ESCITALOPRAM

ESCITALOTED

ESCITALOTED®

 

Category:

selective serotonin reuptake inhibitor (SSRI).                                                       (USP DI)

 

Chemistry:

S-(+)-1-[3(dimethyl-amino)propyl]-1-(p-fluorophenyl)-5-phthalancarbonitrile oxalate. molecular weight C20H21FN2O • C2H2O4 = 414.40

 

 

                                                                                                                               (Martindale)

 

Mechanism of action:

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

 (USP DI)

 

Pharmacokinetics:

(USP DI, Martindale)

 

 

 

Indications:

Major Depressive Disorder

Escitalopram (escitalopram) is indicated for the acute and maintenance treatment of major depressive disorder in adults and in adolescents 12 to 17 years of age A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.

Generalized Anxiety Disorder

Escitalopram is indicated for the acute treatment of Generalized Anxiety Disorder (GAD) in adults 

Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following symptoms: restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, and sleep disturbance.

 (USP DI) 

Contraindications:

Monoamine Oxidase Inhibitors (MAOIs)- 

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 

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- 

Escitalopram is contraindicated in patients with a hypersensitivity to escitalopram or citalopram or any of the inactive ingredients in Escitalopram.

.

(USP DI) 

Warnings & Precautions:

Worsening of Depression and Suicidality Risk

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs.

 

 

 

 

Serotonin Syndrome 

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including Lexapro, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

 

Withdrawal of Therapy

During marketing of Lexapro 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.

 

Seizures

Although anticonvulsant effects of racemic citalopram have been observed in animal studies, Lexapro has not been systematically evaluated in patients with a seizure disorder.

 

Activation of Mania/Hypomania

In placebo-controlled trials of Lexapro in major depressive disorder, activation of mania/hypomania was reported in one (0.1%) of 715 patients treated with Lexapro and in none of the 592 patients treated with placebo

 

Hyponatremia or SIADH

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Lexapro. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), and was reversible when Lexapro was discontinued.

 

Abnormal Bleeding

SSRIs and SNRIs, including Lexapro, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to the risk.

 

Interference with Cognitive and Motor Performance

In a study in normal volunteers, Lexapro 10 mg/day did not produce impairment of intellectual function or psychomotor performance. Because any psychoactive drug may impair judgment, thinking, or motor skills, however, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that Lexapro 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 Lexapro may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Concomitant Illnesses

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

 

 (USP DI)

 

 

Pregnancy:

pregnancy category C.

(USP DI)

 

Breast-feeding:

Racemic citalopram is distributed into human breast milk.

 (USP DI)

 

Drug Interactions:

-Monoamine Oxidase Inhibitors (MAOIs)

-Serotonergic Drugs

-Triptans

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

CNS Drugs-

 

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

Alcohol-

 

Although escitalopram oxalate did not potentiate the cognitive and motor effects of alcohol in a clinical trial, as with other psychotropic medications, the use of alcohol by patients taking escitalopram oxalate is not recommended.

Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin, etc.)-

 

-Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate the risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when escitalopram oxalate is initiated or discontinued.

Cimetidine-

 

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 Cmax 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-

Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for  5 days) had no significant effect on the pharmacokinetics of citalopram or lithium. Nevertheless, plasma lithium levels should be monitored with appropriate adjustment to the lithium dose in accordance with standard clinical practice. Because lithium may enhance the serotonergic effects of escitalopram, caution should be exercised when escitalopram oxalate 

and lithium are coadministered.

 

Pimozide and Celexa-

In a controlled study, a single dose of pimozide 2 mg coadministered 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 Cmax of pimozide. The mechanism of this pharmacodynamic interaction is not known.

 

Sumatriptan-

There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of an SSRI and sumatriptan. If concomitant treatment with sumatriptan and an SSRI (e.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 for 14 days) and carbamazepine (titrated to 400 mg/day for 35 days) did not significantly affect the pharmacokinetics of carbamazepine, a CYP3A4 substrate. Although trough citalopram plasma levels were unaffected, given the enzyme-inducing properties of carbamazepine, the possibility that carbamazepine might increase the clearance of escitalopram should be considered if the two 

drugs are coadministered.

 

Triazolam-

 

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.

Ketoconazole-

 

-Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the Cmax 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 either ritonavir or escitalopram.

CYP3A4 and -2C19 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.

Drugs Metabolized by Cytochrome P4502D6

 

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 oxalate for 21 days in healthy volunteers resulted in a 50% increase in Cmax 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 oxalate and metoprolol had no clinically significant effects on blood pressure or heart rate.

(USP DI)

 

Adverse Reactions:

Insomnia, nausea, increased sweating, sexual dysfunction (ejaculation disorder [primarily ejaculatory delay], decreased libido, anorgasmia), fatigue, somnolence. 

(USP DI)

Over dosage:

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, Lexapro 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

Establish and maintain an airway to ensure adequate ventilation and oxygenation. Gastric evacuation by lavage and use of activated charcoal should be considered. Careful observation and cardiac and vital sign monitoring are recommended, along with general symptomatic and supportive care. Due to the large volume of distribution of escitalopram, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit. There are no specific antidotes for Lexapro.

In managing overdosage, consider the possibility of multiple-drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose.                                                                           (USP DI)

 

Dosage & Administration:

Major Depressive Disorder

Usual adult dose 

The recommended dose of Escitalopram 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. If the dose is increased to 20 mg, this should occur after a minimum of one week.

Generalized Anxiety Disorder

Usual adult dose 

The recommended starting dose of Escitalopram is 10 mg once daily. If the dose is increased to 20 mg, this should occur after a minimum of one week.

Usual pediatric dose

Safety and efficacy have not been established

Usual geriatric dose

Major Depressive Disorder

The recommended dose of Escitalopram is 10 mg once daily for most elderly patients.

(USP DI)

Storage:

Store below 30˚ C and protect from humidity and direct light.

(USP DI)

 

How supplied:

Escitalopram is as available as 10 mg, white, round, scored, odorless & coated tablets and 20 mg, white, oval, biconvex, scored, odorless & coated tablets. There are blisters of 10’s in a box of 30’s.