Escitalopram (Page 8 of 10)

13.2 Animal Toxicology and/or Pharmacology

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.

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

Adolescents

The efficacy of escitalopram oxalate as an acute treatment for major depressive disorder in adolescent patients was established in an 8-week, flexible-dose, placebo-controlled study that compared escitalopram oxalate 10 to 20 mg/day to placebo in outpatients 12 to 17 years of age inclusive who met DSM-IV criteria for major depressive disorder. The primary outcome was change from baseline to endpoint in the Children’s Depression Rating Scale — Revised (CDRS-R). In this study, escitalopram oxalate showed statistically significant greater mean improvement compared to placebo on the CDRS-R.

The efficacy of escitalopram oxalate in the 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 to 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

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/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.

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 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.

14.2 Generalized Anxiety Disorder

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 to 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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Tablets

10 mg Tablets:

Bottle of 30’s count with child-resistant closure NDC 51655-449-52

Storage and Handling
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors

Advise patients, their families and caregivers to look for the emergence of suicidal ideation and behavior, especially during treatment and when the dose is adjusted up or down, and instruct them to report such symptoms to their healthcare provider [ see Boxed Warning and Warnings and Precautions ( 5.1) ].

Serotonin Syndrome

Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of escitalopram oxalate with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines and St. John’s Wort, and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid) [ see Warnings and Precautions ( 5.2) ].

Activation of Mania or Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [ see Warnings and Precautions ( 5.5) ].

Abnormal Bleeding

Patients should be cautioned about the concomitant use of escitalopram oxalate and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [ see Warnings and Precautions ( 5.7) ].

Angle Closure Glaucoma

Patients should be advised that taking escitalopram oxalate can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [ see Warnings and Precautions ( 5.9) ].

Concomitant Medications

Since escitalopram is the active isomer of racemic citalopram (Celexa), the two agents should not be coadministered. Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions.

Continuing the Therapy Prescribed

While patients may notice improvement with escitalopram oxalate therapy in 1 to 4 weeks, they should be advised to continue therapy as directed.

Interference with Psychomotor Performance

Because psychoactive drugs may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram oxalate therapy does not affect their ability to engage in such activities.

Alcohol

Patients should be told that, although escitalopram oxalate has not been shown in experiments with normal subjects to increase the mental and motor skill impairments caused by alcohol, the concomitant use of escitalopram oxalate and alcohol in depressed patients is not advised.

Pregnancy

Advise pregnant women to notify their healthcare providers if they become pregnant or intend to become pregnant during treatment with escitalopram oxalate.

Advise patients that escitalopram oxalate use later in pregnancy may lead to increased risk for neonatal complications requiring prolonged hospitalization, respiratory support, tube feeding, and/or persistent pulmonary hypertension (PPHN) of the newborn [see Use in Specific Populations ( 8.1)].

Advise women that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to escitalopram oxalate during pregnancy [see Use in Specific Populations ( 8.1)].

Lactation

Advise breastfeeding women using escitalopram oxalate to monitor infants for excess sedation, restlessness, agitation, poor feeding and poor weight gain and to seek medical care if they notice these signs [see Use in Specific Populations ( 8.2)].

Need for Comprehensive Treatment Program

Escitalopram oxalate is indicated as an integral part of a total treatment program for MDD that may include other measures (psychological, educational, social) for patients with this syndrome. Drug treatment may not be indicated for all adolescents with this syndrome. Safety and effectiveness of escitalopram oxalate in MDD has not been established in pediatric patients less than 12 years of age. Antidepressants are not intended for use in the adolescent who exhibits symptoms secondary to environmental factors and/or other primary psychiatric disorders. Appropriate educational placement is essential and psychosocial intervention is often helpful. When remedial measures alone are insufficient, the decision to prescribe antidepressant medication will depend upon the physician’s assessment of the chronicity and severity of the patient’s symptoms.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured For:
Accord Healthcare, Inc.,
1009 Slater Road,
Suite 210-B,
Durham, NC 27703,
USA.

Manufactured By:
Intas Pharmaceuticals Limited,
Ahmedabad -380054, India.

10 0653 4 6004258

Issued December 2020

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