How Much Does Escitalopram Oxalate Cost in Mexico vs the USA?

Escitalopram tablets are 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 and pediatric patients 7 years of age and older. Escitalopram oxalate 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 and pediatric patients 7 years and older ( 1 )

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 GAD in Pediatric Patients 7 years and older ( 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 tablets, reduce dose gradually whenever possible ( 2.5 ) 2.1 Major Depressive Disorder Adults The recommended dosage of escitalopram tablets in adults is 10 mg once daily. A fixed-dose trial of escitalopram tablets demonstrated the effectiveness of both 10 mg and 20 mg of escitalopram tablets, 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 tablets 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 tablets 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. Pediatric Patients 7 years of age and older The recommended starting dosage of escitalopram tablets for pediatric patients ages 7 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 2 weeks. 2.3 Administration Information Administer escitalopram tablets orally once daily, in the morning or evening, with or without food. 2.4 Screen for Bipolar Disorder Prior to Starting Escitalopram Tablets Prior to initiating treatment with escitalopram tablets 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 tablets 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 Tablets Symptoms associated with discontinuation of escitalopram tablets 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 tablets. Conversely, at least 14 days should be allowed after stopping escitalopram tablets before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4) ] .

Escitalopram tablets is contraindicated in patients: taking MAOIs with escitalopram tablets or within 14 days of stopping treatment with escitalopram tablets because of an increased risk of serotonin syndrome. The use of escitalopram tablets 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 tablets 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 tablets. Do not use MAOIs intended to treat psychiatric disorders with escitalopram tablets or within 14 days of stopping treatment with escitalopram tablets. Do not use escitalopram tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start escitalopram tablets 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 )

Serotonin Syndrome: Increased risk when co-administered with other serotonergic agents but also when taken alone. If it occurs, discontinue escitalopram oxalate and serotonergic agents and initiate supportive treatment ( 4 , 5.2 ) Discontinuation syndrome: When discontinuing escitalopram oxalate, 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 oxalate 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 oxalate, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Serotonin Syndrome SSRIs, including escitalopram oxalate, 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, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4) and Drug Interactions (7) ]. 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). The concomitant use of escitalopram oxalate with MAOIs is contraindicated. In addition, do not initiate escitalopram oxalate in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking escitalopram oxalate, discontinue escitalopram oxalate before initiating treatment with the MAOI [see Contraindications (4) and Dosage and Administration (2.7) ] . Monitor all patients taking escitalopram oxalate for the emergence of serotonin syndrome. Discontinue treatment with escitalopram oxalate and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of escitalopram oxalate with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.3 Discontinuation Syndrome During marketing of escitalopram oxalate and other SSRIs, there have been spontaneous reports of adverse reactions 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. Monitor for these symptoms when discontinuing treatment with escitalopram oxalate. 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 (2.6) ] . 5.4 Seizures Although anticonvulsant effects of racemic citalopram have been observed in animal studies, escitalopram oxalate 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 escitalopram oxalate, cases of convulsion have been reported in association with escitalopram oxalate treatment. Like other drugs effective in the treatment of major depressive disorder, escitalopram oxalate 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 escitalopram oxalate or another antidepressant may precipitate a mixed/manic episode. In placebo-controlled trials of escitalopram oxalate in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with escitalopram oxalate and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with escitalopram oxalate 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 escitalopram oxalate, screen patients for any personal or family history of bipolar disorder, mania, or hypomania [see Dosage and Administration (2.4) ]. 5.6 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs, including escitalopram oxalate. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when escitalopram oxalate 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 Use in Specific Populations (8.5) ]. Consider discontinuation of escitalopram oxalate 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 Increased Risk of Bleeding Drugs that interfere with serotonin reuptake inhibition, including escitalopram oxalate, increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), other antiplatelet 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. Based on data from the published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Use in Specific Populations (8.1) ]. Bleeding events related to drugs that interfere with serotonin reuptake have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Inform patients about the increased risk of bleeding associated with the concomitant use of escitalopram oxalate and antiplatelet agents or anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Drug Interactions (7) ]. 5.8 Interference with Cognitive and Motor Performance In a study in normal volunteers, escitalopram oxalate 10 mg daily 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 escitalopram oxalate therapy does not affect their ability to engage in such activities. 5.9 Angle Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including escitalopram oxalate, 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 escitalopram oxalate in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using escitalopram oxalate in patients with diseases or conditions that produce altered metabolism or hemodynamic responses. Escitalopram oxalate 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 escitalopram oxalate in hepatically impaired patients is 10 mg daily [see Dosage and Administration (2.5) and Use in Specific Populations (8.6) ]. 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 escitalopram oxalate, however, it should be used with caution in such patients [see Dosage and Administration (2.5) and Use in Specific Populations (8.7) ]. 5.11 Sexual Dysfunction Use of SSRIs, including escitalopram oxalate, 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 escitalopram oxalate 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.

