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Lexapro Description

LEXAPRO

(escitalopram oxalate)

TABLETS/ORAL SOLUTION Rx Only

DESCRIPTION

LEXAPRO (escitalopram oxalate) is an orally administered selective serotonin reuptake inhibitor (SSRI). Escitalopram is the pure S-enantiomer (single isomer) of the racemic bicyclic phthalane derivative citalopram. Escitalopram oxalate is designated S-(+)-1-[3-(dimethyl-amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate with the following structural formula:

•C2H2O4

The molecular formula is C20H21FN2O • C2H2O4 and the molecular weight is 414.40.

Escitalopram oxalate occurs as a fine, white to slightly-yellow powder and is freely soluble in methanol and dimethyl sulfoxide (DMSO), soluble in isotonic saline solution, sparingly soluble in water and ethanol, slightly soluble in ethyl acetate, and insoluble in heptane.

LEXAPRO (escitalopram oxalate) is available as tablets or as an oral solution.

LEXAPRO tablets are film-coated, round tablets containing escitalopram oxalate in strengths equivalent to 5 mg, 10 mg, and 20 mg escitalopram base. The 10 and 20 mg tablets are scored. The tablets also contain the following inactive ingredients: talc, croscarmellose sodium, microcrystalline cellulose/colloidal silicon dioxide, and magnesium stearate. The film coating contains hypromellose, titanium dioxide, and polyethylene glycol.

LEXAPRO oral solution contains escitalopram oxalate equivalent to 1 mg/mL escitalopram base. It also contains the following inactive ingredients: sorbitol, purified water, citric acid, sodium citrate, malic acid, glycerin, propylene glycol, methylparaben, propylparaben, and natural peppermint flavor.

CLINICAL PHARMACOLOGY

Pharmacodynamics

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). In vitro and in vivo studies in animals suggest that escitalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine and dopamine neuronal reuptake. Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with escitalopram. Escitalopram has 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. Escitalopram also does not bind to, or has low affinity for, various ion channels including Na+, K+, Cl-, and Ca++ channels. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular side effects of other psychotropic drugs.

Pharmacokinetics

The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day. Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27-32 hours. With once-daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of escitalopram in plasma in young healthy subjects was 2.2-2.5 times the plasma concentrations observed after a single dose. The tablet and the oral solution dosage forms of escitalopram oxalate are bioequivalent.

Absorption and Distribution

Following a single oral dose (20 mg tablet or solution) of escitalopram, peak blood levels occur at about 5 hours. Absorption of escitalopram is not affected by food.

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%.

Metabolism and Elimination

Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and S - 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 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 N-demethylation of escitalopram.

Population Subgroups

Age - Escitalopram pharmacokinetics in subjects t 65 years of age were compared to younger subjects in a single-dose and a multiple-dose study. Escitalopram AUC and half-life were increased by approximately 50% in elderly subjects, and Cmax was unchanged. 10 mg is the recommended dose for elderly patients (see DOSAGE AND ADMINISTRATION).

Gender - In a multiple-dose study of escitalopram (10 mg/day for 3 weeks) in 18 male (9 elderly and 9 young) and 18 female (9 elderly and 9 young) subjects, there were no differences in AUC, Cmax, and half-life between the male and female subjects. No adjustment of dosage on the basis of gender is needed.

Reduced hepatic function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 10 mg is the recommended dose of escitalopram for most hepatically impaired patients (see DOSAGE AND ADMINISTRATION).

Reduced renal function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of escitalopram in patients with severely reduced renal function (creatinine clearance < 20 mL/min).

Drug-Drug Interactions

In vitro enzyme inhibition data did not reveal an inhibitory effect of escitalopram on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, escitalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. While in vivo data to address this question are limited, results from drug interaction studies suggest that escitalopram, at a dose of 20 mg, has no 3A4 inhibitory effect and a modest 2D6 inhibitory effect. See Drug Interactions under PRECAUTIONS for more detailed information on available drug interaction data.

Clinical Efficacy Trials

Major Depressive Disorder

The efficacy of LEXAPRO as a treatment for major depressive disorder was established in three, 8-week, placebo-controlled studies conducted in outpatients between 18 and 65 years of age who met DSM-IV criteria for major depressive disorder. The primary outcome in all three studies was change from baseline to endpoint in the Montgomery Asberg Depression Rating Scale (MADRS).

A fixed-dose study compared 10 mg/day LEXAPRO and 20 mg/day LEXAPRO to placebo and 40 mg/day citalopram. The 10 mg/day and 20 mg/day LEXAPRO treatment groups showed significantly greater mean improvement compared to placebo on the MADRS. The 10 mg and 20 mg LEXAPRO groups were similar on this outcome measure.

In a second fixed-dose study of 10 mg/day LEXAPRO and placebo, the 10 mg/day LEXAPRO treatment group showed significantly greater mean improvement compared to placebo on the MADRS.

