S-CITADEP Tablets

S-CITADEP Tablets (Escitalopram)

Table of Content

BLACK BOX WARNING
Qualitative and Quantitative Composition
Dosage Form(s) and Strength(s)
Clinical Particulars
Pharmacological Properties
Non-Clinical Properties
Description
Pharmaceutical Particulars
Patient Counselling Information
Details of Manufacturer
Details of Permission or Licence Number with Date
Date of Revision

Prescribing Information
Related Resources

For the use of a Psychiatrist/Neurologist attached to a Hospital/Institution or a Nursing Home only

BLACK BOX WARNING

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS

Antidepressant drugs increased the risk, compared to placebo, of suicidal thinking and behaviour (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of escitalopram or any other antidepressant in a child, adolescent or young adult must balance this risk with the clinical need. Short-term studies did not show as increase in the risk of suicidality with antidepressants, compared to placebo, in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 years and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality or unusual changes in behaviour. Families and caregivers should be advised about the need for close observation and communication with the prescriber. Escitalopram is not approved for use in paediatric patients less than 12 years of age.

Qualitative and Quantitative Composition

S-CITADEP 5 Tablets

Each film-coated tablet contains:

Escitalopram oxalate equivalent to Escitalopram ……… 5 mg

S-CITADEP 10 Tablets

Each film-coated tablet contains:

Escitalopram oxalate equivalent to Escitalopram ……. 10 mg

S-CITADEP 20 Tablets

Each film-coated tablet contains:

Escitalopram oxalate equivalent to Escitalopram ……. 20 mg

Dosage Form(s) and Strength(s)

Film-coated tablet containing Escitalopram oxalate 5 mg, 10 mg and 20 mg.

Clinical Particulars

Therapeutic Indications

Major Depressive Disorder

S-CITADEP Tablets are indicated for the acute and maintenance treatment of major depressive disorder in adults and in adolescents, 12 to 17 years of age.

Panic Disorder with or without Agoraphobia

S-CITADEP Tablets are indicated for the treatment of panic disorder, with or without agoraphobia.

Posology and Method of Administration

Major Depressive Disorder

Initial Treatment

Adolescents

The recommended dose of S-CITADEP Tablets is 10 mg once daily. A flexible-dose trial of S-CITADEP Tablets (10 to 20 mg/day) demonstrated the effectiveness of S-CITADEP. If the dose is increased to 20 mg, this should occur after a minimum of three weeks.

Adult

The recommended dose of S-CITADEP is 10 mg once daily. A fixed-dose trial of S-CITADEP demonstrated the effectiveness of both 10 mg and 20 mg of S-CITADEP, but failed to demonstrate a greater benefit of 20 mg over 10 mg. If the dose is increased to 20 mg, this should occur after a minimum of one week.

Maintenance Treatment

It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of continuing escitalopram 10 or 20 mg/day in adults patients with major depressive disorder who responded while taking escitalopram during an 8-week, acute-treatment phase demonstrated a benefit of such maintenance treatment. Nevertheless, the physician who elects to use S-CITADEP Tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Patients should be periodically reassessed to determine the need for maintenance treatment.

Screen for Bipolar Disorder Prior to Starting Escitalopram

Prior to initiating treatment with escitalopram or another antidepressant, screen patients for a personal family history of bipolar disorder, mania, or hypomania

Discontinuation of Treatment with Escitalopram

Symptoms associated with discontinuation of S-CITADEP Tablets and other SSRIs and selective norepinephrine reuptake inhibitors (SNRIs) have been reported. 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.

Switching Patients to or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of S-CITADEP Tablets therapy. Similarly, at least 14 days should be allowed after stopping S-CITADEP Tablets before starting a MAOI intended to treat psychiatric disorders.

Use of S-CITADEP Tablets with Other MAOIs such as Linezolid or Methylene Blue

Do not start S-CITADEP Tablets 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.

In some cases, a patient already receiving S-CITADEP Tablets 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, S-CITADEP Tablets 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 S-CITADEP Tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

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 is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use

Special Populations

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 should be used with caution in patients with severe renal impairment.

