ESCITALOPRAM OXALATE- escitalopram oxalate_solution

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. Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27-32 hours. 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. The tablet and the oral solution dosage forms of escitalopram oxalate are bioequivalent. Absorption and Distribution The binding of escitalopram to human plasma proteins is approximately 56%. Metabolism and Elimination 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 In vitro Population Subgroups Age Elderly max see Dosage and Administration ( 2. 3 Gender Reduced hepatic function see Dosage and Administration ( 2. 3 Reduced renal function Drug-Drug Interactions In vitro in vitro in vivo in vivo See Drug Interactions ( 7.

Escitalopram Oxalate is a selective serotonin reuptake inhibitor (SSRI) indicated for: 1. 2 Escitalopram Oxalate is indicated for the acute and maintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age [ see Clinical Studies ( 14. 1 A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. Escitalopram Oxalate is indicated for the acute treatment of Generalized Anxiety Disorder (GAD) in adults [ see Clinical Studies ( 14. 2 ) Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance.

Escitalopram Oxalate should be administered once daily, in the morning or evening, with or without food. 2 Indication Recommended Dose MDD ( 2. 1 Adolescents ( 2. 1 Initial: 10 mg once daily Adults ( 2. 1 Initial: 10 mg once daily GAD ( 2. 2 Adults ( 2. 2 Initial: 10 mg once daily No additional benefits seen at 20 mg/day dose ( 2. 4 Initial Treatment Adolescents The recommended dose of escitalopram oxalate is 10 mg once daily. A flexible-dose trial of escitalopram oxalate (10 to 20 mg/day) demonstrated the effectiveness of escitalopram oxalate [ see Clinical Studies 14. 1 Adults see Clinical Studies ( 14. 1 Maintenance Treatment see Clinical Studies ( 14. 1 Initial Treatment Adults The recommended starting dose of escitalopram oxalate is 10 mg once daily. If the dose is increased to 20 mg, this should occur after a minimum of one week. Maintenance Treatment 10 mg/day is the recommended dose for most elderly patients and patients with hepatic impairment. No dosage adjustment is necessary for patients with mild or moderate renal impairment. Escitalopram oxalate should be used with caution in patients with severe renal impairment. Symptoms associated with discontinuation of escitalopram oxalate 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 oxalate. Conversely, at least 14 days should be allowed after stopping escitalopram oxalate before starting an MAOI intended to treat psychiatric disorders [ see Contraindications ( 4. 1 Do not start escitalopram oxalate in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [ see Contraindications ( 4. 1 In some cases, a patient already receiving escitalopram oxalate therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, escitalopram oxalate should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with escitalopram oxalate may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [ see Warnings and Precautions ( 5. 2 The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with escitalopram oxalate is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [ see Warnings and Precautions ( 5.

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 Lannett Company, Inc. at 1-844-834-0530, or FDA at 1-800-FDA-1088 or www. 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 Pediatrics (6 -17 years) Adults Adverse events 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 events without first grouping similar types of events 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 events. 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. Adverse Events Associated with Discontinuation of Treatment Major Depressive Disorder Pediatrics (6 -17 years) Adults Generalized Anxiety Disorder Adults Incidence of Adverse Reactions in Placebo-Controlled Clinical Trials Major Depressive Disorder Pediatrics (6 -17 years) The overall profile of adverse reactions in pediatric patients 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. Adults Table 2 TABLE 2 Treatment-Emergent Adverse Reactions observed with a frequency of >= 2% and greater than placebo for Major Depressive Disorder 1 2 3 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% Generalized Anxiety Disorder Table 3 TABLE 3 Treatment-Emergent Adverse Reactions observed with a frequency of >= 2% and greater than placebo for Generalized Anxiety Disorder 1 2 3 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 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 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. 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 Weight Changes Laboratory Changes ECG Changes max max max Other Reactions Observed During the Premarketing Evaluation of Escitalopram Oxalate ADVERSE REACTIONS Tables 2 & 3 5 Adverse Reactions Reported Subsequent to the Marketing of Escitalopram Blood and Lymphatic System Disorders: anemia, agranulocytis, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia purpura, leukopenia, thrombocytopenia. 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: dyspnea, epistaxis, pulmonary embolism, pulmonary hypertension of the newborn. Skin and Subcutaneous Tissue Disorders: alopecia, angioedema, dermatitis, 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.