In a flexible-dose study, comparing LEXAPRO, titrated between 10 and 20 mg/day, to placebo and citalopram,

titrated between 20 and 40 mg/day, the LEXAPRO treatment group showed significantly greater mean improvement compared to placebo on the MADRS.

Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.

In a longer-term trial, 274 patients meeting (DSM-IV) criteria for major depressive disorder, who had responded during an initial 8-week, open-label treatment phase with LEXAPRO 10 or 20 mg/day, were randomized to continuation of LEXAPRO at their same dose, or to placebo, for up to 36 weeks of observation for relapse. Response during the open-label phase was defined by having a decrease of the MADRS total score to d 12. Relapse during the double-blind phase was defined as an increase of the MADRS total score to t 22, or discontinuation due to insufficient clinical response. Patients receiving continued LEXAPRO experienced a significantly longer time to relapse over the subsequent 36 weeks compared to those receiving placebo.

Generalized Anxiety Disorder

The efficacy of LEXAPRO in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in three, 8-week, multicenter, flexible-dose, placebo-controlled studies that compared LEXAPRO 10-20 mg/day to placebo in outpatients between 18 and 80 years of age who met DSM-IV criteria for GAD. In all three studies, LEXAPRO showed significantly greater mean improvement compared to placebo on the Hamilton Anxiety Scale (HAM-A).

There were too few patients in differing ethnic and age groups to adequately assess whether or not LEXAPRO has differential effects in these groups. There was no difference in response to LEXAPRO between men and women.

INDICATIONS AND USAGE

Major Depressive Disorder

LEXAPRO (escitalopram) is indicated for the treatment of major depressive disorder.

The efficacy of LEXAPRO in the treatment of major depressive disorder was established in three, 8-week, placebo-controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-IV category of major depressive disorder (see CLINICAL PHARMACOLOGY).

A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.

The efficacy of LEXAPRO in hospitalized patients with major depressive disorders has not been adequately studied.

The efficacy of LEXAPRO in maintaining a response, in patients with major depressive disorder who responded during an 8-week, acute-treatment phase while taking LEXAPRO and were then observed for relapse during a period of up to 36 weeks, was demonstrated in a placebo-controlled trial (see Clinical Efficacy Trials under CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use LEXAPRO for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION).

Generalized Anxiety Disorder

LEXAPRO is indicated for the treatment of Generalized Anxiety Disorder (GAD).

The efficacy of LEXAPRO was established in three, 8-week, placebo-controlled trials in patients with GAD (see CLINICAL PHARMACOLOGY).

Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance.

The efficacy of LEXAPRO in the long-term treatment of GAD, that is, for more than 8 weeks, has not been systematically evaluated in controlled trials. The physician who elects to use LEXAPRO for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

CONTRAINDICATIONS

Concomitant use in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated (see WARNINGS).

LEXAPRO is contraindicated in patients with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in LEXAPRO. WARNINGS

Potential for Interaction with Monoamine Oxidase Inhibitors

In patients receiving serotonin reuptake inhibitor drugs in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued SSRI treatment and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Furthermore, limited animal data on the effects of combined use of SSRIs and MAOIs suggest that these drugs may act synergistically to elevate blood pressure and evoke behavioral excitation. Therefore, it is recommended that LEXAPRO should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 14 days should be allowed after stopping LEXAPRO before starting an MAOI.

Serotonin syndrome has been reported in two patients who were concomitantly receiving linezolid, an antibiotic which is a reversible non-selective MAOI.

Clinical Worsening and Suicide Risk

Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality), whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Although 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, a causal role for antidepressants in inducing such behaviors has not been established. Nevertheless, patients being treated with antidepressants should be observed closely for clinical worsening and suicidality, especially at the beginning of a course of drug therapy, or at the time of dose changes, either increases or decreases. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse or whose emergent suicidality is severe, abrupt in onset, or was not part of the patient’s presenting symptoms.

Because of the possibility of co-morbidity between major depressive disorder and other psychiatric and nonpsychiatric disorders, the same precautions observed when treating patients with major depressive disorder should be observed when treating patients with other psychiatric and nonpsychiatric disorders.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients for whom such symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health-care providers. Prescriptions for LEXAPRO should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms (see PRECAUTIONS and DOSAGE AND ADMINISTRATION, Discontinuation of Treatment with LEXAPRO, for a description of the risks of discontinuation of LEXAPRO).

It should be noted that LEXAPRO is not approved for use in treating any indications in the pediatric population.

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that LEXAPRO is not approved for use in treating bipolar depression.

PRECAUTIONS

General

Discontinuation of Treatment with LEXAPRO

During marketing of Lexapro and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with LEXAPRO. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the 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 (see DOSAGE AND ADMINISTRATION).

