VA Class:CN609

AHFS Class:

• Selective Serotonin-reuptake Inhibitors 28:16.04.20

Generic Name(s):

• Escitalopram Oxalate

Chemical Name:

• 1-[3-(Dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydro- S -(+)-5-isobenzofurancarbonitrile oxalate

Molecular Formula:

• C₂₀H₂₁FN₂O•C₂H₂O₄

Escitalopram, the S -enantiomer of citalopram, is a selective serotonin-reuptake inhibitor (SSRI) and an antidepressant.1

Major Depressive Disorder

Escitalopram oxalate is used for the acute and maintenance treatment of major depressive disorder in adults and adolescents 12-17 years of age.1,2,14,16,35,36

Efficacy of escitalopram for the acute management of major depression in adults was established in 3 placebo-controlled studies of 8 weeks' duration in adult outpatients who met DSM-IV criteria for major depressive disorder.1,2 In these studies, 10- and 20-mg daily dosages of escitalopram were more effective than placebo in improving scores on the Montgomery Asberg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Depression (HAM-D), and the Clinical Global Impression Improvement and Severity of Illness Scale.1,2,14 Escitalopram also was more effective than placebo in improving other aspects of depressive disorder, including anxiety, social functioning, and overall quality of life.2 Substantial improvement in MADRS and HAM-D scores was noted in patients receiving either dosage of escitalopram compared with those receiving placebo after 1-2 weeks of therapy.2,14,16 In addition, escitalopram dosages of 10-20 mg daily appeared to be at least as effective as racemic citalopram dosages of 20-40 mg daily.2,16 No age-, race-, or gender-related differences in efficacy were noted in these studies.1

Efficacy of escitalopram for the acute management of major depressive disorder in adolescents 12-17 years of age was established in an 8-week, flexible-dose, placebo-controlled study in outpatients who met DSM-IV criteria for major depressive disorder.1,36 Escitalopram-treated patients in this study demonstrated substantially greater improvement on the Children's Depression Rating Scale-Revised (CDRS-R) compared with those receiving placebo.1,36 Efficacy of escitalopram in the acute treatment of major depressive disorder in adolescents was also established on the basis of extrapolation from an 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20-40 mg daily.1 In this outpatient study conducted in children and adolescents 7-17 years of age who met DSM-IV criteria for major depressive disorder, citalopram-treated patients demonstrated substantially greater improvement on the CDRS-R compared with those receiving placebo; the positive results in this trial came largely from the adolescent subgroup.1 Two additional flexible-dose, placebo-controlled depression studies (one for escitalopram in patients 7-17 years of age and one for citalopram in adolescents) did not demonstrate efficacy.1

In a longer-term study, 274 adults with major depressive disorder who had responded to escitalopram 10 or 20 mg daily during an initial 8-week, open-label, flexible dosage treatment phase were randomized to continue escitalopram at the same dosage or receive placebo for up to 36 weeks of observation for relapse in the double-blind phase.1,35 Relapse during the double-blind phase was defined as an increase in the MADRS total score to 22 or greater or discontinuance due to insufficient clinical response.1,35 Escitalopram-treated patients experienced a substantially longer time to relapse of depression compared with those receiving placebo.1,35 In addition, more placebo recipients relapsed compared with patients receiving escitalopram (cumulative relapse rates were approximately 40 and 26%, respectively).35

Although efficacy of escitalopram as maintenance therapy in adolescent patients has not been systematically evaluated, such efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients.1

The manufacturers state that if escitalopram is used for extended periods, the need for continued therapy should be reassessed periodically.1,29

There is some evidence that escitalopram may offer some clinical advantages compared with citalopram or other selective serotonin-reuptake inhibitors (e.g., increased efficacy, more rapid onset of therapeutic effect, fewer adverse effects); however, additional studies are needed to confirm these initial findings.8,9,10,35

For further information on use of SSRIs in the treatment of major depressive disorder and considerations in choosing the most appropriate antidepressant agent for a particular patient, see Uses: Major Depressive Disorder, in Citalopram Hydrobromide 28:16.04.20.