Table 6 presents clinically important drug interactions with escitalopram oxalate. TABLE 6 Clinically Important Drug Interactions with Escitalopram Oxalate Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: Concomitant use of SSRIs, including escitalopram oxalate, and MAOIs increases the risk of serotonin syndrome. Intervention: Escitalopram oxalate is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.7) , Contraindications (4) , and Warnings and Precautions (5.2) ] . Pimozide Clinical Impact: Concomitant use of racemic citalopram with pimozide increases plasma concentrations of pimozide, a drug with a narrow therapeutic index, and may increase the risk of QT prolongation and/or ventricular arrhythmias compared to use of racemic citalopram alone [see Clinical Pharmacology (12.3) ]. Intervention: Escitalopram oxalate is contraindicated in patients taking pimozide [see Contraindications (4) ]. Other Serotonergic Drugs Clinical Impact: Concomitant use of escitalopram oxalate and other serotonergic drugs (including other SSRIs, SNRIs, triptans, tricyclic antidepressants, opioids, lithium, buspirone, amphetamines, tryptophan, and St. John's Wort) increases the risk of serotonin syndrome. Intervention: Monitor patients for signs and symptoms of serotonin syndrome, particularly during escitalopram oxalate initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of escitalopram oxalate and/or concomitant serotonergic drugs [see Warning and Precautions (5.2) ] . Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.) Clinical Impact: Concomitant use of escitalopram oxalate and an antiplatelet or anticoagulant may potentiate the risk of bleeding. Intervention: Inform patients of the increased risk of bleeding associated with the concomitant use of escitalopram oxalate and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warning and Precautions (5.7) ] . Sumatriptan Clinical Impact: There have been postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. Intervention: If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised [see Warning and Precautions (5.2) ] . Carbamazepine Clinical Impact: 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. Intervention: 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. Drugs Metabolized by CYP2D6 Clinical Impact: 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. Intervention: The clinical significance of this finding is unknown. Exercise caution during coadministration of escitalopram and drugs metabolized by CYP2D6. Concomitant use with SSRIs, SNRIs or Tryptophan is not recommended ( 7 ) Use caution when concomitant use with drugs that affect Hemostasis (NSAIDs, Aspirin, Warfarin) ( 7 )

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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 oxalate 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 oxalate 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 oxalate, 290 placebo) with major depressive disorder and in 273 pediatric patients 7 to 17 years of age (137 escitalopram oxalate, 136 placebo) with generalized anxiety disorder. The safety and effectiveness of escitalopram oxalate 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 oxalate 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 oxalate was not significantly different from the rate of discontinuation for adverse reactions in patients receiving placebo. The rate of discontinuation for adverse reactions in patients assigned to a fixed dose of 20 mg/day escitalopram oxalate was 10%, which was significantly different from the rate of discontinuation for adverse reactions in patients receiving 10 mg/day escitalopram oxalate (4%) and placebo (3%). Adverse reactions that were associated with the discontinuation of at least 1% of patients treated with escitalopram oxalate, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients). Pediatric Patients Adverse reactions in pediatric patients 6 to 17 years of age were associated with discontinuation of 3.5% of 286 patients receiving escitalopram oxalate and 1% of 290 patients receiving placebo. The most common adverse reaction (incidence at least 1% for escitalopram oxalate and greater than placebo) associated with discontinuation was insomnia (1% escitalopram oxalate, 0% placebo). The safety and effectiveness of escitalopram oxalate have not been established in pediatric patients less than 12 years of age with MDD. Generalized Anxiety Disorder Adults