Abnormal Bleeding

Published case reports have documented the occurrence of bleeding episodes in patients treated with psychotropic drugs that interfere with serotonin reuptake. Subsequent epidemiological studies, both of the case-control and cohort design, have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. In two studies, concurrent use of a nonsteroidal anti-inflammatory drug (NSAID) or aspirin potentiated the risk of bleeding (see Drug Interactions). Although these studies focused on upper gastrointestinal bleeding, there is reason to believe that bleeding at other sites may be similarly potentiated. Patients should be cautioned regarding the risk of bleeding associated with the concomitant use of LEXAPRO with NSAIDs, aspirin, or other drugs that affect coagulation.

Hyponatremia

One case of hyponatremia has been reported in association with LEXAPRO treatment. Several cases of hyponatremia or SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported in association with racemic citalopram. All patients with these events have recovered with discontinuation of escitalopram or citalopram and/or medical intervention. Hyponatremia and SIADH have also been reported in association with other marketed drugs effective in the treatment of major depressive disorder.

Activation of Mania/Hypomania

In placebo-controlled trials of LEXAPRO in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with LEXAPRO and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with LEXAPRO treatment. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, LEXAPRO should be used cautiously in patients with a history of mania.

Seizures

Although anticonvulsant effects of racemic citalopram have been observed in animal studies, LEXAPRO has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of LEXAPRO, cases of convulsion have been reported in association with LEXAPRO treatment. Like other drugs effective in the treatment of major depressive disorder, LEXAPRO should be introduced with care in patients with a history of seizure disorder.

Interference with Cognitive and Motor Performance

In a study in normal volunteers, LEXAPRO 10 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that LEXAPRO therapy does not affect their ability to engage in such activities.

Use in Patients with Concomitant Illness

 

LEXAPRO has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.

In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of LEXAPRO in hepatically impaired patients is 10 mg/day (see DOSAGE AND ADMINISTRATION).

Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with LEXAPRO, however, it should be used with caution in such patients (see DOSAGE AND ADMINISTRATION).

Information for Patients

Physicians are advised to discuss the following issues with patients for whom they prescribe LEXAPRO.

In a study in normal volunteers, LEXAPRO 10 mg/day did not impair psychomotor performance. The effect of LEXAPRO on psychomotor coordination, judgment, or thinking has not been systematically examined in controlled studies. Because psychoactive drugs may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that LEXAPRO therapy does not affect their ability to engage in such activities.
 

Patients should be told that, although LEXAPRO has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of LEXAPRO and alcohol in depressed patients is not advised.
 

Patients should be made aware that escitalopram is the active isomer of Celexa (citalopram hydrobromide) and that the two medications should not be taken concomitantly.
 

Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.

Patients should be cautioned about the concomitant use of LEXAPRO and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding.

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Patients should be advised to notify their physician if they are breastfeeding an infant.

While patients may notice improvement with LEXAPRO therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.

Patients and their families should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania, worsening of depression, and suicidal ideation, especially early during antidepressant treatment. Such symptoms should be reported to the patient’s physician, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Laboratory Tests

There are no specific laboratory tests recommended.

 

Concomitant Administration with Racemic Citalopram

Citalopram - Since escitalopram is the active isomer of racemic citalopram (Celexa), the two agents should not be coadministered.

Drug Interactions

CNS Drugs - Given the primary CNS effects of escitalopram, caution should be used when it is taken in combination with other centrally acting drugs.

Alcohol - Although LEXAPRO did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by patients taking LEXAPRO is not recommended. Monoamine Oxidase Inhibitors (MAOIs) - See CONTRAINDICATIONS and WARNINGS.

Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)

Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin potentiated the risk of bleeding. Thus, patients should be cautioned about the use of such drugs concurrently with LEXAPRO.
 

Cimetidine - In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical significance of these findings is unknown.
 

Digoxin - In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.
 

Lithium - Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of escitalopram, caution should be exercised when LEXAPRO and lithium are coadministered.
 

Sumatriptan - There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram) is clinically warranted, appropriate observation of the patient is advised.

Theophylline - Combined administration of racemic citalopram (40 mg/day for 21 days) and the CYP1A2 substrate theophylline (single dose of 300 mg) did not affect the pharmacokinetics of theophylline. The effect of theophylline on the pharmacokinetics of citalopram was not evaluated.
 

Warfarin - Administration of 40 mg/day racemic citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown.
 

Carbamazepine - Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered.
 

Triazolam - Combined administration of racemic citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.
 

Ketoconazole - Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.
 

Ritonavir - Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram.
 

CYP3A4 and -2C19 Inhibitors - In vitro studies indicated that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of escitalopram. However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram.

Because escitalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease escitalopram clearance.

Drugs Metabolized by Cytochrome P4502D6 - In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in Cmax and a 100% increase in AUC of desipramine. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6.