Generalized Anxiety Disorder

Escitalopram is used in the management of generalized anxiety disorder in adults.1 Efficacy for the management of generalized anxiety disorder was established in 3 multicenter, flexible-dose, placebo-controlled studies of 8-weeks' duration in adult outpatients who met DSM-IV criteria for generalized anxiety disorder.1 In these studies, patients receiving 10-20 mg daily of escitalopram had substantially greater mean improvements in scores on the Hamilton Anxiety Scale (HAM-A) than those receiving placebo.1

For further information on the treatment of generalized anxiety disorder, see Uses: Anxiety Disorders, in Paroxetine 28:16.04.20.

Administration

Escitalopram oxalate is administered orally once daily, in the morning or evening, without regard to meals.1 Commercially available escitalopram oxalate tablets and oral solution are bioequivalent.1

Patients receiving escitalopram should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustment.1,12,14,15,29 (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

The manufacturers recommend that at least 2 weeks elapse between discontinuance of a monoamine oxidase (MAO) inhibitor and initiation of escitalopram and vice versa.1,29 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Drug Interactions: Monoamine Oxidase Inhibitors.)

Dosage

Dosage of escitalopram oxalate is expressed in terms of escitalopram.1,29

Major Depressive Disorder

For the acute management of major depressive disorder in adults, the recommended initial dosage of escitalopram is 10 mg once daily.1,29 Although efficacy has been established at dosages of 10 or 20 mg once daily, no additional benefit was observed with the 20-mg dosage in a fixed-dose study.1,2,29 If a dosage exceeding 10 mg daily is considered necessary, dosage may be increased to 20 mg daily after a minimum of 1 week.1,29

For the acute management of major depressive disorder in adolescents 12-17 years of age, the recommended initial dosage of escitalopram is 10 mg once daily.1 Efficacy has been established at dosages of 10-20 mg daily in a flexible-dose study.1,36 If dosage is increased to 20 mg daily, this should occur after a minimum of 3 weeks.1

While the optimum duration of escitalopram oxalate therapy has not been established, many experts state that acute depressive episodes require several months or longer of sustained antidepressant therapy.1,5 In addition, some clinicians recommend that long-term antidepressant therapy be considered in certain patients at risk for recurrence of depressive episodes (such as those with highly recurrent unipolar depression).5 Whether the dosage of escitalopram oxalate required to induce remission is identical to the dosage needed to maintain and/or sustain euthymia is unknown.8 Systematic evaluation of escitalopram oxalate has shown that its antidepressant efficacy is maintained for periods of up to 36 weeks in adults receiving 10-20 mg daily.1,8,35 Nevertheless, the manufacturers recommend that the usefulness of escitalopram be reevaluated periodically in patients receiving long-term therapy.1,29

Generalized Anxiety Disorder

For the management of generalized anxiety disorder in adults, the recommended initial dosage of escitalopram is 10 mg once daily.1,29 If no clinical improvement is apparent, dosage may be increased to 20 mg daily after a minimum of 1 week.1,29

Although the manufacturers state that the efficacy of escitalopram for long-term therapy (i.e., longer than 8 weeks) has not been demonstrated in controlled studies to date, generalized anxiety disorder is a chronic condition.1,29 If escitalopram is used for extended periods, the need for continued therapy with the drug should be reassessed periodically.1,29

Discontinuance of Therapy

Because withdrawal effects may occur with discontinuance of escitalopram and other SSRIs and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), abrupt discontinuance should be avoided whenever possible.1,29 When escitalopram therapy is discontinued, the dosage should be reduced gradually and the patient monitored for possible withdrawal symptoms.1,29 If intolerable symptoms occur following dosage reduction or upon discontinuance of therapy, the drug may be reinstituted at the previously prescribed dosage.1,29 Subsequently, the clinician may continue decreasing the dosage, but at a more gradual rate.1,29 (See Withdrawal of Therapy under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Special Populations

The recommended dosage of escitalopram in most geriatric patients and those with hepatic impairment is 10 mg once daily.1,29

Dosage adjustment in patients with mild to moderate renal impairment is not necessary, but the drug should be used with caution in those with severe renal impairment.1,29

Contraindications

Concurrent or recent (i.e., within 2 weeks) therapy with a monoamine oxidase (MAO) inhibitor.1,29 At least 14 days should elapse between discontinuance of escitalopram and initiation of MAO inhibitor therapy and vice versa.1,29 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Drug Interactions: Monoamine Oxidase Inhibitors.)

