IBINOR

Solution, USP contains escitalopram oxalate, an orally administered 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 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 2O.

• C 2 H 2 O and the molecular weight is 414.40.

Escitalopram oxalate occurs as a fine, white to off white crystalline powder and is freely soluble in methanol and dimethyl sulfoxide (DMSO), soluble in isotonic saline solution, sparingly soluble in water and ethanol, slightly soluble in ethyl acetate, and insoluble in heptane.

Solution, USP is available as a clear, colorless liquid with peppermint flavor.

Solution, USP contains escitalopram oxalate equivalent to 1 mg/mL escitalopram base.

It also contains the following inactive ingredients: sorbitol solution, purified water, citric acid anhydrous, sodium citrate dihydrate, glycerin, propylene glycol, methylparaben, propylparaben, and peppermint flavor.

Escitalopram 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) tablets and LEXAPRO (escitalopram) oral solution.

However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Escitalopram 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 treatment of generalized anxiety disorder (GAD) in adults.

Hypomaniac access, history Manic access, history (d) Lactation Combination with other serotonin medicinal products Cardiopathies Cirhrosis Diabetes Electrochoc Glaucoma, history (de) Closed angle glaucoma Hypokalaemia Hypomagnesaemia Myocardial infarction Congestive heart failure Coronary heart failure Hepatic impairment Severe renal impairment: creatinine clearance < 30 ml/min Slow metabolizer of CYP2C19 Newborn exposed in utero to the medicine Suicidal-prone patient Postpartum Elderly Subject at risk of QT space prolongation Subject at risk of seizure Subject at risk of bleeding Subject under 18 Subject between and 25 years.

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). 12.2 Pharmacodynamics In vitro and in vivo studies in animals suggest that escitalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine and dopamine neuronal reuptake.

Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to 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 ), and benzodiazepine receptors.

Escitalopram also does not bind to, or has low affinity for, various ion channels including Na + , K + , Cl.

• , and Ca ++ channels.

Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular side effects of other psychotropic drugs. 12.3 Pharmacokinetics The single.

• and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of to 30 mg/day. 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 absolute bioavailability of citalopram is about 80% relative to an intravenous dose.

The tablet and the oral solution dosage forms of escitalopram oxalate are bioequivalent.

Following a single oral dose (20 mg tablet or solution) of escitalopram, peak blood levels occur at about 5 hours.

Absorption of escitalopram is not affected by food.

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

The volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable.

Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27-32 hours.

The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance.

Metabolism Escitalopram is metabolized to S-DCT and S-didemethylcitalopram (S-DDCT).

In humans, unchanged escitalopram is the predominant compound in plasma.

At steady state, the concentration of the escitalopram metabolite S-DCT in plasma is approximately one-third that of escitalopram.

The level of

S-DDCT was not detectable in most subjects.

In vitro studies show that escitalopram is at least 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.

S-DCT and S-DDCT also do not bind to various ion channels including Na + , K + , Cl.

In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram.

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.

Pediatric patients to 17 years of age: In a single dose study of 10 mg escitalopram, AUC of escitalopram decreased by 19%, and C max increased by 26% in healthy pediatric subjects to 17 years of age compared to adults.

Following multiple dosing of 40 mg/day citalopram, escitalopram elimination half-life, steady-state C max and AUC were similar in pediatric patients to 17 years of age with MDD compared to adults.

Escitalopram pharmacokinetics in subjects ≥ 65 years of age were compared to adults in a single-dose and a multiple-dose study.

AUC and half-life were increased by approximately 50% in elderly subjects, and C max was unchanged.

Based on data from single.

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

Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects.

In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects.

No information is available about the pharmacokinetics of escitalopram in patients with severely reduced renal function (creatinine clearance < 20 mL/min) .

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.

CYP3A4 and CYP2C19 Inhibitors In vitro studies indicated that CYP3A4 and -2C19 are the primary enzymes involved in the metabolism of escitalopram.

However, coadministration of escitalopram (20 mg) and ritonavir (600 mg), a potent inhibitor of CYP3A4, did not significantly affect the pharmacokinetics of escitalopram.

Because escitalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease escitalopram clearance.

In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of 400 mg twice a day cimetidine for 8 days resulted in an increase in citalopram AUC and C max of 43% and 39%, respectively.

The clinical significance of these findings is unknown.

In subjects who had received 21 days of 40 mg/day racemic citalopram, combined administration of citalopram and digoxin (single dose of 1 mg) did not significantly affect the pharmacokinetics of either citalopram or digoxin.

Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium.

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 are coadministered.

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.

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.

Combined administration of a single dose of ritonavir (600 mg), both a CYP3A4 substrate and a potent inhibitor of CYP3A4, and escitalopram (20 mg) did not affect the pharmacokinetics of either ritonavir or escitalopram.

Combined administration of racemic citalopram (titrated to 40 mg/day for 28 days) and the CYP3A4 substrate triazolam (single dose of 0.25 mg) did not significantly affect the pharmacokinetics of either citalopram or triazolam.

Administration of 20 mg/day escitalopram for 21 days in healthy volunteers resulted in a 50% increase in C max and 82% increase in 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.

Coadministration of escitalopram and metoprolol had no clinically significant effects on blood pressure or heart rate.

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.

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%.

Additional pediatric use information is approved for AbbVie Inc.’s LEXAPRO (escitalopram) tablets and LEXAPRO (escitalopram) oral solution.

However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information.

Mechanism of action

Escitalopram is a selective serotonin reuptake inhibitor (5-HT) with a high affinity for the main binding site.

It also binds to an allosteric site on the serotonin carrier, with a 1000 times lower affinity.