Among the 429 GAD patients who received escitalopram oxalate 10 to 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 reactions that were associated with the discontinuation of at least 1% of patients treated with escitalopram oxalate, and for which the rate was at least twice the placebo rate, were nausea (2%), insomnia (1%), and fatigue (1%). Pediatric Patients Adverse reactions in pediatric patients 7 to 17 years were associated with discontinuation of 2.9% of 137 patients receiving escitalopram oxalate and 1.5% of 136 patients receiving placebo. The most common adverse reaction (incidence at least 1% for escitalopram oxalate and greater than placebo) associated with discontinuation was activation syndrome (1% escitalopram oxalate, 0% placebo), intentional self injury (1% escitalopram oxalate, 0% placebo), epistaxis (1% escitalopram oxalate, 0% placebo), and nausea (1% escitalopram oxalate, 0% placebo). Incidence of Adverse Reactions in Placebo-Controlled Clinical Trials Major Depressive Disorder Adults The most commonly observed adverse reactions in escitalopram oxalate 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. Table 2 enumerates the incidence, rounded to the nearest percent, of adverse reactions that occurred among 715 depressed patients who received escitalopram oxalate at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Reactions included are those occurring in 2% or more of patients treated with escitalopram oxalate and for which the incidence in patients treated with escitalopram oxalate was greater than the incidence in placebo-treated patients. TABLE 2 Adverse Reactions observed with a frequency of ≥ 2% and greater than placebo for Major Depressive Disorder (Adults) Adverse Reaction Escitalopram oxalate Placebo (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 Disorder 1,2 9% <1% Impotence 2 3% <1% Anorgasmia 3 2% <1% 1 Primarily ejaculatory delay. 2 Denominator used was for males only (N=225 escitalopram oxalate; N=188 placebo). 3 Denominator used was for females only (N=490 escitalopram oxalate; N=404 placebo). Pediatric Patients The overall profile of adverse reactions in pediatric patients 6 to 17 years in major depressive disorder was generally similar to that seen in adult studies, as shown in Table 2. However, the following adverse reactions (excluding those which appear in Table 2 and those for which the coded terms were uninformative or misleading) were reported at an incidence of at least 2% for escitalopram oxalate and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion. The safety and effectiveness of escitalopram oxalate have not been established in pediatric patients less than 12 years of age with MDD. Generalized Anxiety Disorder Adults The most commonly observed adverse reactions in escitalopram oxalate 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. Table 3 enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse reactions that occurred among 429 GAD patients who received escitalopram oxalate 10 to 20 mg/day in placebo-controlled trials. Reactions included are those occurring in 2% or more of patients treated with escitalopram oxalate and for which the incidence in patients treated with escitalopram oxalate was greater than the incidence in placebo-treated patients. TABLE 3 Adverse Reactions Observed with a Frequency of ≥ 2% and> placebo for Generalized Anxiety Disorder (Adults) Adverse Reactions Escitalopram oxalate Placebo (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 System Disorder 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% Respiratory System Disorders Yawning 2% 1% Urogenital Ejaculation Disorder 1,2 14% 2% Anorgasmia 3 6% <1% Menstrual Disorder 2% 1% 1 Primarily ejaculatory delay. 2 Denominator used was for males only (N=182 escitalopram oxalate; N=195 placebo). 