Concomitant use with pimozide.1,29 (See Drug Interactions: Antipsychotic Agents and Other Dopamine Antagonists.)

Known hypersensitivity to escitalopram, citalopram, or any ingredient in the formulation.1,29

Warnings/Precautions

Warnings

Worsening of Depression and Suicidality Risk

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants.1,12,14,15,28 This risk may persist until clinically important remission occurs.1,14 Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide.1,12,14,15 However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.1,14 Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders.1,12,14 An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age and a reduced risk was observed in adults 65 years of age or older.1,12,14

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1,12,14,15 Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.1,14,15

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.1,14,15 Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms.1,14 If a decision is made to discontinue therapy, taper escitalopram dosage as rapidly as is feasible but consider the risks of abrupt discontinuance.1,14 (See Discontinuance of Therapy, under Dosage and Administration: Dosage.) FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.1,14

Other Warnings and Precautions

Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions

Potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SSRIs, including escitalopram, and selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) alone, but particularly with concurrent use of other serotonergic drugs (including serotonin [5-hydroxytryptamine; 5-HT] type 1 receptor agonists [“triptans”]), drugs that impair the metabolism of serotonin (e.g., MAO inhibitors), or antipsychotics or other dopamine antagonists.1,18,31 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1,18,31 In its most severe form, serotonin syndrome may resemble NMS, which is characterized by hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation in vital signs, and mental status changes.1,31 Patients receiving escitalopram should be monitored for the development of serotonin syndrome or NMS-like signs and symptoms.1 (See Contraindications and also see Drug Interactions.)

Concurrent or recent (i.e., within 2 weeks) therapy with MAO inhibitors intended to treat depression is contraindicated.1 (See Contraindications and also see Drug Interactions: Monoamine Oxidase Inhibitors.)

If concurrent therapy with escitalopram and a 5-HT₁ receptor agonist (triptan) is clinically warranted, the patient should be observed carefully, particularly during initiation of therapy, when dosage is increased, or when another serotonergic agent is initiated.1,18

Concomitant use of escitalopram and serotonin precursors (e.g., tryptophan) is not recommended.1

If signs and symptoms of serotonin syndrome or NMS occur, treatment with escitalopram and any concurrently administered serotonergic or antidopaminergic agents, including antipsychotic agents, should be immediately discontinued and supportive and symptomatic treatment initiated.1

Withdrawal of Therapy

Withdrawal symptoms, including dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures, have been reported upon discontinuance of escitalopram and other SSRIs and SNRIs, particularly when discontinuance of these drugs is abrupt.1,5,6,7,33 While these reactions are generally self-limiting, there have been reports of serious discontinuance symptoms.1,5,6,7 Therefore, patients should be monitored for such symptoms when discontinuing escitalopram therapy.1 A gradual reduction in dosage rather than abrupt cessation is recommended whenever possible.1 (See Discontinuance of Therapy under Dosage and Administration: Dosage.)