Escitalopram has no or little affinity for a number of receptors including 5-HT 1A, 5-HT 2, dopaminergic D and D 2, alpha 1, alpha and ß-adrenergic, histaminergic H 1, cholinergic (muscarinic) and benzodiazepine and opiate receptors.

Inhibition of 5-HT reuptake is the only probable mechanism of action explaining the pharmacological and clinical properties of escitalopram.

• Liver status (abnormality)
• Hyperprolactinaemia Hyponatremia Urticaria (Uncommon)
• Alopecia (Uncommon)
• Hypersudation (Common)
• Rash (Uncommon)
• Pruritus (Uncommon)
• Fever (Common)
• Edema (Uncommon)
• Fatigue (Common)
• Galactorrhoea Inappropriate antidiuretic hormone secretion syndrome (IADH)
• Anorgasmia (Common)
• Metrorragie (Uncommon)
• Menorrhagia (Uncommon)
• Postpartum haemorrhage
• Echymosis Thrombocytopenia Hepatitis Anaphylactic reaction (Rare)
• Angioedema Weight (increase) (Common)
• Anorexia (Common)
• Weight (decrease) (Uncommon)
• Appetite increased (Common)
• Mydriase (Uncommon)
• Vision disorder (Uncommon)
• Sinusitis (Common)
• Epistaxis (Uncommon)
• Oral dryness (Common)
• Dysgueusia (Uncommon)
• Feeling dizzy (Common)
• Brussels (Uncommon)
• Tinnitus (Uncommon)
• Nervousness (Uncommon)
• Insomnia (Common)
• Female orgasm disorder (Common)
• Panic attack (Uncommon)
• Agitation (Uncommon)
• Anxiety (Common)
• Mental confusion (Uncommon)
• Abnormal dreams (Common)
• Libido (decrease) (Common)
• Sleep disorder (Uncommon)
• Aggressiveness (Rare)
• Depersonalization (Rare)
• Hallucination (Rare)
• Suicidal behaviour Irritability Emotional disorder Mania Manic access
• Suicidal ideation Tachycardia (Uncommon)
• Syncope (Uncommon)
• Bradycardia (Rare)
• Palpitation
• QT space extension Orthostatic hypotension Torsades de pointes Ventricular arrhythmia
• Gastrointestinal haemorrhage (Uncommon)
• Constipation (Common)
• Vomiting (Common)
• Nausea (Very common)
• Diarrhoea (Common)
• Rectorragie Abnormal liver function Joint pain (Common)
• Muscle pain (Common)
• Fracture Headache (Very common)
• Bailing (Common)
• Restless leg syndrome (Common)
• Trembling (Common)
• Paraesthesia (Common)
• Somnolence (Common)
• Dyskinesia Abnormal movement Neurosensory disorder
• Akathisia Convulsions Sensation of electrical discharge Psychomotor hyperactivity
• Serotonin syndrome (Rare)
• Impower (Common)
• Ejaculation disorder (Common)
• Priapism
• Urinary retention.

The following have been reported with escitalopram tablet 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 overdosage ingestions due to the arrhythmia risk.

Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after an escitalopram overdose.

Consider contacting the Poison

Help line or a medical toxicologist for additional overdose management recommendations.

Escitalopram is contraindicated in patients: taking MAOIs with escitalopram or within 14 days of stopping treatment with escitalopram 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.

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. taking pimozide with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in escitalopram.

Do not use

MAOIs intended to treat psychiatric disorders with escitalopram or within 14 days of stopping treatment with escitalopram.

Do not use escitalopram within 14 days of stopping an MAOI intended to treat psychiatric disorders.

In addition, do not start escitalopram in a patient who is being treated with linezolid or intravenous methylene blue Concomitant use of pimozide Known hypersensitivity to escitalopram or citalopram or any of the inactive ingredients.

Indication and Population Recommended Dosage MDD in Adults Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily MDD in Pediatric Patients 12 years and older Initial: 10 mg once daily Recommended: 10 mg once daily Maximum: 20 mg once daily GAD in Adults 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 Administer once daily, morning or evening, with or without food Elderly patients: recommended dosage is 10 mg once daily Hepatic impairment: recommended dosage is 10 mg once daily When discontinuing escitalopram, reduce dose gradually whenever possible 2.1 Major Depressive Disorder Adults The recommended dosage of escitalopram in adults is 10 mg once daily.

A fixed-dose trial of escitalopram demonstrated the effectiveness of both 10 mg and 20 mg of escitalopram, but failed to demonstrate a greater benefit of 20 mg over 10 mg.

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.

Patients 12 years of age and older The recommended dosage of escitalopram 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 in adults is 10 mg once daily.

Additional pediatric use information is approved for AbbVie Inc.’s Lexapro (escitalopram) tablets and LEXAPRO (escitalopram) oral solution.

However, due to AbbVie Inc.’s marketing exclusivity rights, this drug product is not labeled with that information. 2.3 Administration Information Administer escitalopram orally once daily, in the morning or evening, with or without food. 2.4 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. 2.5 Recommended Dosage for Specific Populations The recommended dosage for most elderly patients and patients with hepatic impairment is 10 mg once daily.

The recommended dosage for escitalopram 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. 2.6 Discontinuation of Treatment with Escitalopram 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. 2.7 Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant 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.

Solution, USP, 5 mg/5 mL, a clear, colorless liquid with peppermint flavor 240 mL bottle (8 fluid oz) NDC# 62135-729-37 Unit Dose Cup of 10 mL NDC # 62135-729-10 20 Unit Dose Cups of 10 mL NDC # 62135-729-24 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) .