Metoprolol - Administration of 20 mg/day LEXAPRO for 21 days in healthy volunteers resulted in a 50% increase in Cmax and 82% increase in AUC of the beta-adrenergic blocker metoprolol (given in a single dose of 100 mg). Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Coadministration of LEXAPRO and metoprolol had no clinically significant effects on blood pressure or heart rate.

Electroconvulsive Therapy (ECT) - There are no clinical studies of the combined use of ECT and escitalopram.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Racemic citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of racemic citalopram in mice receiving up to 240 mg/kg/day. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day racemic citalopram. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown.

Mutagenesis

Racemic citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1 537) 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 citalopram 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. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.

Impairment of Fertility

When racemic citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses t 32 mg/kg/day. Gestation duration was increased at 48 mg/kg/day.

Pregnancy

Pregnancy Category C

In a rat embryo/fetal development study, oral administration of escitalopram (56, 112, or 150 mg/kg/day) to pregnant animals during the period of organogenesis resulted in decreased fetal body weight and associated delays in ossification at the two higher doses (approximately t 56 times the maximum recommended human dose [MRHD] of 20 mg/day on a body surface area [mg/m2] basis). Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day is approximately 28 times the MRHD on a mg/m2 basis. No teratogenicity was observed at any of the doses tested (as high as 75 times the MRHD on a mg/m2 basis).

When female rats were treated with escitalopram (6, 12, 24, or 48 mg/kg/day) during pregnancy and through weaning, slightly increased offspring mortality and growth retardation were noted at 48 mg/kg/day which is approximately 24 times the MRHD on a mg/m2 basis. Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was seen at 24 mg/kg/day. The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD on a mg/m2 basis.

In animal reproduction studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses.

In two rat embryo/fetal development studies, oral administration of racemic citalopram (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 (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day. 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. Thus, teratogenic effects of racemic citalopram were observed at a maternally toxic dose in the rat and were not observed in the rabbit.

When female rats were treated with racemic citalopram (4.8, 12.8, or 32 mg/kg/day) from late gestation through weaning, increased offspring mortality during the first 4 days after birth and persistent offspring growth retardation were observed at the highest dose. The no-effect dose was 12.8 mg/kg/day. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses t 24 mg/kg/day. A no-effect dose was not determined in that study.

There are no adequate and well-controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnancy-Nonteratogenic Effects

Neonates exposed to LEXAPRO and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings 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 and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS).

When treating a pregnant woman with LEXAPRO during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).

Labor and Delivery

The effect of LEXAPRO on labor and delivery in humans is unknown.

Nursing Mothers

Racemic citalopram, like many other drugs, is excreted in human breast milk. There have been two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of citalopram by its mother and, in the second case, no follow-up information was available. The decision whether to continue or discontinue either nursing or LEXAPRO therapy should take into account the risks of citalopram exposure for the infant and the benefits of LEXAPRO treatment for the mother.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established (see WARNINGS-Clinical Worsening and Suicide Risk.

Geriatric Use

Approximately 6% of the 1144 patients receiving escitalopram in controlled trials of LEXAPRO in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of LEXAPRO between 10 and 20 mg. The number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of some elderly individuals to effects of LEXAPRO cannot be ruled out.

In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared to young subjects and Cmax was unchanged (see CLINICAL PHARMACOLOGY). 10 mg/day is the recommended dose for elderly patients (see DOSAGE AND ADMINISTRATION).

Of 4422 patients in clinical studies of racemic citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but again, greater sensitivity of some elderly individuals cannot be ruled out.

ADVERSE REACTIONS

Adverse event information for LEXAPRO was collected from 715 patients with major depressive disorder who were exposed to escitalopram and from 592 patients who were exposed to placebo in double-blind, placebo-controlled trials. An additional 284 patients with major depressive disorder were newly exposed to escitalopram in open-label trials. The adverse event information for LEXAPRO in patients with GAD was collected from 429 patients exposed to escitalopram and from 427 patients exposed to placebo in double-blind, placebo-controlled trials.

Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and tabulations that follow, standard World Health Organization (WHO) terminology has been used to classify reported adverse events.

The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed. An event was considered treatment-emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation.

Adverse Events Associated with Discontinuation of Treatment

Major Depressive Disorder

Among the 715 depressed patients who received LEXAPRO in placebo-controlled trials, 6% discontinued treatment due to an adverse event, as compared to 2% of 592 patients receiving placebo. In two fixed-dose studies, the rate of discontinuation for adverse events in patients receiving 10 mg/day LEXAPRO was not significantly different from the rate of discontinuation for adverse events in patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/day LEXAPRO was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day LEXAPRO (4%) and placebo (3%). Adverse events that were associated with the discontinuation of at least 1% of patients treated with LEXAPRO, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients).

Generalized Anxiety Disorder

Among the 429 GAD patients who received LEXAPRO 10-20 mg/day in placebo-controlled trials, 8% discontinued treatment due to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse events that were associated with the discontinuation of at least 1% of patients treated with LEXAPRO, and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%).