If intolerable symptoms occur following dosage reduction or discontinuance of escitalopram, the previously prescribed dosage should be reinstituted until symptoms abate; dosage reductions may then be resumed at a more gradual rate.1

Seizures

Although anticonvulsant effects of racemic citalopram have been observed in animal studies, escitalopram has not been systematically evaluated in patients with seizure disorders.1 Seizures have been reported in patients receiving escitalopram in clinical trials; therefore, as with other antidepressants, escitalopram therapy should be initiated with caution in patients with a history of seizure disorder.1

Activation of Mania/Hypomania

Activation of mania and hypomania has occurred in patients receiving escitalopram or citalopram.1 Escitalopram should be used with caution in patients with a history of mania.1

Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion

Treatment with SNRIs and SSRIs, including escitalopram, may result in hyponatremia.1 In many cases, hyponatremia appears to be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH).1 Cases with serum sodium concentrations lower than 110 mEq/L have been reported.1 Geriatric individuals and patients receiving diuretics or who are otherwise volume depleted may be at greater risk of developing hyponatremia.1 Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls; more severe and/or acute cases have been associated with hallucinations, syncope, seizures, coma, respiratory arrest, and death.1 Discontinuance of escitalopram should be considered and appropriate medical intervention should be initiated in patients with symptomatic hyponatremia.1

Abnormal Bleeding

SNRIs and SSRIs, including escitalopram, may increase the risk of bleeding events.1 Concurrent use of aspirin, nonsteroidal anti-inflammatory agents (NSAIAs), warfarin, and other anticoagulants may add to this risk.1 Case reports and epidemiologic studies have demonstrated an association between the use of drugs that interfere with serotonin reuptake and the occurrence of GI bleeding.1 Bleeding events related to SNRI and SSRI use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.1 The manufacturers recommend that patients be advised of the risk of bleeding associated with the concomitant use of escitalopram and aspirin or other NSAIAs, warfarin, or other drugs that affect coagulation.1,29 (See Drug Interactions: Drugs Affecting Hemostasis.)

Interference with Cognitive and Motor Performance

In a study in healthy volunteers, escitalopram 10 mg daily did not impair intellectual function or psychomotor performance.1 However, because any psychoactive drug may impair judgment, thinking, or motor skills, caution patients about operating hazardous machinery, including driving a motor vehicle, until they are reasonably certain that the drug does not affect their ability to engage in such activities.1

Concomitant Illnesses

Experience with escitalopram in patients with certain concomitant diseases is limited.1 (See Renal Impairment and see Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Escitalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease; such patients were generally excluded from clinical studies.1 The drug should be used with caution in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.1

Concomitant use of SSRIs and MAO inhibitors has been associated with serious, sometimes fatal, reactions, including hyperthermia, rigidity, myoclonus, autonomic instability, and mental status changes; these reactions have resembled serotonin syndrome or NMS.1 (See Contraindications and Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions and see also Drug Interactions: Monoamine Oxidase Inhibitors.)

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

Some neonates exposed to serotonergic antidepressants (e.g., SSRIs, SNRIs) late in the third trimester of pregnancy have developed complications that have sometimes been severe and required prolonged hospitalization, respiratory support, enteral nutrition, and other forms of supportive care in special-care nurseries.1,40,41,42,43,44,45 Such complications may arise immediately upon delivery and usually last several days or up to 2-4 weeks.1,40,41,42,43,44,45 Clinical findings reported in the neonates have included respiratory distress, cyanosis, apnea, seizures, temperature instability or fever, feeding difficulty, dehydration, excessive weight loss, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.1,29,40,41,42,43,44,45 These features appear to be consistent with either a direct toxic effect of serotonergic antidepressants or, possibly, a drug withdrawal syndrome.1,40,41,42,43,44,45 In some cases, the clinical picture was consistent with serotonin syndrome.1,41

Infants exposed to SSRIs in late pregnancy may have an increased risk of persistent pulmonary hypertension of the newborn (PPHN), a rare heart and lung condition associated with substantial neonatal morbidity and mortality.1,27,46,48,54 Although several epidemiologic studies have suggested an increased risk of PPHN with SSRI use during pregnancy,1,27,29,46,48,54 other studies did not demonstrate a statistically significant association.1,46,49,50,51 The US Food and Drug Administration (FDA) states that it is currently unclear whether the use of SSRIs, including escitalopram, during pregnancy can cause PPHN and recommends that clinicians not alter their current clinical practice of treating depression during pregnancy.46

For additional information on the management of depression in women prior to conception and during pregnancy, including treatment algorithms, clinicians may consult the joint American Psychiatric Association and American College of Obstetricians and Gynecologists guidelines (at [Web]).46,52

