculoskeletal effects reported during postmarketing use of escitalopram include muscle cramps, muscle stiffness, muscle weakness (myasthenia), and rhabdomyolysis.

Similar to other SSRIs, treatment with escitalopram has been associated with altered glucose control. Diabetes mellitus, hyperglycemia, and hypoglycemia have been reported during postmarketing use.

General laboratory disorders that have been reported during postmarketing use of escitalopram include hypercholesterolemia and hypokalemia.

Serotonin syndrome has been reported during use of SSRIs alone, during concurrent use of other medications known to increase CNS or peripheral serotonin levels, or during SSRI overdose. Serotonin syndrome is a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome. Symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), and/or seizures. If serotonin syndrome becomes evident during treatment, escitalopram and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated.

Selective serotonin reuptake inhibitors (SSRIs) should be used cautiously in patients with osteopenia or risk factors for osteopenia. Epidemiological studies suggest an association between the use of SSRIs and bone fractures. Some data suggest that chronic treatment with SSRIs may be associated with reduced bone density.

Withdrawal symptoms have been reported with abrupt or rapid discontinuation of SSRIs, including escitalopram. The most commonly reported SSRI withdrawal symptoms include fatigue, stomach pain or nausea, dizziness/light-headedness, tremor, chills, diaphoresis, and incoordination. Other reported symptoms include dysphoric mood, impaired memory, insomnia, irritability, shock sensations, headache, paresthesia and aggression. Withdrawal symptoms usually begin 1 to 3 days after abrupt discontinuation of the SSRI and remit within 1 to 2 weeks. The difference in the incidence of withdrawal symptoms among SSRIs is most likely due to differences in the half-lives of the active moieties, with short-acting SSRIs having a higher likelihood of producing withdrawal symptoms. Nevertheless, gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of withdrawal symptoms. If intolerable symptoms occur following a decrease in the escitalopram dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

A neonatal abstinence syndrome has been reported in infants exposed to serotonergic agents such as escitalopram in utero, with features consistent with either a direct toxic effect of serotonergic agents (e.g., serotonin syndrome), or possibly a drug discontinuation syndrome. After birth, symptoms consistent with withdrawal (e.g., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting) have been noted. Such complications can arise immediately upon delivery. Other symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, and constant crying. Serum concentrations of the serotonergic agent were measurable in the infants affected. Several other symptoms (bloody stools, necrotizing enterocolitis) may have been attributable to rebound platelet activation on withdrawal of the exposure to the SSRI. Neonatal symptoms generally improved over several days. Additionally, a cohort study of 55 women revealed that 22% (12/55) of neonates exposed to an SSRI in the third trimester had complications requiring treatment or extended hospitalization compared with 6% in comparison groups. Complications included respiratory distress (n = 9), hypoglycemia (n = 2) and jaundice (n = 1). The incidence of prematurity in the third trimester SSRI group was significant at 20% vs. 3.7% of controls. Other potential adverse events have also been reported, including a potential association between maternal use of SSRIs in the third trimester and the development of persistent pulmonary hypertension of the newborn (PPHN). Some retrospective studies have not shown an increased risk of PPHN with SSRI exposure. The FDA has stated that an increased risk of PPHN from SSRI exposure cannot be determined due to conflicting data.

As with other SSRIs, decreased weight gain has been observed in children and adolescents receiving escitalopram. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition, but height and weight should be monitored periodically throughout therapy. The mechanism of growth inhibition in children may be due to the suppression of growth hormone secretion, which is known to occur in adults taking SSRIs.

Escitalopram is contraindicated for use in patients with an citalopram hypersensitivity, escitalopram hypersensitivity, or hypersensitivity to any of the formulation components. Also, escitalopram is the active isomer of racemic citalopram and therefore the two drugs should not be taken together as this would constitute duplicative therapy.