Contraindications

Monoamine Oxidase Inhibitors (MAOIs)

The use of MAOIs intended to treat psychiatric disorders with S-CITADEP Tablets or within 14 days of stopping treatment with S-CITADEP Tablets is contraindicated because of an increased risk of serotonin syndrome. The use of S-CITADEP Tablets within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Starting Escitalopram 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.

Pimozide

Concomitant use in patients taking pimozide is contraindicated

Hypersensitivity to escitalopram or citalopram

Hypersensitivity to escitalopram or citalopram or any of the inactive ingredients

Special Warnings and Precautions for Use

General

Suicidal Thoughts and Behaviors in Adolescents and Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in the antidepressant-treated patients age 24 years and younger was greater than in placebo treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most all drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.

Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

Age Range	Drug-Placebo Difference in Number of Patients of Suicidal Thoughts and Behaviors per 1000 Patients Treated
	Increases Compared to Placebo
<18 years old	14 additional patients
18 to 24 years old	5 additional patients
	Decreases Compared to Placebo
25 to 64 years old	1 fewer patient
≥65 years old	6 fewer patient

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Escitalopram, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including escitalopram treatment, but particularly with concomitant use of serotonergic drugs (including triptans tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort) and with drugs which impair the metabolism of serotonin ( in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue)

Serotonin syndrome symptoms may include mental status changes (e.g. agitation, hallucinations, and coma), autonomic instability (e.g. tachycardia, labile blood pressure, and hyperthermia), neuromuscular aberrations (e.g. hyper-reflexia, incoordination) and/or gastrointestinal symptoms (e.g. nausea, vomiting, diarrhoea). Serotonin syndrome, in its most severe form, can resemble NMS, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

The concomitant use of escitalopram with MAOIs intended to treat depression is contraindicated. Escitalopram should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking escitalopram. Escitalopram should be discontinued before initiating treatment with the MAOI.

If concomitant treatment of escitalopram with other serotonergic drugs including, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with escitalopram and any concomitant serotonergic or anti-dopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Seizures

Although anticonvulsant effects of racemic citalopram have been observed in animal studies, escitalopram has not been systematically evaluated in patients with a seizure disorder. These patients were excluded from clinical studies during the product's premarketing testing. In clinical trials of Escitalopram, cases of convulsion have been reported in association with escitalopram treatment. Like other drugs effective in the treatment of major depressive disorder, escitalopram should be introduced with care in patients with a history of seizure disorder.

Hyponatraemia

Hyponatraemia may occur as a result of treatment with SSRIs and SNRIs, including escitalopram. In many cases, this hyponatraemia appears to be the result of the syndrome of inappropriate anti-diuretic hormone secretion (SIADH), and was reversible when escitalopram was discontinued. Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients and patients suffering from cirrhosis may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk. Discontinuation of escitalopram should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest and death.

Abnormal Bleeding

SSRIs and SNRIs, including escitalopram, may increase the risk of bleeding events. Concomitant use of aspirin, NSAIDs, warfarin and other anticoagulants, with medicinal products may add to the risk.. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, purpura, haematomas, epistaxis and petechiae to life-threatening haemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of escitalopram and NSAIDs, aspirin or other drugs that affect coagulation.

Interference with Cognitive and Motor Performance

In a study in normal volunteers, escitalopram 10 mg/day did not produce impairment of intellectual function or psychomotor performance. however, because any psychoactive drug may impair judgment, thinking or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that escitalopram therapy does not affect their ability to engage in such activities.

Angle Closure Glaucoma

Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including Escitalopram may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Discontinuation of Treatment with Escitalopram

During marketing of Escitalopram and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania. While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with Escitalopram. 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.

Activation of Mania or Hypomania

In patients with bipolar disorder, treating a depressive episode with Escitalopram or another antidepressant may precipitate a mixed/manic episode. In placebo-controlled trials of Escitalopram in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with Escitalopram and in none of the 592 patients treated with placebo. One additional case of hypomania has been reported in association with Escitalopram treatment. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorders treated with racemic citalopram and other marketed drugs effective in the treatment of major depressive disorder. Prior to initiating treatment with Escitalopram, screen patients for any personal or family history of bipolar disorder, mania, or hypomania

Use in Patients with Concomitant Illness

Clinical experience with Escitalopram in patients with certain concomitant systemic illnesses is limited. Caution is advisable in using Escitalopram in patients with diseases or conditions that produce altered metabolism or hemodynamic responses.