Incidence of Adverse Events in Placebo-Controlled Clinical Trials

Major Depressive Disorder

Table 1 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 715 depressed patients who received LEXAPRO at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with LEXAPRO and for which the incidence in patients treated with LEXAPRO was greater than the incidence in placebo-treated patients.

The prescriber should be aware that these figures can not be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.

The most commonly observed adverse events in LEXAPRO patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence (see TABLE 1).

TABLE 1

Treatment-Emergent Adverse Events:

Incidence in Placebo-Controlled Clinical Trials for

Major Depressive Disorder*

(Percentage of Patients

Reporting Event)

Body System /                                                                                    LEXAPRO                               Placebo

Adverse Event                                                                                        (N=715)                                 (N=592)

Autonomic Nervous

System Disorders

Dry Mouth

6%

5%

Sweating Increased

5%

2%

Central & Peripheral

Nervous System Disorders

Dizziness

5%

3%

Gastrointestinal Disorders

Nausea

15%

7%

Diarrhea

8%

5%

Constipation

3%

1%

Indigestion

3%

1%

Abdominal Pain

2%

1%

General

Influenza-like Symptoms

5%

4%

Fatigue

5%

2%

Psychiatric Disorders

Insomnia

9%

4%

Somnolence

6%

2%

Appetite Decreased

3%

1%

Libido Decreased

3%

1%

Respiratory System

Disorders

Rhinitis

5%

4%

Sinusitis

3%

2%

Urogenital

Ejaculation Disorder1,2

9%

<1%

Impotence2

3%

<1%

Anorgasmia3

2%

<1%

*Events reported by at least 2% of patients treated with LEXAPRO are reported, except for the following events which had an incidence on placebo t LEXAPRO: headache, upper respiratory tract infection, back pain, pharyngitis, inflicted injury, anxiety.

1Primarily ejaculatory delay.

2Denominator used was for males only (N=225 LEXAPRO; N=1 88 placebo).

3Denominator used was for females only (N=490 LEXAPRO; N=404 placebo).

Generalized Anxiety Disorder

Table 2 enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse events that occurred among 429 GAD patients who received LEXAPRO 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with LEXAPRO and for which the incidence in patients treated with LEXAPRO was greater than the incidence in placebo-treated patients.

The most commonly observed adverse events in LEXAPRO patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were nausea, ejaculation disorder (primarily ejaculatory delay), insomnia, fatigue, decreased libido, and anorgasmia (see TABLE 2).

TABLE 2

Treatment-Emergent Adverse Events: Incidence in Placebo-Controlled

Clinical Trials for Generalized Anxiety Disorder*

(Percentage of Patients Reporting Event)

Body System /

LEXAPRO

Placebo

Adverse Event

(N=429)

(N=427)

Autonomic Nervous System Disorders

Dry Mouth

9%

5%

Sweating Increased

4%

1%

Central & Peripheral

Nervous System Disorders

 

 

Headache

24%

17%

 

Paresthesia

2%

1%

 

Gastrointestinal Disorders

Nausea

18%

8%

 

Diarrhea

8%

6%

 

Constipation

5%

4%

 

Indigestion

3%

2%

 

Vomiting

3%

1%

 

Abdominal Pain

2%

1%

 

Flatulence

2%

1%

 

Toothache

2%

0%

 

General

Fatigue

8%

2%

 

Influenza-like Symptoms

5%

4%

 

Musculoskeletal

Neck/Shoulder Pain

3%

1%

 

Psychiatric Disorders

Somnolence

13%

7%

 

Insomnia

12%

6%

 

Libido Decreased

7%

2%

 

Dreaming Abnormal

3%

2%

 

Appetite Decreased

3%

1%

 

Lethargy

3%

1%

 

Yawning

2%

1%

 

Urogenital

Ejaculation Disorder1,2

14%

2%

 

Anorgasmia3

6%

<1%

 

Menstrual Disorder

2%

1%

 

           

*Events reported by at least 2% of patients treated with LEXAPRO are reported, except for the following events which had an incidence on placebo t LEXAPRO: inflicted injury, dizziness, back pain, upper respiratory tract infection, rhinitis, pharyngitis.

1Primarily ejaculatory delay.

2Denominator used was for males only (N=182 LEXAPRO; N=195 placebo).

3Denominator used was for females only (N=247 LEXAPRO; N=232 placebo).

Dose Dependency of Adverse Events

The potential dose dependency of common adverse events (defined as an incidence rate of t5% in either the 10 mg or 20 mg LEXAPRO groups) was examined on the basis of the combined incidence of adverse events in two fixed-dose trials. The overall incidence rates of adverse events in 10 mg LEXAPRO-treated patients (66%) was similar to that of the placebo-treated patients (6 1%), while the incidence rate in 20 mg/day LEXAPRO-treated patients was greater (86%). Table 3 shows common adverse events that occurred in the 20 mg/day LEXAPRO group with an incidence that was approximately twice that of the 10 mg/day LEXAPRO group and approximately twice that of the placebo group.