3 Denominator used was for females only (N=247 escitalopram oxalate; N=232 placebo). Pediatric Patients The overall profile of adverse reactions in pediatric patients 7 to 17 years in generalized anxiety disorder was generally similar to that seen in adult studies, as shown in Table 3. However, the following adverse reactions (excluding those which appear in Table 3) were reported at an incidence of at least 2% for escitalopram oxalate and greater than placebo: dizziness (3% escitalopram oxalate and 2% placebo), nasopharyngitis (3% escitalopram oxalate and 1% placebo), abdominal discomfort (3% escitalopram oxalate and 1% placebo), anxiety (3% escitalopram oxalate and 1% placebo), irritability (2% escitalopram oxalate and 1% placebo), and anger (2% escitalopram oxalate and 0% placebo). Dose Dependency of Adverse Reactions The potential dose dependency of common adverse reactions (defined as an incidence rate of ≥5% in either the 10 mg or 20 mg escitalopram oxalate groups) was examined on the basis of the combined incidence of adverse reactions in two fixed-dose trials. The overall incidence rates of adverse reactions in 10 mg escitalopram oxalate-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day escitalopram oxalate-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day escitalopram oxalate group with an incidence that was approximately twice that of the 10 mg/day escitalopram oxalate group and approximately twice that of the placebo group. TABLE 4 Incidence of Common Adverse Reactions in Patients with Major Depressive Disorder Adverse Reaction Placebo 10 mg/day 20 mg/day (N=311) Escitalopram oxalate Escitalopram oxalate (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% 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 5 Incidence of Sexual Side Effects in Placebo-Controlled Clinical Trials Adverse Event Escitalopram oxalate Placebo In Males Only (N=407) (N=383) Ejaculation Disorder (primarily ejaculatory delay) 12% 1% Libido Decreased 6% 2% Impotence 2% <1% In Females Only (N=737) (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 Escitalopram oxalate 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 escitalopram oxalate treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving escitalopram oxalate indicated that escitalopram oxalate treatment is not associated with orthostatic changes. Weight Changes Patients treated with escitalopram oxalate in controlled trials did not differ from placebo-treated patients with regard to clinically important change in body weight. Laboratory Changes Escitalopram oxalate 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 escitalopram oxalate treatment. ECG Changes Electrocardiograms from escitalopram oxalate (N=625) and placebo (N=527) groups were compared with respect to outliers defined as subjects with QTc changes over 60 msec from baseline or absolute values over 500 msec post-dose, and subjects with heart rate increases to over 100 bpm or decreases to less than 50 bpm with a 25% change from baseline (tachycardic or bradycardic outliers, respectively). None of the patients in the escitalopram oxalate group had a QTcF interval >500 msec or a prolongation >60 msec compared to 0.2% of patients in the placebo group. The incidence of tachycardic outliers was 0.2% in the escitalopram oxalate and the placebo group. The incidence of bradycardic outliers was 0.5% in the escitalopram oxalate group and 0.2% in the placebo group. QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg) controlled cross-over, escalating multiple dose study in 113 healthy subjects. The maximum mean (95% upper confidence bound) difference from placebo arm were 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and supratherapeutic 30 mg escitalopram given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the C max for the dose of 20 mg is 6.6 (7.9) msec. Escitalopram 30 mg given once daily resulted in mean C max of 1.7-fold higher than the mean C max for the maximum recommended therapeutic dose at steady state (20 mg). The exposure under supratherapeutic 30 mg dose is similar to the steady state concentrations expected in CYP2C19 poor metabolizers following a therapeutic dose of 20 mg. Other Reactions Observed During the Premarketing Evaluation of Escitalopram Oxalate Following is a list of treatment-emergent adverse reactions, as defined in the introduction to the ADVERSE REACTIONS section, reported by the 1428 patients treated with escitalopram oxalate for periods of up to one year in double-blind or open-label clinical trials during its premarketing evaluation. The listing does not include those reactions already listed in Tables 2 & 3 , those reactions for which a drug cause was remote and at a rate less than 1% or lower than placebo, those reactions which were so general as to be uninformative, and those reactions reported only once which did not have a substantial probability of being acutely life threatening. Reactions are categorized by body system. Reactions of major clinical importance are described in the Warnings and Precautions