Escitalopram

1 INDICATIONS AND USAGE Escitalopram is indicated for the treatment of: major depressive disorder (MDD) in adults and pediatric patients 12 years of age and older. generalized anxiety disorder (GAD) in adults. Additional pediatric use information is approved for AbbVie Inc.’s Lexapro (escitalopram) tablets and LEXAPRO (escitalopram) oral solution. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. Escitalopram is a selective serotonin reuptake inhibitor (SSRI) indicated for the: treatment of major depressive disorder (MDD) in adults and pediatric patients 12 years of age and older ( 1 ) treatment of generalized anxiety disorder (GAD) in adults ( 1 )

12 CLINICAL PHARMACOLOGY 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). 12.2 Pharmacodynamics 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-HT 1-7 ) or other receptors including alpha- and beta-adrenergic, dopamine (D 1-5 ), histamine (H 1-3 ), muscarinic (M 1-5 ), 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. 12.3 Pharmacokinetics The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day. 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. Absorption The absolute bioavailability of citalopram is about 80% relative to an intravenous dose. The tablet and the oral solution dosage forms of escitalopram oxalate are bioequivalent. 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. Distribution The binding of escitalopram to human plasma proteins is approximately 56%. The volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable. Elimination Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27-32 hours. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance. Metabolism 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 po

2 DOSAGE AND ADMINISTRATION Indication and Population Recommended Dosage MDD in Adults ( 2.1 ) Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily MDD in Pediatric Patients 12 years and older ( 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 Maximum: 20 mg once daily No additional benefits were seen at 20 mg once daily ( 2.1 ) Administer once daily, morning or evening, with or without food ( 2.3 ) Elderly patients: recommended dosage is 10 mg once daily ( 2.4 ) Hepatic impairment: recommended dosage is 10 mg once daily ( 2.4 , 8.6 ) When discontinuing escitalopram, reduce dose gradually whenever possible ( 2.5 ) 2.1 Major Depressive Disorder Adults The recommended dosage of escitalopram in adults is 10 mg once daily. A fixed-dose trial of escitalopram demonstrated the effectiveness of both 10 mg and 20 mg of escitalopram, but failed to demonstrate a greater benefit of 20 mg over 10 mg [ see Clinical Studies (14.1) ]. Depending on clinical response and tolerability, dosage may be increased to the maximum recommended dosage of 20 mg once daily at an interval of no less than 1 week. Pediatric Patients 12 years of age and older The recommended dosage of escitalopram in pediatric patients 12 years of age and older is 10 mg once daily. Depending on clinical response and tolerability, dosage may be increased to the maximum recommended dosage of 20 mg once daily at an interval of no less than 3 weeks. 2.2 Generalized Anxiety Disorder Adults The recommended starting dosage of escitalopram in adults is 10 mg once daily. Depending on clinical response and tolerability, dosage may be increased to the maximum recommended dosage of 20 mg once daily at an interval of no less than 1 week. Additional pediatric use information is approved for AbbVie Inc.’s Lexapro (escitalopram) tablets and LEXAPRO (escitalopram) oral solution. However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Administration Information Administer escitalopram orally once daily, in the morning or evening, with or without food. 2.4 Screen for Bipolar Disorder Prior to Starting Escitalopram Prior to initiating treatment with escitalopram or another antidepressant, screen patients for a personal family history of bipolar disorder, mania, or hypomania [ see Warnings and Precautions (5.5) ]. 2.5 Recommended Dosage for Specific Populations The recommended dosage for most elderly patients and patients with hepatic impairment is 10 mg once daily [ see Use in Specific Populations ( 8.5 , 8.6 ) ]. The recommended dosage for escitalopram in adults with a creatinine clearance less than 20 mL/minute has not been determined. No dosage adjustment is necessary for patients with mild or moderate renal impairment [ see Use in Specific Populations (8.7) ] . 2.6 Discontinuation of Treatment with Escitalopram Symptoms associated with discontinuation of escitalopram 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. 2.7 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with escitalopram. Conversely, at least 14 days should be allowed after stopping escitalopram before starting an MAOI intended to treat psychiatric disorders [ see Contraindications (4) ].