Avoid abrupt discontinuation of escitalopram if possible. Gradual tapering is recommended during discontinuation of any SSRI to decrease or prevent the occurrence of potential discontinuation symptoms. The most frequent SSRI discontinuation symptoms include dizziness, vertigo, nausea, vomiting, flu-like symptoms, sensory disturbances (e.g., paresthesias, electric shock sensation), sleep disturbances, irritability, anxiety, and/or agitation. Discontinuation symptoms are more likely to occur after withdrawal of SSRIs with a short half-life.

Escitalopram is not FDA-approved for use in pediatric patients younger than 7 years of age. Antidepressants increased the risk of suicidal thoughts and behavior in children and adolescents in short-term studies. Prescribe escitalopram in the smallest quantity consistent with good patient management to reduce the risk of overdose. Monitor all patients receiving antidepressants for any indication closely for clinical worsening, suicidal ideation, and unusual behavioral changes, such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and mania, especially during the first few months of therapy and after any dosage adjustment. Instruct caregivers and patients to immediately notify the prescriber of changes in behavior or suicidal ideation. Consider changing the therapeutic regimen or discontinuing the medication in patients with persistent or worrisome symptoms, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. In a pooled analysis of placebo-controlled trials of antidepressants (n = more than 4,400 pediatric patients and 77,000 adult patients), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. It is unknown if the suicidality risk extends to long-term use (i.e., more than 4 months); however, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression, a known risk factor for suicidal thoughts and behaviors.

Mania or hypomania can be precipitated in predisposed individuals during treatment with an antidepressant, including escitalopram. Children with a family history of bipolar disorder, those who have a diagnosis of bipolar disorder, and those with subthreshold manic symptoms may be at increased risk for developing mania during treatment. In addition, patients with pre-existing bipolar disorder type I, compared to those with subsyndromal or type II bipolar disorder, and those with psychiatric comorbidities may be at increased risk for antidepressant-induced mania. Younger patients may be more likely to experience antidepressant-induced mania. Suicidal ideation appears to be more prevalent in children with or at high risk for bipolar disorder on antidepressants. In a study of 52 patients (mean age of 15 years, ranging from 7 to 22 years) with bipolar disorder or subthreshold manic symptoms, 25.5% had new-onset suicidal ideation within the first 3 months of antidepressant use. Progressive evaluation of youth at risk for bipolar disorder who were exposed to antidepressants (n = 21; age range of 9 to 20 years) suggested psychiatric adverse events such as irritability, aggression, impulsivity, and hyperactivity were more common in younger patients. A major depressive episode may be the initial presentation of bipolar disorder. Patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder prior to initiating treatment. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. The response of patients with a previously established history of bipolar disorder should be closely monitored if therapy with an antidepressant is indicated.

Escitalopram should be used with caution in patients with a history of seizure disorder. These patients were excluded from clinical studies during the premarketing testing. Seizures have been reported rarely in patients taking SSRIs. In clinical trials of escitalopram, cases of convulsion have been reported in association with escitalopram treatment. Escitalopram's effects during electroconvulsive therapy (ECT) have not been evaluated in clinical studies to date.

Renal excretion of unchanged escitalopram is a minor route of elimination. No dosage adjustment is recommended in patients with mild to moderate renal impairment. Escitalopram should be used with caution in pediatric patients with severe renal impairment (i.e., CrCl less than 20 mL/minute) until pharmacokinetic data are available for this population. There is no information on the use of escitalopram in patients with chronic renal failure who receive hemodialysis.

QT prolongation and torsade de pointes (TdP) have been reported with both therapeutic use and overdose of escitalopram; obtain an electrocardiogram in cases of overdose. Use is not recommended in patients with congenital long QT syndrome because it is considered a drug with a known risk of TdP. Use escitalopram with caution in patients with conditions that may increase the risk of QT prolongation including bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, stroke, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Correct electrolyte imbalances prior to treatment initiation. Females, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, hypothermia, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation.

