ESCITALOPRAM- escitalopram_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 to 5 1 to t3 1 to 5 + + - ++ The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day. 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 Sdemethylcitalopram (S-DCT) is about 8% and 10%, respectively. Specific Populations Pediatric Patients Pediatric patients 12 to 17 years of age: In a single dose study of 10 mg escitalopram, AUC of escitalopram decreased by 19%, and C max max [see Use in Specific Populations ( 8. 4 Geriatric Patients max see Dosage and Administration (2. 5 Male and Female Patients Patients with Hepatic Impairment see Dosage and Administration (2. 6 Patients with Renal Impairment [see Use in Specific Populations ( 8. 7 Drug Interaction Studies In vitro in vitro in vivo in vivo [seeDrug 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 Cmax and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram. Ritonavir Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram. 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 and LEXAPRO (escitalopram) oral solution. 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: Error! Hyperlink reference not valid. Error! Hyperlink reference not valid. Escitalopram tablet is indicated for the treatment of: 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.

Indication and Population Recommended Dosage MDD in Adults ( 2. 1 Initial: 10 mg once daily MDD in Pediatric Patients 12 years and older ( 2. 1 Initial: 10 mg once daily GAD in Adults ( 2. 2 Initial: 10 mg once daily 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 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. 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. 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. 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. 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.

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 Accord Healthcare Inc. at 1-866-941-7875 or FDA at 1-800-FDA-1088 orwww. gov/medwatch. The following adverse reactions are discussed in greater detail in other sections of the labeling: [see Warnings and Precautions ( 5. 1 [see Warnings and Precautions ( 5. 2 [see Warnings and Precautions ( 5. 3 [see Warnings and Precautions ( 5. 4 [see Warnings and Precautions ( 5. 5 [see Warnings and Precautions ( 5. 6 [see Warnings and Precautions ( 5. 7 [see Warnings and Precautions ( 5. 8 [see Warnings and Precautions ( 5. 9 [see Warnings and Precautions ( 5. 10 [see Warnings and Precautions ( 5. 11 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. Pediatric Patients 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 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). 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. 1 2 3 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% 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. 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. 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. 1 2 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% 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%). 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 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 2 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 2 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 Cmax for the dose of 20 mg is 6. Escitalopram 30 mg given once daily resulted in mean Cmax of 1. 7-fold higher than the mean Cmax 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 5 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 and LEXAPRO (escitalopram) oral solution. 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 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.

Error! Hyperlink reference not valid. 4 4 Escitalopram tablet is contraindicated in patients: [see Dosage and Administration (2. 2) [see Drug Interactions (7) .

1 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. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth. org/clnical-and-research-programs/pregnancyregistry/antidepressants/ Risk Summary 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 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). 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. 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 2 2 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 2 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 2 2 When female rats were treated with racemic citalopram (4. 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 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 Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Warnings and Precautions ( 5. 1 Juvenile Animal Toxicity Data 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 Cmax was unchanged [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.

7 7 Table 6 presents clinically important drug interactions with escitalopram oxalate. TABLE 2 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. 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 Cmax 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.

OVERDOSAGE
The following have been reported with escitalopram oxalate tablet overdosage: 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 Racemic citalopram was administered in the diet to NMRI/BOM strain mice and COBS WI strain rats for 18 and 24 months, respectively. There was no evidence for carcinogenicity of racemic citalopram in mice receiving up to 240 mg/kg/day. There was an increased incidence of small intestine carcinoma in rats receiving 8 or 24 mg/kg/day racemic citalopram. A no-effect dose for this finding was not established. The relevance of these findings to humans is unknown. Mutagenesis Racemic citalopram was mutagenic in the in vitro in vitro in vitro in vitro/in vivo in vitro in vivo Impairment of Fertility When racemic citalopram was administered orally to 16 male and 24 female rats prior to and throughout mating and gestation at doses of 32, 48, and 72 mg/kg/day, mating was decreased at all doses, and fertility was decreased at doses >= 32 mg/kg/day. Gestation duration was increased at 48 mg/kg/day. Retinal Changes in Rats Pathologic changes (degeneration/atrophy) were observed in the retinas of albino rats in the 2-year carcinogenicity study with racemic citalopram. There was an increase in both incidence and severity of retinal pathology in both male and female rats receiving 80 mg/kg/day. Similar findings were not present in rats receiving 24 mg/kg/day of racemic citalopram for two years, in mice receiving up to 240 mg/kg/day of racemic citalopram for 18 months, or in dogs receiving up to 20 mg/kg/day of racemic citalopram for one year. Additional studies to investigate the mechanism for this pathology have not been performed, and the potential significance of this effect in humans has not been established. Cardiovascular Changes in Dogs In a one-year toxicology study, 5 of 10 beagle dogs receiving oral racemic citalopram doses of 8 mg/kg/day died suddenly between weeks 17 and 31 following initiation of treatment. Sudden deaths were not observed in rats at doses of racemic citalopram up to 120 mg/kg/day, which produced plasma levels of citalopram and its metabolites demethylcitalopram and didemethylcitalopram (DDCT) similar to those observed in dogs at 8 mg/kg/day. A subsequent intravenous dosing study demonstrated that in beagle dogs, racemic DDCT caused QT prolongation, a known risk factor for the observed outcome in dogs.
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. 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 and LEXAPRO (escitalopram) oral solution. However, due to AbbVie Inc. ’s marketing exclusivity rights, this drug product is not labeled with that information.

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