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Suicidal thoughts and behaviors in adolescents and young adults [ see Warnings and Precautions (5.1) ] Serotonin syndrome [ see Warnings and Precautions(5.2) ] Discontinuation syndrome [ see Warnings and Precautions(5.3) ] Seizures [ see Warnings and Precautions (5.4) ] Activation of mania or hypomania [ see Warnings and Precautions (5.5) ] Hyponatremia [ see Warnings and Precautions (5.6) ] Increased Risk of Bleeding [ see Warnings and Precautions (5.7) ] Interference with Cognitive and Motor Performance [ see Warnings and Precautions (5.8) ] Angle-closure glaucoma [ see Warnings and Precautions (5.9) ] Use in Patients with Concomitant Illness [ see Warnings and Precautions (5.10) ] Sexual Dysfunction [ see Warnings and Precautions (5.11) ] Most commonly observed adverse reactions (incidence ≥ 5% and at least twice the incidence of placebo patients) are: insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue and somnolence, decreased libido, and anorgasmia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Clinical Trial Data Sources Adults Adverse reactions information for escitalopram 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 reaction information for escitalopram 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 reactions 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 reactions without first grouping similar types of reactions 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 reactions. The stated frequencies of adverse reactions 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. Pediatric Patients Adverse reaction information for pediatric patients was collected in double-blind placebo-controlled studies in 576 pediatric patients 6 to 17 years of age, (286 escitalopram, 290 placebo) with major depressive disorder. The safety and effectiveness of escitalopram have not been established in pediatric patients less than 12 years of age with MDD or less than 7 years of age with GAD. Adverse Reactions Associated with Discontinuation of Treatment Major Depressive Disorder Adults Among the 715 depressed patients who received escitalopram 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 reactions in patients receiving 10 mg/day escitalopram was not significantly different from the rate of discontinuation for adverse reactions in patients receiving placebo. The rate of discontinuation for

5 WARNINGS AND PRECAUTIONS Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents, but also when taken alone. If it occurs, discontinue escitalopram and serotonergic agents and initiate supportive treatment ( 4 , 5.2 ) Discontinuation syndrome: When discontinuing escitalopram, reduce dosage gradually whenever possible, and monitor for discontinuation symptoms ( 5.3 ) Seizures: Use with caution 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 syndrome of inappropriate antidiuretic hormone secretion ( 5.6 ) Increased Risk of Bleeding: Concomitant use of nonsteroidal anti-inflammatory drugs, aspirin, other antiplatelet drugs, warfarin and other drugs that affect coagulation may increase risk ( 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: Escitalopram 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 escitalopram, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome SSRIs, including escitalopram, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, meperidine, methadone, lithium, tramadol, trypto

4 CONTRAINDICATIONS Escitalopram is contraindicated in patients: taking MAOIs with escitalopram or within 14 days of stopping treatment with escitalopram because of an increased risk of serotonin syndrome. The use of escitalopram within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [ see Dosage and Administration (2.7) and Warnings and Precautions (5.2) ]. Starting escitalopram in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome [ see Dosage and Administration (2.6) and Warnings and Precautions (5.2) ]. taking pimozide [ see Drug Interactions (7) ] with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in escitalopram. Do not use MAOIs intended to treat psychiatric disorders with escitalopram or within 14 days of stopping treatment with escitalopram. Do not use escitalopram within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start escitalopram in a patient who is being treated with linezolid or intravenous methylene blue ( 4 ) Concomitant use of pimozide ( 4 ) Known hypersensitivity to escitalopram or citalopram or any of the inactive ingredients ( 4 )

10 OVERDOSAGE The following have been reported with escitalopram 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 escitalopram overdosage ingestions due to the arrhythmia risk. Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after an escitalopram overdose. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.