Escitalopram has not been systematically evaluated in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were generally excluded from clinical studies during the product's premarketing testing.

In subjects with hepatic impairment, clearance of racemic citalopram was decreased and plasma concentrations were increased. The recommended dose of Escitalopram in hepatically impaired patients is 10 mg/day.

Because escitalopram is extensively metabolized, excretion of unchanged drug in urine is a minor route of elimination. Until adequate numbers of patients with severe renal impairment have been evaluated during chronic treatment with Escitalopram, however, it should be used with caution in such patients.

Drug Interactions

Serotonergic Drugs and Monoamine Oxidase Inhibitors (MAOIs)

Symptoms associated with discontinuation of Escitalopram and other SSRIs and SNRIs have been reported. 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.

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with Escitalopram. Conversely, at least 14 days should be allowed after stopping Escitalopram before starting an MAOI intended to treat psychiatric disorders.

The use of MAOIs intended to treat psychiatric disorders with Escitalopram or within 14 days of stopping treatment with Escitalopram is contraindicated because of an increased risk of serotonin syndrome. The use of Escitalopram within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated.

Triptans

There have been rare post marketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of escitalopram with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases.

CNS Drugs

Given the primary CNS effects of escitalopram, caution should be used when escitalopram is taken in combination with other centrally-acting drugs.

Alcohol

Although escitalopram 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 is not recommended.

Drugs that Interfere with Haemostasis (NSAIDs, Aspirin, Warfarin, etc.)

Serotonin release by platelets plays an important role in haemostasis. 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 a non-steroidal anti-inflammatory drug (NSAID) or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are co-administered with warfarin. Patients receiving warfarin therapy should be carefully monitored when escitalopram is initiated or discontinued.

Cimetidine

In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg/day cimetidine for 8 days resulted in an increase in the citalopram AUC and C_max of 43% and 39%, respectively. The clinical significance of these findings is unknown.

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

Co-administration 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 and lithium is co-administered.

Pimozide and Citalopram

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 of pimozide. The mechanism of this pharmacodynamic interaction is not known.

Sumatriptan

There have been rare post marketing reports describing patients with weakness, hyper-reflexia and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.g. fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram) is clinically warranted, appropriate observation of the patient is advised.

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.

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 which is unknown.

Carbamazepine

Combined administration of racemic citalopram 40 mg/day and carbamazepine (titrated to 400 mg/day) 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 co-administered.

Triazolam

Combined administration of racemic citalopram (titrated to 40 mg/day) and the CYP3A4 substrate, triazolam (single dose of 0.25 mg), did not significantly affect the pharmacokinetics of either citalopram or triazolam.

Ketoconazole

Combined administration of racemic citalopram 40 mg and ketoconazole 200 mg, a potent CYP3A4 inhibitor, decreased the C_max 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 ritonavir or escitalopram.

CYP3A4 and CYP2C19 Inhibitors

In vitro studies indicated that CYP3A4 and CYP2C19 are the primary enzymes involved in the metabolism of escitalopram. However, co-administration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4 and CYP2C19, 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.

In vitro enzyme inhibition data did not reveal an inhibitory effect of escitalopram on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, escitalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. While in vivo data to address this question are limited, results from drug interaction studies suggest that escitalopram, at a dose of 20 mg, has no 3A4 inhibitory effect and a modest 2D6 inhibitory effect.

Drugs Metabolized by CYP4502D6

In vitro studies did not reveal an inhibitory effect of escitalopram on CYP2D6. In addition, steady state levels of racemic citalopram were not significantly different in poor metabolizers and extensive CYP2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with escitalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on escitalopram metabolism. However, there are limited in vivo data suggesting a modest CYP2D6 inhibitory effect for escitalopram, i.e., 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. The clinical significance of this finding is unknown. Nevertheless, caution is indicated in the coadministration of escitalopram and drugs metabolized by CYP2D6.