Use escitalopram with caution in patients who have hepatic disease; the drug is extensively metabolized in the liver, resulting in decreased clearance and increased plasma concentrations in patients with hepatic dysfunction. A lower maximum dosage is recommended for such patients.

Selective serotonin reuptake inhibitors (SSRIs) may cause hyponatremia, which is frequently the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). In some cases, serum sodium levels less than 110 mmol/L have been reported; however, the adverse effect appeared reversible upon discontinuation of the causative SSRI. Patients receiving diuretics or prone to dehydration, and those who are otherwise volume depleted (e.g., hypovolemia) appear to be at greatest risk. Hyponatremia may manifest as headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness which may result in falls. Severe manifestations include hallucinations, syncope, seizure, coma, respiratory arrest, and death. Symptomatic hyponatremia may require discontinuation of escitalopram, as well as implementation of the appropriate medical interventions.

Decreased appetite and weight loss have been observed during administration of SSRIs. Therefore, caution is advisable when administering escitalopram to patients with anorexia nervosa or other conditions where weight loss is undesirable.

Because impairment of judgment, thinking, or motor skills can occur during administration of escitalopram, patients should use caution when engaging in activities requiring coordination and concentration, such as driving (e.g., bicycles, vehicles) or operating machinery, until they are aware of the effects of escitalopram on their cognition.

Monitor patients taking an SSRI for signs and symptoms of bleeding. Platelet aggregation may be impaired by selective serotonin reuptake inhibitors (SSRIs) due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage). Concurrent use of anticoagulant therapy, thrombolytic therapy, or other medications that enhance bleeding potential may increase this risk. Patients taking escitalopram should be instructed to promptly report any bleeding events to the practitioner.

Caution is recommended when prescribing escitalopram to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

Escitalopram is contraindicated for concomitant use in patients receiving MAOI therapy due to the risk for serotonin syndrome. Escitalopram should not be used in combination with an MAOI or within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders. Allow at least 14 days after stopping escitalopram before starting an MAOI intended to treat psychiatric disorders. In addition, do not start escitalopram in a patient who is being treated with linezolid or intravenous methylene blue. Serotonin syndrome has been reported with SSRIs and SNRIs, including escitalopram, both when taken alone, but especially when coadministered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort). If such symptoms occur, discontinue escitalopram and initiate supportive treatment. If concomitant use of escitalopram with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Neonates with in utero exposure to SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs, a drug discontinuation syndrome, or serotonin syndrome. In addition, although available data are conflicting, some epidemiologic reports suggest an association between maternal use of SSRIs in late pregnancy and persistent pulmonary hypertension of the newborn (PPHN). Because PPHN is associated with significant morbidity and mortality, it is important that practitioners are aware of antidepressant exposure to avoid delays in diagnosis and treatment. In a meta-analysis of 7 studies, there was a small but significant association between SSRI exposure in late pregnancy and PPHN; effects were not significant for other variables examined (e.g., study design, congenital malformations, meconium aspiration). Effects of caesarian delivery, maternal body mass index, and preterm delivery were not assessed. PPHN occurs in approximately 1.9 of 1,000 live births in the general population and is a relatively uncommon event; based on this analysis it is estimated that an average of 1 associated case of PPHN would result from 286 to 351 women being treated with an SSRI during late gestation.

The potential for growth inhibition in pediatric patients should be monitored during SSRI therapy. Monitor height and weight periodically while the patient is receiving escitalopram. Data are inadequate to determine whether the chronic use of SSRIs causes long-term growth inhibition; however, decreased weight gain has been observed in children and adolescents receiving SSRIs. The mechanism of growth inhibition in children may be due to the suppression of growth hormone secretion, which is known to occur in adults taking SSRIs.