Lactation

Escitalopram is distributed into human milk.1,23,24,29 Because of the potential for serious adverse effects (e.g., excessive somnolence, decreased feeding, weight loss) in nursing infants, caution should be exercised and nursing infants should be observed for adverse reactions when escitalopram is administered to a nursing woman.1,29

Pediatric Use

Safety and efficacy of escitalopram have not been established in pediatric patients younger than 12 years of age with major depressive disorder.1,8 Safety and effectiveness have been established in adolescents 12-17 years of age for the acute treatment of major depressive disorder.1,36 Although efficacy of escitalopram as maintenance therapy in adolescent patients with major depressive disorder has not been systematically evaluated, such efficacy can be extrapolated from adult data along with comparisons of pharmacokinetic parameters in adults and adolescent patients.1 (See Uses: Major Depressive Disorder.)

Safety and efficacy of escitalopram have not been established in pediatric patients younger than 18 years of age with generalized anxiety disorder.1

Decreased appetite and weight loss have been observed in association with the use of SSRIs.1,29 Therefore, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as escitalopram.1,29

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants).1,14 However, a more recent meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation.28 No suicides occurred in these pediatric trials.1,14,28 These findings should be carefully considered when assessing potential benefits and risks of escitalopram in a child or adolescent for any clinical use.1,14,15,28 (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Geriatric Use

Approximately 6% of patients studied in clinical trials of escitalopram for major depressive disorder and generalized anxiety disorder were 60 years of age or older; geriatric patients in these trials received daily dosages of 10-20 mg daily.1 Experience in geriatric patients in these trials was insufficient to determine whether they respond differently from younger adults; however, increased sensitivity cannot be ruled out.1

In 2 pharmacokinetic studies, the mean area under the plasma concentration-time curve (AUC) and elimination half-life of escitalopram were increased by approximately 50% in geriatric individuals compared with younger individuals and peak escitalopram concentrations were unchanged.1,29 Therefore, the manufacturers state that the recommended dosage of escitalopram in geriatric patients is 10 mg once daily.1,29

SNRIs and SSRIs, including escitalopram, have been associated with clinically important hyponatremia in geriatric patients, who may be at greater risk for this adverse effect.1 (See Hyponatremia/Syndrome of Inappropriate Antidiuretic Hormone Secretion under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.1,12,14 (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Renal Impairment

Escitalopram should be used with caution in patients with severe renal impairment (i.e., creatinine clearance less than 20 mL/minute).1,8 (See Dosage and Administration: Special Populations.)

Hepatic Impairment

In clinical studies, clearance of racemic citalopram was decreased by 37% and elimination half-life was doubled relative to that in patients with normal hepatic function.1 Dosage reduction is recommended for patients with hepatic impairment.1 (See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects reported in approximately 5% or more of patients with generalized anxiety or major depressive disorder receiving escitalopram and with an incidence of at least twice that of placebo include insomnia, nausea, increased sweating, sexual dysfunction (ejaculation disorder [primarily ejaculatory delay], decreased libido, anorgasmia), fatigue, and somnolence.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Inhibitors or inducers of cytochrome P-450 (CYP) 3A4 (e.g., carbamazepine, ketoconazole, ritonavir, triazolam) and 2C19 isoenzymes: clinically important pharmacokinetic interaction unlikely since escitalopram is metabolized by multiple enzyme systems.1,38 However, possibility that carbamazepine may increase clearance of escitalopram should be considered.1

Substrates of CYP2D6 isoenzyme (e.g., desipramine, metoprolol):8 potential pharmacokinetic (increased peak plasma concentrations and AUC of the substrate) interactions.1 Use with caution.1 Increased plasma concentrations of metoprolol have been associated with decreased cardioselectivity.1

Drugs Affecting Hemostasis

Pharmacokinetics of warfarin were not affected by racemic citalopram; however, prothrombin time increased by 5%.1,11 The effects of escitalopram have not been evaluated, and the clinical importance of this interaction is unknown.1,11

Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs) were concurrently administered with warfarin or other anticoagulants.1,11 The manufacturers of escitalopram recommend carefully monitoring patients receiving warfarin during initiation and discontinuance of escitalopram therapy.1,29

Potential pharmacologic (increased risk of bleeding) interaction with aspirin or other nonsteroidal anti-inflammatory agents (NSAIAs); escitalopram and drugs that affect hemostasis should be used concomitantly with caution.1,11,29

Antipsychotic Agents and Other Dopamine Antagonists

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions) if used concurrently with antipsychotic agents or other dopamine antagonists.1 If signs and symptoms of serotonin syndrome or NMS occur, immediately discontinue treatment with escitalopram and any concurrently administered antidopaminergic or serotonergic agents and initiate supportive and symptomatic treatment.1 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Pimozide

In a controlled study, concurrent administration of a single, 2-mg dose of pimozide in individuals receiving citalopram (40 mg once daily for 11 days) was associated with mean increases in the corrected QT (QT_c) interval of approximately 10 msec compared with pimozide given alone.1 Citalopram did not substantially affect the mean area under the plasma concentration-time curve (AUC) or peak plasma concentrations of pimozide.1 The mechanism for this potential pharmacodynamic interaction is not known.1 In addition, concomitant use of citalopram and pimozide rarely may result in potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions.34,37 The manufacturers of escitalopram state that concurrent use of escitalopram and pimozide is contraindicated.1,29

5-HT1 Receptor Agonists (“Triptans”)

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions) if used concurrently with 5-HT₁ receptor agonists (e.g., almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan).1,18 If concomitant use is clinically warranted, the patient should be observed carefully, particularly during treatment initiation, when dosage is increased, or when another serotonergic agent is initiated.1,18 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Monoamine Oxidase Inhibitors

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions).1 Concomitant use of monoamine oxidase (MAO) inhibitors with escitalopram is contraindicated.1 In addition, at least 2 weeks should elapse between discontinuance of an MAO inhibitor and initiation of escitalopram and vice versa.1 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Isoniazid

Potential pharmacologic interaction (potentially serious serotonin syndrome) when isoniazid, an antituberculosis agent that appears to have some MAO-inhibiting activity, is used concomitantly with escitalopram.32

Linezolid

Linezolid, an anti-infective agent that is also a reversible MAO inhibitor, has been associated with drug interactions resulting in serotonin syndrome, including some associated with SSRIs.1,19,20,21,22,55,56 Because of this potential risk, linezolid generally should not be used in patients receiving escitalopram.55 However, the FDA states that certain life-threatening or urgent situations may necessitate immediate linezolid treatment in a patient receiving a serotonergic drug.55 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.55 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.55 Treatment with escitalopram may be resumed 24 hours after the last linezolid dose.55 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.55 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.55 (See Drug Interactions: Serotonergic Drugs, in Linezolid 8:12.28.24.)

Selective Serotonin-reuptake Inhibitors and Selective Serotonin- and Norepinephrine-reuptake Inhibitors

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions); concurrent administration not recommended.1 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Other Serotonergic Drugs

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions) with drugs affecting serotonergic neurotransmission, including tramadol and St. John's wort ( Hypericum perforatum ); use concomitantly with caution.1 If signs and symptoms of serotonin syndrome or NMS occur, immediately discontinue treatment with escitalopram and any concurrently administered serotonergic or antidopaminergic agents and initiate supportive and symptomatic treatment.1 Concurrent administration of escitalopram and serotonin precursors (such as tryptophan) is not recommended.1 (See Serotonin Syndrome or Neuroleptic Malignant Syndrome-like Reactions under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Alcohol

Concomitant use not recommended.1,8

Cimetidine

Potential pharmacokinetic interaction (increased AUC and peak plasma concentrations of citalopram have been observed); effects on escitalopram have not been evaluated.1,8 Clinical importance of this interaction is unknown.1

Citalopram

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions).1

Because escitalopram is the more active isomer of racemic citalopram, the 2 agents should not be used concomitantly.1