Metoprolol

Administration of 20 mg/day escitalopram for 21 days in healthy volunteers resulted in a 50% increase in the C_max and 82% increase in the AUC of the beta-adrenergic blocker, metoprolol (given in a single dose of 100 mg). Increased metoprolol plasma levels have been associated with decreased cardioselectivity. Co-administration of escitalopram and metoprolol had no clinically significant effects on the blood pressure or heart rate.

Electroconvulsive Therapy (ECT)

There are no clinical studies of the combined use of ECT and escitalopram

Use in Special Population

Patients with Renal Impairment

Escitalopram is extensively metabolized; excretion of unchanged drug in urine is a minor route of elimination. In patients with severe renal impairment, treatment with escitalopram should be done with caution.

Patients with Hepatic Impairment

In patients with mild-to-moderate renal function impairment, oral clearance of escitalopram was reduced by 17%. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of escitalopram in patients with severely reduced renal function (creatinine clearance <20 mL/min).

Pregnant Women

Risk Summary

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) and poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including ESCITALOPRAM, during pregnancy. There are risks associated with untreated depression in pregnancy.

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.

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.

Fetal/Neonatal adverse reactions

Neonates exposed to escitalopram and other SSRIs or 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, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycaemia, hypotonia, hypertonia, hyper-reflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of the SSRIs and SNRIs or, possibly, a drug-discontinuation syndrome.

Data

Human Data

Exposure to SSRIs, particularly later in pregnancy, may increase the risk for PPHN. PPHN occurs in 1-2 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 . Maternal toxicity (clinical signs and decreased body weight gain and food consumption), mild at 56 mg/kg/day, was present at all dose levels. The developmental no-effect dose of 56 mg/kg/day is approximately 27 times the MRHD of 20 mg on a mg/m2 basis. No malformations were observed at any of the doses tested (as high as 73 times the MRHD on a mg/m2 basis).

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/m2 basis. Slight maternal toxicity (clinical signs and decreased body weight gain and food consumption) was seen at this dose. Slightly increased offspring mortality was also seen at 24 mg/kg/day. The no-effect dose was 12 mg/kg/day which is approximately 6 times the MRHD of 20 mg on a mg/m2 basis.m 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/m2 basis. This dose was also associated with maternal toxicity (clinical signs, decreased body weight gain). The developmental no-effect dose was 56 mg/kg/day is approximately 9 times the MRHD on a mg/m2 basis. 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, or approximately 5 times the MRHD on a mg/m² basis. Thus, developmental 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, 12.8, 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/m2 basis. The no-effect dose was 12.8 mg/kg/day is approximately 2 times the MRHD on a mg/m2 basis. Similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, approximately 4 times the MRHD on a mg/m² basis. A no-effect dose was not determined in that study.

Lactating Women

Risk Summary

Data from the published literature report the presence of escitalopram and desmethylescitalopram in human milk. There are reports of excessive sedation, restlessness, agitation, poor feeding and poor weight gain in infants exposed to escitalopram, through breast milk. There are no data on the effects of escitalopram or its metabolites on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for escitalopram and any potential adverse effects on the breastfed child from escitalopram or from the underlying maternal condition.

Clinical Considerations

Infants exposed to escitalopram 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 10-20 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.

Paediatric Patients

Safety and effectiveness of escitalopram have been established in adolescents (12 to 17 years of age) for the treatment of major depressive disorder. Although maintenance efficacy in adolescent patients with major depressive disorder 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.

Safety and effectiveness of escitalopram have not been established in paediatric patients (less than 12 years of age) 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.

Safety and effectiveness of escitalopram has not been established in paediatric 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.

Geriatric Patients

Approximately 6% of the 1144 patients receiving escitalopram in controlled trials of Escitalopram in major depressive disorder and GAD were 60 years of age or older; elderly patients in these trials received daily doses of Escitalopram 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 cannot be ruled out.

SSRIs and SNRIs, including escitalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at a greater risk for this adverse event. In two pharmacokinetic studies, the escitalopram half-life was increased by approximately 50% in elderly subjects while the C_max was unchanged. the recommended dose for elderly patients is 10 mg/day.

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.