Description: Escitalopram, a selective serotonin reuptake inhibitor (SSRI), is the S-enantiomer of citalopram. Escitalopram is FDA-approved for the treatment of major depressive disorder in children and adolescents 12 years and older and for treatment of generalized anxiety disorder (GAD) in pediatric patients 7 years and older. Clinical guidelines and treatment algorithms describe a role for SSRIs in treating childhood depression as first-line therapy. In addition, SSRIs are considered first-line therapy for childhood anxiety disorders requiring pharmacologic treatment. Product labels for all antidepressants contain a warning related to an increased risk of suicidality in children and adolescents, particularly during initial treatment. Therefore, the necessity of pharmacologic therapy should be carefully considered in the pediatric population, taking into account the risks of pharmacologic treatment versus clinical need.

For the treatment of major depression:
Oral dosage:
Children and Adolescents 12 to 17 years: 10 mg PO once daily, initially. May increase the dose to 20 mg/day after at least 3 weeks if inadequate response and depending on tolerability. However, a fixed-dose trial failed to demonstrate a greater benefit of the 20 mg over 10 mg. Max: 20 mg/day. Periodically reassess the need for continued treatment.

For the treatment of social phobia (social anxiety disorder)*:
Oral dosage:
Children and Adolescents 10 to 17 years: Initiate at 5 mg/day PO for at least 1 week, then gradually titrate. Max: 20 mg/day PO. Periodically reassess the need for continued treatment. In 1 small open-label study (n = 20), escitalopram was initiated at 5 mg/day PO, increased to 10 mg/day after the first week, and subsequently titrated in 5 mg increments up to a maximum of 20 mg/day based upon efficacy and tolerability. Eighteen patients completed the 12-week trial, and 65% were considered responders. At study end, 60% of patients were receiving 10 mg/day, 20% were receiving 15 mg/day, and 20% were receiving 20 mg/day; the mean daily dose was 13 mg/day.

For the treatment of irritability associated with autistic disorder*:
Oral dosage:
Children and Adolescents 6 to 17 years: Initiate at 5 mg/day PO for at least 1 week, then gradually titrate. Max: 20 mg/day PO. Periodically reassess the need for continued treatment. Data are limited. Results from 1 open-label, forced titration study (n = 28) suggest that escitalopram may be effective in treating some behavioral symptoms associated with autism such as irritability. The mean final dose was 11.1 mg/day PO. The response rate was 61%, with response defined as a 50% or greater reduction in the Aberrant Behavior Checklist (ABC)-Community Version Irritability score. Of the 5 patients who did not complete the 10-week study, 2 were responders but had significant continuing hyperactivity, 1 was a non-responder and had continuing obsessions and compulsions, and 2 had symptoms of disinhibition and aggression.

For the treatment of generalized anxiety disorder (GAD):
Oral dosage:
Children and Adolescents 7 to 17 years: 10 mg PO once daily, initially. May increase the dose to 20 mg/day as needed and tolerated after 2 weeks or more.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 5 years: Safety and efficacy have not been established.
6 years: Safety and efficacy have not been established; however, doses up to 20 mg/day PO have been used off-label for behavioral symptoms related to pervasive developmental disorders.
7 to 12 years: 20 mg/day PO.
-Adolescents
20 mg/day PO.

Patients with Hepatic Impairment Dosing
Escitalopram is extensively metabolized in the liver. Initiate and maintain therapy with 10 mg PO once daily.

Patients with Renal Impairment Dosing
Dosage adjustments are not necessary in patients with mild to moderate renal impairment. Caution is recommended for severe renal impairment (e.g., CrCl less than 20 mL/min) due to lack of data; however, quantitative guidelines for dosage adjustments are not available.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Escitalopram is the the S-enantiomer of the selective serotonin reuptake inhibitor (SSRI) citalopram. Escitalopram is at least 100-fold more potent than the R-enantiomer of citalopram with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate, but a clinical benefit over citalopram or other SSRIs has not been shown. The precise antidepressant effect of SSRIs is not fully understood, but involves selective serotonin reuptake blockade at the neuronal membrane, which enhances the actions of serotonin (5-HT). Initially, SSRIs increase availability of serotonin in the somatodendritic area through serotonin reuptake blockade at the serotonin transport pump. During long-term administration of SSRIs, serotonin autoreceptors are down-regulated and desensitized, allowing the neuron to increase serotonin release in the axon terminal synapses and increase its neuronal impulses. Because of the delay in therapeutic response to SSRIs, it is theorized that the change in the balance of serotonin receptors over time is an important mechanism of effect. The therapeutic action of SSRIs in treating anxiety disorders is thought to occur from potent central serotonin reuptake blockade, although the exact mechanism is unknown. SSRIs have less sedative, anticholinergic, and cardiovascular effects than do tricyclic antidepressants due to dramatically decreased binding to histaminergic, muscarinic, and alpha-adrenergic receptors. The metabolites of escitalopram do not appear to contribute to the pharmacologic activity of the drug.