CNS-active Drugs

Potential pharmacologic interaction when given with other centrally acting drugs; use concomitantly with caution.1

Digoxin

Pharmacokinetic interaction unlikely based on studies with racemic citalopram.1

Lithium

Concurrent administration of racemic citalopram and lithium did not substantially affect the pharmacokinetics of either drug.1,39 However, pending further accumulation of data, the manufacturers of escitalopram recommend that plasma lithium concentrations be monitored in patients concurrently receiving escitalopram and that lithium dosage be adjusted accordingly.1,29

Potential pharmacologic interaction (enhanced serotonergic effects of escitalopram and potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions); use concomitantly with caution.1

Ritonavir

Combined administration of a single 600-mg dose of ritonavir, a CYP3A4 substrate and potent inhibitor of CYP3A4, and escitalopram 20 mg did not substantially affect the pharmacokinetics of either drug.1,38

Sibutramine

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome or NMS-like reactions).1,18 Use concomitantly with caution.1,18

Theophylline

Pharmacokinetics of theophylline were not affected by racemic citalopram.1 The effect of theophylline on the pharmacokinetics of racemic citalopram, however, has not been evaluated.1

Electroconvulsive Therapy

The combined use of electroconvulsive therapy and escitalopram has not been evaluated.1

Description

Escitalopram, a selective serotonin-reuptake inhibitor (SSRI),1 is a bicyclic phthalane-derivative antidepressant.8 Escitalopram is the S -enantiomer of citalopram,1 an SSRI that occurs as a 50:50 racemic mixture of the R - and S -enantiomers.1,4 Escitalopram and citalopram differ structurally from other SSRIs (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) and other currently available antidepressants (e.g., monoamine oxidase inhibitors, tricyclic and tetracyclic antidepressants).4 Escitalopram is at least 100-fold more potent as an inhibitor of the reuptake of serotonin (5-hydroxytryptamine [5-HT]) at the presynaptic membranes and the 5-HT neuronal firing rate than the R -enantiomer and is twice as potent as the racemic mixture.1,2,9 However, further studies are needed to determine whether these differences result in any clinical superiority of escitalopram compared with citalopram.9,10

Like other SSRIs, escitalopram's antidepressant effect is believed to involve potentiation of serotonin activity in the CNS.1,4 Escitalopram appears to have little or no effect on reuptake of other neurotransmitters such as norepinephrine and dopamine.1 In vitro studies also have demonstrated that escitalopram possesses little or no affinity for α- or β-adrenergic, dopamine D_1-5, histamine H_1-3, GABA-benzodiazepine, muscarinic M_1-5, or 5-HT_1-7 receptors or various ion channels (e.g., calcium, chloride, potassium, sodium channels).1

Escitalopram is extensively metabolized, principally by the hepatic cytochrome P-450 (CYP) 2C19 and 3A4 isoenzymes.1 The principal metabolites are less potent inhibitors of serotonin reuptake, suggesting that the metabolites do not substantially contribute to the antidepressant activity of escitalopram.1

Advice to Patients

Importance of providing a copy of written patient information (medication guide) each time escitalopram is dispensed.1,12,14,15 Importance of advising patients to read the patient information before taking escitalopram and each time the prescription is refilled.1

Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment.1,12,14,15 (See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Importance of informing patients of potential risk of serotonin syndrome and neuroleptic malignant syndrome (NMS)-like reactions, particularly with concurrent use of escitalopram and 5-HT₁ receptor agonists (also called triptans), tramadol, tryptophan, other serotonergic agents, or antipsychotic agents.1,18 Importance of immediately contacting clinician if signs and symptoms of these syndromes develop (e.g., restlessness, hallucinations, loss of coordination, fast heart beat, increased body temperature, muscle stiffness, labile blood pressure, diarrhea, coma, nausea, vomiting, confusion).1,18

Risk of psychomotor impairment; importance of exercising caution while operating hazardous machinery, including driving a motor vehicle, until the drug's effects on the individual are known.1