Serotonin Syndrome and MAOIs: Do not use MAOIs intended to treat psychiatric disorders with escitalopram oxalate or within 14 days of stopping treatment with escitalopram oxalate. Do not use escitalopram oxalate within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start escitalopram oxalate in a patient who is being treated with linezolid or intravenous methylene blue ( 4. 3 The use of MAOIs intended to treat psychiatric disorders with escitalopram oxalate or within 14 days of stopping treatment with escitalopram oxalate is contraindicated because of an increased risk of serotonin syndrome. The use of escitalopram oxalate within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated [ see Dosage and Administration ( 2. 2 Starting escitalopram oxalate 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. 2 Concomitant use in patients taking pimozide is contraindicated [ see Drug Interactions 7. 10 Escitalopram Oxalate is contraindicated in patients with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in Escitalopram Oxalate Oral Solution.

Pregnancy: Use only if the potential benefit justifies the potential risk to the fetus ( 8. 4 Pregnancy Category C 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 24 times the MRHD on a mg/m 2 2 In animal reproduction studies, racemic citalopram has been shown to have adverse effects on embryo/fetal and postnatal development, including teratogenic effects, when administered at doses greater than human therapeutic doses. 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. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day. 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. Thus, teratogenic 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, 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. The no-effect dose was 12. 8 mg/kg/day. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses >= 24 mg/kg/day. A no-effect dose was not determined in that study. There are no adequate and well-controlled studies in pregnant women; therefore, escitalopram should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Pregnancy-Non teratogenic Effects Neonates exposed to escitalopram oxalate and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the 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) Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 - 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including escitalopram oxalate) in pregnancy and PPHN. Other studies do not show a significant statistical association. Physicians should also note the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with escitalopram oxalate, the physician should carefully consider both the potential risks of taking an SSRl, along with the established benefits of treating depression with an antidepressant. This decision can only be made on a case by case basis [ see Dosage and Administration ( 2. 1 The effect of escitalopram oxalate on labor and delivery in humans is unknown. Escitalopram is excreted in human breast milk. Limited data from women taking 10-20 mg escitalopram 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. There were two reports of infants experiencing excessive somnolence, decreased feeding, and weight loss in association with breastfeeding from a racemic citalopram-treated mother; in one case, the infant was reported to recover completely upon discontinuation of racemic citalopram by its mother and, in the second case, no follow-up information was available. Caution should be exercised and breastfeeding infants should be observed for adverse reactions when escitalopram oxalate is administered to a nursing woman. The safety and effectiveness of escitalopram oxalate have been established in adolescents (12 to 17 years of age) for the treatment of major depressive disorder [ see Clinical Studies ( 14. 1 The safety and effectiveness of escitalopram oxalate have not been established in pediatric (younger than 12 years of age) patients with major depressive disorder. In a 24-week, open-label safety study in 118 children (aged 7 to 11 years) who had major depressive disorder, the safety findings were consistent with the known safety and tolerability profile for escitalopram oxalate. Safety and effectiveness of escitalopram oxalate has not been established in pediatric patients less than 18 years of age with Generalized Anxiety Disorder. Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as escitalopram oxalate. Approximately 6% of the 1144 patients receiving escitalopram in controlled trials of escitalopram oxalate in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of escitalopram oxalate between 10 and 20 mg. The number of elderly patients in these trials was insufficient to adequately assess for possible differential efficacy and safety measures on the basis of age. Nevertheless, greater sensitivity of some elderly individuals to effects of escitalopram oxalate cannot be ruled out. SSRIs and SNRIs, including escitalopram oxalate, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [ see Hyponatremia ( 5. 6 In two pharmacokinetic studies, escitalopram half-life was increased by approximately 50% in elderly subjects as compared to young subjects and C max see Clinical Pharmacology ( 12. 3 see Dosage and Administration ( 2. 3 Of 4422 patients in clinical studies of racemic citalopram, 1357 were 60 and over, 1034 were 65 and over, and 457 were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but again, greater sensitivity of some elderly individuals cannot be ruled out.

RECENT MAJOR CHANGES
Warnings and Precautions ( 5.2
DRUG INTERACTIONS
Concomitant use with SSRIs, SNRIs or Tryptophan is not recommended ( 7. 6 [ See Dosage and Administration ( 2. 2 [ See Dosage and Administration ( 2. 2 There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of escitalopram oxalate with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [ see Warnings and Precautions ( 5. 2 Given the primary CNS effects of escitalopram, caution should be used when it is taken in combination with other centrally acting drugs. Although 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. Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when escitalopram oxalate is initiated or discontinued. 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 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. Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of escitalopram, caution should be exercised when escitalopram oxalate and lithium are coadministered. In a controlled study, a single dose of pimozide 2 mg co-administered with racemic citalopram 40 mg given once daily for 11 days was associated with a mean increase in QTc values of approximately 10 msec compared to pimozide given alone. Racemic citalopram did not alter the mean AUC or C max There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e. , fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram) is clinically warranted, appropriate observation of the patient is advised. 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. Administration of 40 mg/day racemic citalopram for 21 days did not affect the pharmacokinetics of warfarin, a CYP3A4 substrate. Prothrombin time was increased by 5%, the clinical significance of which is unknown. Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered. 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. Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the C max 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. In vitro In vitro in vivo max Administration of 20 mg/day escitalopram oxalate for 21 days in healthy volunteers resulted in a 50% increase in C max There are no clinical studies of the combined use of ECT and escitalopram.

