ESCITALOPRAM- escitalopram oxalate_tablet, film coated

The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro in vivo 1-7 1-5 1-3 1-5 + + - ++ 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. 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 to 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 1-7 1-5 1-3 1-5 + + - ++ In vitro Excretion Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and S-demethylcitalopram (S-DCT) is about 8% and 10%, respectively. Specific Populations Pediatric Patients max max [see Use in Specific Populations (8. 4) Geriatric Patients Escitalopram pharmacokinetics in subjects >= 65 years of age were compared to adults in a single-dose and a multiple-dose study. Escitalopram AUC and half-life were increased by approximately 50% in elderly subjects, and C max [see Dosage and Administration (2. 5) Use in Specific Populations (8. 5) Male and Female Patients Based on data from single- and multiple-dose studies measuring escitalopram in elderly, young adults, and adolescents, no dosage adjustment on the basis of gender is needed. Patients with Hepatic Impairment Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects [see Dosage and Administration (2. 6) Patients with Renal Impairment In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No information is available about the pharmacokinetics of escitalopram in patients with severely reduced renal function (creatinine clearance < 20 mL/min) [see Use in Specific Populations (8. 7) Drug Interaction Studies In vitro in vitro in vivo in vivo [see Drug Interactions (7) CYP3A4 and CYP2C19 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. 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 Digoxin In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin. Lithium Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. 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 escitalopram oxalate and lithium are coadministered. 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. Ketoconazole Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the C max 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. 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. Metoprolol Administration of 20 mg/day escitalopram oxalate for 21 days in healthy volunteers resulted in a 50% increase in C max Alcohol Escitalopram oxalate 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 escitalopram oxalate is not recommended. 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 these findings is unknown. Additional pediatric use information is approved for AbbVie Inc. ’s LEXAPRO (escitalopram) tablets. However, due to AbbVie Inc. ’s marketing exclusivity rights, this drug product is not labeled with that information.

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. Additional pediatric use information is approved for AbbVie Inc. ’s LEXAPRO (escitalopram) tablets. However, due to AbbVie Inc. ’s marketing exclusivity rights, this drug product is not labeled with that information. 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 ( 1.

Indication and Population Recommended Dosage MDD in Adults ( 2. 1 Initial: 10 mg once daily MDD in Pediatric 2. 1 Initial: 10 mg once daily GAD in Adults ( 2. 2 Initial: 10 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. 6 When discontinuing escitalopram tablets, reduce dose gradually whenever possible ( 2. 5 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) Pediatric Patients 12 years of age and older Adults Additional pediatric use information is approved for AbbVie Inc. ’s LEXAPRO (escitalopram) tablets. However, due to AbbVie Inc. ’s marketing exclusivity rights, this drug product is not labeled with that information. Administer escitalopram tablets orally once daily, in the morning or evening, with or without food. 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) The recommended dosage for most elderly patients and patients with hepatic impairment is 10 mg once daily [see Use in Specific Populations (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) Symptoms associated with discontinuation of escitalopram tablets and other SSRIs and SNRIs have been reported [see Warnings and Precautions (5. 3) 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).

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. gov/medwatch. 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. 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%). 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 2 3 Pediatric Patients 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 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 2 3 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 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. 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 max max 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 Tables 2 & 3 Cardiovascular: Central and Peripheral Nervous System Disorders: Gastrointestinal Disorders: General: Metabolic and Nutritional Disorders: Musculoskeletal System Disorders: Psychiatric Disorders Reproductive Disorders/Female: Respiratory System Disorders: Skin and Appendages Disorders: Special Senses: Urinary System Disorders: Additional pediatric use information is approved for AbbVie Inc. ’s LEXAPRO (escitalopram) tablets. However, due to AbbVie Inc. ’s marketing exclusivity rights, this drug product is not labeled with that information. Adverse Reactions Reported Subsequent to the Marketing of Escitalopram Blood and Lymphatic System Disorders: Cardiac Disorders: Ear and Labyrinth Disorders: Eye Disorders: Gastrointestinal Disorder: General Disorders and Administration Site Conditions: Hepatobiliary Disorders: Immune System Disorders: Investigations: Metabolism and Nutrition Disorders: Musculoskeletal and Connective Tissue Disorders: Nervous System Disorders: Pregnancy, Puerperium and Perinatal Conditions: Psychiatric Disorders: Renal and Urinary Disorders: Reproductive System and Breast Disorders: Respiratory, Thoracic and Mediastinal Disorders: Skin and Subcutaneous Tissue Disorders: Vascular Disorders:.