TABLE 3
Incidence of Common Adverse Events* in Patients with Major
Depressive Disorder Receiving Placebo, 10 mg/day LEXAPRO, or
20 mg/day LEXAPRO

Adverse Event

Placebo

10 mg/day

20 mg/day

 

 

(N=311)

LEXAPRO

LEXAPRO

 

 

 

(N=310)

(N=125)

 

Insomnia

4%

7%

14%

 

Diarrhea

5%

6%

14%

 

Dry Mouth

3%

4%

9%

 

Somnolence

1%

4%

9%

Dizziness

2%

4%

7%

Sweating Increased

<1%

3%

8%

Constipation

1%

3%

6%

Fatigue

2%

2%

6%

Indigestion

1%

2%

6%

*Adverse events with an incidence rate of at

least 5% in either of the LEXAPRO

groups and with an incidence

rate in the 20 mg/day LEXAPRO group that

and the placebo group.

was approximately twice that of the

10 mg/day LEXAPRO group

               

 

Male and Female Sexual Dysfunction with SSRIs

Although changes in sexual desire, sexual performance, and sexual satisfaction often occur as manifestations of a psychiatric disorder, they may also be a consequence of pharmacologic treatment. In particular, some evidence suggests that SSRIs can cause such untoward sexual experiences.

Reliable estimates of the incidence and severity of untoward experiences involving sexual desire, performance, and satisfaction are difficult to obtain, however, in part because patients and physicians may be reluctant to discuss them. Accordingly, estimates of the incidence of untoward sexual experience and performance cited in product labeling are likely to underestimate their actual incidence.

Table 4 shows the incidence rates of sexual side effects in patients with major depressive disorder and GAD in placebo-controlled trials.

TABLE 4

Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials

Adverse Event                                                                       LEXAPRO                                                Placebo

 

 

In Males Only

 

 

(N=407)

 

(N=383)

Ejaculation Disorder

(primarily ejaculatory delay)

12%

 

1%

Libido Decreased

6%

 

2%

Impotence

2%

 

<1%

 

(N=737)

In Females Only

(N=636)

Libido Decreased

3%

 

1%

Anorgasmia

3%

 

<1%

There are no adequately designed studies examining sexual dysfunction with escitalopram treatment. Priapism has been reported with all SSRIs.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Vital Sign Changes

LEXAPRO and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with LEXAPRO treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving LEXAPRO indicated that LEXAPRO treatment is not associated with orthostatic changes.

Weight Changes

Patients treated with LEXAPRO in controlled trials did not differ from placebo-treated patients with regard to clinically important change in body weight.

Laboratory Changes

LEXAPRO and placebo groups were compared with respect to (1) mean change from baseline in various serum

chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with LEXAPRO treatment.

ECG Changes

Electrocardiograms from LEXAPRO (N=625), racemic citalopram (N=351), and placebo (N=527) groups were compared with respect to (1) mean change from baseline in various ECG parameters and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed (1) a decrease in heart rate of 2.2 bpm for LEXAPRO and 2.7 bpm for racemic citalopram, compared to an increase of 0.3 bpm for placebo and (2) an increase in QTc interval of 3.9 msec for LEXAPRO and 3.7 msec for racemic citalopram, compared to 0.5 msec for placebo. Neither LEXAPRO nor racemic citalopram were associated with the development of clinically significant ECG abnormalities.

Other Events Observed During the Premarketing Evaluation of LEXAPRO

Following is a list of WHO terms that reflect treatment-emergent adverse events, as defined in the introduction to the ADVERSE REACTIONS section, reported by the 1428 patients treated with LEXAPRO for periods of up to one year in double-blind or open-label clinical trials during its premarketing evaluation. All reported events are included except those already listed in Tables 1 & 2, those occurring in only one patient, event terms that are so general as to be uninformative, and those that are unlikely to be drug related. It is important to emphasize that, although the events reported occurred during treatment with LEXAPRO, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in less than 1/100 patients but at least 1/1 000 patients. Cardiovascular - Frequent: palpitation, hypertension. Infrequent: bradycardia, tachycardia, ECG abnormal, flushing, varicose vein.

Central and Peripheral Nervous System Disorders - Frequent: light-headed feeling, migraine. Infrequent: tremor, vertigo, restless legs, shaking, twitching, dysequilibrium, tics, carpal tunnel syndrome, muscle contractions involuntary, sluggishness, coordination abnormal, faintness, hyperreflexia, muscular tone increased. Gastrointestinal Disorders - Frequent: heartburn, abdominal cramp, gastroenteritis. Infrequent: gastroesophageal reflux, bloating, abdominal discomfort, dyspepsia, increased stool frequency, belching, gastritis, hemorrhoids, gagging, polyposis gastric, swallowing difficult.

