Escitalopram Oxalate

Indications ( 1 ) 5/2023 Dosage and Administration ( 2.2 , 2.3 , 2.5 ) 5/2023 Dosage and Administration, Use of Escitalopram with Other MAOIs such as Linezolid or Methylene Blue ( 2.7 ) - Removed 5/2023 Warnings and Precautions ( 5.2 , 5.7 ) 8/2023

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

2 DOSAGE AND ADMINISTRATION Indication and Population Recommended Dosage MDD in Adults ( 2.1 ) Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily MDD in Pediatric Patients 12 years and older (2.1) Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily GAD in Adults ( 2.2 ) Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily GAD in Pediatric Patients 7 years and older ( 2.2 ) Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily No additional benefits were seen at 20 mg once daily ( 2.1 ) Administer once daily, morning or evening, with or without food ( 2.3 ) Elderly patients: recommended dosage is 10 mg once daily ( 2.4 ) Hepatic impairment: recommended dosage is 10 mg once daily ( 2.4 , 8.6 ) When discontinuing escitalopram oral solution, reduce dose gradually whenever possible ( 2.5 ) 2.1 Major Depressive Disorder Adults The recommended dosage of escitalopram oral solution in adults is 10 mg once daily. A fixed-dose trial of escitalopram oral solution demonstrated the effectiveness of both 10 mg and 20 mg of escitalopram oral solution, but failed to demonstrate a greater benefit of 20 mg over 10 mg [see Clinical Studies (14.1) ]. Depending on clinical response and tolerability, dosage may be increased to the maximum recommended dosage of 20 mg once daily at an interval of no less than 1 week. Pediatric Patients 12 years of age and older The recommended dosage of escitalopram oral solution in pediatric patients 12 years of age and older is 10 mg once daily. Depending on clinical response and tolerability, dosage may be increased to the maximum recommended dosage of 20 mg once daily at an interval of no less than 3 weeks. 2.2 Generalized Anxiety Disorder Adults The recommended starting dosage of escitalopram oral solution in adults is 10 mg once daily. Depending on clinical response and tolerability, dosage may be increased to the maximum recommended dosage of 20 mg once daily at an interval of no less than 1 week. Pediatric Patients 7 years of age and older The recommended starting dosage of escitalopram oral solution for pediatric patients ages 7 years of age and older is 10 mg once daily. Depending on clinical response and tolerability, dosage may be increased to the maximum recommended dosage of 20 mg once daily at an interval of no less than 2 weeks. 2.3 Administration Information Administer escitalopram oral solution orally once daily, in the morning or evening, with or without food. 2.4 Screen for Bipolar Disorder Prior to Starting Escitalopram Oral Solution Prior to initiating treatment with escitalopram oral solution or another antidepressant, screen patients for a personal family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.5) ]. 2.5 Recommended Dosage for Specific Populations The recommended dosage for most elderly patients and patients with hepatic impairment is 10 mg once daily [see Use in Specific Populations (8.5 , 8.6) ] . The recommended dosage for escitalopram oral solution in adults with a creatinine clearance less than 20 mL/minute has not been determined. No dosage adjustment is necessary for patients with mild or moderate renal impairment [see Use in Specific Populations (8.7) ] . 2.6 Discontinuation of Treatment with Escitalopram Oral Solution Symptoms associated with discontinuation of escitalopram oral solution and other SSRIs and SNRIs have been reported [see Warnings and Precautions (5.3) ] . Patients should be monitored for these symptoms when discontinuing treatment. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate. 2.7 Switching Patients to or from a Mon …

3 DOSAGE FORMS AND STRENGTHS Oral Solution Escitalopram Oral Solution, USP, contains escitalopram oxalate, USP equivalent to 1 mg/mL escitalopram base. • Oral solution: 1 mg per mL

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

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Suicidal thoughts and behaviors in adolescents and young adults [see Warnings and Precautions (5.1) ] Serotonin syndrome [see Warnings and Precautions (5.2) ] Discontinuation syndrome [see Warnings and Precautions (5.3) ] Seizures [ see Warnings and Precautions (5.4) ] Activation of mania or hypomania [see Warnings and Precautions (5.5) ] Hyponatremia [see Warnings and Precautions (5.6) ] Increased Risk of Bleeding [see Warnings and Precautions (5.7) ] Interference with Cognitive and Motor Performance [see Warnings and Precautions (5.8) ] Angle-closure glaucoma [see Warnings and Precautions (5.9) ] Use in Patients with Concomitant Illness [see Warnings and Precautions (5.10) ] Sexual Dysfunction [see Warnings and Precautions (5.11) ] Most commonly observed adverse reactions (incidence ≥ 5% and at least twice the incidence of placebo patients) are: insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue and somnolence, decreased libido, and anorgasmia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Clinical Trial Data Sources Adults Adverse reactions information for escitalopram oral solution 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 oral solution 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 oral solution, 290 placebo) with major depressive disorder and in 273 pediatric patients 7 to 17 years of age (137 escitalopram oral solution, 136 placebo) with generalized anxiety disorder. The safety and effectiveness of escitalopram oral solution 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 oral solution 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 rea …

7 DRUG INTERACTIONS Table 6 presents clinically important drug interactions with escitalopram oral solution. TABLE 6 Clinically Important Drug Interactions with Escitalopram Oral Solution Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact: Concomitant use of SSRIs, including escitalopram oral solution, and MAOIs increases the risk of serotonin syndrome. Intervention: Escitalopram oral solution is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.7) , Contraindications (4) , and Warnings and Precautions (5.2) ] . Pimozide Clinical Impact: Concomitant use of racemic citalopram with pimozide increases plasma concentrations of pimozide, a drug with a narrow therapeutic index, and may increase the risk of QT prolongation and/or ventricular arrhythmias compared to use of racemic citalopram alone [see Clinical Pharmacology (12.3) ]. Intervention: Escitalopram oral solution is contraindicated in patients taking pimozide [see Contraindications (4) ]. Other Serotonergic Drugs Clinical Impact: Concomitant use of escitalopram oral solution 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 oral solution initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of escitalopram oral solution 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 oral solution 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 oral solution and antiplatelet agents and anticoagulants. For patients taking warfarin, carefully monitor the international normalized ratio [see Warning and Precautions (5.7) ] . Sumatriptan Clinical Impact: There have been postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. Intervention: If concomitant treatment with sumatriptan and an SSRI is clinically warranted, appropriate observation of the patient is advised [see Warning and Precautions (5.2) ] . Carbamazepine Clinical Impact: Combined administration of racemic citalopram (40 mg/day for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Intervention: Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two drugs are coadministered. Drugs Metabolized by CYP2D6 Clinical Impact: Coadministration of escitalopram (20 mg/day for 21 days) with the tricyclic antidepressant desipramine (single dose of 50 mg), a substrate for CYP2D6, resulted in a 40% increase in C max and a 100% increase in AUC of desipramine. Intervention: The clinical significance of this finding is unknown. Exercise caution during coadministration of escitalopram and drugs metabolized by CYP2D6. Concomitant use with SSRIs, SNRIs or Tryptophan is not recommended ( 7 ) Use caution when concomitant use with drugs that affect Hemostasis (NSAIDs, Aspirin, Warfarin) ( 7 )

8 USE IN SPECIFIC POPULATIONS 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 ) 8.1 Pregnancy 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 advise patients to register by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/research/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) and Clinical Considerations]. Available data from published epidemiologic studies and postmarketing reports have not established an increased risk of major birth defects or miscarriage. There are risks of persistent pulmonary hypertension of the newborn (PPHN) (see Data) and poor neonatal adaptation (see Clinical Considerations) with exposure to selective serotonin reuptake inhibitors (SSRIs), including escitalopram oral solution, during pregnancy. There are risks associated with untreated depression in pregnancy (see Clinical Considerations). In animal reproduction studies, both escitalopram and racemic citalopram have been shown to have adverse effects on embryo/fetal and postnatal development, including fetal structural abnormalities, when administered at doses greater than human therapeutic doses (see Data) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal risk and/or embryo/fetal risk Women who discontinue antidepressants are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective longitudinal study of 201 pregnant women with a history of major depression, who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Maternal Adverse Reactions Use of escitalopram oral solution 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 oral solution, 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 …

12.1 Mechanism of Action The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT).

11 DESCRIPTION Escitalopram oral solution, USP contains escitalopram oxalate USP, a selective serotonin reuptake inhibitor (SSRI), present as escitalopram oxalate salt. Escitalopram is the pure S-enantiomer (single isomer) of the racemic bicyclic phthalane derivative citalopram. Escitalopram oxalate, USP is designated S-(+)-1-[3(dimethyl-amino)propyl]-1-( p -fluorophenyl)-5-phthalancarbonitrile oxalate with the following structural formula: The molecular formula is C 20 H 21 FN 2 O • C 2 H 2 O 4 and the molecular weight is 414.40. Escitalopram oxalate, USP occurs as a fine, white to slightly-yellow color powder and is freely soluble in methanol and in dimethyl sulfoxide, sparingly soluble in water and in alcohol, very slightly soluble in ethyl acetate and in isopropyl alcohol, insoluble in heptane. Escitalopram oral solution, USP contains 1.29 mg/mL escitalopram oxalate, USP equivalent to 1 mg/mL escitalopram base. It also contains the following inactive ingredients: anhydrous citric acid, glycerin, malic acid, methylparaben, natural peppermint flavor, non-crystallizing sorbital solution, propylene glycol, propylparaben, purified water and sodium citrate dihydrate. FDA approved pH and organic impurities specification differs from the USP pH and organic impurities specification. escitalopraosstructure

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

16 HOW SUPPLIED/STORAGE AND HANDLING Oral Solution Escitalopram oral solution, USP, equivalent 5 mg base/5 mL , is a clear colorless to pale yellow, peppermint flavored solution, available as 240 mL; NDC 65162-705-88. Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].