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) Warnings and Precautions (5. 2) [see Dosage and Administration (2. 6) 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.

Pregnancy: SSRI use, particularly later in pregnancy, may increase the risk for persistent pulmonary hypertension and symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulties, hypotonia, tremor, irritability) in the neonate ( 8. 1 Additional pediatric use information is approved for AbbVie Inc. ’s LEXAPRO (escitalopram) tablets. However, due to AbbVie Inc. ’s marketing exclusivity rights, this drug product is not labeled with that information. Risk Summary [see Warnings and Precautions (5. 7) 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) (see Clinical Considerations) (see Clinical Considerations). (see Data) [see Warnings and Precautions (5. 7) [see Warnings and Precautions (5. 2) 2 2 2 2 2 2 2 2 2 2 2 Risk Summary Data from the published literature report the presence of escitalopram and desmethylescitalopram in human milk (see Data) (see Clinical Considerations) Clinical Considerations Infants exposed to escitalopram oxalate should be monitored for excess sedation, restlessness, agitation, poor feeding and poor weight gain. Data A study of 8 nursing mothers on escitalopram with daily doses of 10 to 20 mg/day showed that exclusively breast-fed infants receive approximately 3. 9% of the maternal weight-adjusted dose of escitalopram and 1. 7% of the maternal weight-adjusted dose of desmethylcitalopram. Major Depressive Disorder The safety and effectiveness of escitalopram oxalate for the treatment of major depressive disorder have been established in pediatric patients 12 years of age and older. Use of escitalopram oxalate for this indication is supported by evidence from adequate and well-controlled studies in adults with additional evidence from an 8-week, flexible-dose, placebo-controlled study that compared escitalopram oxalate 10 mg to 20 mg once daily to placebo in pediatric patients 12 to 17 years of age with major depressive disorder [see Clinical Studies (14. 1) [see Adverse Reactions (6. 1) The safety and effectiveness of escitalopram oxalate for the treatment of major depressive disorder have not been established in pediatric patients younger than 12 years of age. In a 24-week, open- label safety study in 118 pediatric patient (aged 7 to 11 years) who had major depressive disorder, the safety findings were consistent with the known safety and tolerability profile for escitalopram oxalate. Generalized Anxiety Disorder The safety and effectiveness of escitalopram oxalate for the treatment of generalized anxiety disorder have not been established in pediatric patients younger than 7 years of age. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Warnings and Precautions (5. 1) 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 escitalopram oxalate. Juvenile Animal Toxicity Data In a juvenile animal study, male and female rats were administered escitalopram at 5, 40, or 80 mg/kg/day by oral gavage from postnatal day (PND) 21 to PND 69. A delay in sexual maturation was observed in both males and females at >= 40 mg/kg/day with a No Observed Adverse Effect Level (NOAEL) of 5 mg/kg/day. This NOAEL was associated with plasma AUC levels less than those measured at the maximum recommended dose (MRHD) in pediatrics (20 mg). However, there was no effect on reproductive function. Increased motor activity (both ambulatory and fine movements) was observed in females prior to daily dosing at >= 40 mg/kg/day (3. 5 times the MRHD based on AUC levels). A reversible disruption of learning and memory function was observed in males at 80 mg/kg/day with a NOAEL of 40 mg/kg/day, which was associated with an AUC level 3. 5 times those measured at the MRHD in pediatrics. There was no effect on learning and memory function in treated female rats. Additional pediatric use information is approved for AbbVie Inc. Approximately 69 patients (6%) of the 1,144 patients receiving escitalopram in controlled trials of escitalopram oxalate in major depressive disorder and GAD were 60 years of age or older [see Clinical Studies (14. 2) In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in subjects 65 years and older as compared to young subjects and C max [see Clinical Pharmacology (12. 3) [see Dosage and Administration (2. 5) SSRIs, including escitalopram oxalate, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [ see Warnings and Precautions (5. 6) Of 4,422 patients in clinical studies of racemic citalopram, 1,357 were 60 and over, 1,034 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 geriatric and younger patients, but again, greater sensitivity of some elderly individuals cannot be ruled out. Increased citalopram exposure occurs in patients with hepatic impairment [see Clinical Pharmacology (12. 5) Pharmacokinetics of escitalopram oxalate in patients with a creatinine clearance less than 20 mL/minute has not been evaluated. No dosage adjustment is necessary for patients with mild or moderate renal impairment [see Dosage and Administration (2. 5) Clinical Pharmacology (12.