General - Frequent: allergy, pain in limb, fever, hot flushes, chest pain. Infrequent: edema of extremities, chills, tightness of chest, leg pain, asthenia, syncope, malaise, anaphylaxis, fall.

Hemic and Lymphatic Disorders - Infrequent: bruise, anemia, nosebleed, hematoma, lymphadenopathy cervical. Metabolic and Nutritional Disorders - Frequent: increased weight. Infrequent: decreased weight, hyperglycemia, thirst, bilirubin increased, hepatic enzymes increased, gout, hypercholesterolemia.

Musculoskeletal System Disorders - Frequent: arthralgia, myalgia. Infrequent: jaw stiffness, muscle cramp, muscle stiffness, arthritis, muscle weakness, back discomfort, arthropathy, jaw pain, joint stiffness. Psychiatric Disorders - Frequent: appetite increased, lethargy, irritability, concentration impaired. Infrequent: jitteriness, panic reaction, agitation, apathy, forgetfulness, depression aggravated, nervousness, restlessness aggravated, suicide attempt, amnesia, anxiety attack, bruxism, carbohydrate craving, confusion, depersonalization, disorientation, emotional lability, feeling unreal, tremulousness nervous, crying abnormal, depression, excitability, auditory hallucination, suicidal tendency.

Reproductive Disorders/Female* - Frequent: menstrual cramps, menstrual disorder. Infrequent: menorrhagia, breast neoplasm, pelvic inflammation, premenstrual syndrome, spotting between menses.

*% based on female subjects only: N= 905

Respiratory System Disorders - Frequent: bronchitis, sinus congestion, coughing, nasal congestion, sinus headache. Infrequent: asthma, breath shortness, laryngitis, pneumonia, tracheitis.

Skin and Appendages Disorders - Frequent: rash. Infrequent: pruritus, acne, alopecia, eczema, dermatitis, dry skin, folliculitis, lipoma, furunculosis, dry lips, skin nodule.

Special Senses - Frequent: vision blurred, tinnitus. Infrequent: taste alteration, earache, conjunctivitis, vision abnormal, dry eyes, eye irritation, visual disturbance, eye infection, pupils dilated, metallic taste. Urinary System Disorders - Frequent: urinary frequency, urinary tract infection. Infrequent: urinary urgency, kidney stone, dysuria, blood in urine.

Events Reported Subsequent to the Marketing of Racemic Citalopram and Escitalopram

Although no causal relationship to racemic citalopram or escitalopram treatment has been found, the following adverse events have been reported to have occurred in patients and to be temporally associated with racemic citalopram treatment and with escitalopram treatment during postmarketing experience and were not observed during the premarketing evaluation of citalopram or escitalopram: acute renal failure, angioedema, toxic epidermal necrolysis, gastrointestinal hemorrhage, grand mal seizures (or convulsions), neuroleptic malignant syndrome, pancreatitis, QT prolongation, rhabdomyolysis, serotonin syndrome, thrombocytopenia, torsades de pointes.

Events Reported Subsequent to the Marketing of Racemic Citalopram (not observed during the postmarketing experience with escitalopram)

Although no causal relationship to racemic citalopram treatment has been found, the following adverse events have been reported to have occurred in patients and to be temporally associated with racemic citalopram treatment and were not observed during the premarketing evaluation of citalopram: akathisia, allergic reaction, anaphylaxis, choreoathetosis, delirium, dyskinesia, ecchymosis, erythema multiforme, hemolytic anemia, hepatic necrosis, myoclonus, nystagmus, priapism, prolactinemia, prothrombin decreased, spontaneous abortion, thrombosis, and ventricular arrhythmia.

Events Reported Subsequent to the Marketing of Escitalopram (not observed during the postmarketing experience with citalopram)

Although no causal relationship to escitalopram treatment has been found, the following adverse events have been reported to have occurred in patients and to be temporally associated with escitalopram treatment and were not observed during the premarketing evaluation of escitalopram: aggression, atrial fibrillation, seizures, diplopia, dystonia, extrapyramidal disorders, abnormal gait, visual hallucinations, hepatitis, hypotension, myocardial infarction, orthostatic hypotension, pulmonary embolism, SIADH, ventricular tachycardia.

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class LEXAPRO is not a controlled substance.

Physical and Psychological Dependence

Animal studies suggest that the abuse liability of racemic citalopram is low. LEXAPRO has not been systematically studied in humans for its potential for abuse, tolerance, or physical dependence. The premarketing clinical experience with LEXAPRO did not reveal any drug-seeking behavior. However, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate LEXAPRO patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

OVERDOSAGE

Human Experience

There have been reports of LEXAPRO overdose involving doses of up to 600 mg. All patients recovered and no symptoms associated with the overdoses were reported. In clinical trials of racemic citalopram, there were no reports of fatal citalopram overdose involving overdoses of up to 2000 mg. During the postmarketing evaluation of citalopram, like other SSRIs, a fatal outcome in a patient who has taken an overdose of citalopram has been rarely reported.