OVERDOSAGE
In clinical trials of escitalopram, there were reports of escitalopram overdose, including overdoses of up to 600 mg, with no associated fatalities. During the postmarketing evaluation of escitalopram, escitalopram oxalate overdoses involving overdoses of over 1000 mg have been reported. As with other SSRIs, a fatal outcome in a patient who has taken an overdose of escitalopram has been rarely reported. Symptoms most often accompanying escitalopram overdose, alone or in combination with other drugs and/or alcohol, included convulsions, coma, dizziness, hypotension, insomnia, nausea, vomiting, sinus tachycardia, somnolence, and ECG changes (including QT prolongation and very rare cases of torsade de pointes). Acute renal failure has been very rarely reported accompanying overdose. Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of escitalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for escitalopram oxalate. In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.
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 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.
CLINICAL STUDIES
Adolescents The efficacy of escitalopram oxalate in the acute treatment of major depressive disorder in adolescents was established, in part, on the basis of extrapolation from the 8-week, flexible-dose, placebo-controlled study with racemic citalopram 20-40 mg/day. In this outpatient study in children and adolescents 7 to 17 years of age who met DSM-IV criteria for major depressive disorder, citalopram treatment showed statistically significant greater mean improvement from baseline, compared to placebo, on the CDRS-R; the positive results for this trial largely came from the adolescent subgroup. Two additional flexible-dose, placebo-controlled MDD studies (one escitalopram oxalate study in patients ages 7 to 17 and one citalopram study in adolescents) did not demonstrate efficacy. Although maintenance efficacy in adolescent patients has not been systematically evaluated, maintenance efficacy can be extrapolated from adult data along with comparisons of escitalopram pharmacokinetic parameters in adults and adolescent patients. Adults A fixed-dose study compared 10 mg/day escitalopram oxalate and 20 mg/day escitalopram oxalate to placebo and 40 mg/day citalopram. The 10 mg/day and 20 mg/day 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/day escitalopram oxalate and placebo, the 10 mg/day 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 and 20 mg/day, to placebo and citalopram, titrated between 20 and 40 mg/day, the escitalopram oxalate treatment group showed statistically significant greater mean improvement compared to placebo on the MADRS. 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 or 20 mg/day, 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. The efficacy of escitalopram oxalate in the acute treatment of Generalized Anxiety Disorder (GAD) was demonstrated in three, 8-week, multicenter, flexible-dose, placebo-controlled studies that compared escitalopram oxalate 10-20 mg/day to placebo in adult outpatients between 18 and 80 years of age who met DSM-IV criteria for GAD. In all three studies, 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.
Medication Guide
Escitalopram Oxalate (ES-sye-TAL-oh-pram OX-a-late) Read the Medication Guide that comes with Escitalopram Oxalate Oral Solution before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about. What is the most important information I should know about Escitalopram Oxalate? Escitalopram Oxalate and other antidepressant medicines may cause serious side effects, including: 1. Suicidal thoughts or actions: Escitalopram Oxalate and other antidepressant medicines may increase suicidal thoughts or actions first few months of treatment or when the dose is changed. Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. Watch for these changes and call your healthcare provider right away if you notice: Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms. Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you: attempts to commit suicide acting on dangerous impulses acting aggressive or violent thoughts about suicide or dying new or worse depression new or worse anxiety or panic attacks feeling agitated, restless, angry or irritable trouble sleeping an increase in activity or talking more than what is normal for you other unusual changes in behavior or mood Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Escitalopram Oxalate may be associated with these serious side effects: 2. Serotonin Syndrome. This condition can be life-threatening and may include agitation, hallucinations, coma or other changes in mental status coordination problems or muscle twitching (overactive reflexes) racing heartbeat, high or low blood pressure sweating or fever nausea, vomiting, or diarrhea muscle rigidity 3. Severe allergic reactions: trouble breathing swelling of the face, tongue, eyes or mouth rash, itchy welts (hives) or blisters, alone or with fever or joint pain 4. Abnormal bleeding 5. Seizures or convulsions 6. Manic episodes: greatly increased energy severe trouble sleeping racing thoughts reckless behavior unusually grand ideas excessive happiness or irritability talking more or faster than usual 7. Changes in appetite or weight. 