Effects on Ability to Drive and Use Machines

Although escitalopram has been shown not to affect intellectual function or psychomotor performance, any psychoactive medicinal product may impair judgement or skills. Patients should be cautioned about the potential risk of an influence on their ability to drive a car and operate machinery.

Undesirable Effects

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

Pediatrics (6 -17 years)

Adverse events were collected in 576 pediatric patients (286 Escitalopram, 290 placebo) with major depressive disorder in double-blind placebo-controlled studies. Safety and effectiveness of Escitalopram in pediatric patients less than 12 years of age has not been established.

Adults

Adverse events information for Escitalopram 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 event information for Escitalopram 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 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)

Adverse events were associated with discontinuation of 3.5% of 286 patients receiving Escitalopram and 1% of 290 patients receiving placebo. The most common adverse event (incidence at least 1% for Escitalopram and greater than placebo) associated with discontinuation was insomnia (1% Escitalopram, 0% placebo).

Adults

Among the 715 depressed patients who received Escitalopram 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 events in patients receiving 10 mg/day Escitalopram was not significantly different from the rate of discontinuation for adverse events in patients receiving placebo. The rate of discontinuation for adverse events in patients assigned to a fixed dose of 20 mg/day Escitalopram was 10%, which was significantly different from the rate of discontinuation for adverse events in patients receiving 10 mg/day Escitalopram (4%) and placebo (3%). Adverse events that were associated with the discontinuation of at least 1% of patients treated with Escitalopram, and for which the rate was at least twice that of placebo, were nausea (2%) and ejaculation disorder (2% of male patients).

Generalized Anxiety Disorder

Adults

Among the 429 GAD patients who received Escitalopram 10-20 mg/day in placebo-controlled trials, 8% discontinued treatment due to an adverse event, as compared to 4% of 427 patients receiving placebo. Adverse events that were associated with the discontinuation of at least 1% of patients treated with Escitalopram, 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

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 and greater than placebo: back pain, urinary tract infection, vomiting, and nasal congestion.

Adults

The most commonly observed adverse reactions in Escitalopram patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were insomnia, ejaculation disorder (primarily ejaculatory delay), nausea, sweating increased, fatigue, and somnolence.

Table 2 enumerates the incidence, rounded to the nearest percent, of treatment-emergent adverse events that occurred among 715 depressed patients who received

Escitalopram at doses ranging from 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with Escitalopram and for which the incidence in patients treated with Escitalopram was greater than the incidence in placebo-treated patients.

Table 2 Treatment-Emergent Adverse Reactions observed with a frequency of ≥ 2% and greater than placebo for Major Depressive Disorder

Adverse Reaction	Escitalopram (N=715 %	Placebo (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%
Impotence²	3%	<1%
Anorgasmia³	2%	<1%

¹Primarily ejaculatory delay.

²Denominator used was for males only (N=225 Escitalopram; N=188 placebo).

³Denominator used was for females only (N=490 Escitalopram; N=404 placebo).

Generalized Anxiety Disorder

Adults

The most commonly observed adverse reactions in Escitalopram patients (incidence of approximately 5% or greater and approximately twice the incidence in placebo patients) were nausea, ejaculation disorder (primarily ejaculatory delay), insomnia, fatigue, decreased libido, and anorgasmia.

Table 3 enumerates the incidence, rounded to the nearest percent of treatment-emergent adverse events that occurred among 429 GAD patients who received Escitalopram 10 to 20 mg/day in placebo-controlled trials. Events included are those occurring in 2% or more of patients treated with Escitalopram and for which the incidence in patients treated with Escitalopram was greater than the incidence in placebo-treated patients.

Table 3 Treatment-Emergent Adverse Reactions observed with a frequency of ≥ 2% and greater than placebo for Generalized Anxiety Disorder.

Adverse Reaction	Escitalopram (N=715 %	Placebo (N=592) %
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%
Anorgasmia³	6%	<1%
Menstrual Disorder	2%	1%

¹Primarily ejaculatory delay.

²Denominator used was for males only (N=182 Escitalopram; N=195 placebo).

³Denominator used was for females only (N=247 Escitalopram; N=232 placebo).