Postmarketing reports of drug overdoses involving citalopram have included 12 fatalities, 10 in combination with other drugs and/or alcohol and 2 with citalopram alone (3920 mg and 2800 mg), as well as non-fatal overdoses of up to 6000 mg. Symptoms most often accompanying citalopram overdose, alone or in combination with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, somnolence, sinus tachycardia, and convulsions. In more rare cases, observed symptoms included amnesia, confusion, coma, hyperventilation, cyanosis, rhabdomyolysis, and ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and one possible case of torsades de pointes).

Management of Overdose

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 LEXAPRO.

In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

DOSAGE AND ADMINISTRATION

Major Depressive Disorder

Initial Treatment

The recommended dose of LEXAPRO is 10 mg once daily. A fixed-dose trial of LEXAPRO demonstrated the effectiveness of both 10 mg and 20 mg of LEXAPRO, but failed to demonstrate a greater benefit of 20 mg over 10 mg (see Clinical Efficacy Trials under CLINICAL PHARMACOLOGY). If the dose is increased to 20 mg, this should occur after a minimum of one week.

LEXAPRO should be administered once daily, in the morning or evening, with or without food. Special Populations

10 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment.

No dosage adjustment is necessary for patients with mild or moderate renal impairment. LEXAPRO should be used with caution in patients with severe renal impairment.

Treatment of Pregnant Women During the Third Trimester

Neonates exposed to LEXAPRO and other SSRIs or SNRIs, late in the third trimester, have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see PRECAUTIONS). When treating pregnant women with LEXAPRO during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering LEXAPRO in the third trimester.

Maintenance Treatment

It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of continuing LEXAPRO 10 or 20 mg/day for periods of up to 36 weeks in patients with major depressive disorder who responded while taking LEXAPRO during an 8-week, acute-treatment phase demonstrated a benefit of such maintenance treatment (see Clinical Efficacy Trials under CLINICAL PHARMACOLOGY). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

Generalized Anxiety Disorder

Initial Treatment

The recommended starting dose of LEXAPRO is 10 mg once daily. If the dose is increased to 20 mg, this should occur after a minimum of one week.

LEXAPRO should be administered once daily, in the morning or evening, with or without food.

Maintenance Treatment

Generalized anxiety disorder is recognized as a chronic condition. The efficacy of LEXAPRO in the treatment of GAD beyond 8 weeks has not been systematically studied. The physician who elects to use LEXAPRO for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Discontinuation of Treatment with LEXAPRO

Symptoms associated with discontinuation of LEXAPRO and other SSRIs and SNRIs have been reported (see PRECAUTIONS). Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the 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.

Switching Patients To or From a Monoamine Oxidase Inhibitor

At least 14 days should elapse between discontinuation of an MAOI and initiation of LEXAPRO therapy. Similarly, at least 14 days should be allowed after stopping LEXAPRO before starting an MAOI (see CONTRAINDICATIONS and WARNINGS).

HOW SUPPLIED

5 mg Tablets:

Bottle of 100                                       NDC # 0456-2005-01

White to off-white, round, non-scored, film-coated. Imprint "FL" on one side of the tablet and "5" on the other side.

10 mg Tablets:

Bottle of 100                                       NDC # 0456-2010-01

10 x 10 Unit Dose                               NDC # 0456-2010-63

White to off-white, round, scored, film-coated. Imprint on scored side with "F" on the left side and "L" on the right side.

Imprint on the non-scored side with "10".

20 mg Tablets:

Bottle of 100                                       NDC # 0456-2020-0 1

10 x 10 Unit Dose                               NDC # 0456-2020-63

White to off-white, round, scored, film-coated. Imprint on scored side with "F" on the left side and "L" on the right side.

Imprint on the non-scored side with "20".

Oral Solution:

5 mg/5 mL, peppermint flavor (240 mL) NDC # 0456-2101-08

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

ANIMAL TOXICOLOGY

Retinal Changes in Rats

Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with racemic citalopram. 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 citalopram for two years, in mice receiving up to 240 mg/kg/day of racemic citalopram for 18 months, or in dogs receiving up to 20 mg/kg/day of racemic citalopram for one year.

Additional studies to investigate the mechanism for this pathology have not been performed, and the potential significance of this effect in humans has not been established.

Cardiovascular Changes in Dogs

In a one-year toxicology study, 5 of 10 beagle dogs receiving oral racemic citalopram 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 citalopram up to 120 mg/kg/day, which produced plasma levels of citalopram and its metabolites demethylcitalopram and didemethylcitalopram (DDCT) similar to those observed in dogs at 8 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, racemic DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs