Generic Name: ESCITALOPRAM
Brand Name: Lexapro
- Substance Name(s):
- ESCITALOPRAM OXALATE
DRUG INTERACTIONS
7 Concomitant use with SSRIs, SNRIs or Tryptophan is not recommended ( 7.2 ).
Use caution when concomitant use with drugs that affect Hemostasis (NSAIDs, Aspirin, Warfarin) ( 7.6 ).
7.1 Monoamine Oxidase Inhibitors (MAOIs) [See Dosage and Administration ( 2.5 and 2.6 ), Contraindications ( 4.1 ) and Warnings and Precautions ( 5.2 )].
7.2 Serotonergic Drugs [See Dosage and Administration ( 2.5 and 2.6 ), Contraindications ( 4.1 ) and Warnings and Precautions ( 5.2 )].
7.3 Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan.
If concomitant treatment of Lexapro with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [ see Warnings and Precautions ( 5.2 ) ].
7.4 CNS Drugs Given the primary CNS effects of escitalopram, caution should be used when it is taken in combination with other centrally acting drugs.
7.5 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.
7.6 Drugs That Interfere W ith 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 may potentiate the risk of bleeding.
Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin.
Patients receiving warfarin therapy should be carefully monitored when Lexapro is initiated or discontinued.
7.7 Cimetidine In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in citalopram AUC and C max of 43% and 39%, respectively.
The clinical significance of these findings is unknown.
7.8 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.
7.9 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.
7.10 Pimozide and Celexa In a controlled study, a single dose of pimozide 2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone.
Racemic citalopram did not alter the mean AUC or C max of pimozide.
The mechanism of this pharmacodynamic interaction is not known.
7.11 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.
7.12 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.
7.13 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.
7.14 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.
7.15 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.
7.16 Ketoconazole Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the C max and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.
7.17 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.
7.18 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.
7.19 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 C max 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.
7.20 Metoprolol Administration of 20 mg/day Lexapro for 21 days in healthy volunteers resulted in a 50% increase in C max 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.
7.21 Electroconvulsive Therapy (ECT) There are no clinical studies of the combined use of ECT and escitalopram.
OVERDOSAGE
10 The following have been reported with Lexapro tablet overdosage: Seizures, which may be delayed, and altered mental status including coma.
Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, and torsade de pointes.
Hypertension most commonly seen, but rarely can see hypotension alone or with co-ingestants including alcohol.
Serotonin syndrome (patients with a multiple drug overdosage with other proserotonergic drugs may have a higher risk).
Prolonged cardiac monitoring is recommended in Lexapro overdosage ingestions due to the arrhythmia risk.
Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a Lexapro overdose.
Consider contacting a poison center (1-800-221-2222) or a medical toxicologist for overdosage management recommendations.
DESCRIPTION
11 Lexapro® contains escitalopram oxalate, 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: The molecular formula is C 20 H 21 FN 2 O • C 2 H 2 O 4 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 is available as tablets for oral administration.
Lexapro tablets are film-coated, round tablets containing 6.38 mg, 12.75 mg, 25.50 mg escitalopram oxalate in strengths equivalent to 5 mg, 10 mg, and 20 mg, respectively, of 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 1.29 mg/ml 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.
The oral solution is not currently marketed.
The following structural formula for 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.
CLINICAL STUDIES
14 14.1 Major Depressive Disorder Adolescents The efficacy of Lexapro as an acute treatment for major depressive disorder in adolescent patients was established in an 8-week, flexible-dose, placebo-controlled study that compared Lexapro 10-20 mg/day to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for major depressive disorder.
The primary outcome was change from baseline to endpoint in the Children’s Depression Rating Scale – Revised (CDRS-R).
In this study, Lexapro showed statistically significant greater mean improvement compared to placebo on the CDRS-R.
The efficacy of Lexapro in the acute treatment of major depressive disorder in adolescents was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20-40 mg/day.
In this outpatient study in children and adolescents 7 to 17 years of age who met DSM-IV criteria for major depressive disorder, citalopram treatment showed statistically significant greater mean improvement from baseline, compared to placebo, on the CDRS-R; the positive results for this trial largely came from the adolescent subgroup.
Two additional flexible-dose, placebo-controlled MDD studies (one Lexapro study in patients ages 7 to 17 and one citalopram study in adolescents) did not demonstrate efficacy.
Although maintenance efficacy in adolescent patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients.
Adults 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 statistically significant 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 statistically significant 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 statistically significant 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 ≤ 12.
Relapse during the double-blind phase was defined as an increase of the MADRS total score to ≥ 22, or discontinuation due to insufficient clinical response.
Patients receiving continued Lexapro experienced a statistically significant longer time to relapse compared to those receiving placebo.
14.2 Generalized Anxiety Disorder The efficacy of Lexapro in the acute 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 adult outpatients between 18 and 80 years of age who met DSM-IV criteria for GAD.
In all three studies, Lexapro showed statistically significant 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.
HOW SUPPLIED
16 /STORAGE AND HANDLING Tablets 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 # 0456-2020-01 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.
The oral solution is not currently being marketed.
Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15 to 30°C (59° to 86°F).
RECENT MAJOR CHANGES
Warnings and Precautions ( 5.11 ) 09/2021
GERIATRIC USE
8.5 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.
SSRIs and SNRIs, including Lexapro, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Hyponatremia ( 5.6 ) ].
In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared to young subjects and C max was unchanged [ see Clinical Pharmacology ( 12.3 ) ].
10 mg/day is the recommended dose for elderly patients [ see Dosage and Administration ( 2.3 ) ].
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.
DOSAGE FORMS AND STRENGTHS
3 Tablets 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.
Imprinted with “FL” on one side and either “5”, “10”, or “20” on the other side according to their respective strengths.
Oral Solution Lexapro oral solution contains escitalopram oxalate equivalent to 1 mg/mL escitalopram base (not currently being marketed).
Tablets: 5 mg, 10 mg (scored) and 20 mg (scored) Oral solution: 1 mg per mL (not currently being marketed)
MECHANISM OF ACTION
12.1 Mechanism of Action 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).
INDICATIONS AND USAGE
1 Lexapro is a selective serotonin reuptake inhibitor (SSRI) indicated for: Acute and Maintenance Treatment of Major Depressive Disorder (MDD) in adults and adolescents aged 12-17 years ( 1.1 ) Acute Treatment of Generalized Anxiety Disorder (GAD) in adults ( 1.2 ) 1.1 Major Depressive Disorder Lexapro (escitalopram) is indicated for the acute and maintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age [ see Clinical Studies ( 14.1 ) ].
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.
1.2 Generalized Anxiety Disorder Lexapro is indicated for the acute treatment of Generalized Anxiety Disorder (GAD) in adults [ see Clinical Studies ( 14.2 ) ].
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.
PEDIATRIC USE
8.4 Pediatric Use The safety and effectiveness of Lexapro have been established in adolescents (12 to 17 years of age) for the treatment of major depressive disorder [ see Clinical Studies ( 14.1 ) ].
Although maintenance efficacy in adolescent patients with major depressive disorder has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients.
The safety and effectiveness of Lexapro have not been established in pediatric (younger than 12 years of age) patients with major depressive disorder.
In a 24-week, open- label safety study in 118 children (aged 7 to 11 years) who had major depressive disorder, the safety findings were consistent with the known safety and tolerability profile for Lexapro.
Safety and effectiveness of Lexapro has not been established in pediatric patients less than 18 years of age with Generalized Anxiety Disorder.
Decreased appetite and weight loss have been observed in association with the use of SSRIs.
Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as Lexapro.
PREGNANCY
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy.
Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clnical-and-research-programs/pregnancyregistry/antidepressants/ Risk Summary Available data from published epidemiologic studies and postmarketing reports have not established an increased risk of major birth defects or miscarriage.
There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and poor neonatal adaptation (see Clinical Considerations) with exposure to selective serotonin reuptake inhibitors (SSRIs), including LEXAPRO, during pregnancy.
There are risks associated with untreated depression in pregnancy (see Clinical Considerations).
In animal reproduction studies, both escitalopram and racemic citalopram have been shown to have adverse effects on embryo/fetal and postnatal development, including fetal structural abnormalities, when administered at doses greater than human therapeutic doses (see Data) .
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.
All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S.
general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations Disease-associated maternal risk and/or embryo/fetal risk Women who discontinue antidepressants are more likely to experience a relapse of major depression than women who continue antidepressants.
This finding is from a prospective longitudinal study of 201 pregnant women with a history of major depression, who were euthymic and taking antidepressants at the beginning of pregnancy.
Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Fetal/Neonatal adverse reactions Neonates exposed to SSRIs or SNRIs, including Lexapro, late in 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 and Precautions ( 5.2 ) ].
Data Human Data Exposure to SSRIs, particularly later in pregnancy, may increase the risk for PPHN.
PPHN occurs in 1-2 per 1000 live births in the general populations and is associated with substantial neonatal morbidity and mortality.
Animal Data 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 ≥ 55 times the maximum recommended human dose (MRHD) of 20 mg/day on a mg/m 2 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 27 times the MRHD of 20 mg on a mg/m 2 basis.
No malformations were observed at any of the doses tested (as high as 73 times the MRHD on a mg/m 2 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 23 times the MRHD of 20 mg on a mg/m 2 basis.
Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose.
Slightly increased offspring mortality was also seen at 24 mg/kg/day.
The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD of 20 mg on a mg/m 2 basis.
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, which is approximately 18 times the MRHD of 60 mg/day on a mg/m 2 basis.
This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain).
The developmental no-effect dose was 56 mg/kg/day is approximately 9 times the MRHD on a mg/m 2 basis.
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, or approximately 5 times the MRHD on a mg/m 2 basis.
Thus, developmental 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, which is approximately 5 times the MRHD of 60 mg on a mg/m 2 basis.
The no-effect dose was 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m 2 basis.
Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the MRHD on a mg/m 2 basis.
A no-effect dose was not determined in that study.
BOXED WARNING
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior s in pediatric and young adult patients in short-term studies .
Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions ( 5.1 )].
Lexapro is not approved for use in pediatric patients less than 12 years of age [ s ee Use in Specific Populations ( 8.4 )].
WARNING: SUICIDAL THOUGHTS AN D BEHAVIORS See full prescribing information for complete boxed warning.
Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants.
Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors ( 5.1 ).
Lexapro is not approved for use in pediatric patients less than 12 years of age ( 8.4 ).
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Serotonin syndrome has been reported with SSRIs and SNRIs, including Lexapro, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.
John’s Wort).
If such symptoms occur, discontinue Lexapro and initiate supportive treatment.
If concomitant use of Lexapro with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases ( 4 , 5.2 ).
Discontinuation of Treatment with Lexapro: A gradual reduction in dose rather than abrupt cessation is recommended whenever possible ( 5.3 ).
Seizures: Prescribe with care in patients with a history of seizure ( 5.4 ).
Activation of Mania/Hypomania: Screen patients for bipolar disorder.
( 5.5 ).
Hyponatremia: Can occur in association with SIADH ( 5.6 ) Abnormal Bleeding: Use caution in concomitant use with NSAIDs, aspirin, warfarin or other drugs that affect coagulation ( 5.7 ).
Interference with Cognitive and Motor Performance: Use caution when operating machinery ( 5.8 ).
Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.
( 5.9 ) Use in Patients with Concomitant Illness: Use caution in patients with diseases or conditions that produce altered metabolism or hemodynamic responses ( 5.10 ).
Sexual Dysfunction: Lexapro may cause symptoms of sexual dysfunction ( 5.11 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in the antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients.
There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied.
There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD.
The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.
Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months.
However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.
Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes.
Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider.
Consider changing the therapeutic regimen, including possibly discontinuing Lexapro, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Lexapro, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St.
John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).
Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination) seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Patients should be monitored for the emergence of serotonin syndrome.
The concomitant use of Lexapro with MAOIs intended to treat psychiatric disorders is contraindicated.
Lexapro should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.
All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.
No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.
There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking Lexapro.
Lexapro should be discontinued before initiating treatment with the MAOI [see Contraindications ( 4.1 ) and Dosage and Administration ( 2.5 and 2.6 )].
If concomitant use of Lexapro with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, amphetamine and St.
John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.
Treatment with Lexapro and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
5.3 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 ( 2.4 ) ].
5.4 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.
5.5 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with Lexapro or another antidepressant may precipitate a mixed/manic episode.
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.
Prior to initiating treatment with Lexapro, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration ( 2.3 )].
5.6 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Lexapro.
In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when Lexapro was discontinued.
Cases with serum sodium lower than 110 mmol/L have been reported.
Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs.
Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [ see Geriatric Use ( 8.5 )].
Discontinuation of Lexapro should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.
Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
5.7 Abnormal Bleeding SSRIs and SNRIs, including Lexapro, may increase the risk of bleeding events.
Concomitant use of aspirin, nonsteroidal antiinflammatory drugs, warfarin, and other anticoagulants may add to the risk.
Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.
Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.
Patients should be cautioned about the risk of bleeding associated with the concomitant use of Lexapro and NSAIDs, aspirin, or other drugs that affect coagulation.
5.8 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.
5.9 Angle Closure Glaucoma Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including Lexapro may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
5.10 Use in Patients with Concomitant Illness Clinical experience with Lexapro in patients with certain concomitant systemic illnesses is limited.
Caution is advisable in using Lexapro in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.
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 ( 2.3 ) ].
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 ( 2.3 ) ].
5.11 Sexual Dysfunction Use of SSRIs, including Lexapro, may cause symptoms of sexual dysfunction [see Adverse Reactions ( 6.1 )].
In male patients, SSRI use may result in ejaculatory delay or failure, decreased libido, and erectile dysfunction.
In female patients, SSRI use may result in decreased libido and delayed or absent orgasm.
It is important for prescribers to inquire about sexual function prior to initiation of Lexapro and to inquire specifically about changes in sexual function during treatment, because sexual function may not be spontaneously reported.
When evaluating changes in sexual function, obtaining a detailed history (including timing of symptom onset) is important because sexual symptoms may have other causes, including the underlying psychiatric disorder.
Discuss potential management strategies to support patients in making informed decisions about treatment.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Medication Guide ).
Suicidal Thoughts and Behaviors Advise patients, their families and caregivers to look for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to their healthcare provider [ see Boxed Warning and Warnings and Precautions ( 5.1 )] Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of Lexapro with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines and St.
John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [ see Warnings and Precautions ( 5.2 ) ].
Activation of Mania or Hypomania Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [ see Warnings and Precautions ( 5.5 )].
Abnormal Bleeding Patients should be cautioned about the concomitant use of Lexapro and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [ see Warnings and Precautions ( 5.7 ) ].
Angle Closure Glaucoma Patients should be advised that taking Lexapro can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma.
Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy.
Open-angle glaucoma is not a risk factor for angle closure glaucoma.
Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions ( 5.9 )] .
Sexual Dysfunction Advise patients that use of Lexapro may cause symptoms of sexual dysfunction in both male and female patients.
Inform patients that they should discuss any changes in sexual function and potential management strategies with their healthcare provider [see Warnings and Precautions ( 5.11 )] .
Concomitant Medications Since escitalopram is the active isomer of racemic citalopram (Celexa), the two agents should not be coadministered.
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.
Continuing the Therapy Prescribed While patients may notice improvement with Lexapro therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.
Interference with Psychomotor Performance 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.
Alcohol 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.
Pregnan c y Advise pregnant women to notify their healthcare providers if they become pregnant or intend to become pregnant during treatment with LEXAPRO.
Advise patients that LEXAPRO use later in pregnancy may lead to increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension (PPHN) of the newborn [ see Use in Specific Populations ( 8.1 )].
Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to LEXAPRO during pregnancy [ see Use in Specific Populations ( 8.1 )].
Lactation Advise breastfeeding women using LEXAPRO to monitor infants for excess sedation, restlessness, agitation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2 )] .
Need for Comprehensive Treatment Program Lexapro is indicated as an integral part of a total treatment program for MDD that may include other measures (psychological, educational, social) for patients with this syndrome.
Drug treatment may not be indicated for all adolescents with this syndrome.
Safety and effectiveness of Lexapro in MDD has not been established in pediatric patients less than 12 years of age.
Antidepressants are not intended for use in the adolescent who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders.
Appropriate educational placement is essential and psychosocial intervention is often helpful.
When remedial measures alone are insufficient, the decision to prescribe antidepressant medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.
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DOSAGE AND ADMINISTRATION
2 Lexapro should be administered once daily, in the morning or evening, with or without food.
Lexapro should generally be administered once daily, morning or evening with or without food ( 2.1 , 2.2 ).
Indication Recommended Dose MDD in Adolescents ( 2.1 ) Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily MDD in Adults ( 2.1 ) Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily GAD in Adults ( 2.2 ) Initial: 10 mg once daily Recommended: 10 mg once daily No additional benefits seen at 20 mg/day dose ( 2.1 ).
10 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment ( 2.3 ).
No dosage adjustment for patients with mild or moderate renal impairment.
Use caution in patients with severe renal impairment ( 2.3 ).
Discontinuing Lexapro: A gradual dose reduction is recommended ( 2.4 ).
2.1 Major Depressive Disorder Initial Treatment Adolescents The recommended dose of Lexapro is 10 mg once daily.
A flexible-dose trial of Lexapro (10 to 20 mg/day) demonstrated the effectiveness of Lexapro [ see Clinical Studies ( 14.1 ) ].
If the dose is increased to 20 mg, this should occur after a minimum of three weeks.
Adults 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 Studies ( 14.1 ) ].
If the dose is increased to 20 mg, this should occur after a minimum of one week.
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 in adults 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 Studies ( 14.1 )].
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.
Patients should be periodically reassessed to determine the need for maintenance treatment.
2.2 Generalized Anxiety Disorder Initial Treatment Adults 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.
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.
2.3 Screen for Bipolar Disorder Prior to Starting Lexapro Prior to initiating treatment with Lexapro or another antidepressant, screen patients for a personal family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions ( 5.5 )] .
2.
4 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.
2.
5 Discontinuation of Treatment with Lexapro Symptoms associated with discontinuation of Lexapro and other SSRIs and SNRIs have been reported [ see Warnings and Precautions ( 5.3 ) ].
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.
2.
6 Switching a Patient t o or f rom a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Lexapro.
Conversely, at least 14 days should be allowed after stopping Lexapro before starting an MAOI intended to treat psychiatric disorders [ see Contraindications ( 4.1 ) ].
2.
7 Use of Lexapro with Other MAOIs such as Linezolid or Methylene Blue Do not start Lexapro in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome.
In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications ( 4.1 )] .
In some cases, a patient already receiving Lexapro therapy may require urgent treatment with linezolid or intravenous methylene blue.
If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Lexapro should be stopped promptly, and linezolid or intravenous methylene blue can be administered.
The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.
Therapy with Lexapro may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Preca u tions ( 5.2 )] .
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with Lexapro is unclear.
The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Preca u tions ( 5.2 )] .