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 groups) was examined on the basis of the combined incidence of adverse reactions in two fixed-dose trials. The overall incidence rates of adverse events in 10 mg Escitalopram-treated patients (66%) was similar to that of the placebo-treated patients (61%), while the incidence rate in 20 mg/day Escitalopram-treated patients was greater (86%). Table 4 shows common adverse reactions that occurred in the 20 mg/day Escitalopram group with an incidence that was approximately twice that of the 10 mg/day Escitalopram 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 (N=311)	10 mg/day Escitalopram	20 mg/day Escitalopram
		(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	Placebo
	In Males Only
	(N=407)	(N=383)
Ejaculation Disorder (primarily ejaculatory delay)	12%	1%
Libido Decreased	6%	2%
Impotence	2%	<1%
	In Females Only
	(N=737)	(N=636)
Libido Decreased	3%	1%
Anorgasmia	3%	<1%

There are no adequately designed studies examining sexual dysfunction with escitalopram treatment.

Priapism has been reported with all SSRIs.

While it is difficult to know the precise risk of sexual dysfunction associated with the use of SSRIs, physicians should routinely inquire about such possible side effects.

Vital Sign Changes

Escitalopram and placebo groups were compared with respect to (1) mean change from baseline in vital signs (pulse, systolic blood pressure, and diastolic blood pressure) and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses did not reveal any clinically important changes in vital signs associated with Escitalopram treatment. In addition, a comparison of supine and standing vital sign measures in subjects receiving Escitalopram indicated that Escitalopram treatment is not associated with orthostatic changes.

Weight Changes

Patients treated with Escitalopram in controlled trials did not differ from placebo-treated patients with regard to clinically important change in body weight.

Laboratory Changes

Escitalopram and placebo groups were compared with respect to (1) mean change from baseline in various serum chemistry, hematology, and urinalysis variables, and (2) the incidence of patients meeting criteria for potentially clinically significant changes from baseline in these variables. These analyses revealed no clinically important changes in laboratory test parameters associated with Escitalopram treatment.

ECG Changes

Electrocardiograms from Escitalopram (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 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 and the placebo group. The incidence of bradycardic outliers was 0.5% in the Escitalopram 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 4.5 (6.4) and 10.7 (12.7) msec for 10 mg and supratherapeutic 30 mg escitalopram given once daily, respectively. Based on the established exposure-response relationship, the predicted QTcF change from placebo arm (95% confidence interval) under the C_max for the dose of 20 mg is 6.6 (7.9) msec. Escitalopram 30 mg given once daily resulted in mean C_max of 1.7-fold higher than the mean C_max 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

Following is a list of treatment-emergent adverse events, as defined in the introduction to the Unwanted Effect section, reported by the 1428 patients treated with Escitalopram for periods of up to one year in double-blind or open-label clinical trials during its premarketing evaluation. The listing does not include those events already listed in Tables 2 & 3, those events for which a drug cause was remote and at a rate less than 1% or lower than placebo, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Events are categorized by body system.

Cardiovascular - hypertension, palpitation.

Central and Peripheral Nervous System Disorders - light-headed feeling, migraine.

Gastrointestinal Disorders - abdominal cramp, heartburn, gastroenteritis.

General - allergy, chest pain, fever, hot flushes, pain in limb.

Metabolic and Nutritional Disorders - increased weight.

Musculoskeletal System Disorders - arthralgia, myalgia jaw stiffness.

Psychiatric Disorders - appetite increased, concentration impaired, irritability.

Reproductive Disorders/Female - menstrual cramps, menstrual disorder.

Respiratory System Disorders - bronchitis, coughing, nasal congestion, sinus congestion, sinus headache.

Skin and Appendages Disorders - rash.

Special Senses - vision blurred, tinnitus.

Urinary System Disorders - urinary frequency, urinary tract infection.

Post-Marketing Experience

Adverse Reactions Reported Subsequent to the Marketing of Escitalopram

The following adverse reactions have been identified during post-approval use of Escitalopram. 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: 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.

Reporting of Suspected Adverse Reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. If your patient experiences any side-effects, write to drugsafety@cipla.com. You can also report side effects directly via the national pharmacovigilance program of India by calling on 1800 180 3024 or you can report to Cipla Ltd on 1800 267 7779. By reporting side-effects, you can help provide more information on the safety of this product.