8. Low salt (sodium) levels in the blood. headache weakness or feeling unsteady confusion, problems concentrating or thinking or memory problems 9. Visual problems eye pain changes in vision swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Do not stop Escitalopram Oxalate without first talking to your healthcare provider anxiety, irritability, high or low mood, feeling restless or changes in sleep habits headache, sweating, nausea, dizziness electric shock-like sensations, shaking, confusion What is Escitalopram Oxalate? Major Depressive Disorder (MDD) Generalized Anxiety Disorder (GAD) Talk to your healthcare provider if you do not think that your condition is getting better with Escitalopram Oxalate treatment. Who should not take Escitalopram Oxalate? Do not take Escitalopram Oxalate if you: are allergic to escitalopram oxalate or citalopram hydrobromide or any of the ingredients in Escitalopram Oxalate Oral Solution. See the end of this Medication Guide for a complete list of ingredients in Escitalopram Oxalate Oral Solution. take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. Do not take an MAOI within 2 weeks of stopping escitalopram oxalate unless directed to do so by your physician. Do not start escitalopram oxalate if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. People who take Escitalopram Oxalate close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms: high fever uncontrolled muscle spasms stiff muscles rapid changes in heart rate or blood pressure confusion loss of consciousness (pass out) take the antipsychotic medicine pimozide (Orap ) because taking this drug with escitalopram oxalate can cause serious heart problems. What should I tell my healthcare provider before taking Escitalopram Oxalate? Ask if you are not sure. Before starting Escitalopram Oxalate, tell your healthcare provider if you: Are taking certain drugs such as: have liver problems have kidney problems have heart problems have or had seizures or convulsions have bipolar disorder or mania have low sodium levels in your blood have a history of a stroke have high blood pressure have or had bleeding problems are pregnant or plan to become pregnant. It is not known if escitalopram oxalate will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy are breast-feeding or plan to breast-feed. Some escitalopram oxalate may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking escitalopram oxalate. Tell your healthcare provider about all the that you take, Your healthcare provider or pharmacist can tell you if it is safe to take escitalopram oxalate with your other medicines. Do not start or stop any medicine while taking escitalopram oxalate without talking to your healthcare provider first. If you take escitalopram oxalate, you should not take any other medicines that contain escitalopram oxalate or citalopram hydrobromide including: Celexa. How should I take Escitalopram Oxalate? Take Escitalopram Oxalate Oral Solution exactly as prescribed. Your healthcare provider may need to change the dose of Escitalopram Oxalate Oral Solution until it is the right dose for you. Escitalopram Oxalate Oral Solution may be taken with or without food. If you miss a dose of Escitalopram Oxalate Oral Solution, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of Escitalopram Oxalate Oral Solution at the same time. If you take too much Escitalopram Oxalate Oral Solution, call your healthcare provider or poison control center right away, or get emergency treatment. What should I avoid while taking Escitalopram Oxalate? What are the possible side effects of Escitalopram Oxalate? Escitalopram Oxalate may cause serious side effects, including all Common possible side effects in people who take escitalopram oxalate include : Nausea Sleepiness Weakness Dizziness Feeling anxious Trouble sleeping Sexual problems Sweating Shaking Not feeling hungry Dry mouth Constipation Infection Yawning Other side effects in children and adolescents include: increased thirst abnormal increase in muscle movement or agitation nose bleed difficult urination heavy menstrual periods possible slowed growth rate and weight change. Your child’s height and weight should be monitored during treatment with escitalopram oxalate. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of escitalopram oxalate. For more information, ask your healthcare provider or pharmacist. CALL YOUR DOCTOR FOR MEDICAL ADVICE ABOUT SIDE EFFECTS. YOU MAY REPORT SIDE EFFECTS TO THE FDA AT 1-800-FDA-1088. Store Escitalopram Oxalate Oral Solution at 25°C (77°F); excursions permitted to 15 - 30°C (59-86°F). Keep Escitalopram Oxalate Oral Solution bottle closed tightly. Keep Escitalopram Oxalate Oral Solution and all medicines out of the reach of children. For more information about Escitalopram Oxalate Oral Solution call 1-844-834-0530. What are the ingredients in Escitalopram Oxalate Oral Solution? Oral Solution: This Medication Guide has been approved by the U.S. Food and Drug Administration. Trademarks are the property of their respective owners.

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