Pharmacokinetics: Escitalopram is administered orally. Pharmacokinetic parameters are similar to citalopram. Dosing is linear and proportional in a range of 10 to 30 mg/day. The binding of escitalopram to plasma proteins is clinically insignificant. Hepatic metabolism of escitalopram is the primary route for biotransformation. S(+)-desmethylcitalopram is the primary metabolite of escitalopram. In the plasma at steady-state, the concentration of the primary metabolite is one-third that of the parent compound. S(+)-didesmethylcitalopram is a secondary metabolite; both primary and secondary metabolites have minimal biological activity in humans. Due to metabolism by more than one isoenzyme, genetic polymorphism or concurrent use of CYP450 inhibitors is unlikely to have a large effect on net metabolic clearance. The elimination half-life of escitalopram is roughly 27 to 32 hours and that of S(+)-desmethylcitalopram (inactive) is 59 hours. Renal excretion of escitalopram is similar to citalopram with 8% excreted as the unchanged drug and 10% excreted as S(+)-desmethylcitalopram.

Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2C19, CYP3A4, and CYP2D6
Escitalopram is extensively metabolized by 2C19 and 3A4. Because escitalopram is metabolized by multiple isoenzymes, inhibition of a single enzyme, such as CYP3A4, may not significantly decrease escitalopram clearance. No clinically significant effect on the pharmacokinetics of escitalopram was observed in drug interaction studies with the strong CYP3A4 inhibitors ritonavir and ketoconazole, suggesting that drug interactions with other CYP3A4 inhibitors and escitalopram are unlikely. In vitro data indicate that escitalopram does not inhibit 1A2, 2C19, 2C9, 2E1, and 3A4. In vivo data suggest a modest inhibitory effect of escitalopram on CYP2D6.


-Route-Specific Pharmacokinetics
Oral Route
The absolute bioavailability of citalopram is roughly 80%; however, data are not available for escitalopram. The tablet and the oral solution dosage forms are bioequivalent. The absorption of escitalopram is not affected by food. Peak concentrations occur about 5 hours after a single 20 mg dose. Peak concentrations of the major metabolite, S(+)-desmethylcitalopram occurred in 14 hours. Steady-state concentrations are achieved in about 1 week. Clinical trials in adults suggest that a significant onset of antidepressant activity may occur by the end of the first or second week of treatment.


-Special Populations
Pediatrics
Children and Adolescents
After single dose administration, the AUC of escitalopram decreased by 19%, and Cmax increased by 26% in healthy adolescent subjects (12 to 17 years of age) compared to adults. After multiple dosing, the half-life, steady-state, AUC, and Cmax were similar between adolescents and adults.

Hepatic Impairment
During pharmacokinetic evaluation of citalopram in hepatic impairment, clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. Therefore, a reduced initial dose of escitalopram is recommended in patients with hepatic impairment.

Renal Impairment
The pharmacokinetics of escitalopram are not affected by mild or moderate renal impairment. No adjustment of escitalopram dose is needed. In patients with severe renal impairment (CrCl less than 20 mL/minute) there is the potential for reduced clearance since 10% of escitalopram is excreted unchanged; however, no pharmacokinetic information is available in this patient population.