Overdose

Human Experience

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 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.

Management of overdose

Establishing and maintaining 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, haemoperfusion and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for escitalopram. In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control centre for additional information on the treatment of any overdose.

Pharmacological Properties

Mechanism of Action

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

Pharmacodynamic Properties

In vitro and in vivo studies suggests that escitalopram is a highly selective serotonin (5-HT) reuptake inhibitor (SSRI) with a high affinity for the primary binding site, and has minimal effects on norepinephrine and dopamine neuronal reuptake. It also binds to an allosteric site on the serotonin transporter, with a 1,000-fold lower affinity. Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to the inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with escitalopram. Escitalopram has no or very low affinity for serotonergic (5-HT_1–7) or other receptors including alpha- and beta-adrenergic, dopamine (D_1–5), histamine (H_1–3), muscarinic (M_1–5), benzodiazepine and opioid receptors. Escitalopram also does not bind to or has low affinity for various ion channels, including Sodium (Na+), Potassium (K+), Chloride (Cl–) and Calcium (Ca++) channels. Antagonism of the muscarinic, histaminergic and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular side effects of other psychotropic drugs.

Pharmacokinetic Properties

The single- and multiple-dose pharmacokinetics of escitalopram is 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 2.2-2.5 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

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.

The absolute bioavailability of citalopram is about 80% relative to an intravenous dose, and the volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable.

The binding of escitalopram to human plasma proteins is approximately 56%.

Metabolism and Elimination

Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and S-demethylcitalopram (S-DCT) is about 8% and 10%, respectively. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance.

Escitalopram is metabolized to S-demethylcitalopram (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 studies show that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT_1–7) or other receptors, including alpha- and beta-adrenergic, dopamine (D_1–5), histamine (H_1–3), muscarinic (M_1–5) and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels, including Na+, K+, Cl– and Ca++ channels.

In vitro studies using human liver microsomes indicated that cytochrome (CY) P3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram.

Population Subgroups

Age

Adolescents

In a single-dose study of 10 mg escitalopram, the area under the concentration curve (AUC) of escitalopram decreased by 19% and the C_max increased by 26% in healthy adolescent subjects (12 to 17 years of age), compared to adults. Following multiple dosing of 40 mg/day escitalopram, the citalopram elimination half-life, steady-state C_max and the AUC were similar in patients with major depressive disorder (12 to 17 years of age), compared to adult patients. No adjustment of dosage is needed in adolescent patients.

Geriatric

Escitalopram pharmacokinetics in subjects who were ≥65 years of age were compared to younger subjects in a single-dose and a multiple-dose study. Escitalopram AUC and half-life were increased by approximately 50% in elderly subjects and the C_max was unchanged. for elderly patients, 10 mg is the recommended dose.

Gender

Based on data from single- and multiple-dose studies measuring escitalopram in the elderly, young adults and adolescents, no dosage adjustment on the basis of gender is needed.

the recommended dose of escitalopram for most hepatically impaired patients is 10 mg.

Non-Clinical Properties

Animal Toxicology 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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 bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Racemic citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in a coupled in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays.

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.

Description

S-CITADEP contains escitalopram oxalate, an orally administered selective serotonin reuptake inhibitor (SSRI). Escitalopram is the pure S- enantiomer (single isomer) of the racemic bicyclic phthalane derivative citalopram. Escitalopram oxalate is designated S-(+)-1--1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate with the following structural formula:

The molecular formula is C₂₀H₂₁FN₂O • C2H2O4 and the molecular weight is 414.40.

Pharmaceutical Particulars

Incompatibilities

Shelf-life

3 years

Packaging Information

S-CITADEP 5 mg: Blister pack of 10 tablets

S-CITADEP 10 mg: Blister pack of 10 tablets

S-CITADEP 20 mg: Blister pack of 10 tablets

Storage and Handling Instructions

Store in a cool dry place. Protect from light

Patient Counselling Information

What is the most important information I should know about S-CITADEP?

S-CITADEP and other antidepressant medicines may cause serious side effects, including:

1. Suicidal thoughts or actions:

• S-CITADEP and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the 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:

· New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.