Importance of patients being aware that withdrawal effects may occur when stopping escitalopram, especially with abrupt discontinuance of the drug.1

Risks associated with concomitant use of escitalopram with alcohol or racemic citalopram.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements, as well as any concomitant illnesses (e.g., bipolar disorder) or personal or family history of suicidality or bipolar disorder.1,15 Importance of advising patients about the risk of bleeding associated with concomitant use of escitalopram with aspirin or other nonsteroidal anti-inflammatory agents, warfarin, or other drugs that affect coagulation.1,11

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of advising patients that, although they may notice improvement with escitalopram therapy within 1-4 weeks, they should continue therapy as directed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Forest Pharmaceuticals, Inc. Lexapro^® (escitalopram oxalate) tablets and oral solution prescribing information. St. Louis, MO; 2011 May.

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4. Forest Pharmaceuticals, Inc. Celexa (citalopram hydrobromide) prescribing information. (dated 2000 Dec). In: Physicians' desk reference. 56th ed. Montvale, NJ: Medical Economics Company Inc; 2002:1365-9.

5. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry . 2000; 150(Suppl 4):1-45.

6. The European Agency for the Evaluation of Medicinal Products (EMEA). Committee for proprietary medicinal products (CPMP) position paper on selective serotonin uptake inhibitors (SSRIs) and dependency/withdrawal reactions. London, UK; 2000 Apr 12. From EMEA web site. [Web]

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8. Forest Pharmaceuticals, Inc., St. Louis, MO: Personal communication.

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10. Reviewers' comments (personal observations).

11. Priskorn M, Sidhu JS, Larsen F et al. Investigation of multiple dose citalopram on the pharmacokinetics and pharmacodynamics of racemic warfarin. Br J Clin Pharmacol. 1997; 44:199-202.

12. Food and Drug Administration. FDA news: FDA proposes new warnings about suicidal thinking, behavior in young adults who take antidepressant medications. Rockville, MD; 2007 May 2. From the FDA web site. [Web]

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18. US Food and Drug Administration. Public health advisory: combined use of 5-hydroxytryptamine receptor agonists (triptans), selective serotonin reuptake inhibitors (SSRIs) or selective serotonin/norepinephrine reuptake inhibitors (SNRIs) may result in life-threatening serotonin syndrome. Rockville, MD; 2006 Jul 19. From the FDA website. [Web]

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30. Forest Pharmaceuticals, Inc. Celexa^® (citalopram hydrobromide) prescribing information. St. Louis, MO; 2002 Aug.

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42. Moses-Kolko EL, Bogen D, Perel J et al. Neonatal signs after late in utero exposure to serotonin reuptake inhibitors: literature review and implications for clinical applications. JAMA . 2005; 292:2372-85.

43. Sanz EJ, De-Las-Cuevas C, Kiuru A et al. Selective serotonin reuptake inhibitors in pregnant women and neonatal withdrawal syndrome: a database analysis. Lancet . 2005; 365:482-7. [PubMed 15705457]

44. Nordeng H, Lindemann R, Perminov KV et al. Neonatal withdrawal syndrome after in utero exposure to selective serotonin-reuptake inhibitors. Acta Paediatr . 2001; 90:288-91. [PubMed 11332169]

45. Dahl ML, Olhager E, Ahlner J. Paroxetine withdrawal syndrome in a neonate. Br J Psychiatr . 1997; 171:391-2.

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51. Wilson KL, Zelig CM, Harvey JP et al. Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol . 2011; 28:19-24. [PubMed 20607643]

52. Yonkers KA, Wisner KL, Stewart DE et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Obstet Gynecol . 2009; 114:703-13. [Web][PubMedCentral][PubMed 19701065]

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54. Kieler H, Artama M, Engeland A et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. Br Med J . 2012; 344:d8012.

55. US Food and Drug Administration. Drug Safety Communication: Serious CNS reactions possible when linezolid (Zyvox) is given to patients taking certain psychiatric medications. 2011 Jul 26. From FDA website. [Web]

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