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) 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 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.

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 oxalate overdosage ingestions due to the arrhythmia risk. Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a escitalopram oxalate overdose. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.
NONCLINICAL TOXICOLOGY
Carcinogenesis Mutagenesis in vitro in vitro in vitro in vitro/in vivo in vitro in vivo Impairment of Fertility Retinal Changes in Rats Cardiovascular Changes in Dogs.
CLINICAL STUDIES
Adults The efficacy of escitalopram oxalate 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 daily escitalopram oxalate and 20 mg daily escitalopram oxalate to placebo and 40 mg daily citalopram. The 10 mg daily and 20 mg daily escitalopram oxalate treatment groups showed statistically significant greater mean improvement compared to placebo on the MADRS. The 10 mg and 20 mg escitalopram oxalate groups were similar on this outcome measure. In a second fixed-dose study of 10 mg daily escitalopram oxalate and placebo, the 10 mg daily escitalopram oxalate treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS. In a flexible-dose study, comparing escitalopram oxalate, titrated between 10 mg and 20 mg daily, to placebo and citalopram, titrated between 20 mg and 40 mg daily, the escitalopram oxalate 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 escitalopram oxalate 10 mg or 20 mg daily, were randomized to continuation of escitalopram oxalate 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 escitalopram oxalate experienced a statistically significant longer time to relapse compared to those receiving placebo. Pediatric Patients 12 years of age and older The efficacy of escitalopram oxalate as a treatment for major depressive disorder in pediatric patients 12 to 17 years was established in an 8-week, flexible-dose, placebo-controlled study that compared escitalopram oxalate (10 mg to 20 mg daily) to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for major depressive disorder (MDD). The primary outcome was change from baseline to endpoint in the Children’s Depression Rating Scale - Revised (CDRS-R). In this study, escitalopram oxalate showed statistically significant greater mean improvement compared to placebo on the CDRS-R. The efficacy of escitalopram oxalate in the treatment of major depressive disorder in pediatric patients 12 to 17 years was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20 mg to 40 mg daily. In this outpatient study in pediatric patients 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 12 to 17 year subgroup. Two additional flexible-dose, placebo-controlled MDD studies (one escitalopram oxalate study in patients ages 7 to 17 years and one citalopram study patients 13 to 18 years) did not demonstrate efficacy. The safety and effectiveness of escitalopram oxalate have not been established in pediatric patients less than 12 years of age with MDD. Adults The efficacy of escitalopram oxalate in the treatment of generalized anxiety disorder (GAD) in adults was demonstrated in three, 8-week, multicenter, flexible-dose, placebo-controlled studies that compared escitalopram oxalate (10 mg to 20 mg daily) to placebo in outpatients between 18 and 80 years of age who met DSM-IV criteria for GAD. In all three studies, escitalopram oxalate 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 escitalopram oxalate has differential effects in these groups. There was no difference in response to escitalopram oxalate between men and women. Additional pediatric use information is approved for AbbVie Inc. ’s LEXAPRO (escitalopram) tablets. However, due to AbbVie Inc. ’s marketing exclusivity rights, this drug product is not labeled with that information.

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ESCITALOPRAM- escitalopram oxalate_tablet, film coated Product manual source documgent