section (5). Cardiovascular: hypertension, palpitation. Central and Peripheral Nervous System Disorders: light-headed feeling, migraine. Gastrointestinal Disorders: abdominal cramp, heartburn, gastroenteritis. General: allergy, chest pain, fever, hot flushes, pain in limb. Metabolic and Nutritional Disorders: increased weight. Musculoskeletal System Disorders: arthralgia, myalgia jaw stiffness. Psychiatric Disorders : appetite increased, concentration impaired, irritability. Reproductive Disorders/Female: menstrual cramps, menstrual disorder. Respiratory System Disorders: bronchitis, coughing, nasal congestion, sinus congestion, sinus headache. Skin and Appendages Disorders: rash. Special Senses: vision blurred, tinnitus. Urinary System Disorders: urinary frequency, urinary tract infection. 6.2 Post-Marketing Experience Adverse Reactions Reported Subsequent to the Marketing of Escitalopram The following adverse reactions have been identified during post-approval use of escitalopram oxalate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: anemia, agranulocytis, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia purpura, leukopenia, thrombocytopenia. Cardiac Disorders: atrial fibrillation, bradycardia, cardiac failure, myocardial infarction, tachycardia, torsade de pointes, ventricular arrhythmia, ventricular tachycardia. Ear and Labyrinth Disorders: vertigo. Endocrine Disorders: diabetes mellitus, hyperprolactinemia, SIADH. Eye Disorders: angle closure glaucoma, diplopia, mydriasis, visual disturbance. Gastrointestinal Disorder: dysphagia, gastrointestinal hemorrhage, gastroesophageal reflux, pancreatitis, rectal hemorrhage. General Disorders and Administration Site Conditions: abnormal gait, asthenia, edema, fall, feeling abnormal, malaise. Hepatobiliary Disorders: fulminant hepatitis, hepatic failure, hepatic necrosis, hepatitis. Immune System Disorders: allergic reaction, anaphylaxis. Investigations: bilirubin increased, decreased weight, electrocardiogram QT prolongation, hepatic enzymes increased, hypercholesterolemia, INR increased, prothrombin decreased. Metabolism and Nutrition Disorders: hyperglycemia, hypoglycemia, hypokalemia, hyponatremia. Musculoskeletal and Connective Tissue Disorders: muscle cramp, muscle stiffness, muscle weakness, rhabdomyolysis. Nervous System Disorders: akathisia, amnesia, ataxia, choreoathetosis, cerebrovascular accident, dysarthria, dyskinesia, dystonia, extrapyramidal disorders, grand mal seizures (or convulsions), hypoaesthesia, myoclonus, nystagmus, Parkinsonism, restless legs, seizures, syncope, tardive dyskinesia, tremor. Pregnancy, Puerperium and Perinatal Conditions: spontaneous abortion. Psychiatric Disorders: acute psychosis, aggression, agitation, anger, anxiety, apathy, completed suicide, confusion, depersonalization, depression aggravated, delirium, delusion, disorientation, feeling unreal, hallucinations (visual and auditory), mood swings, nervousness, nightmare, panic reaction, paranoia, restlessness, self-harm or thoughts of self-harm, suicide attempt, suicidal ideation, suicidal tendency. Renal and Urinary Disorders: acute renal failure, dysuria, urinary retention. Reproductive System and Breast Disorders: menorrhagia, priapism. Respiratory, Thoracic and Mediastinal Disorders: anosmia, dyspnea, epistaxis, pulmonary embolism, hyposmia, pulmonary hypertension of the newborn. Skin and Subcutaneous Tissue Disorders: alopecia, angioedema, dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS), ecchymosis, erythema multiforme, photosensitivity reaction, Stevens Johnson Syndrome, toxic epidermal necrolysis, urticaria. Vascular Disorders: deep vein thrombosis, flushing, hypertensive crisis, hypotension, orthostatic hypotension, phlebitis, thrombosis.

8.1 Pregnancy Risk Summary Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage [see Warnings and Precautions (5.7) and Clinical Considerations]. 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 escitalopram oxalate, 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. Maternal Adverse Reactions Use of escitalopram oxalate in the month before delivery may be associated with an increased risk of postpartum hemorrhage [see Warnings and Precautions (5.7) ]. Fetal/Neonatal adverse reactions Neonates exposed to SSRIs or SNRIs, including escitalopram oxalate, 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 to 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.