· Pay particular attention to such changes when S-CITADEP is started or when the dose is changed.

Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.

· 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

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

Abnormal bleeding: S-CITADEP and other antidepressant medicines may increase your risk of bleeding or bruising, especially if you take the blood thinner warfarin, a non-steroidal antiinflammatory drug (NSAIDs, like ibuprofen or naproxen), or aspirin.

3. Seizures or convulsions

4. 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

5. Changes in appetite or weight. Children and adolescents should have height and weight monitored during treatment.

6. Low salt (sodium) levels in the blood. Elderly people may be at greater risk for this. Symptoms may include:

· headache

· weakness or feeling unsteady

· confusion, problems concentrating or thinking or memory problems

7. 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 S-CITADEP without first talking to your healthcare provider. Stopping S-CITADEP too quickly may cause serious symptoms including:

· 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 S-CITADEP?

S-CITADEP is a prescription medicine used to treat depression. It is important to talk with your healthcare provider about the risks of treating depression and also the risks of not treating it. You should discuss all treatment choices with your healthcare provider. S-CITADEP is also used to treat:

· Major Depressive Disorder (MDD)

· Panic Disorder with or without Agoraphobia

Talk to your healthcare provider if you do not think that your condition is getting better with S-CITADEP treatment.

Who should not take S-CITADEP?

Do not take S-CITADEP if you:

· are allergic to escitalopram or citalopram or any of the ingredients in S-CITADEP. See the end of this Medication Guide for a complete list of ingredients in S-CITADEP.

· Take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or a pharmacist if you are not sure if you take an MAOI, including linezolid.

· Do not take an MAOI within 2 weeks of stopping S-CITADEP unless directed to do so by your physician

· Do not start S-CITADEP if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

People who take S-CITADEP 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:

o high fever

o uncontrolled muscle spasms o stiff muscles

o rapid changes in heart rate or blood pressure

o confusion

o loss of consciousness (pass out)

· Do not take S-CITADEP with pimozide because taking these two drugs together can cause serious heart problems.

What should I tell my healthcare provider before taking S-CITADEP? Ask if you are not sure.

Before starting S-CITADEP, tell your healthcare provider if you:

· Are taking certain drugs such as:

· Triptans used to treat migraine headache

· Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, amphetamines, or antipsychotics

· Tramadol

· Over-the-counter supplements such as tryptophan or St. John’s Wort

· have liver problem

· 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. Taking S-CITADEP late in oregnancy may lead to an increased risk of certain problems in your newborn. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy

Tell your healthcare provider about all the medicines that you take, including prescription and non-prescription medicines, vitamins, and herbal supplements and some medicines may interact with each other, may not work as well, or may cause serious side effects.

Your healthcare provider or pharmacist can tell you if it is safe to take S-CITADEP with your other medicines. Do not start or stop any medicine while taking S-CITADEP without talking to your healthcare provider first.

How should I take S-CITADEP?

· Take S-CITADEP exactly as prescribed. Your healthcare provider may need to change the dose of S-CITADEP until it is the right dose for you.

· S-CITADEP may be taken with or without food.

· If you miss a dose of S-CITADEP, 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 S-CITADEP at the same time.

· If you take too much S-CITADEP, call your healthcare provider or poison control center right away, or get emergency treatment.

What should I avoid while taking S-CITADEP?

S-CITADEP can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how S-CITADEP affects you. Do not drink alcohol while using S-CITADEP.

What are the possible side effects of S-CITADEP?

S-CITADEP may cause serious side effects, including all of those described in the section entitled “What is the most important information I should know about S-CITADEP?”

Common possible side effects in people who take S-CITADEP 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 S-CITADEP.

Reporting of Suspected Adverse Reactions

How should I store S-CITADEP?

· Store S-CITADEP at 68°F to 77°F (20°C to 25°C); excursions permitted to 59°F to 86°F (15°C to 30°C).

General information about S-CITADEP

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use S-CITADEP for a condition for which it was not prescribed. Do not give S-CITADEP to other people, even if they have the same condition. It may harm them.

What are the ingredients in S-CITADEP?

Active ingredient: escitalopram oxalate

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